Endoscopic Cryoablation Versus Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma.

BACKGROUND AND OBJECTIVE: Cryoablation is a traditional antitumor therapy with good prospects for development. The efficacy of endoscopic management as a kidney-sparing surgery for high-risk upper tract urothelial carcinoma (UTUC) remains controversial. Our aim was to evaluate the impact of endoscopic cryoablation (ECA) versus radical nephroureterectomy (RNU) on survival outcomes, renal function, and complications. METHODS: We retrospectively analyzed data for 116 patients with newly diagnosed high-risk UTUC who underwent either ECA (n = 13) or RNU (n = 103) from March 25, 2019 to December 8, 2021. Propensity score matching (1:4) using the nearest neighbor method was performed before analysis. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), intravesical recurrence-free survival (RFS), the change in renal function, and treatment-emergent adverse events (TEAEs). KEY FINDINGS AND LIMITATIONS: At median follow-up of 28.2 mo for the ECA group and 27.6 mo for the RNU group, 2-yr OS (82% vs 84%), PFS (73% vs 71%), and intravesical RFS (81% vs 83%) rates after matching did not significantly differ. A decline in renal function was observed after RNU, but not after ECA. Five (41.7%) patients in the ECA group reported six TEAEs, and 17 patients (35.4%) in the RNU group reported 20 TEAEs. CONCLUSIONS AND CLINICAL IMPLICATIONS: In comparison to RNU, ECA for UTUC resulted in noninferior oncological outcomes and superior preservation of renal function. PATIENT SUMMARY: Our study suggests that a treatment called endoscopic cryoablation for high-risk cancer in the upper urinary tract can help in preserving kidney function, with similar survival outcomes to those after more extensive surgery. This option can be considered for selected patients with a strong preference for kidney preservation.

Rare type of tracheal agenesis: Unexpected presentation and immediate consideration of emergent esophageal intubation in neonatal resuscitation program. Case reports and review of the literature.

BACKGROUND: Tracheal agenesis, or tracheal atresia, is a rare congenital anomaly. The presence of a tracheoesophageal fistula (TEF) can help with breathing for newborns with tracheal agenesis. In this article, we presented three unique cases and outcomes of neonates with tracheal agenesis along with a review of the literature. METHODS: This study consisted of a single center case series followed by a review of literature. Case reports were generated using both written and electronic medical records from a single hospital. We summarized three unique cases and outcomes of neonates with tracheal agenesis and performed a review of the literature. RESULTS: We identified three cases of tracheal agenesis presented with severe cyanosis without spontaneous crying upon birth. Experienced pediatricians attempted to intubate the babies but were unsuccessful. Endotracheal tubes were subsequently either accidentally or purposely placed into the esophagus, and oxygen saturation levels improved. This suggested tracheal agenesis with TEF. Two cases underwent surgical intervention after resuscitation with esophageal intubation. CONCLUSION: Esophageal intubation may be a life-sustaining ventilation support for patients with tracheal agenesis and TEF at initial resuscitation. Clinicians should suspect tracheal agenesis when a newborn presents with severe cyanosis and voiceless crying upon birth, and esophageal intubation should be immediately attempted.

Proteome, lysine acetylome and succinylome identify post-translational modification of STAT1 as a novel drug target in silicosis.

Inhalation of crystalline silica dust induces incurable lung damage, silicosis and pulmonary fibrosis. However, the mechanisms of the lung injury remain poorly understood, with limited therapeutic options aside from lung transplantation. Post-translational modifications can regulate the function of proteins and play an important role in studying disease mechanisms. To investigate changes in post-translational modifications of proteins in silicosis, combined quantitative proteome, acetylome, and succinylome analyses were performed with lung tissues from silica-injured and healthy mice using liquid chromatography-mass spectrometry. Combined analysis was applied to the three omics datasets to construct a protein landscape. The acetylation and succinylation of the key transcription factor STAT1 were found to play important roles in the silica-induced pathophysiological changes. Modulating the acetylation level of STAT1 with geranylgeranylacetone (GGA) effectively inhibited the progression of silicosis. This report revealed a comprehensive landscape of post-translational modifications in silica-injured mouse, presented a novel therapeutic strategy targeting the post-translational level for silica-induced lung diseases.

The bone marrow endothelial progenitor cell response to septic infection.

