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Abstract Plasma protein‐induced aggregation of nanoparticles (NPs) is a crucial issue in many applications, such as drug delivery. Although great efforts have been made to investigate the protein adsorption kinetics or protein‐induced NPs coalescence in bulk solutions, limited evidence has been uncovered for interfacial circumstances. Diet, disease, medicine, or senility could thoroughly change interfacial physicochemical properties of the inner lining of blood vessels. Implants including stents and artificial heart valves also have varied and evolutionary interfaces. Hence, there is an urgent need to understand the mechanism behind the non‐specific protein adsorption and NP‐protein aggregation in such interfacial cases. Here, we use evanescent light scattering to observe polystyrene NPs‒fibrinogen aggregation at substrates with varying surface properties. A density‐fluctuation correlation function is utilized to reveal the relaxation dynamics of the aggregates. Both time‐resolved and spatial‐correlated evidence shows that the aging process of such soft materials is out‐of‐equilibrium, where the dynamics faster and slower than exponential can coexist in one single relaxation process. Besides, corona formation, inner stress, and interconnection together determine the microstructure, local adhesion, and structural relaxation of the aggregates, which can further correspond to the protein‐to‐NP ratio as well as the surface chemistry of NPs and substrates.

IntroductionUniversity-school (U–S) collaboration has proven to be an effective approach for teacher professional development, but it could be hampered by the lack of shared objects. To understand how shared objects are formed in U–S collaboration, this research established a university-school collaborated Change Laboratory in W primary school based on cultural-historical activity theory, which is under the background of Chinese teaching research activity.MethodsRecordings of meetings throughout the year were transcribed into texts and coded, and then analyzed via the method of grounded theory and contradiction analysis.ResultsThe findings reveal that, in comparison to previous studies regarding shared object formation process, this study identified an special phase named “experimental object,” which highlights the significance of experimentation in U–S collaboration. Also, multiple contradictions are recognized as the driving force for shared object formation which would gradually transform into fundamental conflicts between tools. The main contradictions identified include those between scientific and daily concepts, university culture and school culture, as well as new experiment and old routine.DiscussionThe current study implicates that U–S collaboration is an expansive learning process to acquire unknown knowledge, which necessitates both parties engaging in exploration and experimentation together. Furthermore, shared object formation within U–S collaboration requires participants to focus on developing teaching tools while consciously undergoing changes in aspects such as logic of thinking, culture and routine.

Tylophorine has diverse biological activities; however, the stability, solubility, and central nervous system toxicity have severely limited use of tylophorine. The gem -dimethyl group is an organic chemistry functional group that consists of two methyl groups bonded to the same carbon atom. This feature has gained significant attention in medicinal chemistry due to its unique properties and potential applications in drug design. We applied a new photoredox methodology to tylophorine modification, resulting in a series of gem-dimethyl tylophorine analogues. Among the analogues, compound 4b demonstrated promising activity against a wide range of tumor cell lines and exhibited significantly improved drug-like properties, including enhanced solubility and stability. Compound 4b showed an exceptional inhibitory effect (7.8 nM) against a C481S mutation-induced ibrutinib-resistant non-Hodgkin’s lymphoma cell line, as well as primary tumor cell lines obtained from patients. Importantly, compound 4b exhibited significantly reduced anti-proliferative activity against the normal cell line tested, indicating the potential for an enhanced therapeutic window for compound 4b . Based on these early-stage data, we believe that our study provides a solid foundation for the development of new therapeutic agents for potential drug-resistant cancer treatment in the near future.

Abstract Background Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. This study investigates the therapeutic potential of human Vγ9Vδ2 T cells in GBM treatment. The sensitivity of different glioma specimens to Vγ9Vδ2 T cell-mediated cytotoxicity is assessed using a patient-derived tumor cell clusters (PTCs) model. Methods The study evaluates the anti-tumor effect of Vγ9Vδ2 T cells in 26 glioma cases through the PTCs model. Protein expression of BTN2A1 and BTN3A1, along with gene expression related to lipid metabolism and glioma inflammatory response pathways, is analyzed in matched tumor tissue samples. Additionally, the study explores two strategies to re-sensitize tumors in the weak anti-tumor effect (WAT) group: utilizing a BTN3A1 agonistic antibody or employing bisphosphonates to inhibit farnesyl diphosphate synthase (FPPS). Furthermore, the study investigates the efficacy of genetically engineered Vγ9Vδ2 T cells expressing Car-B7H3 in targeting diverse GBM specimens. Results The results demonstrate that Vγ9Vδ2 T cells display a stronger anti-tumor effect (SAT) in six glioma cases, while showing a weaker effect (WAT) in twenty cases. The SAT group exhibits elevated protein expression of BTN2A1 and BTN3A1, accompanied by differential gene expression related to lipid metabolism and glioma inflammatory response pathways. Importantly, the study reveals that the WAT group GBM can enhance Vγ9Vδ2 T cell-mediated killing sensitivity by incorporating either a BTN3A1 agonistic antibody or bisphosphonates. Both approaches support TCR-BTN mediated tumor recognition, which is distinct from the conventional MHC-peptide recognition by αβ T cells. Furthermore, the study explores an alternative strategy by genetically engineering Vγ9Vδ2 T cells with Car-B7H3, and both non-engineered and Car-B7H3 Vγ9Vδ2 T cells demonstrate promising efficacy in vivo, underscoring the versatile potential of Vγ9Vδ2 T cells for GBM treatment. Conclusions Vγ9Vδ2 T cells demonstrate a robust anti-tumor effect in some glioma cases, while weaker in others. Elevated BTN2A1 and BTN3A1 expression correlates with improved response. WAT group tumors can be sensitized using a BTN3A1 agonistic antibody or bisphosphonates. Genetically engineered Vγ9Vδ2 T cells, i.e., Car-B7H3, show promising efficacy. These results together highlight the versatility of Vγ9Vδ2 T cells for GBM treatment.

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has elicited a worldwide pandemic since late 2019. There has been ~675 million confirmed coronavirus disease 2019 (COVID-19) cases, leading to more than 6.8 million deaths as of March 1, 2023. Five SARS-CoV-2 variants of concern (VOCs) were tracked as they emerged and were subsequently characterized. However, it is still difficult to predict the next dominant variant due to the rapid evolution of its spike (S) glycoprotein, which affects the binding activity between cellular receptor angiotensin-converting enzyme 2 (ACE2) and blocks the presenting epitope from humoral monoclonal antibody (mAb) recognition. Here, we established a robust mammalian cell-surface-display platform to study the interactions of S-ACE2 and S-mAb on a large scale. A lentivirus library of S variants was generated via in silico chip synthesis followed by site-directed saturation mutagenesis, after which the enriched candidates were acquired through single-cell fluorescence sorting and analyzed by third-generation DNA sequencing technologies. The mutational landscape provides a blueprint for understanding the key residues of the S protein binding affinity to ACE2 and mAb evasion. It was found that S205F, Y453F, Q493A, Q493M, Q498H, Q498Y, N501F, and N501T showed a 3–12-fold increase in infectivity, of which Y453F, Q493A, and Q498Y exhibited at least a 10-fold resistance to mAbs REGN10933, LY-CoV555, and REGN10987, respectively. These methods for mammalian cells may assist in the precise control of SARS-CoV-2 in the future.

