Mechanical stress-induced connective tissue growth factor plays a critical role in intestinal fibrosis in Crohn's-like colitis.

Crohn's disease (CD) is an inflammatory bowel disease characterized by transmural inflammation and intestinal fibrosis. Mechanisms of fibrosis in CD are not well understood. Transmural inflammation is associated with inflammatory cell infiltration, stenosis, and distention, which present mechanical stress (MS) to the bowel wall. We hypothesize that MS induces gene expression of profibrotic mediators such as connective tissue growth factor (CTGF), which may contribute to fibrosis in CD. A rodent model of CD was induced by intracolonic instillation of TNBS to the distal colon. TNBS instillation induced a localized transmural inflammation (site I), with a distended colon segment (site P) proximal to site I. We detected significant fibrosis and collagen content not only in site I but also in site P in CD rats by day 7. CTGF expression increased significantly in sites P and I, but not in the segment distal to the inflammation site. Increased CTGF expression was detected mainly in the smooth muscle cells (SMCs). When rats were fed exclusively with clear liquid diet to prevent mechanical distention in colitis, expression of CTGF in sites P and I was blocked. Direct stretch led to robust expression of CTGF in colonic SMC. Treatment of CD rats with anti-CTGF antibody FG-3149 reduced fibrosis and collagen content in both sites P and I and exhibited consistent trends toward normalizing expression of collagen mRNAs. In conclusion, our studies suggest that mechanical stress, by upregulating profibrotic mediators, i.e., CTGF, may play a critical role in fibrosis in CD.NEW & NOTEWORTHY We found that CTGF expression increased significantly not only in the inflammation site but in the distended segment proximal to inflammation in a rodent model of CD-like colitis. Release of mechanical distention prevented CTGF expression in CD rats, whereas direct stretch induced CTGF expression. Treatment with anti-CTGF antibody reduced fibrosis and collagen contents in CD rats. Thus, mechanical stress, via upregulating profibrotic mediators, i.e., CTGF, may play a critical role in fibrosis in CD.

HuR facilitates miR-93-5p-induced activation of MAP3K2 translation via MAP3K2 3'UTR ARE2 in hepatocellular carcinoma.

MicroRNAs (miRNAs) can positively regulate gene expression through an unconventional RNA activation mechanism involving direct targeting 3' untranslated regions (UTRs). Our prior study found miR-93-5p activates mitogen-activated protein kinase kinase kinase 2 (MAP3K2) in hepatocellular carcinoma (HCC) via its 3'UTR. However, the underlying mechanism remains elusive. Here, we identified two candidate AU-rich element (ARE) motifs (ARE1 and ARE2) adjacent to the miR-93-5p binding site located within the MAP3K2 3'UTR using AREsite2. Luciferase reporter and translation assays validated that only ARE2 participated in MAP3K2 activation. Integrative analysis revealed that human antigen R (HuR), an ARE2-associated RNA-binding protein (RBP), physically and functionally interacted with the MAP3K2 3'UTR. Consequently, an HuR-ARE2 complex was shown to facilitate miR-93-5p-mediated upregulation of MAP3K2 expression. Furthermore, bioinformatics analysis and studies of HCC cells and specimens highlighted an oncogenic role for HuR and positive HuR-MAP3K2 expression correlation. HuR is also an enhancing factor in the positive feedback circuit comprising miR-93-5p, MAP3K2, and c-Jun demonstrated in our prior study. The newly identified HuR-ARE2 involvement enriches the mechanism of miR-93-5p-driven MAP3K2 activation and suggests new therapeutic strategies warranted for exploration in HCC.

Rare case of simultaneous occurrence of chronic neutrophil leukemia and T lymphoblastic lymphoma: case report and literature review.

