A predictive model for therapy failure in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor therapy.

Although tyrosine kinase inhibitor (TKI) therapy has markedly improved the survival of people with chronic-phase chronic myeloid leukemia (CML), 20-30% of people still experienced therapy failure. Data from 1,955 consecutive subjects with chronic-phase CML diagnosed by the European LeukemiaNet (ELN) recommendations from 1 center receiving initial TKI imatinib or a second-generation (2G-) TKI therapy were interrogated to develop a clinical prediction model for TKI therapy failure. This model was subsequently validated in 3,454 subjects from 76 other centers. Using the predictive clinical co-variates associated with TKI therapy failure, we developed a model that stratified subjects into low-, intermediate- and high-risk subgroups with significantly different cumulative incidences of therapy failure (p < 0.001). There was good discrimination and calibration in the external validation dataset, and the performance was consistent with that of the training dataset. Our model had the better prediction discrimination than the Sokal and ELTS scores did, with the greater time-dependent area under the receiver-operator characteristic curve (AUROC) values and a better ability to re-defined the risk of therapy failure. Our model could help physicians estimate the likelihood of initial imatinib or 2G-TKI therapy failure in people with chronic-phase CML.

Morvan's syndrome with hypercoagulable condition in a patient positive for anti-CASPR2 antibodies: A case report.

RATIONALE: The phenomenon of hypercoagulability has not been previously documented in individuals with Morvan's syndrome, especially in those associated with contactin-associated protein-like receptor 2 (CASPR2). PATIENT CONCERNS: A previously healthy 32-year-old Chinese male was admitted to the hospital with central and peripheral neurologic symptoms. The patient was tested positive for anti-CASPR2 antibodies, and also presented with an activated coagulation state on admission, characterized by a low activated partial thromboplastin time and a high platelet count. With gradual improvement of clinical symptoms, activated partial thromboplastin time, and platelet count returned to normal. Simultaneously, anti-CASPR2 antibody titers significantly decreased and eventually became undetectable. DIAGNOSES: The patient was diagnosed as Morvan's syndrome with positive anti-CASPAR2 antibodies accompanied with hypercoagulable state. INTERVENTIONS: Plasmapheresis was administered to improve the symptoms combined with prednisolone acetate therapy. OUTCOMES: The patient experienced complete resolution of all symptoms during hospitalization and generally recovery after 2 months of discharge. LESSONS: Emphasis should be directed towards hypercoagulability in individuals diagnosed with Morvan's syndrome, particularly those presenting with positive anti-CASPR2 antibodies. Anticoagulant therapy may represent a novel therapeutic approach for individuals afflicted with Morvan's syndrome and exhibiting positivity for anti-CASPR2 antibodies.

Association between relative muscle strength and cardiovascular disease among middle-aged and older adults in China.

BACKGROUND: The association between sarcopenia and cardiovascular disease (CVD) is well known. However, the clinical diagnosis of sarcopenia is complex and not suitable for early clinical identification and prevention of CVD. Relative muscle strength (RMS) is a relatively quantitative and straightforward indicator, but its association with CVD remains unclear. Hence, the objective of this research was to investigate the correlation between RMS and CVD incidence. METHODS: This was a cross-sectional study, using data from the China Health and Retirement Longitudinal Study (CHARLS) in 2011. CVD events were assessed through self-reported physician diagnoses. The RMS was determined by dividing the maximum grip strength by the appendicular skeletal muscle mass (ASM). This study used multivariate logistic regression and restricted cubic spline (RCS) curves to explore the correlation between RMS and CVD incidence. Additionally, we conducted subgroup analyses to provide additional evidence supporting the association between the two variables. RESULTS: A total of 8,733 people were included in our study, with 1,152 (13.19%) CVD patients and 7,581 (86.81%) non-CVD patients. When the data were grouped according to quartiles (Q) of RMS, the inverse association between CVD and RMS remained statistically significant even after controlling for all potential confounding factors. Compared with participants in Q1 of RMS, the ORs (95% CIs) of CVD among those in Q2-Q4 were 0.99 (0.83, 1.17), 0.81 (0.67, 0.98), and 0.70 (0.57, 0.85), respectively. Moreover, the RCS results showed a negative linear correlation between the RMS and CVD incidence (P for nonlinearity = 0.555). Subgroup analysis revealed no significant interaction in any of the groups except for the sex group (P for interaction = 0.046). CONCLUSION: Our study indicated a stable negative correlation between RMS and CVD incidence. RMS is helpful for the early identification and prevention of CVD.

