Urinary proteomic signature of mineralocorticoid receptor antagonism by spironolactone: evidence from the HOMAGE trial.

OBJECTIVE: Heart failure (HF) is characterised by collagen deposition. Urinary proteomic profiling (UPP) followed by peptide sequencing identifies parental proteins, for over 70% derived from collagens. This study aimed to refine understanding of the antifibrotic action of spironolactone. METHODS: In this substudy (n=290) to the Heart 'Omics' in Ageing Study trial, patients were randomised to usual therapy combined or not with spironolactone 25-50 mg/day and followed for 9 months. The analysis included 1498 sequenced urinary peptides detectable in ≥30% of patients and carboxyterminal propeptide of procollagen I (PICP) and PICP/carboxyterminal telopeptide of collagen I (CITP) as serum biomarkers of COL1A1 synthesis. After rank normalisation of biomarker distributions, between-group differences in their changes were assessed by multivariable-adjusted mixed model analysis of variance. Correlations between the changes in urinary peptides and in serum PICP and PICP/CITP were compared between groups using Fisher's Z transform. RESULTS: Multivariable-adjusted between-group differences in the urinary peptides with error 1 rate correction were limited to 27 collagen fragments, of which 16 were upregulated (7 COL1A1 fragments) on spironolactone and 11 downregulated (4 COL1A1 fragments). Over 9 months of follow-up, spironolactone decreased serum PICP from 81 (IQR 66-95) to 75 (61-90) µg/L and PICP/CITP from 22 (17-28) to 18 (13-26), whereas no changes occurred in the control group, resulting in a difference (spironolactone minus control) expressed in standardised units of -0.321 (95% CI 0.0007). Spironolactone did not affect the correlations between changes in urinary COL1A1 fragments and in PICP or the PICP/CITP ratio. CONCLUSIONS: Spironolactone decreased serum markers of collagen synthesis and predominantly downregulated urinary collagen-derived peptides, but upregulated others. The interpretation of these opposite UPP trends might be due to shrinking the body-wide pool of collagens, explaining downregulation, while some degree of collagen synthesis must be maintained to sustain vital organ functions, explaining upregulation. Combining urinary and serum fibrosis markers opens new avenues for the understanding of the action of antifibrotic drugs. TRIAL REGISTRATION NUMBER: NCT02556450.

Use of egg yolk phospholipids to improve the thermal-oxidative stability of fatty acids, capsaicinoids and carotenoids in chili oil.

Phospholipids can act as antioxidants in food. In this study, egg yolk phospholipids (EPL) and sunflower oil were utilized in making chili oil, and proton nuclear magnetic resonance spectroscopy was employed to quantify the concentrations of fatty acyl groups, carotenoids, capsaicinoids in chili oil according to their specific signals in the spectra. The results showed that the changes in the concentrations of fatty acyl groups in the control samples were greater than those in the EPL-treated samples at the same frying temperature, while the contents of carotenoids and capsaicinoids were significantly lower than those of the EPL-treated samples when fried at 150 °C (p < 0.05). Two-way ANOVA indicated that frying temperature and EPL treatment, as well as their interaction had significant impacts on the thermal-oxidative stability of chili oil (p < 0.05). The results suggest that EPL may act as antioxidants during frying, and EPL can improve the thermal-oxidative stability of chili oil.

Sagittal balance parameters measurement on cervical spine MR images based on superpixel segmentation.

Introduction: Magnetic Resonance Imaging (MRI) is essential in diagnosing cervical spondylosis, providing detailed visualization of osseous and soft tissue structures in the cervical spine. However, manual measurements hinder the assessment of cervical spine sagittal balance, leading to time-consuming and error-prone processes. This study presents the Pyramid DBSCAN Simple Linear Iterative Cluster (PDB-SLIC), an automated segmentation algorithm for vertebral bodies in T2-weighted MR images, aiming to streamline sagittal balance assessment for spinal surgeons. Method: PDB-SLIC combines the SLIC superpixel segmentation algorithm with DBSCAN clustering and underwent rigorous testing using an extensive dataset of T2-weighted mid-sagittal MR images from 4,258 patients across ten hospitals in China. The efficacy of PDB-SLIC was compared against other algorithms and networks in terms of superpixel segmentation quality and vertebral body segmentation accuracy. Validation included a comparative analysis of manual and automated measurements of cervical sagittal parameters and scrutiny of PDB-SLIC's measurement stability across diverse hospital settings and MR scanning machines. Result: PDB-SLIC outperforms other algorithms in vertebral body segmentation quality, with high accuracy, recall, and Jaccard index. Minimal error deviation was observed compared to manual measurements, with correlation coefficients exceeding 95%. PDB-SLIC demonstrated commendable performance in processing cervical spine T2-weighted MR images from various hospital settings, MRI machines, and patient demographics. Discussion: The PDB-SLIC algorithm emerges as an accurate, objective, and efficient tool for evaluating cervical spine sagittal balance, providing valuable assistance to spinal surgeons in preoperative assessment, surgical strategy formulation, and prognostic inference. Additionally, it facilitates comprehensive measurement of sagittal balance parameters across diverse patient cohorts, contributing to the establishment of normative standards for cervical spine MR imaging.