Early increase in the level of endothelial progenitor cells (EPCs) in the systemic circulation occurs in patients with septic infection/sepsis. The significance and underlying mechanisms of this response remain unclear. This study investigated the bone marrow EPC response in adult mice with septic infection induced by intravenous injection (i.v.) of Escherichia coli. For in vitro experiments, sorted marrow stem/progenitor cells (SPCs) including lineage(lin)-stem cell factor receptor (c-kit)+stem cell antigen-1 (Sca-1)-, lin-c-kit+, and lin- cells were cultured with or without lipopolysaccharides (LPSs) and recombinant murine vascular endothelial growth factor (VEGF) in the absence and presence of anti-Sca-1 crosslinking antibodies. In a separate set of experiments, marrow lin-c-kit+ cells from green fluorescence protein (GFP)+ mice, i.v. challenged with heat-inactivated E. coli or saline for 24 h, were subcutaneously implanted in Matrigel plugs for 5 weeks. Marrow lin-c-kit+ cells from Sca-1 knockout (KO) mice challenged with heat-inactivated E. coli for 24 h were cultured in the Matrigel medium for 8 weeks. The marrow pool of EPCs bearing the lin-c-kit+Sca-1+VEGF receptor 2 (VEGFR2)+ (LKS VEGFR2+) and LKS CD133+VEGFR2+ surface markers expanded rapidly following septic infection, which was supported by both proliferative activation and phenotypic conversion of marrow stem/progenitor cells. Increase in marrow EPCs and their reprogramming for enhancing angiogenic activity correlated with cell-marked upregulation of Sca-1 expression. Sca-1 was coupled with Ras-related C3 botulinum toxin substrate 2 (Rac2) in signaling the marrow EPC response. Septic infection caused a substantial increase in plasma levels of IFN-γ, VEGF, G-CSF, and SDF-1. The early increase in circulating EPCs was accompanied by their active homing and incorporation into pulmonary microvasculature. These results demonstrate that the marrow EPC response is a critical component of the host defense system. Sca-1 signaling plays a pivotal role in the regulation of EPC response in mice with septic infection.

LC-MS and MALDI-MSI-based metabolomic approaches provide insights into the spatial-temporal metabolite profiles of Tartary buckwheat achene development.

Tartary buckwheat, celebrated as the "king of grains" for its flavonoid and phenolic acid richness, has health-promoting properties. Despite significant morphological and metabolic variations in mature achenes, research on their developmental process is limited. Utilizing Liquid chromatography-mass spectrometry and atmospheric pressure matrix-assisted laser desorption/ionization mass spectrometry imaging, we conducted spatial-temporal metabolomics on two cultivars during achene development. Metabolic profiles including 17 phenolic acids and 83 flavonoids are influenced by both varietal distinctions and developmental intricacies. Notably, flavonols, as major flavonoids, accumulated with achene ripening and showed a tissue-specific distribution. Specifically, flavonol glycosides and aglycones concentrated in the embryo, while methylated flavonols and procyanidins in the hull. Black achenes at the green achene stage have higher bioactive compounds and enhanced antioxidant capacity. These findings provide insights into spatial and temporal characteristics of metabolites in Tartary buckwheat achenes and serve as a theoretical guide for selecting optimal resources for food production.

Pathogenicity of Streptococcus iniae causing mass mortalities of yellow catfish (Tachysurus fulvidraco) and its induced host immune response.

The outbreak of mass mortality occurred in Tachysurus fulvidraco farm in Hubei province of China. The pathogenic strain of Streptococcus iniae (termed 2022SI08) was isolated and identified from diseased T. fulvidraco, based on morphological, physiological, and biochemical characteristics, as well as 16S rRNA gene sequence and phylogenetic analysis. Further, the whole genome of isolate S. iniae was sequenced and predicted to contain one single circular chromosome of 1,776,777 bp with a GC content of 37.14%. The genomic sequence analysis showed that 2022SI08 was positive for 204 virulent and 127 antibiotic resistant genes. The experimental challenge demonstrated the high pathogenicity of the retrieved isolate of S. iniae, with a median lethal dosage (LD50) 9.53 × 105 CFU/g. Histopathological examination indicated that the 2022SI08 strain could induce extensive tissue cell degeneration, necrosis, hemorrhage, and inflammation in the skin, gill, fin, spleen, liver, kidney, intestine, eye, and brain. Moreover, the innate immune enzyme activities in serum such as acid phosphatase and alkaline phosphatase were increased significantly at 24 and 48 h post infection (hpi) and then decreased at 168 hpi. The transcriptional profile of immune associated gene in T. fulvidraco following bacterial infection was detected at each point of time, and the results revealed clear transcriptional activation of those genes, which proving their reacting and regulatory role during the response of the host against S. iniae infection. The results revealed that S. iniae was an etiological agent in the mass mortalities of T. fulvidraco and this research will be conducive for increasing our understanding on pathogenesis and host defensive system in S. iniae invasion.

