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Millirobots must have low cost, efficient locomotion, and the ability to track target trajectories precisely if they are to be widely deployed. With current materials and fabrication methods, achieving all of these features in one millirobot remains difficult. We develop a series of graphene-based helical millirobots by introducing asymmetric light pattern distortion to a laser-induced polymer-to-graphene conversion process; this distortion resulted in the spontaneous twisting and peeling off of graphene sheets from the polymer substrate. The lightweight nature of graphene in combine with the laser-induced porous microstructure provides a millirobot scaffold with a low density and high surface hydrophobicity. Magnetically driven nickel-coated graphene-based helical millirobots with rapid locomotion, excellent trajectory tracking, and precise drug delivery ability were fabricated from the scaffold. Importantly, such high-performance millirobots are fabricated at a speed of 77 scaffolds per second, demonstrating their potential in high-throughput and large-scale production. By using drug delivery for gastric cancer treatment as an example, we demonstrate the advantages of the graphene-based helical millirobots in terms of their long-distance locomotion and drug transport in a physiological environment. This study demonstrates the potential of the graphene-based helical millirobots to meet performance, versatility, scalability, and cost-effectiveness requirements simultaneously. Millirobots effective application generally depends on cost, scalability, efficient locomotion, and the ability to track target trajectory precisely. Here, authors demonstrate promising graphene-based helical millirobots by introducing asymmetric light pattern distortion to a laser-induced graphene process.

Bound states in the continuum (BICs) in photonic crystals describe the originally leaky Bloch modes that can become bounded when their radiation fields carry topological polarization singularities. However, topological polarization singularities do not carry energy to far field, which limits radiation efficiencies of BICs for light emitting applications. Here, we demonstrate a topological polarization singular laser which has a topological polarization singular channel in the second Brillouin zone and a paired linearly polarized radiation channel in the first Brillouin zone. The presence of the singular channel enables the lasing mode with a higher quality factor than other modes for single mode lasing. In the meanwhile, the presence of the radiation channel secures the lasing mode with high radiation efficiency. The demonstrated topological polarization singular laser operates at room temperature with an external quantum efficiency exceeding 24%. Our work presents a new paradigm in eigenmode engineering for mode selection, exotic field manipulation and lasing. Here the authors develop topological polarization singular lasers that feature paired radiation channels carrying distinct topological properties which leads to single mode lasing with high external quantum efficiency.

Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and β-arrestin-1 are essential for fluid reabsorption because they mediate coupling between an orphan receptor ADGRG2 (GPR64) and the ion channel CFTR. A reduction in protein level or deficiency of ADGRG2, Gq or β-arrestin-1 in a mouse model led to an imbalance in pH homeostasis in the efferent ductules due to decreased constitutive CFTR currents. Efferent ductule dysfunction was rescued by the specific activation of another GPCR, AGTR2. Further mechanistic analysis revealed that β-arrestin-1 acts as a scaffold for ADGRG2/CFTR complex formation in apical membranes, whereas specific residues of ADGRG2 confer coupling specificity for different G protein subtypes, this specificity is critical for male fertility. Therefore, manipulation of the signaling components of the ADGRG2-Gq/β-arrestin-1/CFTR complex by small molecules may be an effective therapeutic strategy for male infertility.

Inhibition of the functional activity of Filamenting temperature-sensitive mutant Z (FtsZ) protein, an essential and highly conserved bacterial cytokinesis protein, is a promising approach for the development of a new class of antibacterial agents. Berberine, a benzylisoquinoline alkaloid widely used in traditional Chinese and native American medicines for its antimicrobial properties, has been recently reported to inhibit FtsZ. Using a combination of in silico structure-based design and in vitro biological assays, 9-phenoxyalkyl berberine derivatives were identified as potent FtsZ inhibitors. Compared to the parent compound berberine, the derivatives showed a significant enhancement of antibacterial activity against clinically relevant bacteria, and an improved potency against the GTPase activity and polymerization of FtsZ. The most potent compound 2 strongly inhibited the proliferation of Gram-positive bacteria, including methicillin-resistant S. aureus and vancomycin-resistant E. faecium, with MIC values between 2 and 4 µg/mL, and was active against the Gram-negative E. coli and K. pneumoniae, with MIC values of 32 and 64 µg/mL respectively. The compound perturbed the formation of cytokinetic Z-ring in E. coli. Also, the compound interfered with in vitro polymerization of S. aureus FtsZ. Taken together, the chemical modification of berberine with 9-phenoxyalkyl substituent groups greatly improved the antibacterial activity via targeting FtsZ.

