HIF-1α and adaptor protein LIM and senescent cell antigen-like domains protein 1 axis promotes tubulointerstitial fibrosis by interacting with vimentin in angiotensin II-induced hypertension.

BACKGROUND AND PURPOSE: Activation of the renin-angiotensin system, as a hallmark of hypertension and chronic kidney diseases (CKD) is the key pathophysiological factor contributing to the progression of tubulointerstitial fibrosis. LIM and senescent cell antigen-like domains protein 1 (LIMS1) plays an essential role in controlling of cell behaviour through the formation of complexes with other proteins. Here, the function and regulation of LIMS1 in angiotensin II (Ang II)-induced hypertension and tubulointerstitial fibrosis was investigated. EXPERIMENTAL APPROACH: C57BL/6 mice were treated with Ang II to induce tubulointerstitial fibrosis. Hypoxia-inducible factor-1α (HIF-1α) renal tubular-specific knockout mice or LIMS1 knockdown AAV was used to investigate their effects on Ang II-induced renal interstitial fibrosis. In vitro, HIF-1α or LIMS1 was knocked down or overexpressed in HK2 cells after exposure to Ang II. KEY RESULTS: Increased expression of tubular LIMS1 was observed in human kidney with hypertensive nephropathy and in murine kidney from Ang II-induced hypertension model. Tubular-specific knockdown of LIMS1 ameliorated Ang II-induced tubulointerstitial fibrosis in mice. Furthermore, we demonstrated that LIMS1 was transcriptionally regulated by HIF-1α in tubular cells and that tubular HIF-1α knockout ameliorates LIMS1-mediated tubulointerstitial fibrosis. In addition, LIMS1 promotes Ang II-induced tubulointerstitial fibrosis by interacting with vimentin. CONCLUSION AND IMPLICATIONS: We conclude that HIF-1α transcriptionally regulated LIMS1 plays a central role in Ang II-induced tubulointerstitial fibrosis through interacting with vimentin. Our finding represents a new insight into the mechanism of Ang II-induced tubulointerstitial fibrosis and provides a novel therapeutic target for progression of CKD.

Intraperitoneal versus intranasal administration of lipopolysaccharide in causing sepsis severity in a murine model: a preliminary comparison.

Community-acquired respiratory infection is the commonest cause of sepsis presenting to emergency departments. Yet current experimental animal models simulate peritoneal sepsis with intraperitoneal (I.P.) injection of lipopolysaccharide (LPS) as the predominant route. We aimed to compare the progression of organ injury between I.P. LPS and intranasal (I.N.) LPS in order to establish a better endotoxemia murine model of respiratory sepsis. Eight weeks old male BALB/c mice received LPS-Escherichia coli doses at 0.15, 1, 10, 20, 40 and 100 mg per kg body weight (e.g. LPS-10 is a dose of 10 mg/kg body weight). Disease severity was monitored by a modified Mouse Clinical Assessment Score for Sepsis (M-CASS; range 0-21). A M-CASS score ≥ 10 or a weight reduction of ≥ 20%, was used as a criterion for euthanasia. The primary outcome was the survival rate (either no death or no need for euthanasia). The progression of disease was specified as M-CASS, body weight, blood glucose, histopathological changes to lung, liver, spleen, kidney, brain and heart tissues. Survival rate in I.P. LPS-20 mice was 0% (2/3 died; 1/3 euthanized with M-CASS > 10) at 24 h. Survival rate in all doses of I.N. LPS was 100% (20/20; 3-4 per group) at 96 h. 24 h mean M-CASS post-I.P. LPS-10 was 6.4/21 significantly higher than I.N. LPS-10 of 1.7/21 (Unpaired t test, P < 0.05). Organ injury was present at 96 h in the I.P. LPS-10 group: lung (3/3; 100%), spleen (3/3; 100%) and liver (1/3; 33%). At 24 h in the I.P. LPS-20 group, kidney injury was observed in the euthanized mouse. At 96 h in the post-I.N. LPS-20 group, only lung injury was observed in 2/3 (67%) mice (Kruskal-Wallis test with Dunn's, P < 0.01). At 24 h in the post-I.N. LPS-100 group all (4/4) mice had evidence of lung injury. Variable doses of I.N. LPS in mice produced lung injury but did not produce sepsis. Higher doses of I.P. LPS induced multi-organ injury but not respiratory sepsis. Lethal models of respiratory virus, e.g., influenza A, might provide alternative avenues that can be explored in future research.