The recent global pandemic was a spillover from the SARS-CoV-2 virus. Viral entry involves the receptor binding domain (RBD) of the viral spike protein interacting with the protease domain (PD) of the cellular receptor, ACE2. We hereby present a comprehensive mutational landscape of the effects of ACE2-PD point mutations on RBD-ACE2 binding using a saturation mutagenesis approach based on microarray-based oligo synthesis and a single-cell screening assay. We observed that changes in glycosylation sites and directly interacting sites of ACE2-PD significantly influenced ACE2-RBD binding. We further engineered an ACE2 decoy receptor with critical point mutations, D30I, L79W, T92N, N322V, and K475F, named C4-1. C4-1 shows a 200-fold increase in neutralization for the SARS-CoV-2 D614G pseudotyped virus compared to wild-type soluble ACE2 and a sevenfold increase in binding affinity to wild-type spike compared to the C-terminal Ig-Fc fused wild-type soluble ACE2. Moreover, C4-1 efficiently neutralized prevalent variants, especially the omicron variant (EC[Formula: see text] ng/mL), and rescued monoclonal antibodies, vaccine, and convalescent sera neutralization from viral immune-escaping. We hope to next investigate translating the therapeutic potential of C4-1 for the treatment of SARS-CoV-2.

Summary: Enhancing chemosensitivity is one of the largest unmet medical needs in cancer therapy. Cyclic GMP-AMP synthase (cGAS) connects genome instability caused by platinum-based chemotherapeutics to type I interferon (IFN) response. Here, by using a high-throughput small-molecule microarray-based screening of cGAS interacting compounds, we identify brivanib, known as a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor, as a cGAS modulator. Brivanib markedly enhances cGAS-mediated type I IFN response in tumor cells treated with platinum. Mechanistically, brivanib directly targets cGAS and enhances its DNA binding affinity. Importantly, brivanib synergizes with cisplatin in tumor control by boosting CD8+ T cell response in a tumor-intrinsic cGAS-dependent manner, which is further validated by a patient-derived tumor-like cell clusters model. Taken together, our findings identify cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment.

Najafian et al. introduce a developmental theory of map formation in the cerebral cortex. The theory proposes that increases in the density of thalamic afferents sampling sensory space make cortical maps to segregate more stimulus dimensions.

As new mutations continue to emerge, the ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus to evade the human immune system and neutralizing antibodies remains a huge challenge for vaccine development and antibody research. The majority of neutralizing antibodies have reduced or lost activity against SARS-CoV-2 variants. In this study, we reported a novel protein surface display system on a mammalian cell for obtaining a higher-affinity antibody in high-throughput manner. Using a saturation mutagenesis strategy through integrating microarray-based oligonucleotide synthesis and single-cell screening assay, we generated a group of new antibodies against diverse prevalent SARS-CoV-2 variants through high-throughput screening the human antibody REGN10987 within 2 weeks. The affinity of those optimized antibodies to seven prevalent mutants was greatly improved, and the EC50 values were no higher than 5 ng/mL. These results demonstrate the robustness of our screening system in the rapid generation of an antibody with higher affinity against a new SARS-CoV-2 variant, and provides a potential application to other protein molecular interactions.

Fiber materials have advantages such as light weight and high strength, corrosion resistance, fatigue resistance, and easy processing and production, and they are widely applied in the repair and renovation of concrete structures. To promote the construction convenience of fiber materials, fiber raw yarn is continuously braided to form fiber-belt-bars. Based on the existing research, the performance of bonding between fiber-belt-bars and a concrete interface was investigated, and pull-out tests were performed to systematically investigate the effects of the fiber-belt-bar cross-sectional size, anchorage length, concrete strength, and fiber type on the bonding performance. The experimental results show that the bond strength reduces with an increase in the anchorage length, increase in cross-sectional size, and decrease in concrete strength, and the effect of fiber type on the bond strength is not obvious. On this basis, a formula for calculating the average bond strength of fiber-belt-bars is proposed. Experiments and calculations determined that the average bond strength between fiber-belt-bar and concrete with a cross-sectional size of 12 mm × 3 mm is 10–30% higher than that with a cross-sectional size of 20 mm × 3 mm for the same anchorage length. Finally, the minimum anchorage length of the fiber-belt-bar is proposed to provide a valuable reference for the use of fiber-belt-bar in concrete projects.

Gravitational decollement is a structural pattern commonly developed in passive continental marginal basins on both sides of the Atlantic Ocean.Two different types of gravity decollement structures with transitional salt and marine mudstone as decollement layers are developed.Based on the stress mechanism, it can be divided into extensional zone, transitional zone and compressional zone successively from the continent to the ocean.In order to clarify the difference between those two types of gravitational decollement structures and their influence on oil and gas accumulation, this paper makes a comparative analysis of two representative basins, the Lower Congo-Congo Fan Basin and the Niger Delta Basin.Through comparing, the differences of structure patterns, sedimentary reservoir distribution characteristics and hydrocarbon accumulation were clarified in the same zone.On the whole, salt gravitational decollement in extensional zone shows that the salt structures are highly active, the oil-gas accumulation conditions are superior, and there are many oil-gas discoveries in this zone.In transitional zone, the intensity of salt activity is moderate and the degree of oil-gas enrichment is the highest.In compressional zone, the salt activity is strong with a large scale salt accumulation, poor source rock and reservoir, and rare oil-gas discoveries.The extensional zone of marine mudstone gravitational decollement is the main oil-gas accumulation area with relatively weak structure activity and good match between the reservoir and source rock.In transitional zone, it has strong extrusion stress, and large amount of mudstone has been accumulated there.The mud diapir is magnificent, and deep-slow diapir structure is the favorable oil-gas accumulation area.The compressional zone is dominated by typical thrust imbricate structure with good match of source rock, reservoir and oil source faults.The oil-gas enrichment in this zone is relatively high.Based on the analysis of those two types of gravitational decollement in source rock, reservoir and hydrocarbon accumulation, this paper have provided some references for the research related to gravitational decollement.