CircCDC42-encoded CDC42-165aa regulates macrophage pyroptosis in Klebsiella pneumoniae infection through Pyrin inflammasome activation.

The circular RNA (circRNA) family is a group of endogenous non-coding RNAs (ncRNAs) that have critical functions in multiple physiological and pathological processes, including inflammation, cancer, and cardiovascular diseases. However, their roles in regulating innate immune responses remain unclear. Here, we define Cell division cycle 42 (CDC42)-165aa, a protein encoded by circRNA circCDC42, which is overexpressed in Klebsiella pneumoniae (KP)-infected alveolar macrophages. High levels of CDC42-165aa induces the hyperactivation of Pyrin inflammasomes and aggravates alveolar macrophage pyroptosis, while the inhibition of CDC42-165aa reduces lung injury in mice after KP infection by inhibiting Pyrin inflammasome-mediated pyroptosis. Overall, these results demonstrate that CDC42-165aa stimulates Pyrin inflammasome by inhibiting CDC42 GTPase activation and provides a potential clinical target for pathogenic bacterial infection in clinical practice.

Detection of hemophilia a genetic variants using third-generation long-read sequencing.

BACKGROUND: Hemophilia A (HA) is an X-linked recessive genetic disorder caused by pathogenic variations of the factor VIII -encoding gene, F8 gene. Due to the large size and diverse types of variations in the F8 gene, causative mutations in F8 cannot be simultaneously detected in one step by traditional molecular analysis, and genetic molecular diagnosis and prenatal screening of HA still face significant difficulties and challenges in clinical practice. Therefore, we aimed to develop and validate an efficient, accurate, and time-saving method for the genetic detection of HA. METHODS: A comprehensive analysis of hemophilia A (CAHEA) method based on long-range PCR and long-read sequencing (LRS) was used to detect F8 gene mutations in 14 clinical HA samples. The LRS results were compared with those of the conventional methods to evaluate the accuracy and sensitivity of the proposed approach. RESULTS: The CAHEA method successfully identified 14 F8 variants in all probands, including 3 small insertion deletions, 4 single nucleotide variants, and 7 intron 22 inversions in a "one-step" manner, of which 2 small deletions have not been reported previously. Moreover, this method provided an opportunity to analyze the mechanism of rearrangement and the pathogenicity of F8 variants. The LRS results were validated and found to be in 100% agreement with those obtained using the conventional method. CONCLUSION: Our proposed LRS-based F8 gene detection method is an accurate and reproducible genetic screening and diagnostic method with significant clinical value. It provides efficient, comprehensive, and accurate genetic screening and diagnostic services for individuals at high risk of HA as well as for premarital and prenatal populations.

A novel selenium analog of HDACi-based twin drug induces apoptosis and cell cycle arrest via CDC25A to improve prostate cancer therapy.

Cancer therapy has moved from single agents to more mechanism-based targeted approaches. In recent years, the combination of HDAC inhibitors and other anticancer chemicals has produced exciting progress in cancer treatment. Herein, we developed a novel prodrug via the ligation of dichloroacetate to selenium-containing potent HDAC inhibitors. The effect and mechanism of this compound in the treatment of prostate cancer were also studied. Methods: The concerned prodrug SeSA-DCA was designed and synthesized under mild conditions. This compound's preclinical studies, including the pharmacokinetics, cell toxicity, and anti-tumor effect on prostate cancer cell lines, were thoroughly investigated, and its possible synergistic mechanism was also explored and discussed. Results: SeSA-DCA showed good stability in physiological conditions and could be rapidly decomposed into DCA and selenium analog of SAHA (SeSAHA) in the tumor microenvironment. CCK-8 experiments identified that SeSA-DCA could effectively inhibit the proliferation of a variety of tumor cell lines, especially in prostate cancer. In further studies, we found that SeSA-DCA could also inhibit the metastasis of prostate cancer cell lines and promote cell apoptosis. At the animal level, oral administration of SeSA-DCA led to significant tumor regression without obvious toxicity. Moreover, as a bimolecular coupling compound, SeSA-DCA exhibited vastly superior efficacy than the mixture with equimolar SeSAHA and DCA both in vitro and in vivo. Our findings provide an important theoretical basis for clinical prostate cancer treatment. Conclusions: Our in vivo and in vitro results showed that SeSA-DCA is a highly effective anti-tumor compound for PCa. It can effectively induce cell cycle arrest and growth suppression and inhibit the migration and metastasis of PCa cell lines compared with monotherapy. SeSA-DCA's ability to decrease the growth of xenografts is a little better than that of docetaxel without any apparent signs of toxicity. Our findings provide an important theoretical basis for clinical prostate cancer treatment.

