CRB1-associated retinal degeneration is dependent on bacterial translocation from the gut.

The Crumbs homolog 1 (CRB1) gene is associated with retinal degeneration, most commonly Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). Here, we demonstrate that murine retinas bearing the Rd8 mutation of Crb1 are characterized by the presence of intralesional bacteria. While normal CRB1 expression was enriched in the apical junctional complexes of retinal pigment epithelium and colonic enterocytes, Crb1 mutations dampened its expression at both sites. Consequent impairment of the outer blood retinal barrier and colonic intestinal epithelial barrier in Rd8 mice led to the translocation of intestinal bacteria from the lower gastrointestinal (GI) tract to the retina, resulting in secondary retinal degeneration. Either the depletion of bacteria systemically or the reintroduction of normal Crb1 expression colonically rescued Rd8-mutation-associated retinal degeneration without reversing the retinal barrier breach. Our data elucidate the pathogenesis of Crb1-mutation-associated retinal degenerations and suggest that antimicrobial agents have the potential to treat this devastating blinding disease.

Biological carbon pump estimate based on multidecadal hydrographic data.

The transfer of photosynthetically produced organic carbon from surface to mesopelagic waters draws carbon dioxide from the atmosphere1. However, current observation-based estimates disagree on the strength of this biological carbon pump (BCP)2. Earth system models (ESMs) also exhibit a large spread of BCP estimates, indicating limited representations of the known carbon export pathways3. Here we use several decades of hydrographic observations to produce a top-down estimate of the strength of the BCP with an inverse biogeochemical model that implicitly accounts for all known export pathways. Our estimate of total organic carbon (TOC) export at 73.4 m (model euphotic zone depth) is 15.00 ± 1.12 Pg C year-1, with only two-thirds reaching 100 m depth owing to rapid remineralization of organic matter in the upper water column. Partitioned by sequestration time below the euphotic zone, τ, the globally integrated organic carbon production rate with τ > 3 months is 11.09 ± 1.02 Pg C year-1, dropping to 8.25 ± 0.30 Pg C year-1 for τ > 1 year, with 81% contributed by the non-advective-diffusive vertical flux owing to sinking particles and vertically migrating zooplankton. Nevertheless, export of organic carbon by mixing and other fluid transport of dissolved matter and suspended particles remains regionally important for meeting the respiratory carbon demand. Furthermore, the temperature dependence of the sequestration efficiency inferred from our inversion suggests that future global warming may intensify the recycling of organic matter in the upper ocean, potentially weakening the BCP.

Microcomb-driven silicon photonic systems.

Microcombs have sparked a surge of applications over the past decade, ranging from optical communications to metrology1-4. Despite their diverse deployment, most microcomb-based systems rely on a large amount of bulky elements and equipment to fulfil their desired functions, which is complicated, expensive and power consuming. By contrast, foundry-based silicon photonics (SiPh) has had remarkable success in providing versatile functionality in a scalable and low-cost manner5-7, but its available chip-based light sources lack the capacity for parallelization, which limits the scope of SiPh applications. Here we combine these two technologies by using a power-efficient and operationally simple aluminium-gallium-arsenide-on-insulator microcomb source to drive complementary metal-oxide-semiconductor SiPh engines. We present two important chip-scale photonic systems for optical data transmission and microwave photonics, respectively. A microcomb-based integrated photonic data link is demonstrated, based on a pulse-amplitude four-level modulation scheme with a two-terabit-per-second aggregate rate, and a highly reconfigurable microwave photonic filter with a high level of integration is constructed using a time-stretch approach. Such synergy of a microcomb and SiPh integrated components is an essential step towards the next generation of fully integrated photonic systems.

Alternating lysis and lysogeny is a winning strategy in bacteriophages due to Parrondo's paradox.

SignificanceBacteriophages, the most widespread reproducing biological entity on Earth, employ two strategies of virus-host interaction: lysis of the host cell and lysogeny whereby the virus genome integrates into the host genome and propagates vertically with it. We present a population model that reveals an effect known as Parrondo's paradox in game theory: Alternating between lysis and lysogeny is a winning strategy for a bacteriophage, even when each strategy individually is at a disadvantage compared with a competing bacteriophage. Thus, evolution of bacteriophages appears to optimize the ratio between the lysis and lysogeny propensities rather than the phage burst size in any individual phase. This phenomenon is likely to be relevant for understanding evolution of other host-parasites systems.

The N-Myc-responsive lncRNA MILIP promotes DNA double-strand break repair through non-homologous end joining.