Rotary ultrasonic machining (RUM) has been proven to be a suitable technology for micro-nano precision manufacturing for hard and brittle ceramics/composite materials. However, the working frequency of the ultrasonic transducer in current RUM is in range from 20 kHz to 30 kHz. Moreover, the tool is tightened by an elastic chuck, which is in low clamping precision, high radial run-out, and unstable ultrasonic energy transmission. In this paper, we developed a novel heat shrinkable RUM ultrasonic transducer with 60 kHz frequency by equivalent circuit and finite element method (FEM). An analytical electromechanical equivalent circuit model was deduced to obtain the initial structure dimensions of the ultrasonic transducer. Three flange mounting structures were proposed to optimize and improve the energy transmission at the working resonant frequency. The influence of the proposed flanges on the resonant frequency of three transducers was analyzed and presented. The designed transducers were manufactured and tested in experiment. It shows that resonant frequencies of these three transducers with step, circular, and plate flange are 62.2 kHz, 61.46 kHz, and 61.4 kHz, and vibration amplitudes in 90 V driving voltage are $1.33\mu \text{m}$ , $4.74\mu \text{m}$ , $5.33\mu \text{m}$ , respectively. The working resonant frequencies by experimental measurement are consistent with the calculation result of the equivalent circuit and FEM. Moreover, the plate flange transducer shows the optimal amplitude capability with enough ultrasonic energy in micro-nano precision manufacturing.

Abstract Background CRISPR/Cas9 systems have been repurposed as canonical genome editing tools in a variety of species, but no application for the model strain Rhodobacter sphaeroides 2.4.1 was unveiled. Results Here we showed two kinds of programmable base editing systems, cytosine base editors (CBEs) and adenine base editors (ABEs), generated by fusing endonuclease Cas9 variant to cytosine deaminase PmCDA1 or heterodimer adenine deaminase TadA–TadA*, respectively. Using CBEs, we were able to obtain C-to-T mutation of single and double targets following the first induction step, with the efficiency of up to 97% and 43%; while the second induction step was needed in the case of triple target, with the screening rate of 47%. Using ABEs, we were only able to gain A-to-G mutation of single target after the second induction step, with the screening rate of 30%. Additionally, we performed a knockout analysis to identify the genes responsible for coenzyme Q10 biosynthesis and found that ubiF, ubiA, ubiG, and ubiX to be the most crucial ones. Conclusions Together, CBEs and ABEs serve as alternative methods for genetic manipulation in Rhodobacter sphaeroides and will shed light on the fundamental research of other bacteria that are hard to be directly edited by Cas9-sgRNA.

Summary: It is still a challenge for synthesizing ‘cellular niche-mimics’ in vitro with satisfactory reproducibility and fidelity to recreate the natural niche components (e.g., extracellular matrices and soluble factors) for stem cell cultivation. Inspired by the massive amplification of hepatic progenitor cells during liver fibrosis in vivo, here we optimized the in vitro liver fibrotic niches and subsequently harvested their bioactive ingredients as niche extracts (NEs). The fibrosis-relevant NE marginally outperformed Matrigel for phenotype maintenance of human embryonic stem cell (hESC)-derived hepatoblasts (HBs) and recapitulation of the pathological angiogenesis of hESC-derived endothelial cells both in 2D culture and 3D liver organoids. Finally, defined NE components (i.e., collagen III, IV, IL-17, IL-18 and M-CSF) were resolved by the quantitative proteomics which exhibited advantage over Matrigel for multi-passaged HB expansion. The pathology-relevant and tissue-specific NEs provide innovative and generalizable strategies for the discovery of optimal cellular niche and bioactive niche compositions.

This paper considers that the history of Chinese civilization is the historical foundation for the nationally protected areas and features the protected areas of China. After 1950, the formation, development and evolution of various protected areas conformed to the fundamental law of development of Chinese civilization. The protected areas are divided into three categories, namely the natural protected areas, cultural protected areas and comprehensive protected areas for the nature and culture. The natural protected areas are composed mainly of the national parks; the cultural protected areas are composed mainly of the Major Historical and Cultural Sites Protected at the National Level; and the comprehensive protected areas are composed mainly of National-level Scenic and Historic Interest Areas. In the new era of building an ecological civilization, it is crucial to develop a national protected area system including the aforementioned three protection systems in accordance with the unified deployment of the Central government. Three protection systems are supposed to cover various protected areas in China and develop a system of nationally protected areas with Chinese characteristics. Keywords: National park, Protected area, Nature, Culture, Nature and culture, System

Abstract Background To investigate the clinical efficacy of minimally invasive direct lateral approach debridement, interbody bone grafting, and interbody fusion in the treatment of the thoracic and lumbar spinal tuberculosis. Methods From January 2013 to January 2016, 35 cases with thoracic and lumbar spinal tuberculosis received direct lateral approach debridement, interbody bone grafting, and interbody fusion. Of the 35 cases, 16 patients were male and 19 were female and the median age was 55.2 (range 25–83). The affected segments were single interspace, and the involved vertebral bodies included: 15 cases of thoracic vertebrae (1 cases of T5/6, 2 cases of T6/7, 4 cases of T7/8, 3 cases of T8/9, 5 cases of T9/10) and 20 cases of lumbar spine (2 cases of L1/2, 6 cases of L2/3, 6 cases of L3/4, 6 cases of L4/5). After MIDLIF operation, all the patients received medication of four anti-tubercular drugs for 12 to18 months. Results The patients were followed up for 7 to 40 months with an average of 18.5 months. The visual analogue scale (VAS) at the last follow-up was 2.8 ± 0.5, which was significantly different from the preoperative VAS (8.2 ± 0.7). After MIDLIF, there was 5 cases occurred with transient numbness in one side of the thigh or inguinal region, and 10 cases suffered from flexion hip weakness. All the bone grafts were fused within 6~ 18 months (average of 11.5 months) after the operation. Conclusion Minimally invasive lateral approach interbody fusion technology have the advantage of less injury and quick recovery after surgery, which is the effective and safe treatment for thoracic and lumbar spinal tuberculosis.

In this paper, we report an effective ultrasound method for the synthesis of Pd/H-MOR, which was used as a catalyst in the Suzuki-Miyaura coupling of aryl halides with phenylboronic acid. The structure and morphology of the as-prepared catalysts were fully characterized by X-ray diffraction (XRD), N2 sorption isotherms, scanning electron microscopy (SEM), and an inductively coupled plasma-atomic emission spectrometer (ICP-AES). The advantages of Pd/H-MOR in the coupling reaction are green solvents, high yields, absence of ligands, and recyclability. The catalysts were easily reused at least ten times without significant deterioration in catalytic activity. In addition, this protocol was used in the marketed anti-tumor drug crizotinib synthesis.

Abstract As the downscaling of electronic devices continues, the problems of leakage currents and heat dissipation become more and more serious. To address these issues, new materials and new structures are explored. Here, we propose an interesting heterostructure made of ultrathin SnO layers on Si(001) surface. Our first-principle calculations show that a single layer of SnO on Si(001) surface is a semiconductor, but a bilayer SnO on the same surface is metallic. This metal-semiconductor dichotomy allows construction of single-2D-material-based electronic devices with low contact resistance and low leakage currents. In particular, due to the interaction between Sn and the Si substrate, the semiconducting monolayer-SnO/Si(001) has a highly anisotropic band structure with a much lighter hole effective mass along one direction than that of Si and most other 2D materials, indicating a high carrier mobility. Furthermore, by combining density functional theory and nonequilibrium Green’s function method, we directly investigate the transport characteristics of a field effect transistor based on the proposed heterostructures, which shows very low contact resistance, negligible leakage current, and easy gate control at a compact channel length.