[Effects of water level on soil seed bank in the floodplain wetland of Juzhang River, China]. / 水位变化对沮漳河河漫滩湿地土壤种子库的影响.

Aiming to understand the responses of soil seed bank to different water levels, we investigated vegetation and soil seed bank along a water level gradient (frequently flooded area, unflooded area) on the floodplain wetland of Juzhang River. We used the structural equation model to explore the direct and indirect effects of water level on soil seed bank, and used non-metric multidimensional scaling (NMDS) to assess the role of soil seed bank for vegetation regeneration. The results showed that the density of transient and persistent seed banks at unflooded area was 36.9% and 7.8% higher than that of frequently flooded area, respectively. Shannon index and Pielou index of seed bank and vegetation were significantly affected by water level and sampling location. Water level significantly affected the similarity between seed bank and aboveground vegetation, and the similarity of persistent seed bank with aboveground vegetation was significantly higher than that with transient seed bank. Structural equation model showed that water level had a direct effect on seed bank density, and indirect effects on density and richness of seed bank via affecting soil pH and NH4+-N content. NMDS results showed that there was no significant difference in the composition of the persistent seed bank and vegetation community in autumn under different water levels, but water level significantly changed the community composition of transient seed bank. Transient seed bank was affected by the vegetation and soil property, while persistent seed bank was determined by aboveground vegetation and water level. Although soil seed bank had low regeneration potential for the vegetation communities in floodplain wetlands, soil seed bank could not be neglected during the restoration of propagule diversity after disturbance in wetlands. Persistent seed bank would be an importance source of diversity of propagules for floodplain wetlands restoration following disturbance.

Assessment of right ventricular dysfunction and its association with excess risk of cardiovascular events in patients undergoing maintenance hemodialysis.

AIMS: Recent accumulating evidence has recently documented a significant prevalence of right ventricular dysfunction (RVD) in end-stage renal disease (ESRD) patients. Tricuspid annular plane systolic excursion (TAPSE)/pulmonary-artery systolic pressure (PASP) ratio assessed with echocardiography might be a useful clinical index of right ventricular (RV) -pulmonary arterial (PA) coupling. The current study aimed to investigate the value of the TAPSE/PASP ratios in patients on maintenance hemodialysis (MHD). METHODS: We studied 83 times echocardiographic tests from 68 patients with MHD. The associations of TAPSE/PASP ratios with echocardiography variables, clinical characteristics, and biochemical parameters were analyzed, as well as the associations of TAPSE/PASP ratios with odds of all-cause mortality, cardiovascular disease (CVD) events and frequent intermittent dialysis hypotension (IDH). RESULTS: Correlation analysis showed TAPSE/PASP ratios positively correlated with LVEF and negatively correlated with E/A and E/e' values. For clinical and biochemical parameters, TAPSE/PASP ratios negatively correlated with BNP, NT-proBNP, age, CRP, and average interdialysis weight gain (ΔBW) and positively correlated with albumin. Logistic regression analysis, which induced the TAPSE/PASP ratio as a continuous variable (per 0.1 mm/mmHg increase), identified that the TAPSE/PASP ratio was associated with decreased CVD events (OR 0.386 [95% CI 0.231-0.645], p < 0.001) and frequent IDH odds (OR 0.571 [95% CI 0.397-0.820], p = 0.002). Moreover, the TAPSE/PASP ratio independently predicted CVD events (adjusted HR 0.539 [95% CI 0.391-0.743], p < 0.001) during a follow-up period of 12 months. CONCLUSIONS: RVD, assessed by echocardiography TAPSE/PASP ratio, was found to be associated with increased risks of CVD events and frequent IDH in patients with MHD.

Lipidomic signatures in patients with early-onset and late-onset Preeclampsia.

