The efficacy and safety of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor, in patients with advanced head and neck mucosal melanoma harboring CDK4 amplification.

BACKGROUND: Mucosal melanoma (MM) is a rare but devastating subtype of melanoma. Our previous studies have demonstrated robust anti-tumor effects of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors in head and neck MM (HNMM) patient-derived xenograft models with CDK4 amplification. Herein, we aimed to investigate the efficacy and safety of dalpiciclib (SHR6390), a CDK4/6 inhibitor, in HNMM patients harboring CDK4 amplification. METHODS: The anti-tumor efficacy of dalpiciclib was assessed by HNMM patient-derived xenograft (PDX) models and patient-derived tumor cells (PDC) in vivo and in vitro. Immunohistochemical analyses and western blot were then performed to assess the markers of cell proliferation and CDK4/6 signaling pathway. For the clinical trial, advanced recurrent and/or metastatic HNMM patients with CDK4 amplification were treated with dalpiciclib 125 mg once daily for 21 consecutive days in 28-day cycles. The primary endpoint was disease control rate (DCR). Secondary endpoints included safety, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Dalpiciclib profoundly suppressed growth of HNMM-PDX and PDC with CDK4 amplification, whereas it showed relatively weak suppression in those with CDK4 wild type compared with vehicle. And dalpiciclib resulted in a remarkable reduction in the expression levels of Ki-67 and phosphorylated Rb compared with control group. In the clinical trial, a total of 17 patients were enrolled, and 16 patients were evaluable. The ORR was 6.3%, and the DCR was 81.3%. The estimated median PFS was 9.9 months (95% CI, 4.8-NA), and the median OS was not reached. The rate of OS at 12 months and 24 months was 68.8% (95% CI, 0.494-0.957) and 51.6% (95% CI, 0.307-0.866), respectively. The most frequent adverse events were neutrophil count decrease, white blood cell count decrease, and fatigue. CONCLUSIONS: Dalpiciclib was well-tolerated and displayed a durable benefit for HNMM patients with CDK4 amplification in this study. Further studies on CDK4 inhibitors and its combination strategy for MM are worth further exploration. TRIAL REGISTRATION: ChiCTR2000031608.

TaGSK3 regulates wheat development and stress adaptation through BR-dependent and BR-independent pathways.

The GSK3/SHAGGY-like kinase plays critical roles in plant development and response to stress, but its specific function remains largely unknown in wheat (Triticum aestivum L.). In this study, we investigated the function of TaGSK3, a GSK3/SHAGGY-like kinase, in wheat development and response to stress. Our findings demonstrated that TaGSK3 mutants had significant effects on wheat seedling development and brassinosteroid (BR) signalling. Quadruple and quintuple mutants showed amplified BR signalling, promoting seedling development, while a sextuple mutant displayed severe developmental defects but still responded to exogenous BR signals, indicating redundancy and non-BR-related functions of TaGSK3. A gain-of-function mutation in TaGSK3-3D disrupted BR signalling, resulting in compact and dwarf plant architecture. Notably, this mutation conferred significant drought and heat stress resistance of wheat, and enhanced heat tolerance independent of BR signalling, unlike knock-down mutants. Further research revealed that this mutation maintains a higher relative water content by regulating stomatal-mediated water loss and maintains a lower ROS level to reduces cell damage, enabling better growth under stress. Our study provides comprehensive insights into the role of TaGSK3 in wheat development, stress response, and BR signal transduction, offering potential for modifying TaGSK3 to improve agronomic traits and enhance stress resistance in wheat.

MT1M regulates gastric cancer progression and stemness by modulating the Hedgehog pathway protein GLI1.