Lead-associated mortality in the US 1999-2020: a time-stratified analysis of a national cohort.

OBJECTIVES: We undertook time-stratified analyses of the National Health and Nutrition Examination Survey in the US to assess time trends (1999-2020) in the associations of blood lead (BL) with blood pressure, mortality, the BL-associated population attributable fraction (PAF). METHODS: Vital status of participants, 20-79 years old at enrolment, was ascertained via the National Death Index. Regressions, mediation analyses and PAF were multivariable adjusted and standardized to 2020 US Census data. RESULTS: In time-stratified analyses, BL decreased from 1.76 µg/dl in 1999-2004 to 0.93 µg/dl in 2017-2020, while the proportion of individuals with BL < 1 µg/dl increased from 19.2% to 63.0%. Total mortality was unrelated to BL (hazard ratio (HR) for a fourfold BL increment: 1.05 [95% confidence interval, CI: 0.93-1.17]). The HR for cardiovascular death was 1.44 (1.01-2.07) in the 1999-2000 cycle, but lost significance thereafter. BL was directly related to cardiovascular mortality, whereas the indirect BL pathway via BP was not significant. Low socioeconomic status (SES) was directly related to BL and cardiovascular mortality, but the indirect SES pathway via BL lost significance in 2007-2010. From 1999-2004 to 2017-2020, cardiovascular PAF decreased (P < 0.001) from 7.80% (0.17-14.4%) to 2.50% (0.05-4.68%) and number of lead-attributable cardiovascular deaths from 53 878 (1167-99 253) to 7539 (160-14 108). CONCLUSION: Due to implementation of strict environmental policies, lead exposure is no longer associated with total mortality, and the mildly increased cardiovascular mortality is not associated with blood lead via blood pressure in the United States.

Pestalotiopsis jiangsuensis sp. nov. Causing Needle Blight on Pinus massoniana in China.

Pinus massoniana Lamb. is an important, common afforestation and timber tree species in China. Species of Pestalotiopsis are well-known pathogens of needle blight. In this study, the five representative strains were isolated from needle blight from needles of Pi. massoniana in Nanjing, Jiangsu, China. Based on multi-locus phylogenetic analyses of the three genomic loci (ITS, TEF1, and TUB2), in conjunction with morphological characteristics, a new species, namely Pestalotiopsis jiangsuensis sp. nov., was described and reported. Pathogenicity tests revealed that the five representative strains of the species described above were pathogenic to Pi. massoniana. The study revealed the diversity of pathogenic species of needle blight on Pi. massoniana. This is the first report of needle blight caused by P. jiangsuensis on Pi. massoniana in China and worldwide. This provides useful information for future research on management strategies of this disease.

Extracellular vesicles derived from mesenchymal stem cells mediate extracellular matrix remodeling in osteoarthritis through the transport of microRNA-29a.