BACKGROUND: Preeclampsia is a pregnancy-specific clinical syndrome and can be subdivided into early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE) according to the gestational age of delivery. Patients with preeclampsia have aberrant lipid metabolism. This study aims to compare serum lipid profiles of normal pregnant women with EOPE or LOPE and screening potential biomarkers to diagnose EOPE or LOPE. METHODS: Twenty normal pregnant controls (NC), 19 EOPE, and 19 LOPE were recruited in this study. Untargeted lipidomics based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to compare their serum lipid profiles. RESULTS: The lipid metabolism profiles significantly differ among the NC, EOPE, and LOPE. Compared to the NC, there were 256 and 275 distinct lipids in the EOPE and LOPE, respectively. Furthermore, there were 42 different lipids between the LOPE and EOPE, of which eight were significantly associated with fetal birth weight and maternal urine protein. The five lipids that both differed in the EOPE and LOPE were DGTS (16:3/16:3), LPC (20:3), LPC (22:6), LPE (22:6), PC (18:5e/4:0), and a combination of them were a potential biomarker for predicting EOPE or LOPE. The receiver operating characteristic analysis revealed that the diagnostic power of the combination for distinguishing the EOPE from the NC and for distinguishing the LOPE from the NC can reach 1.000 and 0.992, respectively. The association between the lipid modules and clinical characteristics of EOPE and LOPE was investigated by the weighted gene co-expression network analysis (WGCNA). The results demonstrated that the main different metabolism pathway between the EOPE and LOPE was enriched in glycerophospholipid metabolism. CONCLUSIONS: Lipid metabolism disorders may be a potential mechanism of the pathogenesis of preeclampsia. Lipid metabolites have the potential to serve as biomarkers in patients with EOPE or LOPE. Furthermore, lipid metabolites correlate with clinical severity indicators for patients with EOPE and LOPE, including fetal birth weight and maternal urine protein levels.

Chinese herbal medicine Shufeng Jiedu capsule for mild to moderate COVID-19: a multicenter, randomized, double-blind, placebo-controlled phase II trial.

Background: The COVID-19 pandemic has had a profound global impact, although the majority of recently infected cases have presented with mild to moderate symptoms. Previous clinical studies have demonstrated that Shufeng Jiedu (SFJD) capsule, a Chinese herbal patent medicine, effectively alleviates symptoms associated with the common cold, H1N1 influenza, and COVID-19. This study aimed to assess the efficacy and safety of SFJD capsules in managing symptoms of mild to moderate COVID-19 infection. Methods: A randomized, double-blind, placebo-controlled trial was conducted from May to December 2022 at two hospitals in China. Mild and moderate COVID-19-infected patients presenting respiratory symptoms within 3 days from onset were randomly assigned to either the SFJD or placebo groups in a 1:1 ratio. Individuals received SFJD capsules or a placebo three times daily for five consecutive days. Participants were followed up for more than 14 days after their RT-PCR nucleoid acid test for SARS-CoV-2 turned negative. The primary outcome measure was time to alleviate COVID-19 symptoms from baseline until the end of follow-up. Results: A total of 478 participants were screened; ultimately, 407 completed the trial after randomization (SFJD, n = 203; placebo, n = 204). No statistically significant difference in baseline parameters was observed between the two groups. The median time to alleviate all symptoms was 7 days in the SFJD group compared to 8 days in the placebo group (p = 0.037). Notably, the SFJD group significantly attenuated fever/chills (p = 0.04) and headache (p = 0.016) compared to the placebo group. Furthermore, the median time taken to reach normal body temperature within 24 h was reduced by 7 hours in the SFJD group compared to the placebo group (p = 0.033). No deaths or instances of serious or critical conditions occurred during this trial period; moreover, no serious adverse events were reported. Conclusion: The trial was conducted in a unique controlled hospital setting, and the 5-day treatment with SFJD capsules resulted in a 1-day reduction in overall symptoms, particularly headache and fever/chills, among COVID-19-infected participants with mild or moderate symptoms. Compared to placebo, SFJD capsules were found to be safe with fewer side effects. SFJD capsules could potentially serve as an effective treatment for alleviating mild to moderate symptoms of COVID-19. Clinical Trial Registration: https://www.isrctn.com/, identifier ISRCTN14236594.

Comparing ranibizumab, dexamethasone implant, and combined therapy for macular edema secondary to branch retinal vein occlusion: a clinical trial.