Synergistic effects of graphene microgrooves and electrical stimulation on M2 macrophage polarization.

Macrophages play a crucial role in host response and wound healing, with M2 polarization contributing to the reduction of foreign-body reactions induced by the implantation of biomaterials and promoting tissue regeneration. Electrical stimulation (ES) and micropatterned substrates have a significant impact on the macrophage polarization. However, there is currently a lack of well-established cell culture platforms for studying the synergistic effects of these two factors. In this study, we prepared a graphene free-standing substrate with 20 µm microgrooves using capillary forces induced by water evaporation. Subsequently, we established an ES cell culture platform for macrophage cultivation by integrating a self-designed multi-well chamber cell culture device. We observed that graphene microgrooves, in combination with ES, significantly reduce cell spreading area and circularity. Results from immunofluorescence, ELISA, and flow cytometry demonstrate that the synergistic effect of graphene microgrooves and ES effectively promotes macrophage M2 phenotypic polarization. Finally, RNA sequencing results reveal that the synergistic effects of ES and graphene microgrooves inhibit the macrophage actin polymerization and the downstream PI3K signaling pathway, thereby influencing the phenotypic transition. Our results demonstrate the potential of graphene-based microgrooves and ES to synergistically modulate macrophage polarization, offering promising applications in regenerative medicine.

FLNA overexpression promotes papillary thyroid cancer aggression via the FAK/AKT signaling pathway.

Background: Filamin A (FLNA) is a member of the filamin family and has been found to be critical for the progression of several cancers. However, its biological function in papillary thyroid cancer (PTC) remains largely unexplored. Methods: Data from The Cancer Genome Atlas (TCGA) databases were utilized to analyze the FLNA expression level and its influence on the clinical implications of patients with PTC. Gene Expression Omnibus (GEO) and qRT-PCR was used to verify the expression levels of FLNA in PTC. Kaplan-Meier survival analysis was conducted to evaluate the prognostic value of FLNA in PTC. Transwell assays and wound healing were performed to examine the biological function of FLNA knockdown in PTC cells. Gene set enrichment analysis (GSEA) and Western blotting were conducted to investigate the potential mechanisms underlying the role of FLNA in PTC progression. In addition, the relationship between FLNA expression and the tumor immune microenvironment (TME) in PTC was explored. Results: FLNA was significantly upregulated in PTC tissues. High expression levels of FLNA was correlated with advanced TNM stage, T stage, and N stage, as well as poor disease-free interval (DFI) and progression-free interval (PFI) time in PTC patients. Moreover, we found that FLNA knockdown inhibited the migration and invasion of PTC cells. Mechanistically, FLNA knockdown inhibited epithelial-mesenchymal transition (EMT) in PTC and affected the activation of the FAK/AKT signaling pathway. In addition, FLNA expression was associated with TME in PTC. Conclusion: FLNA may be regarded as a new therapeutic target for PTC patients.

A 52-Year-Old Woman With Dysarthria, Ataxia, Xanthelasmas, and Miliary Pulmonary Nodules.

CASE PRESENTATION: A 52-year-old woman with no significant medical history was referred to our hospital for expedited workup of progressive dysarthria and ataxia over the past year. Prior CT angiography of the head and neck showed no relevant neurologic findings but did reveal miliary lesions in the lung apices, which was later confirmed via dedicated CT chest scan (Fig 1). Review of systems was negative for any respiratory, constitutional, or rheumatologic symptoms, except for new xanthelasma-like lesions over her forehead. She previously had smoked with 20 pack-years and had no TB risk factors. MRI of the face showed a 21-mm mass within the left external temporal fascia. MRI of the head showed diffuse leptomeningeal enhancement, right frontal lobe enhancement, and cerebellar and brainstem T2/fluid-attenuated inversion recovery hyperintensity, which prompted her admission to hospital.