Gastric cancer (GC) is a highly prevalent and aggressive malignancy with a poor prognosis. Recent evidence suggested that metallothionein 1 M (MT1M) may play a critical role in cancer development, progression, and drug resistance; however, its role in GC remains largely unknown. In this study, we investigated the expression and function of MT1M in GC both in vitro and in vivo. We found that MT1M expression was significantly downregulated in GC tissues and cell lines. Decreased expression of MT1M was associated with worse clinical prognosis, particularly in patients treated with 5-fluorouracil. Low expression of MT1M was indicative of poor overall survival (OS, HR 0.56 [95% CI 0.37-0.84], P < 0.005), first progression survival (FP, HR 0.54 [95% CI 0.36-0.79], P < 0.005), and post-progression survival (PPS, HR 0.65 [95% CI 0.45-0.94], P < 0.05). We also demonstrated that overexpression of MT1M inhibited cell proliferation and induced apoptosis in GC cells and in tumor xenografts, and it improved chemosensitivity to 5-fluorouracil. Furthermore, we found that MT1M overexpression could inhibit stem cell characteristics by targeting GLI1 and affecting GLI1 ubiquitination. Collectively, these findings indicated that MT1M may act as a tumor suppressor in GC and could serve as a potential therapeutic target to attenuate stemness and chemotherapy resistance of GC.

Effect of Saccharomyces cerevisiae, Torulaspora delbrueckii and malolactic fermentation on fermentation kinetics and sensory property of black raspberry wines.

Alcoholic fermentation (AF) and malolactic fermentation (MLF) both have significant influence on the production of black raspberry wine. In this study, three microbes associated with AF and MLF including S. cerevisiae, T. delbrueckii and O. oeni were used to investigate their combined effect on basic compositional, volatile and sensory property of black raspberry wine, and four fermentation trials including single S. cerevisiae inoculation plus spontaneous MLF (BSU) and controlled MLF with O. oeni (BSO), sequential culture of T. delbrueckii and S. cerevisiae plus spontaneous MLF (BTSU) and controlled MLF (BTSO) were tested and compared. Fermentation results showed MLF in BSU, BSO and BTSO were successful, with respective period of 40, 25 and 23 days, whereas a stuck MLF occurred in BTSU. Volatile compounds were determined by HS-GC-IMS method, with a total of 45 aromas identified. BTSO was distinguished by a significant higher signal intensity of many fruity esters and a lower production of several alcohols and terpenes, which was in agreement with its perception result of strong 'fruity' and slight note of 'solvent' and 'herbaceous' during quantitative descriptive analysis. On the contrary, BSU was found to reinforce the synthesis of most detected volatiles, resulting in the enhancement of both beneficial and off-flavour compounds, therefore scoring lower in the 'global aroma' descriptor. Principal component analysis showed BSU and BSO were similar in the volatile composition, whereas BTSO was quite different. Overall, BTSO had greater potential to be used in the production of black raspberry wine.

Elevated sodium chloride drives type I interferon signaling in macrophages and increases antiviral resistance.

Type I IFN production and signaling in macrophages play critical roles in innate immune responses. High salt (i.e. high concentrations of NaCl) has been proposed to be an important environmental factor that influences immune responses in multiple ways. However, it remains unknown whether high salt regulates type I IFN production and signaling in macrophages. Here, we demonstrated that high salt promoted IFNß production and its signaling in both human and mouse macrophages, and consequentially primed macrophages for strengthened immune sensing and signaling when challenged with viruses or viral nucleic acid analogues. Using both pharmacological inhibitors and RNA interference we showed that these effects of high salt on IFNß signaling were mediated by the p38 MAPK/ATF2/AP1 signaling pathway. Consistently, high salt increased resistance to vesicle stomatitis virus (VSV) infection in vitro. In vivo data indicated that a high-salt diet protected mice from lethal VSV infection. Taken together, these results identify high salt as a crucial regulator of type I IFN production and signaling, shedding important new light on the regulation of innate immune responses.

T-Cell Mineralocorticoid Receptor Controls Blood Pressure by Regulating Interferon-Gamma.

