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In-plane polarized ferroelectric thin films typically exhibit complicated multidomain states, not desirable for optoelectronic device performance. Here, the authors combine interfacial symmetry engineering and anisotropic strain to design single-domain in-plane polarized ferroelectric BaTiO3 films.

Laser frequency combs emit a spectrum of equally spaced peaks that can provide precise frequency references useful for astronomy. Here, the authors demonstrate a frequency comb using electro-optical modulation, which has a line spacing that is resolvable using grating spectrographs unlike the mode-locking approach.

Erythropoietic protoporphyria (EPP) is a genetic disease characterized by protoporphyrin IX-mediated painful phototoxicity. Currently, options for the management of EPP-associated phototoxicity are limited and no oral medication is available. Here, we investigated a novel therapy against EPP-associated phototoxicity by targeting the ATP-binding cassette subfamily G member 2 (ABCG2), the efflux transporter of protoporphyrin IX. Oral ABCG2 inhibitors were developed, and they successfully prevented EPP-associated phototoxicity in a genetically engineered EPP mouse model. Mechanistically, ABCG2 inhibitors suppress protoporphyrin IX release from erythroid cells and reduce the systemic exposure to protoporphyrin IX in EPP. In summary, our work establishes a novel strategy for EPP therapy by targeting ABCG2 and provides oral ABCG2 inhibitors that can effectively prevent protoporphyrin IX-mediated phototoxicity in mice., Competing Interests: Competing interests: X.M., J.Z., and J.L. are inventors on a patent (WO2020236901) and hold equity in Portal Therapeutics, Inc. K.E.A. reports receiving consulting fees, advisory board fees and grants to the university from Alnylam Pharmaceuticals, Recordati Rare Diseases, Mitsubishi Tanabe Pharma America, Disc Medicine and Portal Therapeutics. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Respiratory syncytial virus (RSV) poses a significant public health challenge, especially among children. Although palivizumab and nirsevimab, neutralizing antibodies (nAbs) targeting the RSV F protein, have been used for prophylaxis, their limitations underscore the need for more effective alternatives. Herein, we present a potent and broad nAb, named 5B11, which exhibits nanogram level of unbiased neutralizing activities against both RSV-A and -B subgroups. Notably, 5B11 shows a ~20-fold increase in neutralizing efficacy compared to 1129 (the murine precursor of palivizumab) and approximately a 3-fold increase in neutralizing efficacy against B18537 in comparison to nirsevimab. Cryo-electron microscopy analysis reveals 5B11's mechanism of action by targeting a highly conserved epitope within site V, offering a promising strategy with potentially lower risk of escape mutants. Antiviral testing in a female cotton rat model demonstrated that low-dose (1.5 mg/kg) administration of 5B11 achieved comparable prophylactic efficacy to that achieved by high-dose (15 mg/kg) of 1129. Furthermore, the humanized 5B11 showed a superior in vivo antiviral activity against B18537 infection compared to nirsevimab and palivizumab. Therefore, 5B11 is a promising RSV prophylactic candidate applicable to broad prevention of RSV infection., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Robust high-order optical vortices are much in demand for applications in optical manipulation, optical communications, quantum entanglement and quantum computing. However, in numerous experimental settings, a controlled generation of optical vortices with arbitrary orbital angular momentum remains a challenge. Here, we present a concept of "optical vortex ladder" for the stepwise generation of optical vortices through Sisyphus pumping of pseudospin modes in photonic graphene. The ladder is applicable in various lattices with Dirac-like structures. Instead of conical diffraction and incomplete pseudospin conversion under conventional Gaussian beam excitations, the vortices produced in the ladder arise from non-trivial topology and feature diffraction-free Bessel profiles, thanks to the refined excitation of the ring spectrum around the Dirac cones. By employing a periodic "kick" to the photonic graphene, effectively inducing the Sisyphus pumping, the ladder enables tunable generation of optical vortices of any order even when the initial excitation does not involve any orbital angular momentum. The optical vortex ladder stands out as an intriguing non-Hermitian dynamical system, and, among other possibilities, opens a pathway for applications of topological singularities in beam shaping and wavefront engineering., (© 2024. The Author(s).)