Chronic neutrophil leukemia (CNL) is a rare and life-threatening disease. Cases of CNL combined with lymphoma are rare. Here, we report a case of CNL with T-acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) in a 28-year-old male. After a regimen of ruxolitinib, VICLP (Vincristine, Idarubicin, Cyclophosphamide, Prednisone, Peg-asparaginase) regimen, high-dose cytarabine, and methotrexate regimens, the patient's bone marrow condition partially resolved. However, when the disease relapsed four months later, despite attempts with selinexor, venetoclax, and CAG(aclarubicin hydrochloride, Algocytidine, Granulocyte Stimulating Factor) chemotherapy, the leukocytes and peripheral blood primitive cells reduced, but the bone marrow did not achieve remission. This pathogenesis may be related to microenvironmental immune escape under prolonged inflammatory stimulation and gene disruption affecting protein function due to colony-stimulating factor 3 receptor gene (CSF3R) mutations. For this type of disease, early intervention may delay disease progression.

Ultra-Tough Graphene Oxide/DNA 2D Hydrogel with Intrinsic Sensing and Actuation Functions.

Hydrogel devices with mechanical toughness and tunable functionalities are highly desirable for practical long-term applications such as sensing and actuation elements for soft robotics. However, existing hydrogels have poor mechanical properties, slow rates of response, and low functionality. In this work, two-dimensional hydrogel actuators are proposed and formed on the self-assembly of graphene oxide (GO) and deoxynucleic acid (DNA). The self-assembly process is driven by the GO-induced transition of double stranded DNA (dsDNA) into single stranded DNA (ssDNA). Thus, the hydrogel's structural unit consists of two layers of GO covered by ssDNA and a layer of dsDNA in between. Such heterogeneous architectures stabilized by multiple hydrogen bondings have Young's modulus of up to 10 GPa and rapid swelling rates of 4.0 × 10-3 to 1.1 × 10-2 s-1, which surpasses most types of conventional hydrogels. It is demonstrated that the GO/DNA hydrogel actuators leverage the unique properties of these two materials, making them excellent candidates for various applications requiring sensing and actuation functions, such as artificial skin, wearable electronics, bioelectronics, and drug delivery systems.

Design, synthesis, and biological evaluation of 2,4-diaminopyrimidine derivatives as potent Hematopoietic Progenitor Kinase 1 (HPK1) inhibitors.

HPK1 also referred to as MAP4K1, belongs to the category of mammalian STE20-like protein serine/threonine kinases. Its physiological function involves the down-regulation of T cell signals, and it is regarded as a new immune checkpoint of tumor immunology. In this study, we commenced our investigation with the hit compounds, focusing the efforts on structural optimization and SAR exploration to identify a novel class of 2,4-diaminopyrimidine HPK1 inhibitors. Notably, compound 14g exhibited a remarkable inhibitory effect on HPK1 kinase (IC50 = 0.15 nM), significantly suppressed the phosphorylation of the downstream adaptor protein SLP76 (pSLP76 IC50 = 27.92 nM), and effectively stimulated the secretion of the T cell activation marker IL-2 (EC50 = 46.64 nM). In vitro microsomal stability assay, compound 14g showed moderate stability in HLMs with T1/2 = 38.2 min and CLint = 36.4 µL·min-1·mg-1 proteins. In vivo pharmacokinetic studies, compound 14g demonstrated heightened plasma exposure (AUC0-inf = 644 ng·h·mL-1), extended half-life (T1/2 = 9.98 h), and reduced plasma clearance (CL = 52.3 mL·min-1·kg-1) compared to the reference compound after a single intravenous dose of 2 mg/kg in rats. These results indicated that compound 14g emerged as a promising inhibitor of HPK1.

Chemical Epigenetic Regulation Secondary Metabolites Derived from Aspergillus sydowii DL1045 with Inhibitory Activities for Protein Tyrosine Phosphatases.