Matrine and icariin can inhibit bovine viral diarrhoea virus replication by promoting type I interferon response in vitro.

Introduction: Bovine viral diarrhoea virus (BVDV) can cause diarrhoea (BVD) in an animal herd, leading to heavy economic losses. There are limited drugs available for treating and controlling BVD. This research aims to investigate the antiviral and immunoregulatory effects of two traditional Chinese herb extracts against BVDV infection. The extracts are matrine and icariin, which have been proved to have immunostimulant and antiviral effects. Material and Methods: A cell counting kit-8 assay was used to analyse the toxicity of matrine and icariin to Madin-Darby bovine kidney (MDBK) cells. The model of MDBK cells infected with BVDV was utilised to uncover the antiviral mechanism of matrine and icariin, which along with their immunoregulatory ability was evaluated by quantitative reverse-transcription PCR and ELISA. Results: The results showed that matrine and icariin can significantly inhibit the gene expression level of the BVDV 5' untranslated region through various pathways. Both matrine and icariin can statistically upregulate the gene expression level of interferon alpha, interferon beta (IFN-ß), toll-like receptor 3, retinoic acid-inducible gene I and interferon regulatory factor 3, and raise the concentration of IFN-ß after BVDV infection. Conclusion: This study proves that both matrine and icariin have inhibitory effects on BVDV replication by activating IFN production and the IFN signalling pathway. The finding is promising and should open up the possibility of larger-scale in vitro research followed by in vivo experiments evaluating matrine and icariin as therapeutic agents in BVD cases.

CDK12 is a potential biomarker for diagnosis, prognosis and immunomodulation in pan-cancer.

Cell cycle-dependent protein kinase 12 (CDK12) plays a key role in a variety of carcinogenesis processes and represents a promising therapeutic target for cancer treatment. However, to date, there have been no systematic studies addressing its diagnostic, prognostic and immunological value across cancers. Here, we found that CDK12 was significantly upregulated in various types of cancers, and it expression increased with progression in ten cancer types, including breast cancer, cholangiocarcinoma and colon adenocarcinoma. Moreover, the ROC curves indicated that CDK12 showed diagnostic value in eight cancer types. High CDK12 expression was associated with poor prognosis in eight types of cancer, including low-grade glioma, mesothelioma, melanoma and pancreatic cancer. Furthermore, we conducted immunoassays to explore the exact mechanisms underlying CDK12-induced carcinogenesis, which revealed that increased expression of CDK12 allowed tumours to evade immune surveillance and upregulate immune checkpoint genes. Additionally, mutational studies have shown that amplification and missense mutations are the predominant mutational events affecting CDK12 across cancers. These findings establish CDK12 as a significant biological indicator of cancer diagnosis, prognosis, and immunotherapeutic targeting. Early surveillance and employment of CDK12 inhibitors, along with concomitant immunotherapy interventions, may enhance the clinical outcomes of cancer patients.

SARS-CoV-2 envelope protein impairs airway epithelial barrier function and exacerbates airway inflammation via increased intracellular Cl- concentration.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection disrupts the epithelial barrier and triggers airway inflammation. The envelope (E) protein, a core virulence structural component of coronaviruses, may play a role in this process. Pathogens could interfere with transepithelial Cl- transport via impairment of the cystic fibrosis transmembrane conductance regulator (CFTR), which modulates nuclear factor κB (NF-κB) signaling. However, the pathological effects of SARS-CoV-2 E protein on airway epithelial barrier function, Cl- transport and the robust inflammatory response remain to be elucidated. Here, we have demonstrated that E protein down-regulated the expression of tight junctional proteins, leading to the disruption of the airway epithelial barrier. In addition, E protein triggered the activation of Toll-like receptor (TLR) 2/4 and downstream c-Jun N-terminal kinase (JNK) signaling, resulting in an increased intracellular Cl- concentration ([Cl-]i) via up-regulating phosphodiesterase 4D (PDE4D) expression in airway epithelial cells. This elevated [Cl-]i contributed to the heightened airway inflammation through promoting the phosphorylation of serum/glucocorticoid regulated kinase 1 (SGK1). Moreover, blockade of SGK1 or PDE4 alleviated the robust inflammatory response induced by E protein. Overall, these findings provide novel insights into the pathogenic role of SARS-CoV-2 E protein in airway epithelial damage and the ongoing airway inflammation during SARS-CoV-2 infection.