Flavonoid glycosides exhibit compromised bioavailability due to low membrane permeability. To address this limitation, we acetylated flavonoids through enzymatic reactions to increase bioavailability. This study first reported that Hesperetin-7- O -glucoside (Hes-7-G) was acetylated by galactoside acetyltransferase (GAT), and the apparent permeability ( P app ) of the Caco-2 monolayer was increased by 69%, indicating the acetylated Hes-7-G application potential to improve bioavailability. Subsequently, we designed GAT mutants through comprehensive computational and experimental methods to improve the acetylation efficiency and elucidate the catalytic mechanism. Molecular Dynamics (MD) simulations found that Tyr483 and Met127 are key residues that control flavonoid binding through dynamic van der Waals interactions, while His115 and Thr113 mediated proton transfer accounts for 85–90% of the catalytic activity. Rational substitution of Pro148 with alanine (P148A) increased the flexibility of the cofactor binding ring and increased the catalytic efficiency ( K cat /K M ) by 21%. Average non-covalent interaction (aNCI) analysis revealed that regional selectivity in the glucose portion was controlled by hydrophobic interactions with Tyr483 and hydrogen bonding with Gly125, and rhamnose substitution caused spatial conflict. This work deciphered the structure-activity relationship of GAT, established a framework for protein engineering, and highlighted enzyme-driven acetylation as a sustainable strategy for optimizing flavonoid pharmacokinetics. Key points • Engineered acetyltransferase enhances flavonoid glycoside absorption. • P148A mutation improves catalytic efficiency. • Insight into the catalytic mechanism of GAT by flavonoid glycoside substrates.

Background The 5-fuorouracil, oxaliplatin and irinotecan (FOLFOXIRI) regimen is the standard first-line treatment for advanced pancreatic cancer (APC). Capecitabine, an oral prodrug of 5-fluorouracil, offers a more convenient and potentially safer alternative. We evaluated the efficacy and safety of the XELOXIRI regimen (capecitabine, oxaliplatin, irinotecan) in Chinese patients with APC. Methods This real-world study evaluated consecutive patients treated with the XELOXIRI regimen as first-line chemotherapy for APC at a national cancer center in China from August 2019 to June 2024. Treatment efficacy was assessed using the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS), and safety was assessed using adverse events (AEs). Results Fifty-six patients were enrolled (median age, 60 years [range, 33–71]; 35 males, 21 females). Seventeen had locally advanced unresectable disease and 39 had metastatic disease. After a median follow-up of 19.8 months, the ORR was 33.9% (95% confidence interval [CI]: 21.8–47.8), disease control rate was 82.1% (95% CI: 69.6–91.1), and median response duration was 6.2 months (95% CI: 3.6-NA). Six patients with locally advanced disease and one with lung metastasis underwent R0 resection, with one achieving a pathological complete response. Median OS for the entire cohort was 16.2 months (95% CI: 10.6–23.2) and median PFS was 6.3 months (95% CI: 5.3-9.0). OS rates at 6, 12, and 18 months were 92.2%, 56.7%, and 35.6%, respectively; PFS rates were 53.9%, 20.2%, and 6.7%. For those who underwent R0 resection, median OS was not reached and median PFS was 12.3 months (95% CI: 11.9-NA).Treatment-related AEs (TRAEs)occurred in 94.6% of patients, with Grade 3 or higher TRAEs in 44.6%. No Grade 5 TRAEs or treatment-related deaths were observed. Conclusion The XELOXIRI regimen demonstrated promising efficacy and manageable toxicity in the treatment of APC, providing a practical alternative to FOLFOXIRI, with similar outcomes and easier administration.