Protein tyrosine phosphatases (PTPs) are ubiquitous in living organisms and are promising drug targets for cancer, diabetes/obesity, and autoimmune disorders. In this study, a histone deacetylase inhibitor called suberoylanilide hydroxamic acid (SAHA) was added to a culture of marine fungi (Aspergillus sydowii DL1045) to identify potential drug candidates related to PTP inhibition. Then, the profile of the induced metabolites was characterized using an integrated metabolomics strategy. In total, 46% of the total SMs were regulated secondary metabolites (SMs), among which 20 newly biosynthesized metabolites (10% of the total SMs) were identified only in chemical epigenetic regulation (CER) broth. One was identified as a novel compound, and fourteen compounds were identified from Aspergillus sydowii first. SAHA derivatives were also biotransformed by A. sydowii DL1045, and five of these derivatives were identified. Based on the bioassay, some of the newly synthesized metabolites exhibited inhibitory effects on PTPs. The novel compound sydowimide A (A11) inhibited Src homology region 2 domain-containing phosphatase-1 (SHP1), T-cell protein tyrosine phosphatase (TCPTP) and leukocyte common antigen (CD45), with IC50 values of 1.5, 2.4 and 18.83 µM, respectively. Diorcinol (A3) displayed the strongest inhibitory effect on SHP1, with an IC50 value of 0.96 µM. The structure-activity relationship analysis and docking studies of A3 analogs indicated that the substitution of the carboxyl group reduced the activity of A3. Research has demonstrated that CER positively impacts changes in the secondary metabolic patterns of A. sydowii DL1045. The compounds produced through this approach will provide valuable insights for the creation and advancement of novel drug candidates related to PTP inhibition.

Microbial entropy change and external dissipation process of urban sewer ecosystem.

As the initial stage of the sewage treatment system, the degradation of pollutants inevitably involves an entropy change process. Microorganisms play a vital role, where they interact with pollutants and constantly adjust own ecosystem. However, there is a lack of research on the entropy change and external dissipation processes within the sewer system. In this study, considering the characteristics of microbial population changes in the biofilm within the urban sewage pipe network, entropy theory is applied to characterize the attributes of different microorganisms. Through revealing the entropy change of the microbial population and chemical composition, a coupling relationship between the functional bacteria diversity, organic substances composition, and external dissipation in the pipeline network is proposed. The results show that the changes of nutrient availability, microbial community structure, and environmental conditions all affect the changes of information entropy in the sewer network. This study is critical for assessing the understanding of ecological dynamics and energy flows within these systems and can help researchers and operation managers develop strategies to optimize wastewater treatment processes, mitigate environmental impacts, and promote sustainable management practices.

Harnessing Cooperative Multivalency in Thioguanine for Surface-Enhanced Raman Scattering (SERS)-Based Differentiation of Polyfunctional Analytes Differing by a Single Functional Group.

Small-molecule receptors are increasingly employed to probe various functional groups for (bio)chemical analysis. However, differentiation of polyfunctional analogs sharing multiple functional groups remains challenging for conventional mono- and bidentate receptors because their insufficient number of binding sites limits interactions with the least reactive yet property-determining functional group. Herein, we introduce 6-thioguanine (TG) as a supramolecular receptor for unique tridentate receptor-analyte complexation, achieving ≥97 % identification accuracy among 16 polyfunctional analogs across three classes: glycerol derivatives, disubstituted propane, and vicinal diols. Crucially, we demonstrate distinct spectral changes induced by the tridentate interaction between TG's three anchoring points and all the analyte's functional groups, even the least reactive ones. Notably, hydrogen bond (H-bond) networks formed in the TG-analyte complexes demonstrate additive effects in binding strength originating from good bond linearity, cooperativity, and resonance, thus strengthening complexation events and amplifying the differences in spectral changes induced among analytes. It also enhances spectral consistency by selectively forming a sole configuration that is stronger than the respective analyte-analyte interaction. Finally, we achieve 95.4 % accuracy for multiplex identification of a mixture consisting of multiple polyfunctional analogs. We envisage that extension to other multidentate non-covalent interactions enables the development of interference-free small molecule-based sensors for various (bio)chemical analysis applications.

Preparation and characterization of chitosan/ZnO-Ag composite microcapsules and their applications in solar energy harvesting and electromagnetic interference shielding.