BACKGROUND: Macular edema (ME) is a common complication following branch retinal vein occlusion (BRVO) and is also the main reason for visual impairment. This study aimed to compare the efficacy and safety of intravitreal ranibizumab (IVR) or dexamethasone implant (IDI) monotherapy, as well as the combination of IVR and IDI injections, in patients with ME secondary to branch retinal vein occlusion (BRVO). METHODS: This multicenter, prospective, and comparative study included 292 patients with unilateral ME involvement (total of 292 eyes) secondary to BRVO. The patients were randomly assigned to three groups and followed up for 12 months. Patients in group 1 (n = 96) were treated with 3-dose loading IVR injections followed by a pro re nata (PRN) regimen. Patients in group 2 (n = 98) received IVR combined with IDI injection, followed by IVR PRN regimen. Patients in group 3 (n = 98) were treated with IDI injection, followed by repeated IDI injection based on clinical necessity. Best corrected visual acuity (BCVA), central retinal thickness (CRT), complications, and frequency of injections were recorded and compared between the three groups. RESULTS: At baseline, the three groups did not differ in age, gender, duration of ME, BCVA, IOP, and CRT (P > 0.05). Mean number of total injections per eye within 12 months were 7.1 ± 2.3 (range 4-9) in group 1, 3.7 ± 1.5 (range 2-6) in group 2, and 1.8 ± 0.4 (range 1-3) in group 3. There was a statistical difference in the number of injections between group 1 and group 2 (P = 0.037). Eyes in group 3 received fewer injections than those in group 2, but the difference was not statistically significant (P = 0.052). BCVA improvement and CRT reduction were achieved in all groups and there was no significant difference between the three groups at the end of the 12th month. However, IOP elevation and cataract progression were more frequent in group 3, especially in those patients who received repeated IDI injections. CONCLUSION: Three therapeutic regimens had comparable efficacy in treating ME secondary to BRVO. Combination therapy had an advantage in maintaining good effect with fewer re-injections and complications. TRIAL REGISTRATION INFORMATION: The study complied with the principles of the Declaration of Helsinki and was approved by Xi'an Aier Ancient City Eye Hospital, Xi'an Aier Eye Hospital, and Xianyang Aier Eye Hospital ethics committees (2022SF-367).

Identification of ubiquitination-related hub genes in chronic myeloid leukemia cell by bioinformatics analysis.

Purpose: Chronic myeloid leukemia stem cells (CML-LSCs) are posited as the primary instigators of resistance to tyrosine kinase inhibitors (TKIs) and recurrence of CML. Ubiquitination, a post-translational modification, has been implicated in the worsening process of CML. A more detailed understanding of their crosstalk needs further investigation. Our research aims to explore the potential ubiquitination-related genes in CML-LSC using bioinformatics analysis that might be the target for the eradication of LSCs. Methods: The ubiquitination modification-related differentially expressed genes (UUC-DEGs) between normal hematopoietic stem cells (HSCs) and LSCs were obtained from GSE47927 and iUUCD database. Subsequently, the hub UUC-DEGs were identified through protein-protein interaction (PPI) network analysis utilizing the STRING database and the MCODE plug-in within the Cytoscape platform. The upstream regulation network of the hub UUC-DEGs was studied by hTFtarget, PROMO, miRDB and miRWalk databases respectively. Then the correlation between the hub UUC-DEGs and the immune cells was analyzed by the CIBERSORT algorithm and "ggcorrplot" package. Finally, we validated the function of hub UUC-DEGs in CML animal models, CML cell lines and CD34+ cells of the GSE24739 dataset. Results: There is a strong association between the 4 hub UUC genes (AURKA, Fancd2, Cdc20 and Uhrf1) of LSCs and the infiltration of CD4+/CD8+ T cells, NK cells and monocytes. 8 TFs and 23 miRNAs potentially targeted these 4 hub genes were constructed. Among these hub genes, Fancd2, Cdc20 and Uhrf1 were found to be highly expressed in CML-LSC, which knocking down resulted in significant inhibition of CML cell proliferation. Conclusions: From the perspective of bioinformatics analysis, UHRF1 and CDC20 were identified as the novel key ubiquitination-related genes in CML-LSCs and the pathogenesis of CML.

Dual-signal ratiometric electrochemiluminescence biosensor based on Au NPs-induced low-potential emission of PFO Pdots and LSPR-ECL mechanism for ultra-sensitive detection of microRNA-141.