The Role of the Gut-Joint Axis in the Care of Psoriatic Arthritis: A Two-Sample Bidirectional Mendelian Randomization Study.

INTRODUCTION: Observational studies and clinical trials have supported the association between gut microbiota and psoriatic arthritis. However, the causal link between gut microbiota and psoriatic arthritis is still unclear. METHODS: A two-sample bi-directional Mendelian randomization analysis was performed using the summary statistics of gut microbiota from the largest available genome-wide association study meta-analysis (n = 13,266) conducted by the MiBioGen consortium. The summary statistics of psoriatic arthritis were extracted directly from the FinnGen consortium, which consists of 3186 psoriatic arthritis patients and 24,086 controls. Sensitivity analyses were conducted to assess the validity of our findings. Enrichment analyses were used to investigate the biofunction and pathways. RESULTS: Inverse variance weighted (IVW) estimates suggested that family Rikenellaceae (P = 0.032) and genus Ruminococcaceae UCG011 (P = 0.014) had a detrimental effect on psoriatic arthritis. We also noticed the negative association between the class Methanobacteria (P = 0.032), order Methanobacteriales (P = 0.032), family Methanobacteriaceae (P = 0.032), genus Eubacterium fissicatena group (P = 0.010), genus Methanobrevibacter (P = 0.031), and genus Butyricicoccus (P = 0.041) with psoriatic arthritis. Sensitivity analyses showed that genus Butyricicoccus had pleiotropy and heterogeneity. According to the results of reverse MR analysis, the causal effect of psoriatic arthritis was found on six taxa, respectivelyc family Clostridiaceae1, family Defluviitaleaceae, genus Butyrivibrio, genus Defluviitaleaceae UCG011, genus Clostridium sensu stricto1, and genus Ruminococcaceae UCG011. CONCLUSION: This two-sample bidirectional Mendelian randomization analysis suggested that the gut microbiota had a causal effect on psoriatic arthritis and implied the potential role of probiotics in the management and prevention of psoriatic arthritis.

Assessing the Chemical-Free Oxidation of Trace Organic Chemicals by VUV/UV as an Alternative to Conventional UV/H2O2.

Low-pressure mercury lamps with high-purity quartz can emit both vacuum-UV (VUV, 185 nm) and UV (254 nm) and are commercially available and promising for eliminating recalcitrant organic pollutants. The feasibility of VUV/UV as a chemical-free oxidation process was verified and quantitatively assessed by the concept of H2O2 equivalence (EQH2O2), at which UV/H2O2 showed the same performance as VUV/UV for the degradation of trace organic contaminants (TOrCs). Although VUV showed superior H2O activation and oxidation performance, its performance highly varied as a function of light path length (Lp) in water, while that of UV/H2O2 proportionally decreased with decreasing H2O2 dose regardless of Lp. On increasing Lp from 1.0 to 3.0 cm, the EQH2O2 of VUV/UV decreased from 0.81 to 0.22 mM H2O2. Chloride and nitrate hardly influenced UV/H2O2, but they dramatically inhibited VUV/UV. The competitive absorbance of VUV by chloride and nitrate was verified as the main reason. The inhibitory effect was partially compensated by •OH formation from the propagation reactions of chloride or nitrate VUV photolysis, which was verified by kinetic modeling in Kintecus. In water with an Lp of 2.0 cm, the EQH2O2 of VUV/UV decreased from 0.43 to 0.17 mM (60.8% decrease) on increasing the chloride concentration from 0 to 15 mM and to 0.20 mM (53.5% decrease) at 4 mM nitrate. The results of this study provide a comprehensive understanding of VUV/UV oxidation in comparison to UV/H2O2, which underscores the suitability and efficiency of chemical-free oxidation with VUV/UV.