RATIONALE: Hypertension remains to be a global public health burden and demands novel intervention strategies such as targeting T cells and T-cell-derived cytokines. Mineralocorticoid receptor (MR) antagonists have been clinically used to treat hypertension. However, the function of T-cell MR in blood pressure (BP) regulation has not been elucidated. OBJECTIVE: We aim to determine the role of T-cell MR in BP regulation and to explore the mechanism. METHODS AND RESULTS: Using T-cell MR knockout mouse in combination with angiotensin II-induced hypertensive mouse model, we demonstrated that MR deficiency in T cells strikingly decreased both systolic and diastolic BP and attenuated renal and vascular damage. Flow cytometric analysis showed that T-cell MR knockout mitigated angiotensin II-induced accumulation of interferon-gamma (IFN-γ)-producing T cells, particularly CD8+ population, in both kidneys and aortas. Similarly, eplerenone attenuated angiotensin II-induced elevation of BP and accumulation of IFN-γ-producing T cells in wild-type mice. In cultured CD8+ T cells, T-cell MR knockout suppressed IFN-γ expression whereas T-cell MR overexpression and aldosterone both enhanced IFN-γ expression. At the molecular level, MR interacted with NFAT1 (nuclear factor of activated T-cells 1) and activator protein-1 in T cells. Finally, T-cell MR overexpressing mice manifested more elevated BP compared with control mice after angiotensin II infusion and such difference was abolished by IFN-γ-neutralizing antibodies. CONCLUSIONS: MR may interact with NFAT1 and activator protein-1 to control IFN-γ in T cells and to regulate target organ damage and ultimately BP. Targeting MR in T cells specifically may be an effective novel approach for hypertension treatment.

Long Non-Coding RNA MEG3 Downregulation Triggers Human Pulmonary Artery Smooth Muscle Cell Proliferation and Migration via the p53 Signaling Pathway.

BACKGROUND/AIMS: Increasing evidence has demonstrated a significant role of long non-coding RNAs (lncRNAs) in diverse biological processes, and many of which are likely to have functional roles in vascular remodeling. However, their functions in pulmonary arterial hypertension (PAH) remain largely unknown. Pulmonary vascular remodeling is an important pathological feature of PAH, leading to increased vascular resistance and reduced compliance. Pulmonary artery smooth muscle cells (PASMCs) dysfunction is involved in vascular remodeling. Long noncoding RNAs are potential regulators of PASMCs function. Herein, we determined whether long noncoding RNA-maternally expressed gene 3 (MEG3) was involved in PAH-related vascular remodeling. METHODS: The arterial wall thickness was examined by hematoxylin and eosin (H&E) staining in distal pulmonary arteries (PAs) isolated from lungs of healthy volunteers and PAH patients. The expression level of MEG3 was analyzed by qPCR. The effects of MEG3 on human PASMCs were assessed by cell counting Kit-8 assay, BrdU incorporation assay, flow cytometry, scratch-wound assay, immunofluorescence, and western blotting in human PASMCs. RESULTS: We revealed that the expression of MEG3 was significantly downregulated in lung and PAs of patients with PAH. MEG3 knockdown affected PASMCs proliferation and migration in vitro. Moreover, inhibition of MEG3 regulated the cell cycle progression and made more smooth muscle cells from the G0/G1 phase to the G2/M+S phase and the process could stimulate the expression of PCNA, Cyclin A and Cyclin E. In addition, we found that the p53 pathway was involved in MEG3-induced smooth muscle cell proliferation. CONCLUSIONS: This study identified MEG3 as a critical regulator in PAH and demonstrated the potential of gene therapy and drug development for treating PAH.

Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Neointimal Hyperplasia and Suppresses Macrophage Inflammation Through SGK1-AP1/NF-κB Pathways.

OBJECTIVE: Restenosis after percutaneous coronary intervention remains to be a serious medical problem. Although mineralocorticoid receptor (MR) has been implicated as a potential target for treating restenosis, the cellular and molecular mechanisms are largely unknown. This study aims to explore the functions of macrophage MR in neointimal hyperplasia and to delineate the molecular mechanisms. APPROACH AND RESULTS: Myeloid MR knockout (MMRKO) mice and controls were subjected to femoral artery injury. MMRKO reduced intima area and intima/media ratio, Ki67- and BrdU-positive vascular smooth muscle cells, expression of proinflammatory molecules, and macrophage accumulation in injured arteries. MMRKO macrophages migrated less in culture. MMRKO decreased Ki67- and BrdU-positive macrophages in injured arteries. MMRKO macrophages were less Ki67-positive in culture. Conditioned media from MMRKO macrophages induced less migration, Ki67 positivity, and proinflammatory gene expression of vascular smooth muscle cells. After lipopolysaccharide treatment, MMRKO macrophages had decreased p-cFos and p-cJun compared with control macrophages, suggesting suppressed activation of activator protein-1 (AP1). Nuclear factor-κB (NF-κB) pathway was also inhibited by MMRKO, manifested by decreased p-IκB kinase-ß and p-IκBα, increased IκBα expression, decreased nuclear translocation of p65 and p50, as welll as decreased phosphorylation and expression of p65. Finally, overexpression of serum-and-glucocorticoid-inducible-kinase-1 (SGK1) attenuated the effects of MR deficiency in macrophages. CONCLUSIONS: Selective deletion of MR in myeloid cells limits macrophage accumulation and vascular inflammation and, therefore, inhibits neointimal hyperplasia and vascular remodeling. Mechanistically, MR deficiency suppresses migration and proliferation of macrophages and leads to less vascular smooth muscle cell activation. At the molecular level, MR deficiency suppresses macrophage inflammatory response via SGK1-AP1/NF-κB pathways.