The antitumor performance of PROteolysis-TArgeting Chimeras (PROTACs) is limited by its insufficient tumor specificity and poor pharmacokinetics. These disadvantages are further compounded by tumor heterogeneity, especially the presence of cancer stem-like cells, which drive tumor growth and relapse. Herein, we design a region-confined PROTAC nanoplatform that integrates both reactive oxygen species (ROS)-activatable and hypoxia-responsive PROTAC prodrugs for the precise manipulation of bromodomain and extraterminal protein 4 expression and tumor eradication. These PROTAC nanoparticles selectively accumulate within and penetrate deep into tumors via response to matrix metalloproteinase-2. Photoactivity is then reactivated in response to the acidic intracellular milieu and the PROTAC is discharged due to the ROS generated via photodynamic therapy specifically within the normoxic microenvironment. Moreover, the latent hypoxia-responsive PROTAC prodrug is restored in hypoxic cancer stem-like cells overexpressing nitroreductase. Here, we show the ability of region-confined PROTAC nanoplatform to effectively degrade BRD4 in both normoxic and hypoxic environments, markedly hindering tumor progression in breast and head-neck tumor models., (© 2024. The Author(s).)

Amyotrophic Lateral Sclerosis (ALS), like many other neurodegenerative diseases, is highly heritable, but with only a small fraction of cases explained by monogenic disease alleles. To better understand sporadic ALS, we report epigenomic profiles, as measured by ATAC-seq, of motor neuron cultures derived from a diverse group of 380 ALS patients and 80 healthy controls. We find that chromatin accessibility is heavily influenced by sex, the iPSC cell type of origin, ancestry, and the inherent variance arising from sequencing. Once these covariates are corrected for, we are able to identify ALS-specific signals in the data. Additionally, we find that the ATAC-seq data is able to predict ALS disease progression rates with similar accuracy to methods based on biomarkers and clinical status. These results suggest that iPSC-derived motor neurons recapitulate important disease-relevant epigenomic changes., (© 2024. The Author(s).)

Dissipative Kerr-soliton combs are laser pulses regularly sustained by a localized solitary wave on top of a continuous-wave background inside a nonlinear resonator. Usually, the intrinsic interactions between the background light and solitons are weak and localized. Here, we demonstrate a strong interaction between the generated soliton comb and the background light in a Brillouin-Kerr microcomb system. This strong interaction enables the generation of a monostable single-soliton microcomb on a silicon chip. Also, new phenomena related to soliton physics including solitons hopping between different states as well as controlling the formations of the soliton states by the pump power, are observed owing to such strong interaction. Utilizing this monostable single-soliton microcomb, we achieve the 100% deterministic turnkey operation successfully without any feedback controls. Importantly, it allows to output turnkey ultra-low-noise microwave signals using a free-running pump., (© 2024. The Author(s).)

Van der Waals (vdW) ferroelectrics have attracted significant attention for their potential in next-generation nano-electronics. Two-dimensional (2D) group-IV monochalcogenides have emerged as a promising candidate due to their strong room temperature in-plane polarization down to a monolayer limit. However, their polarization is strongly coupled with the lattice strain and stacking orders, which impact their electronic properties. Here, we utilize four-dimensional scanning transmission electron microscopy (4D-STEM) to simultaneously probe the in-plane strain and out-of-plane stacking in vdW SnSe. Specifically, we observe large lattice strain up to 4% with a gradient across ~50 nm to compensate lattice mismatch at domain walls, mitigating defects initiation. Additionally, we discover the unusual ferroelectric-to-antiferroelectric domain walls stabilized by vdW force and may lead to anisotropic nonlinear optical responses. Our findings provide a comprehensive understanding of in-plane and out-of-plane structures affecting domain properties in vdW SnSe, laying the foundation for domain wall engineering in vdW ferroelectrics., (© 2023. The Author(s).)

Argonaute proteins (Agos) bind short nucleic acids as guides and are directed by them to recognize target complementary nucleic acids. Diverse prokaryotic Agos (pAgos) play potential functions in microbial defense. The functions and mechanisms of a group of full-length yet catalytically inactive pAgos, long-B pAgos, remain unclear. Here, we show that most long-B pAgos are functionally connected with distinct associated proteins, including nucleases, Sir2-domain-containing proteins and trans-membrane proteins, respectively. The long-B pAgo-nuclease system (BPAN) is activated by guide RNA-directed target DNA recognition and performs collateral DNA degradation in vitro. In vivo, the system mediates genomic DNA degradation after sensing invading plasmid, which kills the infected cells and results in the depletion of the invader from the cell population. Together, the BPAN system provides immunoprotection via abortive infection. Our data also suggest that the defense strategy is employed by other long-B pAgos equipped with distinct associated proteins., (© 2023. The Author(s).)

