Explore the vast range of titles available.

[1], in which the investigators explored the relationship between the adsorption effect and the filtration flow rate in a cytokine-adsorbing hemofilter (CAH) during continuous renal replacement therapy (CRRT), by systematically analyzing polymethyl methacrylate (PMMA) and polyethylenimine-coated polyacrylonitrile (AN69ST) membrane performance across varying dialysate (QD) and filtration (QF) flow rates (< 600 mL/h convection volume), the study reveals two key phenomena: (1) membrane-independent enhancement of small solute (creatinine) clearance with increasing QD and QF and (2) stable cytokine (IL-6/IL-8) adsorption clearance across all tested flow configurations. Given the inclusion of PMMA in the comparator groups, these observational data may underestimate the true clinical benefit of AN69ST. [...]Kudo et al. provided valuable mechanistic data possibly informing CAH-CRRT optimization; however, the study’s in vitro design and limited convection parameters warrant cautious clinical extrapolation.

Hydrogen peroxide (H 2 O 2 ) is an important signaling molecule in plant developmental processes and stress responses. However, whether H 2 O 2 -mediated signaling crosstalks with plant hormone signaling is largely unclear. Here, we show that H 2 O 2 induces the oxidation of the BRASSINAZOLE-RESISTANT1 (BZR1) transcription factor, which functions as a master regulator of brassinosteroid (BR) signaling. Oxidative modification enhances BZR1 transcriptional activity by promoting its interaction with key regulators in the auxin-signaling and light-signaling pathways, including AUXIN RESPONSE FACTOR6 (ARF6) and PHYTOCHROME INTERACTING FACTOR4 (PIF4). Genome-wide analysis shows that H 2 O 2 -dependent regulation of BZR1 activity plays a major role in modifying gene expression related to several BR-mediated biological processes. Furthermore, we show that the thioredoxin TRXh5 can interact with BZR1 and catalyzes its reduction. We conclude that reversible oxidation of BZR1 connects H 2 O 2 -mediated and thioredoxin-mediated redox signaling to BR signaling to regulate plant development. Hydrogen peroxide and brassinosteroids (BR) both regulate plant development and stress responses. Here Tian et al. show that hydrogen peroxide can trigger oxidation of the BR-responsive BZR1 transcription factor and promote its transcriptional activity, thereby linking BR and redox signaling.

Chimeric antigen receptor (CAR‐T) cell therapy is a newly developed immunotherapy strategy and has achieved satisfactory outcomes in the treatment of hematological malignancies. However, some adverse effects related to CAR‐T cell therapy have to be resolved before it is widely used in clinics as a cancer treatment. Furthermore, the application of CAR‐T cell therapy in the treatment of solid tumors has been hampered by numerous limitations. Therefore, it is essential to explore novel strategies to improve the therapeutic effect of CAR‐T cell therapy. In this review, we summarized the recently developed strategies aimed at optimizing the generation of CAR‐T cells and improving the anti‐tumor efficiency of CAR‐T cell therapy. Furthermore, the discovery of new targets for CAR‐T cell therapy and the combined treatment strategies of CAR‐T cell therapy with chemotherapy, radiotherapy, cancer vaccines and nanomaterials are highlighted. The review summarizes and discusses recently developed or optimized strategies including the delivery of CAR gene, drug administration regimen, the CAR with molecular switch or logic gate control, allogeneic and super CAR‐T, double targets CAR‐T, CAR‐T targets for exploration, utilization of nano‐antibody/nanomaterials and gene‐editing, combination with radiotherapy, chemotherapy and vaccine, to improve the therapeutic effects of CAR‐T cells therapies.

Single-cell pH-sensing and accurate detection and label-free fast identification of cancer-cells are two long-standing pursuits in cell and life science, as intracellular pH plays a crucial role in many cellular events and fates, while the latter is vital for early cancer theranostics. Numerous methods based on functionalized nanoparticles and fluorescence probes have been developed for cell pH-sensing, but are often hindered for single-cell studies by their main drawbacks of complicated probe preparation and labeling, low sensitivity and poor reproducibility. Here we report a simple and reliable method for single-cell pH imaging and sensing by innovative combined use of UV-Vis microspectroscopy and common pH indicators. Accurate and sensitive pH detection on single-cell or sub-cell level with good reproducibility is achieved by the method, which enables facile single-cell pH profiling and label-free rapid identification of cancer-cells (due to distinguishable intracellular pH levels) for early cancer diagnosis, and may open a new avenue for pH-related single-cell studies.