BACKGROUND: Knee osteoarthritis (KOA) is a common orthopedic condition with an uncertain etiology, possibly involving genetics and biomechanics. Factors like changes in chondrocyte microenvironment, oxidative stress, inflammation, and immune responses affect KOA development. Early-stage treatment options primarily target symptom relief. Mesenchymal stem cells (MSCs) show promise for treatment, despite challenges. Recent research highlights microRNAs (miRNAs) within MSC-released extracellular vesicles that can potentially promote cartilage regeneration and hinder KOA progression. This suggests exosomes (Exos) as a promising avenue for future treatment. While these findings emphasize the need for effective KOA progression management, further safety and efficacy validation for Exos is essential. AIM: To explore miR-29a's role in KOA, we'll create miR-29a-loaded vesicles, testing for early treatment in rat models. METHODS: Extraction of bone marrow MSC-derived extracellular vesicles, preparation of engineered vesicles loaded with miR-29a using ultrasonication, and identification using quantitative reverse transcription polymerase chain reaction; after establishing a rat model of KOA, rats were randomly divided into three groups: Blank control group injected with saline, normal extracellular vesicle group injected with normal extracellular vesicle suspension, and engineered extracellular vesicle group injected with engineered extracellular vesicle suspension. The three groups were subjected to general behavioral observation analysis, imaging evaluation, gross histological observation evaluation, histological detection, and immunohistochemical detection to compare and evaluate the progress of various forms of arthritis. RESULTS: General behavioral observation results showed that the extracellular vesicle group and engineered extracellular vesicle group had better performance in all four indicators of pain, gait, joint mobility, and swelling compared to the blank control group. Additionally, the engineered extracellular vesicle group had better pain relief at 4 wk and better knee joint mobility at 8 wk compared to the normal extracellular vesicle group. Imaging examination results showed that the blank control group had the fastest progression of arthritis, the normal extracellular vesicle group had a relatively slower progression, and the engineered extracellular vesicle group had the slowest progression. Gross histological observation results showed that the blank control group had the most obvious signs of arthritis, the normal extracellular vesicle group showed signs of arthritis, and the engineered extracellular vesicle group showed no significant signs of arthritis. Using the Pelletier gross score evaluation, the engineered extracellular vesicle group had the slowest progression of arthritis. Results from two types of staining showed that the articular cartilage of rats in the normal extracellular vesicle and engineered extracellular vesicle groups was significantly better than that of the blank control group, and the engineered extracellular vesicle group had the best cartilage cell and joint surface condition. Immunohistochemical detection of type II collagen and proteoglycan showed that the extracellular matrix of cartilage cells in the normal extracellular vesicle and engineered extracellular vesicle groups was better than that of the blank control group. Compared to the normal extracellular vesicle group, the engineered extracellular vesicle group had a better regulatory effect on the extracellular matrix of cartilage cells. CONCLUSION: Engineered Exos loaded with miR-29a can exert anti-inflammatory effects and maintain extracellular matrix stability, thereby protecting articular cartilage, and slowing the progression of KOA.

Mortality and Cardiovascular End Points In Relation to the Aortic Pulse Wave Components: An Individual-Participant Meta-Analysis.

BACKGROUND: Wave separation analysis enables individualized evaluation of the aortic pulse wave components. Previous studies focused on the pressure height with overall positive but differing results. In the present analysis, we assessed the associations of the pressure of forward and backward (Pfor and Pref) pulse waves with prospective cardiovascular end points, with extended analysis for time to pressure peak (Tfor and Tref). METHODS: Participants in 3 IDCARS (International Database of Central Arterial Properties for Risk Stratification) cohorts (Argentina, Belgium, and Finland) aged ≥20 years with valid pulse wave analysis and follow-up data were included. Pulse wave analysis was done using the SphygmoCor device, and pulse wave separation was done using the triangular method. The primary end points consisted of cardiovascular mortality and nonfatal cardiovascular and cerebrovascular events. Multivariable-adjusted Cox regression was used to calculate hazard ratios. RESULTS: A total of 2206 participants (mean age, 57.0 years; 55.0% women) were analyzed. Mean±SDs for Pfor, Pref, Tfor, and Tfor/Tref were 31.0±9.1 mm Hg, 20.8±8.4 mm Hg, 130.8±35.5, and 0.51±0.11, respectively. Over a median follow-up of 4.4 years, 146 (6.6%) participants experienced a primary end point. Every 1 SD increment in Pfor, Tfor, and Tfor/Tref was associated with 27% (95% CI, 1.07-1.49), 25% (95% CI, 1.07-1.45), and 32% (95% CI, 1.12-1.56) higher risk, respectively. Adding Tfor and Tfor/Tref to existing risk models improved model prediction (∆Uno's C, 0.020; P<0.01). CONCLUSIONS: Pulse wave components were predictive of composite cardiovascular end points, with Tfor/Tref showing significant improvement in risk prediction. Pending further confirmation, the ratio of time to forward and backward pressure peak may be useful to evaluate increased afterload and signify increased cardiovascular risk.