The topology type and the functionalization of pores play an important role in regulating the performance of covalent organic frameworks. Herein, we designed and synthesized the covalent organic framework with hetero-environmental pores using predesigned asymmetrical dialdehyde monomer. According to the results of structural characterization, crystallinity investigation, and theoretical calculation, the hetero-environmental pores of the obtained framework are regarded as the alternant arrangement. The distinctive hetero pore structure leads the designed material to show more advantages as compared with control materials in loading both hydrophobic and hydrophilic antibiotics for wound healing. This dual-antibiotic strategy can expand the antibacterial range as compared with the single antibiotic one, and reduce the generation of drug resistance. In summary, this strategy for designing covalent organic frameworks with hetero-environmental pores can extend the structural variety and provide a pathway for improving the practical application performance of these materials., (© 2023. The Author(s).)

Magnetic topological semimetals allow for an effective control of the topological electronic states by tuning the spin configuration. Among them, Weyl nodal line semimetals are thought to have the greatest tunability, yet they are the least studied experimentally due to the scarcity of material candidates. Here, using a combination of angle-resolved photoemission spectroscopy and quantum oscillation measurements, together with density functional theory calculations, we identify the square-net compound EuGa 4 as a magnetic Weyl nodal ring semimetal, in which the line nodes form closed rings near the Fermi level. The Weyl nodal ring states show distinct Landau quantization with clear spin splitting upon application of a magnetic field. At 2 K in a field of 14 T, the transverse magnetoresistance of EuGa 4 exceeds 200,000%, which is more than two orders of magnitude larger than that of other known magnetic topological semimetals. Our theoretical model suggests that the non-saturating magnetoresistance up to 40 T arises as a consequence of the nodal ring state., (© 2023. Springer Nature Limited.)

Metagenomic or metabarcoding data are often used to predict microbial interactions in complex communities, but these predictions are rarely explored experimentally. Here, we use an organism abundance correlation network to investigate factors that control community organization in mine tailings-derived laboratory microbial consortia grown under dozens of conditions. The network is overlaid with metagenomic information about functional capacities to generate testable hypotheses. We develop a metric to predict the importance of each node within its local network environments relative to correlated vitamin auxotrophs, and predict that a Variovorax species is a hub as an important source of thiamine. Quantification of thiamine during the growth of Variovorax in minimal media show high levels of thiamine production, up to 100 mg/L. A few of the correlated thiamine auxotrophs are predicted to produce pantothenate, which we show is required for growth of Variovorax, supporting that a subset of vitamin-dependent interactions are mutualistic. A Cryptococcus yeast produces the B-vitamin pantothenate, and co-culturing with Variovorax leads to a 90-130-fold fitness increase for both organisms. Our study demonstrates the predictive power of metagenome-informed, microbial consortia-based network analyses for identifying microbial interactions that underpin the structure and functioning of microbial communities., (© 2023. Springer Nature Limited.)

Genetic variants in chromatin regulators are frequently found in neurodevelopmental disorders, but their effect in disease etiology is rarely determined. Here, we uncover and functionally define pathogenic variants in the chromatin modifier EZH1 as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 methyltransferases of the PRC2 complex. Unlike the other PRC2 subunits, which are involved in cancers and developmental syndromes, the implication of EZH1 in human development and disease is largely unknown. Using cellular and biochemical studies, we demonstrate that recessive variants impair EZH1 expression causing loss of function effects, while dominant variants are missense mutations that affect evolutionarily conserved aminoacids, likely impacting EZH1 structure or function. Accordingly, we found increased methyltransferase activity leading to gain of function of two EZH1 missense variants. Furthermore, we show that EZH1 is necessary and sufficient for differentiation of neural progenitor cells in the developing chick embryo neural tube. Finally, using human pluripotent stem cell-derived neural cultures and forebrain organoids, we demonstrate that EZH1 variants perturb cortical neuron differentiation. Overall, our work reveals a critical role of EZH1 in neurogenesis regulation and provides molecular diagnosis for previously undefined neurodevelopmental disorders., (© 2023. The Author(s).)