Unconventional human CD61 pairing with CD103 promotes TCR signaling and antigen-specific T cell cytotoxicity.

Cancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103+ T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61+ tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies.

Aviation Mutagenesis Alters the Content of Volatile Compounds in Dahongpao (Camellia sinensis) Leaves and Improves Tea Quality.

Aviation mutagenesis is a fast and efficient breeding method. In this study, we analyzed the effect of aviation mutagenesis on volatile compounds and odor characteristics in Dahongpao fresh leaves and gross tea for the first time. The results showed that aviation mutagenesis significantly increased the total volatile compounds of Dahongpao fresh leaves and gross tea. Aviation mutagenesis most critically significantly increased the content of beta-myrcene in Dahongpao fresh leaves, prompting its conversion to beta-pinene, cubebol, beta-phellandrene, zingiberene, (Z,Z)-3,6-nonadienal, and 6-pentyloxan-2-one after processing, which in turn enhanced the fruity, green, spicy, and woody odor characteristics of the gross tea. This study provided a reference for further exploration of aviation mutagenic breeding of Camellia sinensis.

Engineered extracellular vesicles carrying let-7a-5p for alleviating inflammation in acute lung injury.

BACKGROUND: Acute lung injury (ALI) is a life-threatening respiratory condition characterized by severe inflammation and lung tissue damage, frequently causing rapid respiratory failure and long-term complications. The microRNA let-7a-5p is involved in the progression of lung injury, inflammation, and fibrosis by regulating immune cell activation and cytokine production. This study aims to use an innovative cellular electroporation platform to generate extracellular vesicles (EVs) carring let-7a-5p (EV-let-7a-5p) derived from transfected Wharton's jelly-mesenchymal stem cells (WJ-MSCs) as a potential gene therapy for ALI. METHODS: A cellular nanoporation (CNP) method was used to induce the production and release of EV-let-7a-5p from WJ-MSCs transfected with the relevant plasmid DNA. EV-let-7a-5p in the conditioned medium were isolated using a tangential flow filtration (TFF) system. EV characterization followed the minimal consensus guidelines outlined by the International Society for Extracellular Vesicles. We conducted a thorough set of therapeutic assessments, including the antifibrotic effects using a transforming growth factor beta (TGF-ß)-induced cell model, the modulation effects on macrophage polarization, and the influence of EV-let-7a-5p in a rat model of hyperoxia-induced ALI. RESULTS: The CNP platform significantly increased EV secretion from transfected WJ-MSCs, and the encapsulated let-7a-5p in engineered EVs was markedly higher than that in untreated WJ-MSCs. These EV-let-7a-5p did not influence cell proliferation and effectively mitigated the TGF-ß-induced fibrotic phenotype by downregulating SMAD2/3 phosphorylation in LL29 cells. Furthermore, EV-let-7a-5p regulated M2-like macrophage activation in an inflammatory microenvironment and significantly induced interleukin (IL)-10 secretion, demonstrating their modulatory effect on inflammation. Administering EVs from untreated WJ-MSCs slightly improved lung function and increased let-7a-5p expression in plasma in the hyperoxia-induced ALI rat model. In comparison, EV-let-7a-5p significantly reduced macrophage infiltration and collagen deposition while increasing IL-10 expression, causing a substantial improvement in lung function. CONCLUSION: This study reveals that the use of the CNP platform to stimulate and transfect WJ-MSCs could generate an abundance of let-7a-5p-enriched EVs, which underscores the therapeutic potential in countering inflammatory responses, fibrotic activation, and hyperoxia-induced lung injury. These results provide potential avenues for developing innovative therapeutic approaches for more effective interventions in ALI.

Piezo1 contributes to alveolar bone remodeling by activating ß-catenin under compressive stress.