Abstract Pressure-induced polyamorphism in Ce-based metallic glass has attracted significant interest in condensed matter physics. In this paper, we discover that in association with the polyamorphism of La32Ce32Al16Ni5Cu15 bulk metallic glass, the acoustic velocities, measured up to 12.3 GPa using ultrasonic interferometry, exhibit velocity minima at 1.8 GPa for P wave and 3.2 GPa for S wave. The low and high density amorphous states are distinguished by their distinct pressure derivatives of the bulk and shear moduli. The elasticity, permanent densification, and polyamorphic transition are interpreted by the topological rearrangement of solute-centered clusters in medium-range order (MRO) mediated by the 4f electron delocalization of Ce under pressure. The precisely measured acoustic wave travel times which were used to derive the velocities and densities provided unprecedented data to document the evolution of the bulk and shear elastic moduli associated with a polyamorphic transition in La32Ce32Al16Ni5Cu15 bulk metallic glass and can shed new light on the mechanisms of polyamorphism and structural evolution in metallic glasses under pressure.

Summary: Visual information is processed in the cortex by ON and OFF pathways that respond to light and dark stimuli. Responses to darks are stronger, faster, and driven by a larger number of cortical neurons than responses to lights. Here, we demonstrate that these light-dark cortical asymmetries reflect a functional specialization of ON and OFF pathways for different stimulus properties. We show that large long-lasting stimuli drive stronger cortical responses when they are light, whereas small fast stimuli drive stronger cortical responses when they are dark. Moreover, we show that these light-dark asymmetries are preserved under a wide variety of luminance conditions that range from photopic to low mesopic light. Our results suggest that ON and OFF pathways extract different spatiotemporal information from visual scenes, making OFF local-fast signals better suited to maximize visual acuity and ON global-slow signals better suited to guide the eye movements needed for retinal image stabilization. : Mazade et al. find pronounced differences in the stimulus preferences of cortical pathways signaling lights (ON) and darks (OFF) in visual scenes. ON-preferred stimuli are large and steady, while OFF are small and brief. These results suggest an ON/OFF pathway specialization in global-slow and local-fast vision. Keywords: visual cortex, area V1, receptive field, thalamus, retina, LGN, thalamocortical, luminance, adaptation, image stabilization

Stimulus orientation in the primary visual cortex of primates and carnivores is mapped into a geometrical mosaic but the functional implications of these maps remain debated. Here the authors reveal an association between the structure of cortical orientation maps in cats, and the functions of local cortical circuits in processing patterns and contours.

MiR-122 levels correlate with metastasis in human liver cancer but not in mouse models. Here the authors show that miR-122 targets TGFßR1 in mice but TGFß1 in humans, that swapping this specificity affects metastasis, and that many other receptor-ligand pairs are differentially targeted by miRNAs across species.

Homologous recombination (HR) is often used to achieve targeted gene integration because of its higher precision and operability compared with microhomology-mediated end-joining (MMEJ) or non-homologous end-joining (NHEJ). It appears to be inefficient for gene integration in animal cells and embryos due to occurring only during cell division. Here we developed genome-wide high-throughput screening and a subsequently paired crRNA library screening to search for genes suppressing homology-directed repair (HDR). We found that, in the reporter system, HDR cells with knockdown of SHROOM1 were enriched as much as 4.7-fold than those with control. Down regulating SHROOM1 significantly promoted gene integration in human and mouse cells after cleavage by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9), regardless of the donor types. The knock-in efficiency of mouse embryos could also be doubled by the application of SHROOM1 siRNA during micro-injection. The increased HDR efficiency of SHROOM1 deletion in HEK293T cells could be counteracted by YU238259, an HDR inhibitor, but not by an NHEJ inhibitor. These results indicated that SHROOM1 was an HDR-suppressed gene and that the SHROOM1 knockdown strategy may be useful for a variety of applications, including gene editing to generate cell lines and animal models for studying gene function and human diseases.

The low frequency magnetic field detection ability of magnetoresistive (MR)sensor is seriously affected by 1/f noise. At present, the method to suppress the influence of low frequency noise is mainly to modulate the measured magnetic field by mechanical resonance. In this paper, a novel modulation concept employing a magnetoelectric coupling effect is proposed. A design method of modulation structure based on an equivalent magnetic circuit model (EMCM) and a single domain model of in-plane moment was established. An EMCM was established to examine the relationship between the permeability of flux modulation film (FMF) and modulation efficiency, which was further verified through a finite element simulation model (FESM). Then, the permeability modulated by the voltage of a ferroelectric/ferromagnetic (FE/FM) multiferroic heterostructure was theoretically studied. Combining these studies, the modulation structure and the material were further optimized, and a FeSiBPC/PMN-PT sample was prepared. Experimental results show that the actual magnetic susceptibility modulation ability of FeSiBPC/PMN-PT reached 150 times, and is in good agreement with the theoretical prediction. A theoretical modulation efficiency higher than 73% driven by a voltage of 10 V in FeSiBPC/PMN-PT can be obtained. These studies show a new concept for magnetoelectric coupling application, and establish a new method for magnetic field modulation with a multiferroic heterostructure.

In this report, novel glycosylpyridyl-triazole@nickel nanoparticles (GPT-Ni) were successfully prepared via click chemistry and were fully characterized by various spectroscopy measurements. The as-prepared catalysts could be used as a recyclable catalyst for the catalytic acylation of amines by employing N,N-dimethylacetamide (DMA), N,N-dimethylpropionamide (DMP), and N,N-dimethylformamide (DMF) as acylation reagents in water, providing the corresponding amides in good yields. The practicability of this methodology is highlighted by the good recyclability of the catalyst. A unique mechanism was proposed for the catalytic process.

The transcription activator-like (TAL) effector targets specific host promoter through its central DNA-binding domain, which comprises multiple tandem repeats (TALE repeats). Recent structural analyses revealed that the TALE repeats form a superhelical structure that tracks along the forward strand of the DNA duplex. Here, we demonstrate that TALE repeats specifically recognize a DNA-RNA hybrid where the DNA strand determines the binding specificity. The crystal structure of a designed TALE in complex with the DNA-RNA hybrid was determined at a resolution of 2.5 Å. Although TALE repeats are in direct contact with only the DNA strand, the phosphodiester backbone of the RNA strand is inaccessible by macromolecules such as RNases. Consistent with this observation, sequence-specific recognition of an HIV-derived DNA-RNA hybrid by an engineered TALE efficiently blocked RNase H-mediated degradation of the RNA strand. Our study broadens the utility of TALE repeats and suggests potential applications in processes involving DNA replication and retroviral infections.