In this study, we have for the first time constructed a ratiometric ECL biosensor for the ultrasensitive detection of microRNAs (miRNAs) using gold nanoparticles (Au NPs) to trigger both the low-potential emission from conjugated polymer poly(9,9-dioctylfluorene-2,7-diyl) dots (PFO Pdots) and the LSPR-ECL effect with sulfur-doped boron nitride quantum dots (S-BN QDs). PFO Pdots were first applied to the Au NPs-modified electrode, followed by covalent binding to capture the hairpin H1. Immediately thereafter, a small amount of miRNA-141 was able to generate a large amount of output DNA (OP) by traversing the target cycle. OP, H3-S-BN QDs, and H4-glucose oxidase (H4-GOD) were then added sequentially to the Au NPs-modified electrode surface, and the hybridization chain reaction (HCR) was initiated. This resulted in the introduction of a large amount of GOD into the system, which catalyzed the in situ formation of the co-reactant hydrogen peroxide (H2O2) from the substrate glucose. Due to the electron transfer effect, the production of H2O2 led to the ECL quenching of PFO Pdots. Meanwhile, H2O2 served as a co-reactant of S-BN QDs, resulting in strong ECL emission of S-BN QDs at the cathode. Furthermore, the cathodic ECL intensity of S-BN QDs was further enhanced by an LSPR-ECL mechanism between Au NPs and S-BN QDs. By measuring the ratio of ECL intensities at two excitation potentials, this approach could provide sensitive and reliable detection of miRNA-141 in the range of 0.1 fM ∼10 nM, with a detection limit of 0.1 fM.

Safety and efficacy of flumatinib as later-line therapy in patients with chronic myeloid leukemia.

To evaluate the efficacy and safety of flumatinib in the later-line treatment of Chinese patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CP-CML previously treated with tyrosine kinase inhibitors (TKIs). Patients with CML-CP were evaluated for the probabilities of responses including complete hematologic response (CHR), cytogenetic response, and molecular response (MR) and adverse events (AEs) after the later-line flumatinib therapy. Of 336 enrolled patients with median age 50 years, median duration of treatment with flumatinib was 11.04 (2-25.23) months. Patients who achieved clinical responses at baseline showed maintenance of CHR, complete cytogenetic response (CCyR)/2-log molecular response (MR2), major molecular response (MMR), and 4-log molecular response or deep molecular response (MR4/DMR) in 100%, 98.9%, 98.6%, and 92.9% patients, respectively. CHR, CCyR/MR2, MMR, and MR4/DMR responses were achieved in 86.4%, 52.7%, 49.6%, and 23.5% patients respectively, which showed the lack of respective clinical responses at baseline. The patients without response at baseline, treated with flumatinib as 2L TKI, having no resistance to prior TKI or only resistance to imatinib, with response to last TKI, and with BCR::ABL ≤10% had higher CCyR/MR2, MMR, or MR4/DMR. The AEs observed during the later-line flumatinib treatment were tolerable and consistent with those reported with the first-line therapy. Flumatinib was effective and safe in patients who are resistant or intolerant to other TKIs. In particular, 2L flumatinib treatment induced high response rates and was more beneficial to patients without previous 2G TKI resistance, thus serving as a probable treatment option for these patients.

An "off-on-enhanced on" electrochemiluminescence biosensor based on resonance energy transfer and surface plasmon coupled 3D DNA walker for ultra-sensitive detection of microRNA-21.

In this study, a novel electrochemiluminescence (ECL) biosensor was developed to detect microRNA-21 (miRNA-21) with high sensitivity by leveraging the combined mechanisms of resonance energy transfer (RET) and surface plasmon coupling (SPC). Initially, the glassy carbon electrode (GCE) were coated with Cu-Zn-In-S quantum dots (CZIS QDs), known for their defect-related emission suitable for ECL sensing. Subsequently, a hairpin DNA H3 with gold nanoparticles (Au NPs) attached at the end was modified over the surface of the quantum dots. The Au NPs could effectively quench the ECL signals of CZIS QDs via RET. Further, a significant amount of report DNA was generated through the action of a 3D DNA walker. When the report DNA opened H3-Au NPs, the hairpin structure experienced a conformational change to a linear shape, increasing the gap between the CZIS QDs and the Au NPs. Consequently, the localized surface plasmon resonance ECL (LSPR-ECL) effect replaced ECL resonance energy transfer (ECL-RET). Moreover, the report DNA was released following the addition of H4-Au NPs, resulting in the formation of Au dimers and a surface plasma-coupled ECL (SPC-ECL) effect that enhanced the ECL intensity to 6.97-fold. The integration of new ECL-RET and SPC-ECL biosensor accurately quantified miRNA-21 concentrations from 10-8 M to 10-16 M with a limit of detection (LOD) of 0.08 fM, as well as successfully applied to validate human serum samples.