INTRODUCTION: The mechanosensitive ion channel, Piezo1, is responsible for transducing mechanical stimuli into intracellular biochemical signals and has been identified within periodontal ligament cells (PDLCs). Nonetheless, the precise biologic function of Piezo1 in the regulation of alveolar bone remodeling by PDLCs during compressive forces remains unclear. Therefore, this study focused on elucidating the role of the Piezo1 channel in alveolar bone remodeling and uncovering its underlying mechanisms. METHODS: PDLCs were subjected to compressive force and Piezo1 inhibitors. Piezo1 and ß-catenin expressions were quantified by quantitative reverse transcription polymerase chain reaction and Western blot. The intracellular calcium concentration was measured using Fluo-8 AM staining. The osteogenic and osteoclastic activities were assessed using alkaline phosphatase staining, enzyme-linked immunosorbent assay, quantitative reverse transcription polymerase chain reaction, and Western blot. In vivo, orthodontic tooth movement was used to determine the effects of Piezo1 on alveolar bone remodeling. RESULTS: Piezo1 and activated ß-catenin expressions were upregulated under compressive force. Piezo1 inhibition reduced ß-catenin activation, osteogenic differentiation, and osteoclastic activities. ß-catenin knockdown reversed the increased osteogenic differentiation but had little impact on osteoclastic activities. In vivo, Piezo1 inhibition led to decreased tooth movement distance, accompanied by reduced ß-catenin activation and expression of osteogenic and osteoclastic markers on the compression side. CONCLUSIONS: The Piezo1 channel is a key mechanotransduction component of PDLCs that senses compressive force and activates ß-catenin to regulate alveolar bone remodeling.

CD1a and skin T cells: a pathway for therapeutic intervention.

The CD1 and MR1 protein families present lipid antigens and small molecules to T cells, complementing well-studied major histocompatibility complex-peptide mechanisms. The CD1a subtype is highly and continuously expressed within the skin, most notably on Langerhans cells, and has been demonstrated to present self and foreign lipids to T cells, highlighting its cutaneous sentinel role. Alteration of CD1a-dependent T-cell responses has recently been discovered to contribute to the pathogenesis of several inflammatory skin diseases. In this review, we overview the structure and role of CD1a and outline the current evidence implicating CD1a in the development of psoriasis, atopic dermatitis and allergic contact dermatitis.

Tartary buckwheat protein-phenol conjugate prepared by alkaline-based environment: Identification of covalent binding sites of phenols and alterations in protein structural and functional characteristics.

Tartary buckwheat protein-rutin/quercetin covalent complex was synthesized in alkaline oxygen-containing environment, and its binding sites, conformational changes and functional properties were evaluated by multispectral technique and proteomics. The determination of total sulfhydryl and free amino groups showed that rutin/quercetin can form a covalent complex with BPI and could significantly reduce the group content. Ultraviolet-visible spectrum analysis showed that protein could form new characteristic peaks after binding with rutin/quercetin. Circular dichroism spectrum analysis showed that rutin and quercetin caused similar changes in the secondary structure of proteins, both promoting ß-sheet to α-helix, ß-ture and random coil transformation. The fluorescence spectrometry results showed that the combination of phenols can cause the fluorescence quenching, and the combination of rutin was stronger than the quercetin. Proteomics showed that there were multiple covalent binding sites between phenols and protein. Rutin had a high affinity for arginine, and quercetin and cysteine had high affinity. Meanwhile, the combination of rutin/quercetin and protein had reduced the surface hydrophobic ability of the protein, and improved the foaming, stability and antioxidant properties of the protein. This study expounded the mechanism of the combination of BPI and rutin/quercetin, and analysed the differences of the combination of protein and phenols in different structures. The findings can provide a theoretical basis for the development of complexes in the area of food.

Comparative study of dietary phenols with Tartary buckwheat protein (2S/13S): impact on structure, binding sites and functionality of protein.