Novel magnetically recyclable Fe3O4@Pd nanoparticles (NPs) were favorably synthesized by fixing palladium on the surface of nitrogen-doped magnetic nanocomposites. These catalysts were fully characterized by Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), transmission electron microscopy (TEM), thermogravimetric analysis (TG), and X-ray photoelectron spectroscopy (XPS). The prepared catalyst exhibited good catalytic activity for Suzuki–Miyaura coupling reactions of aryl or heteroaryl halides (I, Br, Cl) with arylboronic acids. These as-prepared catalysts could be readily isolated from the reaction liquid by an external magnet and reused at least ten times with excellent yields achieved. In addition, using this protocol, the marketed drug crizotinib (anti-tumor) could be easily synthesized.

The coastline of China is approximately 18,000 km long. In most coastal cities, seawater intrusion is a serious threat to groundwater resources. Nine shallow monitoring wells were constructed to study the dynamics of shallow groundwater level and salinity in the coastal plain region of Jiangsu province, China. Results showed that precipitation, evaporation, and river stage affected the groundwater level in our study area. Positive correlations were observed among the groundwater level, precipitation, and river stage; then negative correlation existed between the groundwater level and evaporation. The influencing factors on the groundwater level were in the order precipitation > river stage > evaporation. Sufficient precipitation during the wet season diluted the groundwater salinity. After the dilution, between two continuous precipitation events, the groundwater salinity increased as the groundwater level decreased. During the dry season, the groundwater salinity rapidly increased and reached its peak in December. The groundwater salinity in December was 23 times higher than that in July. The groundwater level and salinity in this study were generally associated with the season. Climate factors led to fluctuation of groundwater levels and salinity during the wet season, and seawater intrusion increased the groundwater salinity during the dry season.

In a wide range of studies, the emergence of orientation selectivity in primary visual cortex has been attributed to a complex interaction between feed-forward thalamic input and inhibitory mechanisms at the level of cortex. Although it is well known that layer 4 cortical neurons are highly sensitive to the timing of thalamic inputs, the role of the stimulus-driven timing of thalamic inputs in cortical orientation selectivity is not well understood. Here we show that the synchronization of thalamic firing contributes directly to the orientation tuned responses of primary visual cortex in a way that optimizes the stimulus information per cortical spike. From the recorded responses of geniculate X-cells in the anesthetized cat, we synthesized thalamic sub-populations that would likely serve as the synaptic input to a common layer 4 cortical neuron based on anatomical constraints. We used this synchronized input as the driving input to an integrate-and-fire model of cortical responses and demonstrated that the tuning properties match closely to those measured in primary visual cortex. By modulating the overall level of synchronization at the preferred orientation, we show that efficiency of information transmission in the cortex is maximized for levels of synchronization which match those reported in thalamic recordings in response to naturalistic stimuli, a property which is relatively invariant to the orientation tuning width. These findings indicate evidence for a more prominent role of the feed-forward thalamic input in cortical feature selectivity based on thalamic synchronization.

The chemically-synthesized siRNA duplex has become a powerful and widely used tool for RNAi loss-of-function studies, but suffers from a high off-target effect problem. Recently, endoribonulease-prepared siRNA (esiRNA) has been shown to be an attractive alternative due to its lower off-target effect and cost effectiveness. However, the current manufacturing method for esiRNA is complicated, mainly in regards to purification and normalization on a large-scale level. In this study, we present a magnetic bead-integrated chip that can immobilize amplification or transcription products on beads and accomplish transcription, digestion, normalization and purification in a robust and convenient manner. This chip is equipped to manufacture ready-to-use esiRNAs on a large-scale level. Silencing specificity and efficiency of these esiRNAs were validated at the transcriptional, translational and functional levels. Manufacture of several normalized esiRNAs in a single well, including those silencing PARP1 and BRCA1, was successfully achieved, and the esiRNAs were subsequently utilized to effectively investigate their synergistic effect on cell viability. A small esiRNA library targeting 68 tyrosine kinase genes was constructed for a loss-of-function study, and four genes were identified in regulating the migration capability of Hela cells. We believe that this approach provides a more robust and cost-effective choice for manufacturing esiRNAs than current approaches, and therefore these heterogeneous RNA strands may have utility in most intensive and extensive applications.

The timing of spiking activity across neurons is a fundamental aspect of the neural population code. Individual neurons in the retina, thalamus, and cortex can have very precise and repeatable responses but exhibit degraded temporal precision in response to suboptimal stimuli. To investigate the functional implications for neural populations in natural conditions, we recorded in vivo the simultaneous responses, to movies of natural scenes, of multiple thalamic neurons likely converging to a common neuronal target in primary visual cortex. We show that the response of individual neurons is less precise at lower contrast, but that spike timing precision across neurons is relatively insensitive to global changes in visual contrast. Overall, spike timing precision within and across cells is on the order of 10 ms. Since closely timed spikes are more efficient in inducing a spike in downstream cortical neurons, and since fine temporal precision is necessary to represent the more slowly varying natural environment, we argue that preserving relative spike timing at a approximately 10-ms resolution is a crucial property of the neural code entering cortex.

In the lateral geniculate nucleus (LGN) of the thalamus, visual stimulation produces two distinct types of responses known as tonic and burst. Due to the dynamics of the T-type Ca(2+) channels involved in burst generation, the type of response evoked by a particular stimulus depends on the resting membrane potential, which is controlled by a network of modulatory connections from other brain areas. In this study, we use simulated responses to natural scene movies to describe how modulatory and stimulus-driven changes in LGN membrane potential interact to determine the luminance sequences that trigger burst responses. We find that at low resting potentials, when the T channels are de-inactivated and bursts are relatively frequent, an excitatory stimulus transient alone is sufficient to evoke a burst. However, to evoke a burst at high resting potentials, when the T channels are inactivated and bursts are relatively rare, prolonged inhibitory stimulation followed by an excitatory transient is required. We also observe evidence of these effects in vivo, where analysis of experimental recordings demonstrates that the luminance sequences that trigger bursts can vary dramatically with the overall burst percentage of the response. To characterize the functional consequences of the effects of resting potential on burst generation, we simulate LGN responses to different luminance sequences at a range of resting potentials with and without a mechanism for generating bursts. Using analysis based on signal detection theory, we show that bursts enhance detection of specific luminance sequences, ranging from the onset of excitatory sequences at low resting potentials to the offset of inhibitory sequences at high resting potentials. These results suggest a dynamic role for burst responses during visual processing that may change according to behavioral state.