The ubiquitin E3 ligase APC/CCdc20 mediates mitotic degradation of OGT.

O-linked ß-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is the sole enzyme that catalyzes all O-GlcNAcylation reactions intracellularly. Previous investigations have found that OGT levels oscillate during the cell division process. Specifically, OGT abundance is downregulated during mitosis, but the underlying mechanism is lacking. Here we demonstrate that OGT is ubiquitinated by the ubiquitin E3 ligase, anaphase promoting complex/cyclosome (APC/C)-cell division cycle 20 (Cdc20). We show that APC/CCdc20 interacts with OGT through a conserved destruction box (D-box): Arg-351/Leu-354, the abrogation of which stabilizes OGT. As APC/CCdc20-substrate binding is often preceded by a priming ubiquitination event, we also used mass spectrometry and mapped OGT Lys-352 to be a ubiquitination site, which is a prerequisite for OGT association with APC/C subunits. Interestingly, in The Cancer Genome Atlas, R351C is a uterine carcinoma mutant, suggesting that mutations of the D-box are linked with tumorigenesis. Paradoxically, we found that both R351C and the D-box mutants (R351A/L354A) inhibit uterine carcinoma in mouse xenograft models, probably due to impaired cell division and proliferation. In sum, we propose a model where OGT Lys-352 ubiquitination primes its binding with APC/C, and then APC/CCdc20 partners with OGT through the D-box for its mitotic destruction. Our work not only highlights the key mechanism that regulates OGT during the cell cycle, but also reveals the mutual coordination between glycosylation and the cell division machinery.

Response of photosynthetic characteristics and antioxidant system in the leaves of safflower to NaCl and NaHCO3.

KEY MESSAGE: Compared with NaCl, NaHCO3 caused more serious oxidative damage and photosynthesis inhibition in safflower by down-regulating the expression of related genes. Salt-alkali stress is one of the important factors that limit plant growth. NaCl and sodium bicarbonate (NaHCO3) are neutral and alkaline salts, respectively. This study investigated the physiological characteristics and molecular responses of safflower (Carthamus tinctorius L.) leaves treated with 200 mmol L-1 of NaCl or NaHCO3. The plants treated with NaCl treatment were less effective at inhibiting the growth of safflower, but increased the content of malondialdehyde (MDA) in leaves. Meanwhile, safflower alleviated stress damage by increasing proline (Pro), soluble protein (SP), and soluble sugar (SS). Both fresh weight and dry weight of safflower was severely decreased when it was subjected to NaHCO3 stress, and there was a significant increase in the permeability of cell membranes and the contents of osmotic regulatory substances. An enrichment analysis of the differentially expressed genes (DEGs) using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes identified significant enrichment of photosynthesis and pathways related to oxidative stress. Furthermore, a weighted gene co-expression network analysis (WGCNA) showed that the darkgreen module had the highest correlation with photosynthesis and oxidative stress traits. Large numbers of transcription factors, primarily from the MYB, GRAS, WRKY, and C2H2 families, were predicted from the genes within the darkgreen module. An analysis of physiological indicators and DEGs, it was found that under saline-alkali stress, genes related to chlorophyll synthesis enzymes were downregulated, while those related to degradation were upregulated, resulting in inhibited chlorophyll biosynthesis and decreased chlorophyll content. Additionally, NaCl and NaHCO3 stress downregulated the expression of genes related to the Calvin cycle, photosynthetic antenna proteins, and the activity of photosynthetic reaction centers to varying degrees, hindering the photosynthetic electron transfer process, suppressing photosynthesis, with NaHCO3 stress causing more pronounced adverse effects. In terms of oxidative stress, the level of reactive oxygen species (ROS) did not change significantly under the NaCl treatment, but the contents of hydrogen peroxide and the rate of production of superoxide anions increased significantly under NaHCO3 stress. In addition, treatment with NaCl upregulated the levels of expression of the key genes for superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), the ascorbate-glutathione cycle, and the thioredoxin-peroxiredoxin pathway, and increased the activity of these enzymes, thus, reducing oxidative damage. Similarly, NaHCO3 stress increased the activities of SOD, CAT, and POD and the content of ascorbic acid and initiated the glutathione-S-transferase pathway to remove excess ROS but suppressed the regeneration of glutathione and the activity of peroxiredoxin. Overall, both neutral and alkaline salts inhibited the photosynthetic process of safflower, although alkaline salt caused a higher level of stress than neutral salt. Safflower alleviated the oxidative damage induced by stress by regulating its antioxidant system.