Phase change microcapsules are known for their latent heat storage capability. However, the efficient absorption and utilization of solar energy by these microcapsules remains a significant challenge. In this study, we successfully prepared composite phase change microcapsules containing ZnO-Ag nanospheres, chitosan, and paraffin. These microcapsules demonstrated remarkable photothermal conversion efficiency. ZnO was found to effectively absorb ultraviolet light, while the plasmonic resonance of Ag was utilized to absorb and make use of light energy in the visible region. Moreover, due to the synergistic absorption and reflection of electromagnetic waves by ZnO-Ag nanoparticles and graphene, the well-dispersed chitosan/ZnO-Ag composite microcapsules and graphene in the fabric coating demonstrated exceptional electromagnetic shielding performance. In addition, the coated fabric based on composite microcapsules exhibited excellent antibacterial properties, effectively inhibiting the growth of bacteria such as S. aureus and E. coli. This antibacterial performance adds to their potential applications in various fields. These multifunctional phase change microcapsules offer vast potential for the effective utilization of solar energy, serving as efficient photothermal conversion and energy storage materials.

Oxidant-mediated radical reactions of the azole fungicide TEB in aquatic media: Degradation mechanism and toxicity evolution.

The degradation of tebuconazole (TEB) by UV/H2O2, UV/NaClO, and ozonation was investigated in this research. The experimental findings unveiled that under the specified conditions, the degradation percentages of TEB were raised to 99% within 40 s, 5 min, and 3 min for UV/H2O2, UV/NaClO and ozonation, respectively. The mineralization percentages within 1 h were 59%, 31% and 8% for the three AOPs. UV/H2O2 and UV/NaClO technologies mainly acted through OH·, while O3 treatment primarily relied on the free radicals such as 1O2 and O2·-. UV-based AOPs achieved almost complete dechlorination within 1 h, whereas O3 treatment had a less effective dechlorination, reaching only 27.61%. Notably, UV alone achieved a dechlorination percentage of 43.07%. By identifying the TPs, we found that the three AOPs shared three similar degradation pathways. The degradation mechanism of TEB mainly entailed the removal of the benzene ring, tert-butyl group and triazolyl group. Toxicity assessment revealed an initial increase followed by a gradual decrease in toxicity for UV/NaClO and O3 treatments, whereas UV/H2O2 treatment exhibited a sustained decrease. This was due to the presence of TP278 and TP303 by UV/NaClO and TP168 and TP153 by ozonation. After estimating the costs of the three AOPs, UV/H2O2 standed out as the best choice for achieving a 90% degradation percentage and exhibiting lower toxicity performance, while O3 treatment was favored for low TOC demands. These research findings provided valuable reference for understanding the degradation mechanism and developing a new technology of the removal of TEB.

FAPI PET Missed Widespread Bone Marrow Metastases From Follicular Thyroid Cancer That Were Detected by FDG PET.

ABSTRACT: A 62-year-old woman with follicular thyroid cancer who had received total thyroidectomy and multiple rounds of radioactive iodine therapy underwent both 18 F-FDG and 18 F-FAPI PET/CT. 18 F-FAPI PET failed to reveal widespread bone marrow metastases that were clear visualized on 18 F-FDG PET. This case highlights that FAPI PET may not be used to describe bone metastases in detail in follicular thyroid cancer patients, as it is not a sensitive method to detect bone marrow metastases.

Comparative Efficacy and Safety of Potassium-Competitive Acid Blockers vs. Proton Pump Inhibitors for Peptic Ulcer with or without Helicobacter pylori Infection: A Systematic Review and Network Meta-Analysis.