Protein phosphorylation, a widely occurring and significant post-translational modification, is integral to various biological processes. We previously utilized a protein affinity probe to identify genes damaged by cisplatin, revealing that it inflicts substantial damage on protein kinase and protein phosphatase genes. In this study, we investigated cisplatin-induced alterations in the global proteome and phosphoproteome of A549 cells. Employing Fe-IMAC beads and tyrosine phosphorylation enrichment antibodies, we identified 6944 protein groups and 18,274 phosphorylation sites on 4915 proteins across three biological replicates of both cisplatin-treated A549 cells and control cells. Among these, 730 tyrosine phosphorylation sites were identified-marking the most substantial discovery of such sites in A549 cells following cisplatin treatment. Bioinformatics analysis indicated that the proteins exhibiting significant phosphorylation level changes predominantly involved in RNA processing, modification, transcription, translation, and the spliceosome. This suggests that cisplatin-induced damage to protein kinases and phosphatases may disrupt the normal function of these proteins, consequently impairing DNA replication, RNA translation, and shearing, ultimately culminating in tumor cell death. Moreover, we cross-referenced our proteomic data with our previously obtained cisplatin-damaged genes, observing that the majority of down-regulated proteins derived from cisplatin-induced gene damage. The data are available on ProteomeXchange under the identifier PXD053902., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Fulminant viral hepatitis (FH) represents a significant clinical challenge, with its pathogenesis not yet fully elucidated. Heat shock protein (HSP)70, a molecular chaperone protein with a broad range of cytoprotective functions, is upregulated in response to stress. However, the role of HSP70 in FH remains to be investigated. Notably, HSP70 expression is upregulated in the livers of coronavirus-infected mice and patients. Therefore, we investigated the mechanistic role of HSP70 in coronavirus-associated FH pathogenesis. FH was induced in HSP70-deficient (HSP70 KO) mice or in WT mice treated with the HSP70 inhibitor VER155008 when infected with the mouse hepatitis virus strain A59 (MHV-A59). MHV-A59-infected HSP70 KO mice exhibited significantly reduced liver damage and mortality. This effect was attributed to decreased infiltration of monocyte-macrophages and neutrophils in the liver of HSP70 KO mice, resulting in lower levels of inflammatory cytokines such as IL-1β, TNFα, and IL-6, and a reduced viral load. Moreover, treatment with the HSP70 inhibitor VER155008 protected mice from MHV-A59-induced liver damage and FH mortality. In summary, HSP70 promotes coronavirus-induced FH pathogenesis by enhancing the infiltration of monocyte-macrophages and neutrophils and promoting the secretion of inflammatory cytokines. Therefore, HSP70 is a potential therapeutic target in viral FH intervention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Curcumin, a bioactive compound, showed versatile in anti-inflammatory and anti-cancer ability, while their biological fate in elderly is unclear. In this study, curcumin-loaded nanoparticles based on octyl succinate hydrate (OSA) starch and sodium caseinate were prepared and the in vitro elderly digestion and absorption fate was investigated. The loading capacity of curcumin-loaded nanoparticles prepared from OSA starch (HI), sodium caseinate (SC) and OSA starch‑sodium caseinate (HS) were all higher than 15%. Curcumin release behavior of the three nanoparticles during in vitro digestion conformed to first-order kinetics. Meanwhile, the transport efficiency of curcumin for HI, SC, and HS increased significantly than the free curcumin (near 1-fold), and the permeability were 1.9, 2.0, and 2.0 times, respectively. The gene expressions of TNF-α, SREBP2 and NPC1L1 in the organoids were enhanced than control group. This study provided scientific reference and guidance for encapsulation of curcumin and digestion and absorption properties in elderly., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Photosensitizers (PSs) with effective two-photon absorption in the therapeutic window are the key to two-photon photodynamic therapy. However, the traditional exogenous PSs usually lead to rejection in the body. Besides, the precise visualization of treatments proposes new demands and challenges for the design of PSs. Accordingly, in this work, a series of quasi-intrinsic PSs are obtained based on the artificial base 2-amino-8-(1'-β-d-2'-deoxyribofuranosyl)-imidazo[1,2-α]-1,3,5-triazin-4(8 H )-one (P). The calculations show that the structural modification could enhance the two-photon absorption and fluorescence emission, which is beneficial for tumor localization. Furthermore, the reduced singlet-triplet energy gaps and enhanced spin-orbit coupling contribute to the rapid intersystem crossing process, which results in a triplet state with high quantum yields. To ensure the phototherapeutic performance of the newly designed PSs, we also examined the vertical electron affinity and vertical ionization potential for generation of superoxide anions, as well as the T 1 energy required to produce singlet oxygen.

Background: Renal denervation (RDN) can lower blood pressure (BP) in patients with hypertension in both the presence and absence of medication. This is a sham-controlled trial investigating the safety and efficacy of RDN in China., Methods: This prospective, multicenter, randomized, patient- and outcome-assessor-blinded, sham-controlled trial investigated radiofrequency RDN in patients with hypertension on standardized triple antihypertensive therapy. Eligible patients were randomized 1:1 to undergo RDN using a multi-electrode radiofrequency catheter (Iberis; Shanghai Angiocare Medical Technology, Shanghai, China) or a sham procedure. The primary efficacy outcome was the between-group difference in baseline-adjusted change in mean 24-hour ambulatory systolic BP from randomization to 6 months., Results: Of 217 randomized patients (mean age, 45.3±10.2 years; 21% female), 107 were randomized to RDN and 110 were randomized to sham control. At 6 months, there was a greater reduction in 24-hour systolic BP in the RDN (-13.0±12.1 mm Hg) compared with the sham control group (-3.0±13.0 mm Hg; baseline-adjusted between-group difference, -9.4 mm Hg [95% CI, -12.8 to -5.9]; P <0.001). Compared with sham, 24-hour diastolic BP was lowered by -5.0 mm Hg ([95% CI, -7.5 to -2.4]; P <0.001) 6 months after RDN, and office systolic and diastolic BP was lowered by -6.4 mm Hg ([95% CI, -10.5 to -2.3]; P =0.003) and -5.1 mm Hg ([95% CI, -8.2 to -2.0]; P =0.001), respectively. One patient in the RDN group experienced an access site complication (hematoma), which resolved without sequelae. No other major device- or procedure-related safety events occurred through follow-up., Conclusions: In this trial of Chinese patients with uncontrolled hypertension on a standardized triple pharmacotherapy, RDN was safe and reduced ambulatory and office BP at 6 months compared with sham., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02901704., Competing Interests: X. Jiang is supported by Iberis-HTN trial fund from Shanghai Angiocare Medical Technology, CAMS Innovation Fund for Medical Sciences (grant Nos. 2021-I2M-C&T-B-026 and 2021-I2M-C&T-B-027). He has received speaker honoraria fees from Medtronic and Terumo. Felix Mahfoud is supported by Deutsche Gesellschaft für Kardiologie, Deutsche Forschungsgemeinschaft (SFB TRR219, Project ID 322900939), and Deutsche Herzstiftung. He has received scientific support from Ablative Solutions, Medtronic, and ReCor Medical, and speaker honoraria/consulting fees from Ablative Solutions, Amgen, Astra-Zeneca, Bayer, Boehringer Ingelheim, Inari, Medtronic, Merck, ReCor Medical, Servier, and Terumo. L. Lauder received speaker honoraria/consulting fees from AstraZeneca, Medtronic, Pfizer, and ReCor. Brad Hubbard is an employee of EastPoint Innovation Center. X. Hu is an employee of Shanghai Angiocare Medical Technology. R. Gao received institutional research grants from Shanghai Angiocare Medical Technology (Shanghai, China) and Biotyx Medical (Shenzhen, China). The remaining authors report no conflicts of interest related to this article.