Regioselective Alkynylation and Alkenylation at the More Hindered C-B Bond of 1,2-Bis(Boronic) Esters.

Selective transformations at the more sterically hindered sites of organic molecules represent a frontier in the ability to precisely modify molecules. The lack of effective synthetic methods stands in stark contrast to the large number of encumbered sites encountered in molecules of interest. Here, we demonstrate that 1,2-bis(boronates) undergo selective alkynylation and alkenylation at the more sterically hindered C-B bond. Our preliminary mechanistic studies disclosed that this reaction can proceed through two convergent pathways involving direct coupling of sterically encumbered site versus 1,2-boron migratory coupling. Notably, this method facilitated convenient access to alkenyl and alkynyl boron products, which can be diversified by an array of transformations.

Effective substances and molecular mechanisms guided by network pharmacology: An example study of Scrophulariae Radix treatment of hyperthyroidism and thyroid hormone-induced liver and kidney injuries.

ETHNOPHARMACOLOGICAL RELEVANCE: Scrophulariae Radix (Xuanshen [XS]) has been used for several years to treat hyperthyroidism. However, its effective substances and pharmacological mechanisms in the treatment of hyperthyroidism and thyroid hormone-induced liver and kidney injuries have not yet been elucidated. AIM OF THE STUDY: This study aimed to explore the pharmacological material basis and potential mechanism of XS therapy for hyperthyroidism and thyroid hormone-induced liver and kidney injuries based on network pharmacology prediction and experimental validation. MATERIALS AND METHODS: Based on 31 in vivo XS compounds identified using ultra-performance liquid chromatography tandem quadruple exactive orbitrap high-resolution accurate-mass spectrometry (UPLC-QE-HRMS), a network pharmacology approach was used for mechanism prediction. Systematic networks were constructed to identify the potential molecular targets, biological processes (BP), and signaling pathways. A component-target-pathway network was established. Mice were administered levothyroxine sodium through gavage for 30 d and then treated with different doses of XS extract with or without propylthiouracil (PTU) for 30 d. Blood, liver, and kidney samples were analyzed using an enzyme-linked immunosorbent assay (ELISA) and western blotting. RESULTS: A total of 31 prototypes, 60 Phase I metabolites, and 23 Phase II metabolites were tentatively identified in the plasma of rats following the oral administration of XS extract. Ninety-six potential common targets between the 31 in vivo compounds and the diseases were identified. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that Bcl-2, BAD, JNK, p38, and ERK1/2 were the top targets. XS extract with or without PTU had the following effects: inhibition of T3/T4/fT3/fT4 caused by levothyroxine; increase of TSH levels in serum; restoration of thyroid structure; improvement of liver and kidney structure and function by elevating the activities of anti-oxidant enzymes catalase (CAT),superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px); activation anti-apoptotic proteins Bcl-2; inhibition the apoptotic protein p-BAD; downregulation inflammation-related proteins p-ERK1/2, p-JNK, and p-p38; and inhibition of the aggregation of pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6, as well as immune cells in the liver. CONCLUSION: XS can be used to treat hyperthyroidism and liver and kidney injuries caused by thyroid hormones through its anti-oxidant, anti-inflammatory, and anti-apoptotic properties. In addition, serum pharmacochemical analysis revealed that five active compounds, namely 4-methylcatechol, sugiol, eugenol, acetovanillone, and oleic acid, have diverse metabolic pathways in vivo and exhibit potential as effective therapeutic agents.

OSTEO18, a novel urinary proteomic signature, associated with osteoporosis in heart transplant recipients.