Nanotechnology-based analytical techniques for the detection of contaminants in aquatic products.

Food safety of aquatic products has attracted considerable attention worldwide. Although a series of conventional bioassays and instrumental methods have been developed for the detection of pathogenic bacteria, heavy metal residues, marine toxins, and biogenic amines during the production and storage of fish, shrimp, crabs et al., the nanotechnology-based analyses still have their advantages and are promising since they are cost-efficient, highly sensitive and selective, easy to conduct, facial design, often require no sophisticated instruments but with excellent detection performance. This review aims to summarize the advances of various biosensing strategies for bacteria, metal ions, and small molecule contaminants in aquatic products during the last five years, The review highlights the development in nanotechnologies applied for biorecognition process, signal transduction and amplification methods in each novel approach, the nuclease-mediated DNA amplification, nanomaterials (noble metal nanoparticle, metal-organic frameworks, carbon dots), lateral flow-based biosensor, surface-enhanced Raman scattering, microfluidic chip, and molecular imprinting technologies were especially emphasized. Moreover, this study provides a view of current accomplishments, challenges, and future development directions of nanotechnology in aquatic product safety evaluation.

Age, growth, reproduction and mortality of Xenocypris argentea (Günther,1868) in the lower reaches of the Tangwang River, China.

To investigate various population biological parameters of Xenocypris argentea in the lower reaches of the Tangwang River (China), a comprehensive study was conducted for the first time. A total of 1,003 samples were collected from April to November 2022. The collected samples revealed that female X. argentea had total lengths ranging from 12.4 cm to 25.7 cm (weighing 15.86 g to 159.55 g), and male X. argentea had total lengths ranging from 10.8 cm to 23.9 cm (weighing 9.27 g to 121.06 g). The age of the samples was determined using otolith analysis, indicating that the ages ranged from 1 to 5 years old in both females and males. The length-weight relationships were further analyzed, uncovering the allometric growth index (b) was 3.1296 for females, indicating a positive allometric growth pattern. Differently, males exhibited a b value of 3.0274, suggesting an isometric growth pattern. Furthermore, the von Bertalanffy growth formula provided insights into the growth characteristics of X. argentea, revealing an asymptotic total length (L∞) of 36.096 cm and a growth coefficient (K) of 0.121. The analysis of the gonadal somatic index (GSI) and ovarian development period indicated that the spawning period occurred from April to July, with peak spawning in June. The study also explored fecundity-related traits, finding that individual absolute fecundity (FA) ranged from 11,364 eggs to 56,377 eggs, while eviscerated body weight relative fecundity (FW) ranged from 209 eggs/g to 823 eggs/g. The exploitation rate (E) for X. argentea was calculated as 0.574, suggesting that the population of X. argentea has been overexploited. By revealing previously unknown data on the key life history traits of X. argentea, this study has provided valuable insights that are crucial for the development of conservation strategies and policies.

Increasing the Amounts of Bioactive Components in American Ginseng (Panax quinquefolium L.) Leaves Using Far-Infrared Irradiation.