Objective: IBD is characterised by dysbiosis, but it remains unclear to what extent dysbiosis develops in unaffected at-risk individuals. To address this, we investigated age-related patterns of faecal and serum markers of dysbiosis in high-risk multiplex IBD families (two or more affected first-degree relatives)., Design: Faecal and serum samples were collected from multiplex IBD and control families (95 IBD, 292 unaffected, 51 controls). Findings were validated in independent cohorts of 616 and 1173 subjects including patients with IBD, infants born to mothers with IBD and controls. 16S rRNA gene sequencing and global untargeted metabolomics profiling of faeces and serum were performed., Results: Microbial and metabolomic parameters of dysbiosis progressively decreased from infancy until age 8. This microbial maturation process was slower in infants born to mothers with IBD. After age 15, dysbiosis steadily increased in unaffected relatives throughout adulthood. Dysbiosis was accompanied by marked shifts in the faecal metabolome and, to a lesser extent, the serum metabolome. Faecal and serum metabolomics dysbiosis indices were validated in an independent cohort. Dysbiosis was associated with elevated antimicrobial serologies but not with faecal calprotectin. Dysbiosis metrics differentiated IBD from non-IBD comparably to serologies, with a model combining calprotectin, faecal metabolomics dysbiosis index and serology score demonstrating highest accuracy., Conclusion: These findings support that dysbiosis exists as a pre-disease state detectable by faecal and serum biomarkers for IBD risk prediction. Given the expansion of disease-modifying agents and non-invasive imaging, the indices developed here may facilitate earlier diagnoses and improved management in at-risk individuals., Competing Interests: Competing interests: GB, AH, EL-S and JW are current employees of Johnson & Johnson Innovative Medicine. MD and J-FC are consultants for Johnson & Johnson Innovative Medicine and Prometheus Labs. All other authors do not have disclosures., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

There is still a gap between the food processing and carotenoids release and structure degradation during digestion. This study investigated the effect of heating and coconut oil addition on the digestion behavior of tomatoes during in vitro dynamic digestion. Coconut oil and heating increased gastric retention, and the value of heat-treated tomatoes with coconut oil maintained at a highest level throughout the gastric digestion. The contents of lycopene and β-carotene increased after heating and coconut oil addition. After stimulated intestinal digestion, coconut oil and heating increased the particle size of tomato slurry. Besides, heat-treated tomatoes released more particles under the light microscopy and SEM observation, while the oil-treated tomatoes showed rougher cell surfaces. Heating and coconut oil also significantly increased the bioaccessibility of lycopene to 70 % ± 5 % and 81 % ± 4 %, respectively. These findings would provide theoretical guidance to develop tomato-derived foods with high bioaccessibility., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Stimulus-responsive organic room temperature phosphorescence (RTP) materials exhibit variations in their luminescent characteristics (lifetime and efficiency) upon exposure to external stimuli, including force, heat, light and acid-base conditions, the development of stimulus-responsive RTP molecules becomes imperative. However, the inner responsive mechanism is unclear, theoretical investigations to reveal the relationship among hydrostatic pressures, molecular structures and photophysical properties are highly desired. Herein, taking the Se-containing RTP molecule (SeAN) as a model, based on the dispersion corrected density functional theory (DFT-D), the combined quantum mechanics and molecular dynamics (QM/MM) method and thermal vibration correlation function (TVCF) theory, the influences of hydrostatic pressure on molecular structures, transition properties as well as lifetimes and efficiencies of RTP molecule are theoretically studied. Results show that extended lifetime and enhanced efficiency are observed at 2 Gpa compared with molecule at normal pressure, and this is related with the small reorganization energy and large oscillator strength. Moreover, due to the small energy gap (0.34 eV) and remarkable spin-orbit coupling (SOC) constant (8.56 cm - 1 ) between first singlet excited state and triplet state, fast intersystem crossing (ISC) process is determined for molecule at 6 Gpa. Furthermore, the intermolecular interactions are visualized using independent gradient model based on Hirshfeld partition (IGMH) and the changes of molecular packing modes, SOC values, lifetimes and efficiencies with pressures are detected. These results reveal the relationship between molecular structures and RTP properties. Our work provides theoretical insights into the hydrostatic pressure response mechanism and could promote the development new efficient stimulus-responsive molecules., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The procedure of anterior cruciate ligament (ACL) allograft preparation can be divided into fresh-frozen method (FF-allograft) or freeze-dried method (FD-allograft). This study aims to biomechanically and histologically compare the graft to bone tunnel integration between the two allografts. In-vitro results indicated that FF-allograft and FD-allograft showed excellent biocompatibility and biomechanics, while FD-allograft showed a denser collagen fiber arrangement than FF-allograft and autograft. Then, in-vivo preformation of the FF-allograft, FD-allograft, and autograft on bone tunnel integration was evaluated via a canine ACL reconstruction model. In-vivo results indicated that no signs of infection or osteoarthritis were shown in the femur-graft-tibia complexes, but more vascularity and synovitis formed around the implanted FF-allograft. Micro-computed tomography showed that peri-graft bone in the FF-allograft group was significantly increased and remodeled compared with the FD-allograft group; Histologically, the FF-allograft group exhibited similar graft-bone tunnel healing to the FD-allograft group. Tartrate-resistant acid phosphatase (TRAP) staining showed significantly more osteoclasts presented in the FD-allograft group compared to the FF-allograft group. Meanwhile, a significantly higher failure load was shown in the FF-allograft group when compared with the FD-allograft group (P < 0.05). In conclusion, the FF-allograft integrated more firmly into the bone tunnel than the FD-allograft when used in ACL reconstruction., (© 2024. The Author(s).)