5-Aminolevulinic acid-based photodynamic therapy heavily depends on the biological transformation efficiency of 5-aminolevulinic acid to protoporphyrin IX, while the lack of an effective delivery system and imaging navigation are major hurdles in improving the accumulation of protoporphyrin IX and optimizing therapeutic parameters. Herein, we leverage a synthetic biology approach to construct a transdermal theranostic microneedle patch integrated with 5-aminolevulinic acid and catalase co-loaded tumor acidity-responsive copper-doped calcium phosphate nanoparticles for efficient 5-aminolevulinic acid-based photodynamic therapy by maximizing the enrichment of intratumoral protoporphyrin IX. We show that continuous oxygen generation by catalase in vivo reverses tumor hypoxia, enhances protoporphyrin IX accumulation by blocking protoporphyrin IX efflux (downregulating hypoxia-inducible factor-1α and ferrochelatase) and upregulates protoporphyrin IX biosynthesis (providing exogenous 5-aminolevulinic acid and upregulating ALA-synthetase). In vivo fluorescence/photoacoustic duplex imaging can monitor intratumoral oxygen saturation and protoporphyrin IX metabolic kinetics simultaneously. This approach thus facilitates the optimization of therapeutic parameters for different cancers to realize Ca 2+ /Cu 2+ -interferences-enhanced repeatable photodynamic therapy, making this theranostic patch promising for clinical practice., (© 2022. The Author(s).)

Gastroscopic biopsy provides the only effective method for gastric cancer diagnosis, but the gold standard histopathology is time-consuming and incompatible with gastroscopy. Conventional stimulated Raman scattering (SRS) microscopy has shown promise in label-free diagnosis on human tissues, yet it requires the tuning of picosecond lasers to achieve chemical specificity at the cost of time and complexity. Here, we demonstrate that single-shot femtosecond SRS (femto-SRS) reaches the maximum speed and sensitivity with preserved chemical resolution by integrating with U-Net. Fresh gastroscopic biopsy is imaged in <60 s, revealing essential histoarchitectural hallmarks perfectly agreed with standard histopathology. Moreover, a diagnostic neural network (CNN) is constructed based on images from 279 patients that predicts gastric cancer with accuracy >96%. We further demonstrate semantic segmentation of intratumor heterogeneity and evaluation of resection margins of endoscopic submucosal dissection (ESD) tissues to simulate rapid and automated intraoperative diagnosis. Our method holds potential for synchronizing gastroscopy and histopathological diagnosis., (© 2022. The Author(s).)

Non-invasive visualization of dynamic molecular events in real-time via molecular imaging may enable the monitoring of cascade catalytic reactions in living systems, however effective imaging modalities and a robust catalytic reaction system are lacking. Here we utilize three-dimensional (3D) multispectral photoacoustic (PA) molecular imaging to monitor in vivo cascade catalytic therapy based on a dual enzyme-driven cyclic reaction platform. The system consists of a two-dimensional (2D) Pd-based nanozyme conjugated with glucose oxidase (GOx). The combination of nanozyme and GOx can induce the PA signal variation of endogenous molecules. Combined with the PA response of the nanozyme, we can simultaneously map the 3D PA signals of dynamic endogenous and exogenous molecules associated with the catalytic process, thus providing a real-time non-invasive visualization. We can also treat tumors under the navigation of the PA imaging. Therefore, our study demonstrates the imaging-guided potential of 3D multispectral PA imaging in feedback-looped cascade catalytic therapy., (© 2022. The Author(s).)

Neuroblastoma is a pediatric malignancy with heterogeneous clinical outcomes. To better understand neuroblastoma pathogenesis, here we analyze whole-genome, whole-exome and/or transcriptome data from 702 neuroblastoma samples. Forty percent of samples harbor at least one recurrent driver gene alteration and most aberrations, including MYCN, ATRX, and TERT alterations, differ in frequency by age. MYCN alterations occur at median 2.3 years of age, TERT at 3.8 years, and ATRX at 5.6 years. COSMIC mutational signature 18, previously associated with reactive oxygen species, is the most common cause of driver point mutations in neuroblastoma, including most ALK and Ras-activating variants. Signature 18 appears early and is continuous throughout disease evolution. Signature 18 is enriched in neuroblastomas with MYCN amplification, 17q gain, and increased expression of mitochondrial ribosome and electron transport-associated genes. Recurrent FGFR1 variants in six patients, and ALK N-terminal structural alterations in five samples, identify additional patients potentially amenable to precision therapy.