BACKGROUND: This research was to investigate the interaction mechanism between 2S albumin and 13S globulin (2S and 13S, the most important storage proteins in Tartary buckwheat seeds) and three phenols (rutin, quercetin and myricetin) regarding the structural and antioxidant properties of their complexes. RESULTS: There are differences in the binding affinity of phenols for 2S and 13S. Rutin had a higher binding affinity for 2S, myricetin had a higher binding affinity for 13S, and 13S exhibited a higher affinity toward phenols than did 2S. Binding with phenols significantly changed the secondary and tertiary structures of 2S and 13S, decreased the surface hydrophobic value and enhanced the antioxidant capacity. Molecular docking and isothermal titration calorimetry showed that the binding processes were spontaneous and that there were hydrogen bonds, hydrophobic bonds and van der Waals force interactions between phenols and proteins. CONCLUSION: These findings could provide meaningful guidance for the further application of buckwheat protein complex. © 2023 Society of Chemical Industry.

A high-throughput two-cell assay for interrogating inhibitory signaling pathways in T cells.

The recent success of immunotherapies relying on manipulation of T-cell activation highlights the value of characterising the mediators of immune checkpoint signaling. CRISPR/Cas9 is a popular approach for interrogating signaling pathways; however, the lack of appropriate assays for studying inhibitory signaling in T cells is limiting the use of large-scale perturbation-based approaches. Here, we adapted an existing Jurkat cell-based transcriptional reporter assay to study both activatory and inhibitory (PD-1-mediated) T-cell signaling using CRISPR-based genome screening in arrayed and pooled formats. We targeted 64 SH2 domain-containing proteins expressed by Jurkat T cells in an arrayed screen, in which individual targets could be assessed independently, showing that arrays can be used to study mediators of both activatory and inhibitory signaling. Pooled screens succeeded in simultaneously identifying many of the known mediators of proximal activating and inhibitory T-cell signaling, including SHP2 and PD-1, confirming the utility of the method. Altogether, the data suggested that SHP2 is the major PD-1-specific, SH2 family mediator of inhibitory signaling. These approaches should allow the systematic analysis of signaling pathways in T cells.

Clinical features of macular telangiectasia type 2 and comparison of staging system in Taiwanese patients.

PURPOSE: The purpose of this study is to report the clinical characteristics of macular telangiectasia type 2 (MacTel 2) in Taiwan. MATERIALS AND METHODS: Retrospective analysis of patients diagnosed with MacTel 2 over a 7-year period in Changhua Christian Hospital. Best-corrected visual acuity (BCVA), fundus photography, fluorescein angiography, optical coherence tomography (OCT), and OCT angiography (OCTA) images were reviewed. Differences in BCVA and central macular thickness (CMT) were compared between the initial/baseline and final visits. The staging was performed according to the Gass and Blodi classification and OCTA. RESULTS: There were 38 eyes in 19 patients were collected (Male: Female = 5:14). The mean age at diagnosis was 65.90 ± 8.26 years and the follow-up duration was 39.26 ± 28.31 months. All patients had both eyes affected, and eight of the 19 patients had a history of diabetes mellitus (DM). The mean initial logarithm of the minimum angle of resolution (logMAR) BCVA was 0.40 ± 0.31 and the mean final logMAR BCVA was 0.61 ± 0.53. Difference of BCVA equal or more than two lines between both eyes was noted in 63.1% (12 of 19) of patients at the initial visit and in 78.9% (15 of 19) of patients at the final follow-up. The mean CMT was 224.42 ± 38.50 µm at baseline and 222.05 ± 40.27 µm at the final visit. OCT illustrated macular hole in three eyes of three patients. At the final follow-up, retinal-choroidal anastomosis was noted in 17 eyes. Subretinal neovascularization (SRNV) was not present in any eye. CONCLUSION: Bilateral involvement, asymmetrical BCVA in both eyes, low incidence of SRNV, and high prevalence of DM were characteristics of patients of MacTel 2 in Taiwan.

A Robust GPS Navigation Filter Based on Maximum Correntropy Criterion with Adaptive Kernel Bandwidth.