Novel potassium-competitive acid blockers (P-CABs) have emerged as effective acid-suppressive drugs in recent years, replacing proton pump inhibitors (PPIs). We aim to compare the efficacy and safety of P-CABs versus PPIs in the treatment of peptic ulcers with or without Helicobacter pylori (H. pylori) infection. We searched in PubMed, Embase, WOS, Cochrane Library, ClinicalTrials.gov, CNKI, and Wanfang databases (all years up to January 2024). Efficacy and safety outcomes were evaluated using odds ratio (OR) and 95% confidence intervals (CI). The Surface Under the Cumulative Ranking (SUCRA) probabilities were used to rank each intervention. Among 14,056 studies screened, 56 studies involving 9792 participants were analyzed. Vonoprazan demonstrated the best efficacy in ulcer healing rate and H. pylori eradication rate (SUCRA = 86.4% and 90.7%, respectively). Keverprazan ranked second in ulcer healing rates (SUCRA = 76.0%) and was more effective in pain remission rates (SUCRA = 91.7%). The risk of adverse events was low for keverprazan (SUCRA = 11.8%) and tegoprazan (SUCRA = 12.9%), and moderate risk for vonoprazan (SUCRA = 44.3%) was demonstrated. Compared to lansoprazole, vonoprazan exhibited a higher risk of drug-related adverse events (OR: 2.15; 95% CI: 1.60-2.89) and serious adverse events (OR: 2.22; 95% CI: 1.11-4.42). Subgroup analysis on patients with H. pylori-positive peptic ulcers showed that vonoprazan was at the top of the SUCRA rankings, followed by keverprazan. Vonoprazan showed superior performance in peptic ulcers, especially for patients with H. pylori-positive peptic ulcers. However, the risk of adverse events associated with vonoprazan should be noted. Keverprazan has also shown good therapeutic outcomes and has performed better in terms of safety.

A disproportionality analysis of adverse events caused by GnRHas from the FAERS and JADER databases.

Background: Gonadotrophin-releasing hormone analogs (GnRHas) play a significant role in addressing gynecological diseases, central precocious puberty, and cancer. However, ensuring the safety of GnRHas in real-world applications requires continuous vigilance. In light of this, we undertook a disproportionality analysis focused on adverse events (AEs) associated with GnRHas using data from both the FDA Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report (JADER). We evaluated GnRHas-associated AEs and characterized the clinical priority of unlisted AEs caused by each GnRHa from the different databases. Methods: In the disproportionality analysis, we applied two adjusted algorithms to identify signals related to GnRHas in the FAERS and JADER databases from 2004 to 2023. Additionally, we utilized the Statistical Analysis System (SAS, 9.4) to examine potential and high-aROR (adjusted reporting odds ratio) signals associated with GnRHas. We performed clinical priority assessment for suspicious PTs and an analysis of serious/non-serious outcomes. We also gathered information on the onset times of AEs linked with GnRHas from both databases. Results: From January 2004 to September 2023, FAERS and JADER recorded a total of 50,360,413 and 1,440,200 AEs, respectively. Employing two algorithms, the suspicious preferred terms (PTs) related to leuprolide (Leu) were 562 potential PTs (44 unlisted in specifications), followed by goserelin (Gos) with 189 PTs (28 unlisted), triptorelin (Tri) with 172 PTs (28 unlisted), and Leu-JADER with 85 PTs (10 unlisted). At the same PT level, the differences in GnRHas between the two databases were observed, such as cardiac failure, diabetes mellitus, liver disorder, dementia, suicidal ideation, interstitial lung disease, urinary disorders, and hypertensive crisis. In an analysis of serious vs. non-serious outcomes, a total of 43 AEs of Leu were more likely to be reported as serious AEs with p < 0.05 (such as asthenia, urinary retention, diabetes mellitus, interstitial lung disease, gait disturbance, and so on), following by Tri (6 AEs), and Gos (4 AEs). Based on the clinical priority score, 41 PTs of Leu, 26 PTs of Tri, 24 PTs of Gos, and 8 PTs of Leu-JADER were graded as weak. There were 3 PTs of Leu, 2 PTs of Tri, 4 PTs of Gos, and 2 PTs of Leu-JADER that were graded as moderate. Notably, in the assessment of the relevant evidence, 2 PTs (loss of libido and urinary tract toxicity caused by Leu), 1 PT (electrolyte imbalance caused by Tri), and 2 PTs (anorexia and suicidal ideation caused by Gos) showed a strong level of evidence with "++." The differences in the signal strength of the same PTs from two databases were also worth noting. Moreover, the median onset time for GnRHas (Leu, Tri, and Gos) was 23 days (0, 298), 22 days (0, 181), and 217 days (29, 706), respectively, as median (Q1, Q3). Conclusion: An examination of two databases revealed suspicious AEs associated with GnRHas. Our study found potential new AE signals of GnRHas and supported continuous clinical monitoring, pharmacovigilance, regional differences, and further studies of GnRHas.