Pu-erh tea displays cholesterol-lowering properties, but the underlying mechanism has not been elucidated. Theabrownin is one of the most active and abundant pigments in Pu-erh tea. Here, we show that theabrownin alters the gut microbiota in mice and humans, predominantly suppressing microbes associated with bile-salt hydrolase (BSH) activity. Theabrownin increases the levels of ileal conjugated bile acids (BAs) which, in turn, inhibit the intestinal FXR-FGF15 signaling pathway, resulting in increased hepatic production and fecal excretion of BAs, reduced hepatic cholesterol, and decreased lipogenesis. The inhibition of intestinal FXR-FGF15 signaling is accompanied by increased gene expression of enzymes in the alternative BA synthetic pathway, production of hepatic chenodeoxycholic acid, activation of hepatic FXR, and hepatic lipolysis. Our results shed light into the mechanisms behind the cholesterol- and lipid-lowering effects of Pu-erh tea, and suggest that decreased intestinal BSH microbes and/or decreased FXR-FGF15 signaling may be potential anti-hypercholesterolemia and anti-hyperlipidemia therapies.

We report the isolation and spectroscopic identification of the eight-coordinated alkaline earth metal-dinitrogen complexes M(N 2 ) 8 (M=Ca, Sr, Ba) possessing cubic (O h ) symmetry in a low-temperature neon matrix. The analysis of the electronic structure reveals that the metal-N 2 bonds are mainly due to [M(d π )]→(N 2 ) 8 π backdonation, which explains the observed large red-shift in N-N stretching frequencies. The adducts M(N 2 ) 8 have a triplet ( 3 A 1g ) electronic ground state and exhibit typical bonding features of transition metal complexes obeying the 18-electron rule. We also report the isolation and bonding analysis of the charged dinitrogen complexes [M(N 2 ) 8 ] + (M=Ca, Sr).

Homochirality is very important in the formation of advanced biological structures, but the origin and evolution mechanisms of homochiral biological structures in complex hierarchical process is not clear at the single-molecule level. Here we demonstrate the single-molecule investigation of biological homochirality in the hierarchical peptide assembly, regarding symmetry break, chirality amplification, and chirality transmission. We find that homochirality can be triggered by the chirality unbalance of two adsorption configuration monomers. Co-assembly between these two adsorption configuration monomers is very critical for the formation of homochiral assemblies. The site-specific recognition is responsible for the subsequent homochirality amplification and transmission in their hierarchical assembly. These single-molecule insights open up inspired thoughts for understanding biological homochirality and have general implications for designing and fabricating artificial biomimetic hierarchical chiral materials.

A microscopic understanding of the growth mechanism of two-dimensional materials is of particular importance for controllable synthesis of functional nanostructures. Because of the lack of direct and insightful observations, how to control the orientation and the size of two-dimensional material grains is still under debate. Here we discern distinct formation stages for MoS2 flakes from the thermolysis of ammonium thiomolybdates using in situ transmission electron microscopy. In the initial stage (400 °C), vertically aligned MoS2 structures grow in a layer-by-layer mode. With the increasing temperature of up to 780 °C, the orientation of MoS2 structures becomes horizontal. When the growth temperature reaches 850 °C, the crystalline size of MoS2 increases by merging adjacent flakes. Our study shows direct observations of MoS2 growth as the temperature evolves, and sheds light on the controllable orientation and grain size of two-dimensional materials.

High-performance piezoelectrics are lead-based solid solutions that exhibit a so-called morphotropic phase boundary, which separates two competing phases as a function of chemical composition; as a consequence, an intermediate low-symmetry phase with a strong piezoelectric effect arises. In search for environmentally sustainable lead-free alternatives that exhibit analogous characteristics, we use a network of competing domains to create similar conditions across thermal inter-ferroelectric transitions in simple, lead-free ferroelectrics such as BaTiO3 and KNbO3. Here we report the experimental observation of thermotropic phase boundaries in these classic ferroelectrics, through direct imaging of low-symmetry intermediate phases that exhibit large enhancements in the existing nonlinear optical and piezoelectric property coefficients. Furthermore, the symmetry lowering in these phases allows for new property coefficients that exceed all the existing coefficients in both parent phases. Discovering the thermotropic nature of thermal phase transitions in simple ferroelectrics thus presents unique opportunities for the design of 'green' high-performance materials.