Both the roots and leaves of American ginseng contain ginsenosides and polyphenols. The impact of thermal processing on enhancing the biological activities of the root by altering its component composition has been widely reported. However, the effects of far-infrared irradiation (FIR), an efficient heat treatment method, on the bioactive components of the leaves remain to be elucidated. In the present study, we investigated the effects of FIR heat treatment between 160 and 200 °C on the deglycosylation and dehydration rates of the bioactive components in American ginseng leaves. As the temperature was increased, the amounts of common ginsenosides decreased while those of rare ginsenosides increased. After FIR heat treatment of American ginseng leaves at an optimal 190 °C, the highest total polyphenolic content and kaempferol content were detected, the antioxidant activity was significantly enhanced, and the amounts of the rare ginsenosides F4, Rg6, Rh4, Rk3, Rk1, Rg3, and Rg5 were 41, 5, 37, 64, 222, 17, and 266 times higher than those in untreated leaves, respectively. Moreover, the radical scavenging rates for 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) and the reducing power of the treated leaf extracts were 2.17, 1.86, and 1.77 times higher, respectively. Hence, FIR heat treatment at 190 °C is an efficient method for producing beneficial bioactive components from American ginseng leaves.

Polysaccharide- and protein-based edible films combined with microwave technology for meat preservation.

To reduce food-borne bacterial infection caused by food spoilage, developing highly efficient food packing film is still an urgent need for food preservation. Herein, microwave-assisted antibacterial nanocomposite films CaO2@PVP/EA/CMC-Na (CP/EC) were synthesized using waste eggshell as precursor, egg albumen (EA) and sodium carboxymethylcellulose (CMCNa) as matrix by casting method. The size of CaO2@PVP (CP) nanoparticles with monodisperse spherical structures was 100-240 nm. When microwave and CP nanoparticles (0.05 mg/mL) were treated for 5 min, the mortality of E. coli and S. aureus could reach >97 %. Under microwave irradiation (6 min), the bactericidal rate of 2.5 % CP/EC film against E. coli and S. aureus reached 98.6 % and 97.2 %, respectively. After adding CP nanoparticles, the highest tensile strength (TS) and elongation at break (EB) of CP/EC film reached 19.59 MPa and 583.43 %, respectively. At 18 °C, the proliferation of bacterial colonies on meat can be significantly inhibited by 2.5 % CP/EC film. Detailed characterization showed that the excellent meat preservation activity was due to the synergistic effect of dynamic effect generated by ROS and thermal effect of microwave. This study provides a promising approach for the packaging application of polysaccharide- and protein-based biomass nanocomposite antibacterial edible films.

Cascade Nanoreactor Employs Mitochondrial-Directed Chemodynamic and δ-ALA-Mediated Photodynamic Synergy for Deep-Seated Oral Cancer Therapy.

The management of oral squamous cell carcinoma (OSCC) poses significant challenges, leading to organ impairment and ineffective treatment of deep-seated tumors, adversely affecting patient prognosis. A cascade nanoreactor that integrates photodynamic therapy (PDT) and chemodynamic therapy (CDT) for comprehensive multimodal OSCC treatment is introduced. Utilizing iron oxide and mesoporous silica, the FMMSH drug delivery system, encapsulating the photosensitizer prodrug δ-aminolevulinic acid (δ-ALA), is developed. Triphenylphosphine (TPP) modification facilitates mitochondrial targeting, while tumor cell membrane (TCM) coating provides homotypic targeting. The dual-targeting δ-ALA@FMMSH-TPP-TCM demonstrate efficacy in eradicating both superficial and deep tumors through synergistic PDT/CDT. Esterase overexpression in OSCC cells triggers δ-ALA release, and excessive hydrogen peroxide in tumor mitochondria undergoes Fenton chemistry for CDT. The synergistic interaction of PDT and CDT increases cytotoxic ROS levels, intensifying oxidative stress and enhancing apoptotic mechanisms, ultimately leading to tumor cell death. PDT/CDT-induced apoptosis generates δ-ALA-containing apoptotic bodies, enhancing antitumor efficacy in deep tumor cells. The anatomical accessibility of oral cancer emphasizes the potential of intratumoral injection for precise and localized treatment delivery, ensuring focused therapeutic agent delivery to maximize efficacy while minimizing side effects. Thus, δ-ALA@FMMSH-TPP-TCM, tailored for intratumoral injection, emerges as a transformative modality in OSCC treatment.

Improving the storage quality and suppressing off-flavor generation of winter jujube by precise micro-perforated MAP.