Background: Immunosuppressive treatment in heart transplant (HTx) recipient causes osteoporosis. The urinary proteomic profile (UPP) includes peptide fragments derived from the bone extracellular matrix. Study aims were to develop and validate a multidimensional UPP biomarker for osteoporosis in HTx patients from single sequenced urinary peptides identifying the parent proteins. Methods: A single-center HTx cohort was analyzed. Urine samples were measured by capillary electrophoresis coupled with mass spectrometry. Cases with osteoporosis and matching controls were randomly selected from all available 389 patients. In derivation case-control dataset, 1576 sequenced peptides detectable in ≥30 % of patients. Applying statistical analysis on these, an 18-peptide multidimensional osteoporosis UPP biomarker (OSTEO18) was generated by support vector modeling. The 2 replication datasets included 118 and 94 patients. For further validation, the whole cohort was analyzed. Statistical methods included logistic regression and receiver operating characteristic curve (ROC) analysis. Results: In derivation dataset, the AUC, sensitivity and specificity of OSTEO18 were 0.83 (95 % CI: 0.76-0.90), 74.3 % and 87.1 %, respectively. In replication datasets, results were confirmatory. In the whole cohort (154 osteoporotic patients [39.6 %]), the ORs for osteoporosis increased (p < 0.0001) across OSTEO18 quartiles from 0.39 (95 % CI: 0.25-0.61) to 3.14 (2.08-4.75). With full adjustment for known osteoporosis risk factors, OSTEO18 improved AUC from 0.708 to 0.786 (p = 0.0003) for OSTEO18 categorized (optimized threshold: 0.095) and to 0.784 (p = 0.0004) for OSTEO18 as continuously distributed classifier. Conclusion: OSTEO18 is a clinically meaningful novel biomarker indicative of osteoporosis in HTx recipients and is being certified as in-vitro diagnostic.

Seven new species of Alternaria (Pleosporales, Pleosporaceae) associated with Chinese fir, based on morphological and molecular evidence.

Chinese fir (Cunninghamialanceolata) is a special fast-growing commercial tree species in China and has significant ecological and economic value. However, it experienced damage from leaf blight caused by pathogenic fungi of the genus Alternaria. To determine the diversity of Alternaria species associated with leaf blight of Chinese fir in China, infected leaves were collected from five major cultivation provinces (Fujian, Henan, Hunan, Jiangsu and Shandong provinces). A total of 48 fungal strains of Alternaria were obtained. Comparison of morphology and phylogenetic analyses, based on nine loci (ITS, SSU, LSU, GAPDH, RPB2, TEF1, Alt a1, endoPG and OPA10-2) of the representative isolates as well as the pairwise homoplasy index tests, revealed that the fungal strains belonged to seven undescribed taxa of Alternaria, which are described here and named as Alternariacunninghamiicolasp. nov., A.dongshanqiaoensissp. nov., A.hunanensissp. nov., A.kunyuensissp. nov., А. longqiaoensissp. nov., A.shandongensissp. nov. and A.xinyangensissp. nov. In order to prove Koch's postulates, pathogenicity tests on detached Chinese fir leaves revealed significant pathogenicity amongst these species, of which A.hunanensis is the most pathogenic to Chinese fir. This study represents the first report of A.cunninghamiicola, A.dongshanqiaoensis, A.hunanensis, A.kunyuensis, A.longqiaoensis, A.shandongensis and A.xinyangensis causing leaf blight on Chinese fir. Knowledge obtained in this study enhanced our understanding of Alternaria species causing leaf blight on Chinese fir and was crucial for the disease management and the further studies in the future.

Morphological and phylogenetic analyses reveal three new species of Fusarium (Hypocreales, Nectriaceae) associated with leaf blight on Cunninghamialanceolata in China.

Chinese fir (Cunninghamialanceolata) is a special fast-growing commercial tree species in China with high economic value. In recent years, leaf blight disease on C.lanceolata has been observed frequently. The diversity of Fusarium species associated with leaf blight on C.lanceolata in China (Fujian, Guangxi, Guizhou, and Hunan provinces) was evaluated using morphological study and molecular multi-locus analyses based on RNA polymerase second largest subunit (RPB2), translation elongation factor 1-alpha (TEF-1α), and RNA polymerase largest subunit (RPB1) genes/region as well as the pairwise homoplasy index tests. A total of five Fusarium species belonging to four Fusarium species complexes were recognized in this study. Two known species including Fusariumconcentricum and F.fujikuroi belonged to the F.fujikuroi species complex, and three new Fusarium species were described, i.e., F.fujianense belonged to the F.lateritium species complex, F.guizhouense belonged to the F.sambucinum species complex, and F.hunanense belonged to the F.solani species complex. To prove Koch's postulates, pathogenicity tests on C.lanceolata revealed a wide variation in pathogenicity and aggressiveness among the species, of which F.hunanense HN33-8-2 caused the most severe symptoms and F.fujianense LC14 led to the least severe symptoms. To our knowledge, this study also represented the first report of F.concentricum, F.fujianense, F.fujikuroi, F.guizhouense, and F.hunanense causing leaf blight on C.lanceolata in China.