The 2030 Agenda for Sustainable Development issued by the United Nations is an important foundation for countries to achieve common economic, social and environmental development. Important progress has been made in the evaluation of the Sustainable Development Goals (SDGs) in Hainan Island; nevertheless, there is still a lack of understanding around the trade-offs and synergies between the SDGs. Studying the trade-offs and synergies between Hainan Island's sustainable development goals is of great significance for the coordinated development of these goals and the promotion of the construction of free trade ports. Therefore, based on the United Nations Sustainable Development Assessment System and the existing SDG indicator system on Hainan Island, this paper identifies and quantifies the trade-offs and synergies within and between SDGs and targets on the county scale. Based on the different impacts of different spatial, dimensional and geographical directions, the results show the following: (1) Hainan Province made good progress on multiple SDGs between 2010 and 2021. (2) The most significant synergies between SDGs exist between SDG1 (No Poverty) and SDG10 (Reduce Inequalities), while the most significant trade-offs exist between SDG2 (Zero Hunger) and SDG4 (Quality Education). (3) Obvious spatial characteristics in trade-offs and synergies exist, with the highest level of synergy being in the Haikou and Sanya Economic Circles and their surrounding areas, and in the central region of Hainan Island which has a higher level of trade-offs. (4) The synergistic effect between the SDG targets and indicators in Hainan is much greater than the trade-off effect: the four aspects of people's livelihood improvement, economic development, resource utilization and environmental quality all show synergistic effects in different regions., (© 2024. The Author(s).)

Purpose: Esophageal squamous cell carcinoma (ESCC) frequently exhibits skip metastasis to lymph nodes; however, non-invasive imaging techniques capable of directly visualizing metastatic lymph nodes (MLN) are still lacking. Although biopsy is the clinical standard method, it is invasive and poses risks to patient health. This study aims to detect MLN in an intralymphatic tumor metastasis model of ESCC using the CXCR4-targeted tracer [ 64 Cu]Cu-NOTA-CP01., Procedures: The CXCR4 expression in ESCC cell lines was assessed using Western blot and immunofluorescence. An intralymphatic tumor metastasis model was established and monitored using bioluminescence imaging (BLI). Small animal PET studies and biodistribution studies were performed to evaluate the specificity of [ 64 Cu]Cu-NOTA-CP01 for MLN. Histopathology evaluation was employed to check for the presence of metastatic tumor cells and to assess CXCR4 expression levels in the metastatic lymph nodes., Results: The intralymphatic tumor metastasis model was successfully established using the EC109/Luc cell line, which exhibited high CXCR4 expression, as verified by BLI. PET/CT imaging showed that the MLN uptakes in the baseline group were significantly inhibited in the blocking group. The ratios of MLN/muscle and MLN/blood were also significantly higher in the baseline group than in the blocking group. Ex vivo PET/CT imaging of MLN corroborated the in vivo data. Biodistribution studies further supported the PET imaging studies, showing rapid clearance of the tracer from the blood and major organs, with significantly higher MLN/muscle and MLN/blood ratios in the baseline group compared to the blocking group. Histopathological staining verified positive CXCR4 expression in these lymph nodes containing metastatic tumor cells., Conclusions: Targeting CXCR4 with [ 64 Cu]Cu-NOTA-CP01 for PET imaging of lymph nodes metastasis represents a promising approach that warrants further investigation. These findings have the potential to enhance diagnostic and therapeutic strategies for individuals with lymph nodes metastasis of ESCC., (© 2024. The Author(s), under exclusive licence to World Molecular Imaging Society.)

Purpose: To compare the oncological outcomes between standard radical cystectomy (SRC) and organ-sparing cystectomy (OSC) in male patients diagnosed with bladder cancer., Methods: Patients with stage Ta-T3 bladder cancer who underwent OSC or SRC were identified from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. The association between preoperative factors and the implementation of OSC was analyzed using logistic regression. Propensity score matching (PSM) was employed to balance baseline characteristics between the two groups. Patients' overall survival (OS) and cancer-specific survival (CSS) were estimated using the Kaplan-Meier method. Subgroup analyses based on the T stage were also conducted., Results: A total of 7264 patients were included, with 96.8% (7033 patients) receiving SRC and 3.2% (231 patients) receiving OSC. Patients with higher T stages and high-grade tumors were less likely to undergo OSC. After PSM, OSC was associated with significantly worse OS and CSS than SRC. Subgroup analysis revealed that OSC did not lead to worse OS and CSS in non-muscle invasive bladder cancer and T2 stage patients, but it resulted in significantly worse outcomes in T3 stage patients., Conclusion: Our study indicates that OSC is associated with poorer oncological outcomes compared to SRC, particularly in patients with advanced-stage tumors. These findings suggest the need for stringent selection criteria for OSC in bladder cancer patients. Given the negative impact on prognosis, stage T3 should potentially be considered a contraindication for OSC. Further evidence is required to confirm these assertions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Mesenchymal stromal cells (MSCs) exhibit significant potential in the context of cell therapy because of their capacity to perform a range of interconnected functions in damaged tissues, including immune modulation, hematopoietic support, and tissue regeneration. MSCs are hypoimmunogenic because of their diminished expression of major histocompatibility molecules, absence of costimulatory molecules, and presence of coinhibitory molecules. While autologous MSCs reduce the risk of rejection and infection, variability in cell numbers and proliferation limits their potential applications. Conversely, allogeneic MSCs (allo-MSCs) possess broad clinical applications unconstrained by donor physiology. Nonetheless, preclinical and clinical investigations highlight that transplanted allo-MSCs are subject to immune attack from recipients. These cells exhibit anti-inflammatory and proinflammatory phenotypes contingent on the microenvironment. Notably, the proinflammatory phenotype features enhanced immunogenicity and diminished immunosuppression, potentially triggering allogeneic immune reactions that impede long-term clinical efficacy. Consequently, preserving the low immunogenicity of allo-MSCs in vivo and mitigating immune rejection in diverse microenvironments represent crucial challenges for the widespread clinical application of MSCs. In this review, we elucidate the immune regulation of allo-MSCs, specifically focusing on two distinct subgroups, MSC1 and MSC2, that exhibit varying polarization states and immunogenicity. We discuss the factors and underlying mechanisms that induce MSC immunogenicity and polarization, highlighting the crucial role of major histocompatibility complex class I/II molecules in rejection post-transplantation. Additionally, we summarize the immunogenic regulatory targets and applications of allo-MSCs and outline strategies to address challenges in this promising field, aiming to enhance allo-MSC therapeutic efficacy for patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Keratoconus (KC) is a complex corneal disorder with a well-recognized genetic component. In this study, we aimed to expand the genetic spectrum of 200 Chinese patients with keratoconus and their unaffected parents. Trio-based whole-exome sequencing was performed in 200 patients with sporadic keratoconus and their unaffected parents. The variants identified in candidate genes for keratoconus were analyzed using multiple bioinformatics tools. Finally, we identified 7 variants in 5 candidate genes for keratoconus in 5 patients. The c.T464C variant in the IMPDH1 gene was defined as likely pathogenic according to the guidelines of the American College of Medical Genetics and Genomics, and the remaining variants in candidate genes (TRANK1, SLC4A11, CERKL, IFT172) were defined as uncertain significance. Our results expand the genetic spectrum in KC, highlight the genetic heterogeneity of this disease and provide important clues for future functional validation., Competing Interests: Declaration of competing interest No conflicting relationship exists for any author., (Copyright © 2024 Elsevier Ltd. All rights reserved.)