Therapeutic role of miR-26a on cardiaorenal injury in mice model of angiotensin-II induced chronic kidney disease through inhibition of LIMS1/ILK pathway.

BACKGROUND: Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. METHODS: We generated a microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t-test were used to analyze the data. RESULTS: Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. CONCLUSIONS: Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.

Tubule-specific cyclin-dependent kinase 12 knockdown potentiates kidney injury through transcriptional elongation defects.

Direct tubular injury caused by several medications, especially chemotherapeutic drugs, is a common cause of AKI. Inhibition or loss of cyclin-dependent kinase 12 (CDK12) triggers a transcriptional elongation defect that results in deficiencies in DNA damage repair, producing genomic instability in a variety of cancers. Notably, 10-25% of individuals developed AKI after treatment with a CDK12 inhibitor, and the potential mechanism is not well understood. Here, we found that CDK12 was downregulated in the renal tubular epithelial cells in both patients with AKI and murine AKI models. Moreover, tubular cell-specific knockdown of CDK12 in mice enhanced cisplatin-induced AKI through promotion of genome instability, apoptosis, and proliferative inhibition, whereas CDK12 overexpression protected against AKI. Using the single molecule real-time (SMRT) platform on the kidneys of CDK12RTEC+/- mice, we found that CDK12 knockdown targeted Fgf1 and Cast through transcriptional elongation defects, thereby enhancing genome instability and apoptosis. Overall, these data demonstrated that CDK12 knockdown could potentiate the development of AKI by altering the transcriptional elongation defect of the Fgf1 and Cast genes, and more attention should be given to patients treated with CDK12 inhibitors to prevent AKI.

[Network Meta-analysis of Chinese patent medicines in treatment of coronary heart disease complicated with heart failure].

The efficacy and safety of different Chinese patent medicines in the treatment of coronary heart disease complicated with heart failure were evaluated by network Meta-analysis. The randomized controlled trial(RCT) of Chinese patent medicines for coronary heart disease complicated with heart failure was retrieved from CNKI, Wanfang, VIP, SinoMed, PubMed, Web of Science, EMbase, and Cochrane Library with the time interval from inception to July 5, 2023. The quality of the included RCT was evaluated by the Cochrane's risk of bias assessment tool, and a network Meta-analysis was performed in Stata 16.0. Finally, a total of 82 RCTs were included, involving 9 298 patients and 11 Chinese patent medicines. Network Meta-analysis yielded the following results based on the surface under the cumulative ranking curve(SUCRA).(1)In terms of improving the clinical response rate, the top three interventions were Qishen Yiqi Dripping Pills + conventional western medicine, Zhenyuan Capsules + conventional western medicine, and Tongxinluo Capsules + conventional western medicine.(2) In terms of increasing left ventricular ejection fraction(LVEF), the top three interventions were Shexiang Baoxin Pills + conventional western medicine, Compound Danshen Dripping Pills + conventional western medicine, and Tongxinluo Capsules + conventional western medicine.(3) In terms of reducing left ventricular end-diastolic diameter(LVEDD), the top three interventions were Shexiang Tongxin Dripping Pills + conventional western medicine, Tongxinluo Capsules + conventional western medicine, and Shexiang Baoxin Pills + conventional western medicine.(4) In terms of reducing N-terminal pro-brain natriuretic peptide(NT-proBNP), the top three interventions were Shexiang Baoxin Pills + conventional western medicine, Qi-shen Yiqi Dripping Pills + conventional western medicine, and Compound Danshen Dripping Pills + conventional western medicine.(5) In terms of reducing hyper-sensitive C-reactive protein(hs-CRP), the top three interventions were Naoxintong Capsules + conventional western medicine, Shexiang Baoxin Pills + conventional western medicine, and Compound Danshen Dripping Pills + conventional western medicine.(6) In terms of increasing the distance of the six-minute walking trail(6MWT), the top three interventions were Zhen-yuan Capsules + conventional western medicine, Qili Qiangxin Capsules + conventional western medicine, and Qishen Yiqi Dripping Pills + conventional western medicine. The results showed that Chinese patent medicines combined with conventional western medicine can effectively improve the clinical response rate, LVEF, and 6MWT and reduce LVEDD, NT-proBNP, and hs-CRP. However, due to the overall low quality of the articles included and the few articles of some Chinese patent medicines, direct comparison between diffe-rent Chinese patent medicines remains to be carried out and the results need to be further verified.