Clinical value of oral contrast-enhanced ultrasonography in diagnosis of gastric tumors.

BACKGROUND: The incidence of gastric cancer remains high, and it is the sixth most common cancer and the fourth leading cause of cancer deaths worldwide. Oral contrast-enhanced ultrasonography is a simple, non-invasive, and painless method for the diagnosis of gastric tumors. AIM: To explore the diagnostic value of oral contrast-enhanced ultrasonography for the detection of gastric tumors. METHODS: The screening results based on oral contrast-enhanced ultrasonography and electronic gastroscopy were compared with those of the postoperative pathological examination. RESULTS: Among 42 patients with gastric tumors enrolled in the study, the diagnostic accordance rate was 95.2% for oral contrast-enhanced ultrasonography (n = 40) and 90.5% for electronic gastroscopy (n = 38) compared with postoperative pathological examination. The Kappa value of consistency test with pathological findings was 0.812 for oral contrast-enhanced ultrasonography and 0.718 for electronic gastroscopy, and there was no significant difference between them (P = 0.397). For the TNM staging of gastric tumors, the accuracy rate of oral contrast-enhanced ultrasonography was 81.9% for the overall T staging and 50%, 77.8%, 100%, and 100% for T1, T2, T3, and T4 staging, respectively. The sensitivity and specificity were both 100% for stages T3 and T4. The diagnostic accuracy rate of oral contrast-enhanced ultrasonography was 93.8%, 80%, 100%, and 100% for stages N0, N1-N3, M0, and M1, respectively. CONCLUSION: The accordance rate of qualitative diagnosis by oral contrast-enhanced ultrasonography is comparable to that of gastroscopy, and it could be used as the preferred method for the early screening of gastric tumors.

Prenatal diagnosis and treatment for fetal angiotensin converting enzyme deficiency.

OBJECTIVE: To elucidate an etiology in a case with persistent oligohydramnios by prenatal diagnosis and actively treat the case to achieve good prognosis. METHODS: We performed whole exome sequencing (WES) of DNA from the fetus and parents. Serial amnioinfusions were conducted until birth. Pressors were required to maintain normal blood pressure. The infant angiotensin-converting enzyme (ACE) activity, angiotensin II (Ang II, a downstream product of ACE), and compensatory enzymes (CEs) activities were measured. Compensatory enzyme activities in plasma from age-matched healthy controls were also detected. RESULTS: We identified a fetus with a severe ACE mutation prenatally. The infant was born prematurely without pulmonary dysplasia. Hypotension and anuria resolved spontaneously. He had almost no ACE activity, but his Ang II level and CE activity exceeded the upper limit of the normal range and the upper limit of the 95% confidence interval of controls, respectively. His renal function also largely recovered. CONCLUSION: Fetuses with ACE mutations can be diagnosed prenatally through WES. Serial amnioinfusion permits the continuation of pregnancy in fetal ACE deficiency. Compensatory enzymes for defective ACE appeared postnatally. Renal function may be spared by preterm delivery; furthermore, for postnatal vasopressor therapy to begin, improving renal perfusion pressure before nephrogenesis has been completed.

HMGB1-RAGE axis contributes to myocardial ischemia/reperfusion injury via regulation of cardiomyocyte autophagy and apoptosis in diabetic mice.

Patients with acute myocardial infarction complicated with diabetes are more likely to develop myocardial ischemia/reperfusion (I/R) injury (MI/RI) during reperfusion therapy. Both HMGB1 and RAGE play important roles in MI/RI. However, the specific mechanisms of HMGB1 associated with RAGE are not fully clarified in diabetic MI/RI. This study aimed to investigate whether the HMGB1-RAGE axis induces diabetic MI/RI via regulating autophagy and apoptosis. A db/db mouse model of MI/RI was established, where anti-HMGB1 antibody and RAGE inhibitor (FPS-ZM1) were respectively injected after 10 min of reperfusion. The results showed that treatment with anti-HMGB1 significantly reduced the infarct size, serum LDH, and CK-MB level. Similar situations also occurred in mice administrated with FPS-ZM1, though the HMGB1 level was unchanged. Then, we found that treatment with anti-HMGB1 or FPS-ZM1 performed the same effects in suppressing the autophagy and apoptosis, as reflected by the results of lower LAMP2 and LC3B levels, increased Bcl-2 level, reduced BAX and caspase-3 levels. Moreover, the Pink1/Parkin levels were also inhibited at the same time. Collectively, this study indicates that the HMGB1-RAGE axis aggravated diabetic MI/RI via apoptosis and Pink1/Parkin mediated autophagy pathways, and inhibition of HMGB1 or RAGE contributes to alleviating those adverse situations.