Post-marketing safety concerns with palbociclib: a disproportionality analysis of the FDA adverse event reporting system.

OBJECTIVES: To explore the association between palbociclib and related adverse events (AEs) in the real world through U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: The signal strength of palbociclib-related AEs was done by disproportionality analysis. Clinical priority of palbociclib-related AEs was scored and ranked by assessing five different features. Outcome analysis, time to onset analysis, dose-report /AEs number analysis, and stratification analysis were all performed. RESULTS: There were 61,821 'primary suspected (PS)' reports of palbociclib and 195,616 AEs associated with palbociclib. The four algorithms simultaneously detected 18 positive signals at the SOC level, and 65 positive signals at the PT level. Bone marrow failure, neuropathy, peripheral, pleural effusion, myelosuppression, pulmonary edema, and pulmonary thrombosis were also found to have positive signals. Gender (female vs male, χ2 = 5.287, p = 0.022) and age showed significant differences in serious and non-serious reports. Palbociclib-related AEs had a median onset time of 79 days (interquartile range [IQR] 20-264 days). CONCLUSIONS: The study identified potential Palbociclib-related AEs and offered warnings for special AEs, providing further data for palbociclib safety studies in breast cancer patients. Nonetheless, prospective clinical trials are needed to validate these results and explain their relationship.

Vonoprazan-associated Clostridioides difficile infection: an analysis of the Japanese Adverse Drug Event Report and the FDA Adverse Event Reporting System.

Background: Prolonged or excessive use of acid suppressants may increase the risk of Clostridioides difficile infection (CDI) by altering the intestinal microecosystem. Vonoprazan, a novel potassium-competitive acid blocker, exhibits a faster and more sustained acid-suppressive effect than proton pump inhibitors (PPIs). Therefore, vonoprazan may have a greater impact on the gut microbiota, potentially resulting in CDI. Objectives: This study aimed to explore the potential relationship between acid suppressants and CDI by the Japan Adverse Drug Event Report (JADER) and the FDA Adverse Event Reporting System (FAERS) databases. Design: A retrospective analysis of the JADER and FAERS databases was examined by disproportionality analysis. Methods: We performed signal detection analyses of CDI induced by vonoprazan and PPIs using the JADER and FAERS databases. The association between acid suppressants and CDI was calculated using the reporting odds ratio (ROR) and corresponding 95% confidence interval (95% CI). When the lower limit of the 95% CI is exceeded by 1, the association is considered statistically significant. Results: In the JADER database, the ROR (95% CI) for vonoprazan and PPIs based on suspect drug reports was 15.84 (12.23-20.50) and 2.51 (1.92-3.28), respectively. In the FAERS database, the ROR (95% CI) for vonoprazan and PPIs based on primary and secondary suspect drug reports was 11.50 (6.36-20.82) and 1.42 (1.34-1.51), respectively. Subgroup analysis showed that elderly patients aged 60 years and older were more strongly associated with CDI. The ROR (95% CI) for vonoprazan and PPIs in patients aged 60 years and older in the JADER database was 15.35 (11.59-20.33) and 1.65 (1.14-2.39), respectively. Similarly, the ROR (95% CI) for vonoprazan and PPIs in the FAERS database was 12.56 (6.26-25.20) and 1.43 (1.31-1.57), respectively. Excluding the effect of Helicobacter pylori (H. pylori) infection, the use of acid suppressants was still associated with CDI. Conclusion: While signal detection analysis based on the JADER and FAERS databases could not establish causality, our study demonstrated that both vonoprazan and PPIs were significantly associated with CDI. Vonoprazan showed a stronger association with CDI in both databases.