A colorimetric sensing strategy based on chitosan-stabilized platinum nanoparticles for quick detection of α-glucosidase activity and inhibitor screening.

α-Glucosidase (α-Glu) is implicated in the progression and pathogenesis of type II diabetes (T2D). In this study, we developed a rapid colorimetric technique using platinum nanoparticles stabilized by chitosan (Ch-PtNPs) to detect α-Glu activity and its inhibitor. The Ch-PtNPs facilitate the conversion of 3,3',5,5'-tetramethylbenzidine (TMB) into oxidized TMB (oxTMB) in the presence of dissolved O2. The catalytic hydrolysis of 2-O-α-D-glucopyranosyl-L-ascorbic acid (AA-2G) by α-Glu produces ascorbic acid (AA), which reduces oxTMB to TMB, leading to the fading of the blue color. However, the presence of α-Glu inhibitors (AGIs) hinders the generation of AA, allowing Ch-PtNPs to re-oxidize colorless TMB back to blue oxTMB. This unique phenomenon enables the colorimetric detection of α-Glu activity and AGIs. The linear range for α-Glu was found to be 0.1-1.0 U mL-1 and the detection limit was 0.026 U mL-1. Additionally, the half-maximal inhibition value (IC50) for acarbose, an α-Glu inhibitor, was calculated to be 0.4769 mM. Excitingly, this sensing platform successfully detected α-Glu activity in human serum samples and effectively screened AGIs. These promising findings highlight the potential application of the proposed strategy in clinical diabetes diagnosis and drug discovery.

Overexpression of FHL1 suppresses papillary thyroid cancer proliferation and progression via inhibiting Wnt/ß-catenin pathway.

PURPOSE: The four and a half LIM domain protein 1 (FHL1) has been found to act as a tumor suppressor in several cancers. However, the clinical and functional significance, as well as underlying molecular mechanisms of FHL1 in papillary thyroid cancer (PTC) are largely unknown. METHODS: Bioinformatics analyses, qRT-PCR and Western blotting were used to investigate the expression of FHL1 in PTC. Cell proliferation was measured using CCK8, Edu, colony formation, and flow cytometry assays. Cell migration and invasion were examined by wound healing and Transwell assays. qRT-PCR, Western blot, immunofluorescence and Top/Fop reporter assays were performed to assess the underlying mechanisms. RESULTS: FHL1 expression was significantly downregulated in PTC. FHL1 downregulation negatively correlated with stage, T classification, and N classification of the patients. The downregulation of FHL1 is associated with poor prognosis. Overexpression of FHL1 inhibited PTC cells' proliferation, invasion, migration and Wnt/ß-catenin pathway activity. LiCl partially restored the inhibitory effects of FHL1 on aggressive phenotypes and Wnt/ß-catenin pathway activity of PTC cells. CONCLUSION: FHL1 is downregulated in PTC and its expression is associated with better clinical outcomes for patients with the disease. FHL1 acts as a tumor suppressor via, at least partially, suppressing Wnt/ß-catenin pathway.

Chronic myeloid leukemia with two rare fusion gene transcripts of atypical BCR::ABL: A case report and literature review.