Uremic cardiomyopathy (UCM) is a leading cause of death in patients with chronic kidney disease. This study aimed to explore the role and underlying mechanisms of neutrophil extracellular traps (NETs) in UCM. A UCM mouse model was constructed using 5/6 nephrectomy and treated with the NET inhibitor DNaseI. Cardiac fibroblasts were incubated with 200 ng/mL of NETs to establish an in vitro model. Physiological parameters of mice were measured, and commercial kits were used to detect MPO-DNA, IL-1β, and IL-6 levels. Hematoxylin-eosin and TUNEL staining were performed to evaluate myocardial injury and apoptosis. Immunofluorescence was used to detect MPO, CitH3, and caspase-1 expression. Sytox Green staining and CCK-8 assay were applied to assess NET formation and determine the optimal NET concentration. Western blot was conducted to detect collagen1, α-SMA, NLRP3, GSDMD-N, and caspase-1 expression. Transmission electron microscopy was performed to observe pyroptosis. UCM mice exhibited impaired kidney and cardiac function, indicating the successful establishment of the UCM model. MPO-DNA levels were elevated in UCM mice, suggesting NET formation. DNaseI treatment significantly reduced MPO and CitH3 expression, inhibiting NET formation in UCM mice. NET inhibition improved renal function and alleviated cardiac injury. Furthermore, NET inhibition reduced inflammation, apoptosis, and pyroptosis in UCM mice. Neutrophils isolated from UCM mice, as well as PMA, induced NET formation. NETs significantly enhanced fibrosis and pyroptosis in myocardial fibroblasts. NETs may promote UCM progression by inducing pyroptosis in myocardial fibroblasts.

[...]prior trials comparing IRRT and CRRT emphasized dose parity between modalities (i.e., ensuring equivalent total solute clearance when comparing outcomes) [7], a factor not addressed in this study. Without dose data, the study cannot disentangle whether outcomes reflect modality efficacy, dosing adequacy, or the balance between solute control and hemodynamic tolerance. [...]Uchino et al.’s observational study found no mortality difference between Japanese low-dose CRRT and historical international standards, but confounding factors such as patient selection and concurrent therapies cannot be ruled out [8].

This study is to investigate whether the cardiac microvascular endothelial cells (CMECs) can regulate the autophagy of cardiomyocytes (CMs) by secreting lncRNA-ANRIL/miR-181b exosomes, thus participating in the occurrence of uremic cardiovascular disease (CVD). A 5/6 nephrectomy uremia model was established, with the mice injected with ANRIL-shRNA lentivirus vector, miR-181b agomir, and related control reagents, containing the serum creatinine and urea nitrogen measured. The renal tissue sections of mice were stained with Periodic Acid-Schiff (PAS), TUNEL, and Hematoxylin-Eosin (HE) performed on myocardial tissue sections of mice. ANRIL-shRNA, miR-181b mimics, and related control reagents were transfected into CMECs, in which the exosomes were extracted and co-cultured with CMs. The expressions of ANRIL, miR-181b and ATG5 were detected by qRT-PCR, and the expressions of autophagy related proteins by Western blot, as well as the binding of ANRIL and miR-181b by the double luciferase reporter gene experiment. ANRIL down-regulation or miR-181b up-regulation can increase the weight of mice with uremia, as well as the expressions of p62 and miR-181b, and reduce the content of serum creatinine and urea nitrogen, the damage of kidney and myocardial tissues, the number of apoptotic cells in myocardial tissues, as well as the expressions of ANRIL, ATG5, Beclin1, and LC3. CMs can absorb the exosomes of CMECs. Compared with IS+ CMEC-Exo group, the expressions of ANRIL and ATG5 in CMs of IS+ CMEC-Exo + sh lncRNA ANRIL and IS+CMEC-Exo+miR-181b mimics groups was down-regulated, as well as the expressions of ATG5, Beclin1, and LC3, while miR-181b expression was up-regulated as well as P62 expression. CMECs can regulate autophagy of CMs by releasing exosomes containing ANRIL and miR-181b.