Multiple forms of interference and noise that impact the receiver's capacity to receive and interpret satellite signals, and consequently the preciseness of positioning and navigation, may be present during the processing of Global Positioning System (GPS) navigation. The non-Gaussian noise predominates in the signal owing to the fluctuating character of both natural and artificial electromagnetic interference, and the algorithm based on the minimum mean-square error (MMSE) criterion performs well when assuming Gaussian noise, but drops when assuming non-Gaussian noise. The maximum correntropy criteria (MCC) adaptive filtering technique efficiently reduces pulse noise and has adequate performance in heavy-tailed noise, which addresses the issue of filter performance caused by the presence of non-Gaussian or heavy-tailed unusual noise values in the localizing measurement noise. The adaptive kernel bandwidth (AKB) technique employed in this paper applies the calculated adaptive variables to generate the kernel function matrix, in which the adaptive factor can modify the size of the kernel width across a reasonably appropriate spectrum, substituting the fixed kernel width for the conventional MCC to enhance the performance. The conventional maximum correntropy criterion-based extended Kalman filter (MCCEKF) algorithm's performance is significantly impacted by the value of the kernel width, and there are certain predetermined conditions in the selection based on experience. The MCCEKF with a fixed adaptive kernel bandwidth (MCCEKF-AKB) has several advantages due to its novel concept and computational simplicity, and gives a qualitative solution for the study of random structures for generalized noise. Additionally, it can effectively achieve the robust state estimation of outliers with anomalous values while guaranteeing the accuracy of the filtering.

The anticancer compound JTE-607 reveals hidden sequence specificity of the mRNA 3' processing machinery.

JTE-607 is an anticancer and anti-inflammatory compound and its active form, compound 2, directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in pre-messenger RNA (pre-mRNA) 3' processing. Surprisingly, compound 2-mediated inhibition of pre-mRNA cleavage is sequence specific and the drug sensitivity is predominantly determined by sequences flanking the cleavage site (CS). Using massively parallel in vitro assays, we identified key sequence features that determine drug sensitivity. We trained a machine learning model that can predict poly(A) site (PAS) relative sensitivity to compound 2 and provide the molecular basis for understanding the impact of JTE-607 on PAS selection and transcription termination genome wide. We propose that CPSF73 and associated factors bind to the CS region in a sequence-dependent manner and the interaction affinity determines compound 2 sensitivity. These results have not only elucidated the mechanism of action of JTE-607, but also unveiled an evolutionarily conserved sequence specificity of the mRNA 3' processing machinery.

Dapagliflozin-entresto protected kidney from renal hypertension via downregulating cell-stress signaling and upregulating SIRT1/PGC-1α/Mfn2-medicated mitochondrial homeostasis.

This study tested whether combined dapagliflozin and entresto would be superior to mere one therapy on protecting the residual renal function and integrity of kidney parenchyma in hypertensive kidney disease (HKD) rat. In vitro results showed that the protein expressions of oxidative-stress/mitochondrial-damaged (NOX-1/NOX-2/oxidized-protein/cytosolic-cytochrome-C)/apoptotic (mitochondrial-Bax/cleaved caspeases 3, 9)/cell-stress (p-ERK/p-JNK/p-p38) biomarkers were significantly increased in H2O2-treated NRK-52E cells than those of controls that were reversed by dapagliflozin or entresto treatment. Adult-male SD rats (n = 50) were equally categorized into group 1 (sham-operated-control), group 2 (HKD by 5/6 nephrectomy + DOCA-salt/25 mg/kg/subcutaneous injection/twice weekly), group 3 (HKD + dapagliflozin/orally, 20 mg/kg/day for 4 weeks since day 7 after HKD induction), group 4 (HKD + entresto/orally, 100 mg/kg/day for 4 weeks since day 7 after HKD induction), and group 5 (HKD + dapagliflozin + entresto/the procedure and treatment strategy were identical to groups 2/3/4). By day 35, circulatory levels of blood-urine-nitrogen (BUN)/creatinine and urine protein/creatinine ratio were lowest in group 1, highest in group 2, and significantly lower in group 5 than in groups 3/4, but no difference between groups 3/4. Histopathological findings showed the kidney injury score/fibrotic area/cellular expressions of oxidative-stress/kidney-injury-molecule (8-OHdG+/KIM-1+) exhibited an identical trend, whereas the cellular expressions of podocyte components (synaptopodin/ZO-1/E-cadherin) exhibited an opposite pattern of BUN level among the groups. The protein expressions of oxidative stress/mitochondrial-damaged (NOX-1/NOX-2/oxidized protein/cytosolic-cytochrome-C/cyclophilin-D)/apoptotic (mitochondrial-Bax/cleaved-caspase 3)/mitochondrial-fission (PINK1/Parkin/p-DRP1)/autophagic (LC3BII/LC3BI ratio, Atg5/beclin-1)/MAPK-family (p-ERK/p-JNK/p-p38) biomarkers displayed a similar pattern, whereas the protein expression of mitochondria-biogenesis signaling (SIRT1/PGC-1α-Mfn2/complex I-V) displayed an opposite pattern of BUN among the groups. In conclusion, combined dapagliflozin-entresto therapy offered additional benefits on protecting the residual kidney function and architectural integrity in HKD rat.