Introduction: Traditional modified atmosphere packaging (MAP) cannot meet the preservation requirements of winter jujube, and the high respiration rate characteristics of winter jujube will produce an atmosphere component with high CO2 concentration in traditional MAP. Micro-perforated MAP is suitable for the preservation of winter jujube due to its high permeability, which can effectively remove excess CO2 and supply O2. In this study, a microporous film preservation system that can be quickly applied to winter jujube was developed, namely PMP-MAP (precise micro-perforated modified atmosphere packaging). An experiment was designed to store winter jujube in PMP-MAP at 20°C and 2°C, respectively. The quality, aroma and antioxidant capacity, etc. of winter jujube at the storage time were determined. Methods: In this study, the optimal micropore area required for microporous film packaging at different temperatures is first determined. To ensure the best perforation effect, the effects of various factors on perforation efficiency were studied. The gas composition within the package was predicted using the gas prediction equation to ensure that the gas composition of the perforated package achieved the desired target. Finally, storage experiments were designed to determine the quality index of winter jujube, including firmness, total soluble solids, titratable acid, reddening, and decay incidence. In addition, sensory evaluation, aroma and antioxidant capacity were also determined. Finally, the preservation effect of PMP-MAP for winter jujube was evaluated by combining the above indicators. Results and discussion: At the end of storage, PMP-MAP reduced the respiration rate of winter jujube, which contributed to the preservation of high total soluble solids and titratable acid levels, and delayed the reddening and decay rate of winter jujube. In addition, PMP-MAP maintained the antioxidant capacity and flavor of winter jujube while inhibiting the occurrence of alcoholic fermentation and off-flavors. This can be attributed to the effective gas exchange facilitated by PMP-MAP, thereby preventing anaerobic stress and quality degradation. Therefore, the PMP-MAP approach is an efficient method for the storage of winter jujube.

Antifungal mechanism of phenyllactic acid against Mucor investigated through proteomic analysis.

The primary inhibitory targets of phenyllactic acid (PLA, including D-PLA and L-PLA) on Mucor were investigated using Mucor racemosus LD3.0026 isolated from naturally spoiled cherry, as an indicator fungi. The results demonstrated that the minimum inhibitory concentration (MIC) of PLA against Mucor was 12.5 mmol·L-1. Results showed that the growing cells at the tip of the Mucor were not visibly deformed, and there was no damage to the cell wall following PLA treatment; however, PLA damaged the cell membrane and internal structure. The results of isobaric tags for relative and absolute quantification (iTRAQ) indicated that the Mucor mitochondrial respiratory chain may be the target of PLA, potentially inhibiting the energy supply of Mucor. These results indicate that the antifungal mechanism of PLA against mold is independent of its molecular configuration. The growth of Mucor is suppressed by PLA, which destroys the organelle structure in the mycelium and inhibits energy metabolism.

The Influence of Lactiplantibacillus plantarum and Oenococcus oeni Starters on the Volatile and Sensory Properties of Black Raspberry Wine.

Malolactic fermentation (MLF) by different lactic acid bacteria has a significantly influence on the aromatic and sensory properties of wines. In this study, four strains including two Oenococcus oeni (commercial O-Mega and native DS04) and two Lactiplantibacillus plantarum (commercial NoVA and native NV27) were tested for their performances over MLF and effects on the basic composition, volatile components and sensory property of black raspberry wine. Results of microbial growth kinetics showed Lactiplantibacillus strains had higher fermentation efficiency than Oenococcus. The volatile compounds were determined by GC-IMS; NoVA and NV27 had higher production of volatile esters, and DS04 synthesized more amounts of acetate esters and several alcohols. In terms of sensory evaluation, NV27 and DS04 showed great aroma properties due to the enhanced fruity and sweet aroma. Furthermore, PLS was used for the establishment of the relationship between volatiles and sensory odors and sensory data interpretation.

Patch-Based Separable Transformer for Visual Recognition.