Diverse natural products are synthesized in plants by specialized metabolic enzymes, which are often lineage-specific and derived from gene duplication followed by functional divergence. However, little is known about the contribution of primary metabolism to the evolution of specialized metabolic pathways. Betalain pigments, uniquely found in the plant order Caryophyllales, are synthesized from the aromatic amino acid L-tyrosine (Tyr) and replaced the otherwise ubiquitous phenylalanine-derived anthocyanins. This study combined biochemical, molecular and phylogenetic analyses, and uncovered coordinated evolution of Tyr and betalain biosynthetic pathways in Caryophyllales. We found that Beta vulgaris, which produces high concentrations of betalains, synthesizes Tyr via plastidic arogenate dehydrogenases (TyrAa/ADH) encoded by two ADH genes (BvADHα and BvADHβ). Unlike BvADHβ and other plant ADHs that are strongly inhibited by Tyr, BvADHα exhibited relaxed sensitivity to Tyr. Also, Tyr-insensitive BvADHα orthologs arose during the evolution of betalain pigmentation in the core Caryophyllales and later experienced relaxed selection and gene loss in lineages that reverted from betalain to anthocyanin pigmentation, such as Caryophyllaceae. These results suggest that relaxation of Tyr pathway regulation increased Tyr production and contributed to the evolution of betalain pigmentation, highlighting the significance of upstream primary metabolic regulation for the diversification of specialized plant metabolism.

We designed Proteolysis Targeting Chimeras (PROTACs) to target Tropomyosin Receptor Kinase A (TRKA) and Rearranged during Transfection (RET) oncogenic proteins. We analyzed a series of 22 PROTACs, based on the RET and TRKA small molecule inhibitor Pz-1 and ligands of E3 ligase complex component Cereblon (CRBN). The compounds were tested in TPC-1 and KM12 cells, derived from papillary thyroid carcinoma and colorectal carcinoma, and harboring the CCDC6-RET and TPM3-TRKA oncoproteins, respectively. We identified several RET and TPM3-TRKA PROTACs, able to induce their degradation. Consistently, one of the most active degraders, compound 9 , exhibited a strong anti-proliferative effect in several cancer cell lines derived from human medullary and papillary thyroid, lung and colon cancers, displaying either RET or TRKA-derived oncoproteins, with an IC 50 dose of one digit nM. Mechanistically, TPM3-TRKA degradation by compound 9 was dependent on CRBN-mediated polyubiquitination and proteasomal degradation; accordingly, it was hindered by inhibitors of the proteasome (MG132) or Cullins (MLN4924), by dominant negative Cullin 4A mutant, and by free pomalidomide. Saturating amounts of compound 9 featured loss of activity, consistently with the bivalent binding of a PROTAC (“hook effect”). Finally, a compound 9 derivative, compound 20 , induced in vivo degradation of TMP3-TRKA in KM12 cells mouse xenografts. In conclusion, our study indicated that PROTAC-mediated degradation is an efficient strategy to intercept RET and TRKA oncogenic signaling.

• The timing and extent of cell division are crucial for the correct patterning of multicellular organism. In Arabidopsis, root ground tissue maturation involves the periclinal cell division of the endodermis to generate two cell layers: endodermis and middle cortex. However, the molecular mechanism underlying this pattern formation remains unclear. • Here, we report that phytohormone brassinosteroid (BR) and redox signal hydrogen peroxide (H₂O₂) interdependently promote periclinal division during root ground tissue maturation by regulating the activity of SHORT-ROOT (SHR), a master regulator of root growth and development. • BR-activated transcription factor BRASSINAZOLE RESISTANT1 (BZR1) directly binds to the promoter of SHR to induce its expression, and physically interacts with SHR to increase the transcripts of RESPIRATORY BURST OXIDASE HOMOLOGs (RBOHs) and elevate the levels of H₂O₂, which feedback enhances the interaction between BZR1 and SHR. Additionally, genetic analysis shows that SHR is required for BZR1-promoted periclinal division, and BZR1 enhances the promoting effects of SHR on periclinal division. • Together, our finding reveals that the transcriptional module of BZR1-SHR fine-tunes periclinal division during root ground tissue maturation in response to hormone and redox signals.