Identification and Fungicide Screening of Fungal Species Associated with Walnut Anthracnose in Shaanxi and Liaoning Provinces, China.

Walnut is cultivated around the world for its precious woody nut and edible oil. Recently, walnut infected by Colletotrichum spp. resulted in a great yield and quality loss. In August and September 2014, walnut fruits with anthracnose were sampled from two commercial orchards in Shaanxi and Liaoning provinces, and five representative isolates were used in this study. To identify the pathogen properly, four genes per region (internal transcribed spacer, glyceraldehyde-3-phosphate dehydrogenase, actin, and chitin synthase) were sequenced and used in phylogenetic studies. Based on multilocus phylogenetic analysis, five isolates clustered with Colletotrichum fioriniae, including its ex-type, with 100% bootstrap support. The results of multilocus phylogenetic analyses, morphology, and pathogenicity confirmed that C. fioriniae was one of the walnut anthracnose pathogens in China. All 13 fungicides tested inhibited mycelial growth and spore germination. Flusilazole, fluazinam, prochloraz, and pyraclostrobin showed the strongest suppressive effects on the mycelial growth than the others, the average EC50 values ranged from 0.09 to 0.40 µg/ml, and there was not any significant difference (P < 0.05). Pyraclostrobin, thiram, and azoxystrobin were the most effective fungicides on spore germination (P < 0.05), and the EC50 values ranged from 0.01 to 0.44 µg/ml. Pyraclostrobin, azoxystrobin, fluazinam, flusilazole, mancozeb, thiram, and prochloraz exhibited a good control effect on walnut anthracnose caused by C. fioriniae, and preventive activities were greater than curative activities. Pyraclostrobin at 250 a.i. µg/ml and fluazinam at 500 a.i. µg/ml provided the highest preventive and curative efficacy, and the values ranged from 81.3 to 82.2% and from 72.9 to 73.6%, respectively. As a consequence, mancozeb and thiram could be used at the preinfection stage, and pyraclostrobin, azoxystrobin, flusilazole, fluazinam, and prochloraz could be used at the early stage for effective prevention and control of walnut anthracnose caused by C. fioriniae. The results will provide more significant instructions for controlling the disease effectively in northern China.

Colletotrichum nanjingense sp. nov. and C. gloeosporioides s.s. Causing Leaf Tip Blight on Jasminum mesnyi in Nanjing, Jiangsu, China.

Jasminum mesnyi Hance is an important medicinal and ornamental plant. This species is native to South Central China and Vietnam and grows primarily in the subtropical biomes. In June 2022, 17 Colletotrichum strains were isolated from leaf tip blight on foliage of J. mesnyi in Nanjing, Jiangsu, China. Based on morphological characteristics and multilocus phylogenetic analyses of six genomic loci (ITS, CAL, ACT, TUB2, CHS-1, and GAPDH), a new species, namely, C. nanjingense, and a known species, namely, C. gloeosporioides s.s., were described and reported. Pathogenicity tests revealed that both species were pathogens causing leaf tip blight on J. mesnyi. The results provided necessary information for disease control and enhanced our understanding of the diversity of Colletotrichum species in China.

Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia.

Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft resource and perform integrated genomics, transcriptomics and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized phase II-like preclinical trial in patient-derived xenografts, imetelstat effectively diminishes AML burden and preferentially targets subgroups containing mutant NRAS and oxidative stress-associated gene expression signatures. Unbiased, genome-wide CRISPR/Cas9 editing identifies ferroptosis regulators as key mediators of imetelstat efficacy. Imetelstat promotes the formation of polyunsaturated fatty acid-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress. Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing substantial disease control in AML.