Characteristic cembrane-type diterpenoids with nitric oxide inhibitory activity from the gum resin of Boswellia carterii Birdw.

Five new characteristic cembrane-type diterpenoids (olibacartiols A-E, 1-5) were acquired from the gum resin of Boswellia carterii. The structures of these diterpenoids were characterized by detailed spectroscopic analysis, and compounds 1-3 were unambiguously confirmed by single-crystal X-ray diffraction experiments. The anti-inflammatory activities of the isolated compounds were evaluated using LPS-induced BV2 cell model and compounds 2-5 showed moderate NO inhibitory effects with IC50 values of 8.84 ± 1.02, 9.82 ± 1.95, 9.75 ± 2.24, and 7.39 ± 1.24 µM, respectively.

Causes, risks and care circumstances associated with death in older adults diagnosed with HIV in a tertiary centre in Malaysia.

BACKGROUND: A substantial number of older adults succumb soon after HIV diagnosis despite ART. We explored the causes, risk factors and circumstances before death among older adults acquring HIV. METHODS: We recruited individuals newly diagnosed at our centre from 2016-2020 and analysed data of those who died. Patients were stratified to older (≥50 years) or younger (<50 years) based on their age at diagnosis and attributes were compared. The Cox proportional multivariable model was used to identify factors associated with all-cause mortality. RESULTS: Among 75 deaths reported, the majority of deaths were AIDS-related and late presentation was common in both age groups. The majority of deaths occurred in the first 12 months after care presentation and over two-thirds in both groups disengaged from care prior to death. Older age remained an independent factor associated with death after adjusting for confounders including opportunistic infections, late presentation to care, ART initiation and chronic comorbidities at presentation. CONCLUSION: Most causes of death in our setting were AIDS-related and associated with late care presentation both in young and older individuals, although older age at diagnosis remained an independent risk factor. Our findings highlight the urgent need to encourage prompt ART initiation following diagnosis, especially in older adults.

Early-life inflammation increases ethanol consumption in adolescent male mice.

Recent studies have demonstrated that stress during the critical windows of development can evoke a cascade of neurological changes that can result in neuropsychiatric disorders later in life. In this study, we examined the effect of early-life inflammation on ethanol consumption in adolescent mice. C57BL/6J mice were assigned to either the control or Lipopolysaccharide (LPS) group on postnatal day 14 (P14). In the latter group, LPS at a dose of 50 µg/kg was injected intraperitoneally. The mice were weaned at P21, and behavior tests were performed at P45. Ethanol consumption was assessed using a two-bottle choice drinking paradigm. Anxiety-like behaviors were assessed by marble burying test (MBT), open field (OF), and elevated plus maze (EPM). Ethanol-induced loss of righting reflex (LORR), hypothermia and ethanol metabolism were assessed to evaluate ethanol intoxication. P14 LPS-injected adolescent male mice exhibited significantly increased ethanol preference and consumption, with a similar taste preference for saccharin and avoidance of quinine. The adolescent male mice showed increased anxiety-like behaviors in the OF and EPM tests, and an increased duration of LORR, without affecting the hypothermic effects of ethanol and ethanol metabolism. Interestingly, these behavioral changes were not obvious in female mice. In conclusion, our data indicate that early-life inflammation may be a risk factor for ethanol consumption in adolescents with greater changes observed in male mice. SIGNIFICANCE STATEMENT: Our study is the first preclinical model to report the enhancement effect of early-life inflammation on ethanol consumption in adolescent male mice and our findings provide a valuable mouse model to examine the neurobiological mechanisms mediating the long-lasting effects of early-life inflammation on alcohol use disorders vulnerability.