RATIONALE: Imatinib is a standard treatment for Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML), but its efficacy in rare BCR::ABL variants is underexplored. PATIENT CONCERNS: A 67-year-old woman was admitted to the Second Affiliated Hospital of Xi'an Jiaotong University in March 2022 due to elevated white blood cells. DIAGNOSIS: Karyotype analysis revealed clonal abnormalities involving the variant t(9;22) and positive results for atypical BCR::ABL variants (e14a3 and e13a3). The clinical diagnosis was CML, chronic phase, Ph+, with rare BCR::ABL-e13a3- and BCR::ABL-e14a3-positive findings. INTERVENTION: The patient was administered daily imatinib mesylate (400 mg). OUTCOMES: After 4 weeks, a swift molecular response was observed: BCR::ABL-e13a3 transcript level at 2.82 × 10-1 (28.24%), and BCR::ABL-e14a3 transcript level at 4.68 × 10-1 (46.76%). Within 3 months, a complete cytogenetic response was achieved, with a Ph chromosome ratio of 0. Early molecular response was evident as BCR::ABL-e13a3 transcript level reached 5.11 × 10-3 (0.51%), and BCR::ABL-e14a3 transcript level at 6.26 × 10-3 (0.63%). The imatinib mesylate treatment continued without significant toxicity. LESSONS: This case emphasizes the potential effectiveness of imatinib mesylate in managing rare BCR::ABL fusion gene variants of CML. Screening for these atypical variants is advised for suspected CML patients who test negative for common BCR::ABL fusion gene variants. The presented case underscores the positive outcomes achieved with imatinib treatment for a patient with rare BCR::ABL variants, contributing valuable insights for the management of similar cases. Screening for unusual fusion gene variants should be a consideration in CML diagnosis for comprehensive treatment strategies.

Targeted Delivery of Sucrose-Coated Nanocarriers with Chemical Cargoes to the Plant Vasculature Enhances Long-Distance Translocation.

Current practices for delivering agrochemicals are inefficient, with only a fraction reaching the intended targets in plants. The surfaces of nanocarriers are functionalized with sucrose, enabling rapid and efficient foliar delivery into the plant phloem, a vascular tissue that transports sugars, signaling molecules, and agrochemicals through the whole plant. The chemical affinity of sucrose molecules to sugar membrane transporters on the phloem cells enhances the uptake of sucrose-coated quantum dots (sucQD) and biocompatible carbon dots with ß-cyclodextrin molecular baskets (suc-ß-CD) that can carry a wide range of agrochemicals. The QD and CD fluorescence emission properties allowed detection and monitoring of rapid translocation (<40 min) in the vasculature of wheat leaves by confocal and epifluorescence microscopy. The suc-ß-CDs more than doubled the delivery of chemical cargoes into the leaf vascular tissue. Inductively coupled plasma mass spectrometry (ICP-MS) analysis showed that the fraction of sucQDs loaded into the phloem and transported to roots is over 6.8 times higher than unmodified QDs. The sucrose coating of nanoparticles approach enables unprecedented targeted delivery to roots with ≈70% of phloem-loaded nanoparticles delivered to roots. The use of plant biorecognition molecules mediated delivery provides an efficient approach for guiding nanocarriers containing agrochemicals to the plant vasculature and whole plants.

Determinants of depressive symptoms in patients with heart failure based on the hopelessness theory of depression.

AIMS: Depressive symptoms are common in patients with heart failure (HF) and are associated with adverse outcomes in this group. This study examined depressive symptoms and associated determinants in patients with HF based on the hopelessness theory of depression. METHODS AND RESULTS: In this cross-sectional study, a total of 282 patients with HF were recruited from 3 cardiovascular units of a university hospital. Symptom burden, optimism, maladaptive cognitive emotion regulation strategies (MCERSs), hopelessness, and depressive symptoms were assessed using self-reported questionnaires. A path analysis model was established to evaluate the direct and indirect effects. The prevalence of depressive symptoms was 13.8% in the patients. Symptom burden had the greatest direct effect on depressive symptoms (ß = 0.406; P < 0.001), optimism affected depressive symptoms both directly and indirectly with hopelessness as the mediator (direct: ß = -0.360; P = 0.001; indirect: ß = -0.169; P < 0.001), and MCERSs only had an indirect effect on depressive symptoms with hopelessness as the mediator (ß = 0.035; P < 0.001). CONCLUSION: In patients with HF, symptom burden, decreased optimism, and hopelessness contribute to depressive symptoms directly. What is more, decreased optimism and MCERS lead to depressive symptoms indirectly via hopelessness. Accordingly, interventions aimed at decreasing symptom burden, enhancing optimism, and reducing the use of MCERSs, while declining hopelessness, may be conducive to relieving depressive symptoms in patients with HF.