Metagenomics-based exploration of key soil microorganisms contributing to continuously planted Casuarina equisetifolia growth inhibition and their interactions with soil nutrient transformation.

Casuarina equisetifolia (C. equisetifolia) is an economically important forest tree species, often cultivated in continuous monoculture as a coastal protection forest. Continuous planting has gradually affected growth and severely restricted the sustainable development of the C. equisetifolia industry. In this study, we analyzed the effects of continuous planting on C. equisetifolia growth and explored the rhizosphere soil microecological mechanism from a metagenomic perspective. The results showed that continuous planting resulted in dwarfing, shorter root length, and reduced C. equisetifolia seedling root system. Metagenomics analysis showed that 10 key characteristic microorganisms, mainly Actinoallomurus, Actinomadura, and Mycobacterium, were responsible for continuously planted C. equisetifolia trees. Quantitative analysis showed that the number of microorganisms in these three genera decreased significantly with the increase of continuous planting. Gene function analysis showed that continuous planting led to the weakening of the environmental information processing-signal transduction ability of soil characteristic microorganisms, and the decrease of C. equisetifolia trees against stress. Reduced capacity for metabolism, genetic information processing-replication and repair resulted in reduced microbial propagation and reduced microbial quantity in the rhizosphere soil of C. equisetifolia trees. Secondly, amino acid metabolism, carbohydrate metabolism, glycan biosynthesis and metabolism, lipid metabolism, metabolism of cofactors and vitamins were all significantly reduced, resulting in a decrease in the ability of the soil to synthesize and metabolize carbon and nitrogen. These reduced capacities further led to reduced soil microbial quantity, microbial carbon and nitrogen, microbial respiration intensity, reduced soil enzyme nutrient cycling and resistance-related enzyme activities, a significant reduction in available nutrient content of rhizosphere soils, a reduction in the ion exchange capacity, and an impediment to C. equisetifolia growth. This study provides an important basis for the management of continuously planted C. equisetifolia plantations.

ABCB1 Regulates Immune Genes in Breast Cancer.

Background: Resistance to standard chemotherapy is a critical problem for breast cancer patients. The ATP-binding cassette (ABC) superfamily transporters actively pump out drugs and play an important role in chemoresistance. ABCB1 (ABC subfamily B, member 1, also named as multidrug resistance protein 1, MDR1) and suppressive myeloid-derived suppressor cells (MDSCs) potentially involve in chemoresistance of breast cancer. The relationship between ABCB1 and immune genes in breast cancer has not been widely studied. Methods: Microarray and RNA sequencing data were obtained from The Cancer Genome Atlas Breast Invasive Carcinoma in Genomic Data Commons Data Portal and Gene Expression Omnibus database. A patient-derived xenograft (PDX) model of HER2+ breast cancer was established to investigate the association between ABCB1 and immune genes in breast cancer. Results: Expression of ABCB1 increased in doxorubicin-selected MCF-7/ADR cells. High expression of ABCB1 mRNA is correlated with lymph-node metastasis and worse overall survival in patients with breast cancer. ABCB1 is positively correlated with IL6, CSF1, CSF3, and PTGS2. In the HER2+ stage IIA breast cancer PDX model, both doxorubicin and paclitaxel suppressed growth of P2 tumors. IL6, CSF1, CSF3, and PTGS2 expression were suppressed by paclitaxel but not doxorubicin. Intrasplenic MDSCs, including CD11b+Ly6G+ and CD11b+Ly6C+ cells, were more abundant than intratumor MDSCs in PDX-carrying nude mice. Clinically, the patient developed cancer recurrence after adjuvant chemotherapy with doxorubicin-based regimen and was well controlled after paclitaxel-trastuzumab combined therapy. Conclusion: ABCB1 was a poor predictor of HER2+ LN- breast cancer. Regulation of immune genes by ABCB1 contributed to cancer recurrence and treatment effect. The PDX model was suitable for investigation the expression of target genes and expansion of immune cells.