Introduction: Vonoprazan is a new type of acid suppressant, which has a stronger effect on acid inhibition than traditional proton pump inhibitors (PPIs). Vonoprazan may have a greater impact on the gut microbiota, which may increase the risk of Clostridioides difficile infection (CDI). The FDA created the FDA Adverse Event Reporting System (FAERS) database to support the post-market surveillance program. The PMDA created the Japan Adverse Drug Reaction Event Report (JADER) database to specifically collect adverse reaction reports in Japan. To further understand the potential relationship between acid suppressants and CDI, this study was analyzed using the JADER and FAERS databases. Methods: This study analyzed cases of CDI reported after the use of acid suppressants in the JADER and FAERS databases. Results: The analysis revealed that vonoprazan and PPIs are significantly associated with CDI in both databases. Notably, vonoprazan exhibited a stronger association compared to PPIs. Subgroup analysis indicated that this association was more pronounced in elderly patients aged 60 years and older. Additionally, excluding the influence of Helicobacter pylori (H. pylori) did not diminish the association between acid suppressants and CDI. Conclusion: Although signal detection analysis based on the JADER and FAERS databases could not establish causality, the results showed that both vonoprazan and PPIs were significantly associated with CDI. Vonoprazan was also more strongly associated with CDI than PPIs, which could be a potential safety concern, and further clinical studies are needed to confirm this finding.

Vonoprazan and Clostridioides difficile infection risk.

Detection of Retinal Microvascular Changes with Optical Coherence Tomography Angiography in Patients with Acute Leukemia Without Retinopathy.

INTRODUCTION: Acute leukemia often affects microcirculation perfusion. This study aimed to investigate retinal microvascular changes in patients with acute leukemia without retinopathy during clinical remission using optical coherence tomography angiography (OCTA) and to determine the correlation of these changes with systemic laboratory values. METHODS: Thirty-eight patients in remission from acute leukemia with no retinopathy (NLR group) and 36 age-matched healthy individuals (control group) were included in this cross-sectional study. OCTA parameters, including the central foveal thickness (CFT), foveal avascular zone (FAZ) area, FAZ perimeter, acircularity index (AI), foveal density (FD300), and the vessel densities (VDs) of the superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris were analyzed in a 6 × 6 mm2 macular scan. Correlation and multiple linear regression analyses were conducted to identify potential systemic characteristics associated with these OCTA metrics. RESULTS: AI (P = 0.034) and FD300 (P < 0.001) differed significantly between the NLR and control groups. The VD of SCP in the parafovea (P = 0.001) and of DCP in both the parafovea (P = 0.011) and perifovea (P = 0.001) were significantly lower in the NLR group than in the control group. In a multiple linear regression analysis, the reduced VD of the perifoveal DCP was significantly correlated with the increased international normalized ratio (standardized beta [STD ß] = - 0.356; P = 0.047). CONCLUSIONS: Macular microvascular changes can be observed during remission from acute leukemia antecedent to clinically visible retinal lesions. Hematological disturbances may be associated with microvascular impairments in preclinical leukemic retinopathy.

Whole-Genome Sequencing Reveals Rare Off-Target Mutations in MC1R-Edited Pigs Generated by Using CRISPR-Cas9 and Somatic Cell Nuclear Transfer.

The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system has been widely used to create animal models for biomedical and agricultural use owing to its low cost and easy handling. However, the occurrence of erroneous cleavage (off-targeting) may raise certain concerns for the practical application of the CRISPR-Cas9 system. In this study, we created a melanocortin 1 receptor (MC1R)-edited pig model through somatic cell nuclear transfer (SCNT) by using porcine kidney cells modified by the CRISPR-Cas9 system. We then carried out whole-genome sequencing of two MC1R-edited pigs and two cloned wild-type siblings, together with the donor cells, to assess the genome-wide presence of single-nucleotide variants and small insertions and deletions (indels) and found only one candidate off-target indel in both MC1R-edited pigs. In summary, our study indicates that the minimal off-targeting effect induced by CRISPR-Cas9 may not be a major concern in gene-edited pigs created by SCNT.