The computational complexity of transformers limits it to be widely deployed onto frameworks for visual recognition. Recent work Dosovitskiy et al. 2021 significantly accelerates the network processing speed by reducing the resolution at the beginning of the network, however, it is still hard to be directly generalized onto other downstream tasks e.g.object detection and segmentation like CNN. In this paper, we present a transformer-based architecture retaining both the local and global interactions within the network, and can be transferable to other downstream tasks. The proposed architecture reforms the original full spatial self-attention into pixel-wise local attention and patch-wise global attention. Such factorization saves the computational cost while retaining the information of different granularities, which helps generate multi-scale features required by different tasks. By exploiting the factorized attention, we construct a Separable Transformer (SeT) for visual modeling. Experimental results show that SeT outperforms the previous state-of-the-art transformer-based approaches and its CNN counterparts on three major tasks including image classification, object detection and instance segmentation.1.

A human mucosal melanoma organoid platform for modeling tumor heterogeneity and exploring immunotherapy combination options.

Mucosal melanoma (MM), an aggressive rare subtype of melanoma, is distinct from cutaneous melanoma and has poor prognoses. We addressed the lack of cell models for MM by establishing 30 organoids of human oral MM (OMM), which retained major histopathological and functional features of parental tumors. Organoid groups derived from chronologically or intratumorally distinct lesions within the same individual displayed heterogeneous genetics, expression profiles, and drug responses, indicating rapid tumor evolution and poor clinical response. Furthermore, transcriptome analysis revealed receptor tyrosine kinases (RTKs) signaling, particularly NGFR, a nerve growth factor receptor, was significantly up-regulated in OMMs and organoids from patients resistant to anti-programmed cell death protein 1 (anti-PD-1) therapy. Combining anti-PD-1 with anlotinib (a phase 2 multitarget RTK inhibitor for OMM) or NGFR knockdown enhanced the effective activity of immune cells in organoid-immune cell coculture systems. Together, our study suggested that OMM organoids serve as faithful models for exploring tumor evolution and immunotherapy combination strategies.

Synergized Tricomponent All-Inorganics Solid Electrolyte for Highly Stable Solid-State Li-Ion Batteries.

Garnet-type oxide Li6.4 La3 Zr1.4 Ta0.6 O12 (LLZTO) features superior ionic conductivity and good stability toward lithium (Li) metal, but requires high-temperature sintering (≈1200 °C) that induces high fabrication cost, poor mechanical processability, and high interface resistance. Here, a novel high-performance tricomponent composite solid electrolyte (CSE) comprising LLZTO-4LiBH4 /xLi3 BN2 H8 is reported, which is prepared by ball milling the LLZTO-4LiBH4  mixture followed by hand milling with Li3 BN2 H8 . Green pellets fabricated by heating the cold-pressed CSE powders at 120 °C offer ultrafast room-temperature ionic conductivity (≈1.73 × 10-3  S cm-1  at 30 °C) and ultrahigh Li-ion transference number (≈0.9999), which enable the Li|Li symmetrical cells to cycle over 1600 h at 30 °C with only 30 mV of overpotential. Moreover, the Li|CSE|TiS2  full cells deliver 201 mAh g-1  of capacity with long cyclability. These outstanding performances are due to the low open porosity in the electrolyte pellets as well as the high intrinsic ionic conductivity and easy deformability of Li3 BN2 H8 .

A Dueling-Competent Signal-Sensing Module Guides Precise Delivery of Cargo Proteins into Target Cells by Engineered Pseudomonas aeruginosa.

To recognize and manipulate a specific microbe of a crowded community is a highly challenging task in synthetic biology. Here we introduce a highly selective protein delivery platform, termed DUEC, which responds to direct contact of attacking cells by engineering the tit-for-tat/dueling response of H1-T6SS (type VI secretion system) in Pseudomonas aeruginosa. Using a Cre-recombinase-dependent reporter, we screened H1-T6SS-secreted substrates and developed Tse6N as the most effective secretion tag for Cre delivery. DUEC cells can discriminately deliver the Tse6N-Cre cargo into the cytosol of T6SS+ but not T6SS- Vibrio cholerae cells. DUEC could also deliver a nuclease cargo, Tse6N-NucSe1, to selectively kill provoking cells in a mixed community. These data demonstrate that the DUEC cell not only is a prototypical physical-contact sensor and delivery platform but also may be coupled with recombination-based circuits with the potential for complex tasks in mixed microbial communities.