Oestrogen receptor (ER) activation leads to the formation of DNA double strand breaks (DSB), promoting genomic instability and tumour heterogeneity. The single-stranded DNA cytosine deaminase APOBEC3B (A3B) serves as a co-activator of ER and is implicated in inducing DSBs at transcriptional enhancers regulated by ER. Using whole-genome sequencing in an engineered cell model lacking base excision repair (BER) function, we demonstrate that A3B preferentially targets transcriptionally active regulatory regions in an R-loop-dependent manner. Strand-specific DNA:RNA immunoprecipitation sequencing (ssDRIP-seq) and ssDNA-associated protein immunoprecipitation sequencing (SPI-seq) confirm that A3B binds to and deaminates ssDNA within R-loops, a process facilitated by ER transactivation. Furthermore, BER-mediated processing of A3B-induced uracil bases contributes to the formation of R-loop-associated DSBs, which are essential for ER-regulated gene activation. These findings establish a role for A3B in R-loop homeostasis and transcriptional regulation, with implications for understanding ER-driven genomic instability and potential therapeutic targeting of A3B. Oestrogen receptor activation generates DNA breaks at regulatory elements that control gene expression. This study shows that APOBEC3B is required for these breaks, by deaminating cytosines within R-loops at oestrogen receptor-regulated enhancers.

The global application of engineered nanomaterials and nanoparticles (ENPs) in commercial products, industry, and medical fields has raised some concerns about their safety. These nanoparticles may gain access into rivers and marine environments through industrial or household wastewater discharge and thereby affect the ecosystem. In this study, we investigated the effects of silver nanoparticles (AgNPs) and zinc oxide nanoparticles (ZnONPs) on zebrafish embryos in aquatic environments. We aimed to characterize the AgNP and ZnONP aggregates in natural waters, such as lakes, reservoirs, and rivers, and to determine whether they are toxic to developing zebrafish embryos. Different toxic effects and mechanisms were investigated by measuring the survival rate, hatching rate, body length, reactive oxidative stress (ROS) level, apoptosis, and autophagy. Spiking AgNPs or ZnONPs into natural water samples led to significant acute toxicity to zebrafish embryos, whereas the level of acute toxicity was relatively low when compared to Milli-Q (MQ) water, indicating the interaction and transformation of AgNPs or ZnONPs with complex components in a water environment that led to reduced toxicity. ZnONPs, but not AgNPs, triggered a significant delay of embryo hatching. Zebrafish embryos exposed to filtered natural water spiked with AgNPs or ZnONPs exhibited increased ROS levels, apoptosis, and lysosomal activity, an indicator of autophagy. Since autophagy is considered as an early indicator of ENP interactions with cells and has been recognized as an important mechanism of ENP-induced toxicity, developing a transgenic zebrafish system to detect ENP-induced autophagy may be an ideal strategy for predicting possible ecotoxicity that can be applied in the future for the risk assessment of ENPs.

Recently, the study of acoustic vortex beams has attracted a great attention owing to its potential applications in medical ultrasound imaging and trapping particles. In some special applications of medical ultrasound, it generally needs the simultaneous realization of vortex focusing and asymmetric propagation in three-dimensional (3D) space. However, the design of a two-dimensional (2D) device with asymmetric acoustic vortex focusing (AAVF) remains a challenge. To overcome it, we experimentally demonstrate a 2D AAVF lens composed of three types of binary-phase mode converters. By simultaneously introducing the phase profiles of acoustic focusing and vortex caused by the mode converters, we design a 2DAAVF lens with the topological charge n = 2, i.e., the sound energy can pass through the lens from the upper side and forms a vortex focus in 3D space; however, it cannot transmit through the lens from the other side. The vortex focusing and asymmetric transmission arise from the phase manipulation and the conversion between the zero-order and first-order waves caused by the mode converters, respectively. The measured fractional bandwidth can reach about 0.19. The proposed lens has the advantages of high-performance AAVF, broad bandwidth and complex sound modulation in 3D space, which provides diverse routes for designing 3D multi-functional sound devices with promising applications in medical ultrasound.