Corrosion Behavior and Mechanical Property of 5182 Aluminum/DP780 Steel Resistance Spot Welding Joints.

Corrosion behavior is critical to the application of lightweight aluminum/steel joints using new resistance spot welding (RSW) technology. The study investigated the corrosion mechanism and the shear strength of RSW joints comprising 1.2 mm 5182 aluminum and 1.5 mm DP780 galvanized steel. Electrochemical corrosion tests were conducted on the base materials and various positions of the welds in a 3.5% NaCl solution. This result revealed that the corrosion susceptibility of the interfacial intermetallic compound (IMC) layer was not accelerated by the aluminum nugget because of the noble corrosion potential. Subsequently, the spray acceleration test was employed to investigate the corrosion mechanism. It is noteworthy that microcracks, as well as regions enriched with silicon and oxygen at the interface front, are preferential to corrosion during salt spray exposure, instead of the IMC layer. Moreover, the shear strength of the joints decreases with the reduction in the effective joint area after the salt spray exposure of the weld joints. This research systematically explored the corrosion behavior and its relationship with the mechanical properties of Al alloy/steel RSW joints.

Characteristics of fungi formation in urban sewer at different flow conditions: Distribution, metabolism, and pathogenicity.

Fungi are the significant components of the sewer ecology system which can consume substances and exhibit pathogenicity. However, the characteristics of fungi formation and metabolism in the complex sewer environment have not been revealed in depth. In this study, gradient flow conditions were conducted in a pilot sewer and the formation characteristics of fungi were synthetically investigated. The results showed that the low flow rate at 0.1-0.4 m/s led to the loose morphology of biofilms, while the overly loose environment did not allow fungi communities to thrive in sewer. The dense biofilms were found at the middle flow condition (0.4-0.6 m/s), and the fungal communities with degradation functions were exuberant at this condition (such as Tremellales with relative abundance of 6.18% and Talaromyces with relative abundance of 6.51%). In particular, eleven kinds of fungi with known pathogenicity of the sewer biofilm were found in this study, and it is worth noting that the abundance of pathogenic fungi at medium flow rates is significantly higher than that at other flow conditions (higher than 10 %). While, excessive flow shear force (0.8-1.2 m/s) led to biofilm shedding which caused hindering the proper generation of fungi. In summary, the pollutant transformation and pathogenic exposure conducted by fungi communities could affect the sewer management process significantly, and this study could provide research foundation for wastewater quality prediction and management of pathogenic risk in sewer systems.

Identification of ZIP8-induced ferroptosis as a major type of cell death in monocytes under sepsis conditions.

Sepsis is a heterogenous syndrome with concurrent hyperinflammation and immune suppression. A prominent feature of immunosuppression during sepsis is the dysfunction and loss of monocytes; however, the major type of cell death contributing to this depletion, as well as its underlying molecular mechanisms, are yet to be identified. In this study, we confirmed the monocyte loss in septic patients based on a pooled gene expression data of periphery leukocytes. Using the collected reference gene sets from databases and published studies, we identified ferroptosis with a greater capacity to distinguish between sepsis and control samples than other cell death types. Further investigation on the molecular drivers, by a genetic algorithm-based feature selection and a weighted gene co-expression network analysis, revealed that zrt-/irt-like protein 8 (ZIP8), encoded by SLC39A8, was closely associated with ferroptosis of monocytes during sepsis. We validated the increase of ZIP8 of monocytes with in vivo and in vitro experiments. The in vitro studies also showed that downregulation of ZIP8 alleviated the lipopolysaccharide-induced lipid peroxidation, as well as restoring the reduction of GPX4, FTH1 and xCT. These findings suggest that ferroptosis might be a key factor in the loss of monocytes during sepsis, and that the heightened expression of ZIP8 may facilitate this progression.