The protooncoprotein N-Myc, which is overexpressed in approximately 25% of neuroblastomas as the consequence of MYCN gene amplification, has long been postulated to regulate DNA double-strand break (DSB) repair in neuroblastoma cells, but experimental evidence of this function is presently scant. Here, we show that N-Myc transcriptionally activates the long noncoding RNA MILIP to promote nonhomologous end-joining (NHEJ) DNA repair through facilitating Ku70-Ku80 heterodimerization in neuroblastoma cells. High MILIP expression was associated with poor outcome and appeared as an independent prognostic factor in neuroblastoma patients. Knockdown of MILIP reduced neuroblastoma cell viability through the induction of apoptosis and inhibition of proliferation, retarded neuroblastoma xenograft growth, and sensitized neuroblastoma cells to DNA-damaging therapeutics. The effect of MILIP knockdown was associated with the accumulation of DNA DSBs in neuroblastoma cells largely due to decreased activity of the NHEJ DNA repair pathway. Mechanistical investigations revealed that binding of MILIP to Ku70 and Ku80 increased their heterodimerization, and this was required for MILIP-mediated promotion of NHEJ DNA repair. Disrupting the interaction between MILIP and Ku70 or Ku80 increased DNA DSBs and reduced cell viability with therapeutic potential revealed where targeting MILIP using Gapmers cooperated with the DNA-damaging drug cisplatin to inhibit neuroblastoma growth in vivo. Collectively, our findings identify MILIP as an N-Myc downstream effector critical for activation of the NHEJ DNA repair pathway in neuroblastoma cells, with practical implications of MILIP targeting, alone and in combination with DNA-damaging therapeutics, for neuroblastoma treatment.

Rational Design of 2D Metal Halide Perovskites with Low Congruent Melting Temperature and Large Melt-Processable Window.

Metal halide perovskites (MHPs) have garnered significant attention due to their distinctive optical and electronic properties, coupled with excellent processability. However, the thermal characteristics of these materials are often overlooked, which can be harnessed to cater to diverse application scenarios. We showcase the efficacy of lowering the congruent melting temperature (Tm) of layered 2D MHPs by employing a strategy that involves the modification of flexible alkylammonium through N-methylation and I-substitution. Structural-property analysis reveals that the N-methylation and I-substitution play pivotal roles in reducing hydrogen bond interactions between the organic components and inorganic parts, lowering the rotational symmetry number of the cation and restricting the residual motion of the cations. Additional I···I interactions enhance intermolecular interactions and lead to improved molten stability, as evidenced by a higher viscosity. The 2D MHPs discussed in this study exhibit low Tm and wide melt-processable windows, e.g., (DMIPA)2PbI4 showcasing a low Tm of 98 °C and large melt-processable window of 145 °C. The efficacy of the strategy was further validated when applied to bromine-substituted 2D MHPs. Lowering the Tm and enhancing the molten stability of the MHPs hold great promise for various applications, including glass formation, preparation of high-quality films for photodetection, and fabrication of flexible devices.

Room-Temperature Anisotropic Actuation Driven by a Synergistic Order-Disorder and Displacive Phase Transition in a Ferroelectric Crystal.

Actuating materials convert different forms of energy into mechanical responses. To satisfy various application scenarios, they are desired to have rich categories, novel functionalities, clear structure-property relationships, fast responses, and, in particular, giant and reversible shape changes. Herein, we report a phase transition-driven ferroelectric crystal, (rac-3-HOPD)PbI3 (3-HOPD = 3-hydroxypiperidine cation), showing intriguingly large and anisotropic room-temperature actuating behaviors. The crystal consists of rigid one-dimensional [PbI3] anionic chains running along the a-axis and discrete disk-like cations loosely wrapping around the chains, leaving room for anisotropic shape changes in both the b- and c-axes. The shape change is switched by a ferroelectric phase transition occurring at around room temperature (294 K), driven by the exceptionally synergistic order-disorder and displacive phase transition. The rotation of the cations exerts internal pressure on the stacking structure to trigger an exceptionally large displacement of the inorganic chains, corresponding to a crystal lattice transformation with length changes of +24.6% and -17.5% along the b- and c-axis, respectively. Single crystal-based prototype devices of circuit switches and elevators have been fabricated by exploiting the unconventional negative temperature-dependent actuating behaviors. This work provides a new model for the development of multifunctional mechanically responsive materials.

Infrared laser moxibustion for cancer-related fatigue in breast cancer survivors: a randomized controlled trial.

BACKGROUND: Cancer-related fatigue (CRF) is a pervasive, persistent, and distressing symptom experienced by cancer patients, for which few treatments are available. We investigated the efficacy and safety of infrared laser moxibustion (ILM) for improving fatigue in breast cancer survivors. METHODS: A three-arm, randomized, sham-controlled clinical trial (6-week intervention plus 12-week observational follow-up) was conducted at a tertiary hospital in Shanghai, China. The female breast cancer survivors with moderate to severe fatigue were randomized 2:2:1 to ILM (n = 56) sham ILM (n = 56), and Waitlist control (WLC)(n = 28) groups. Patients in the ILM and sham ILM (SILM) groups received real or sham ILM treatment, 2 sessions per week for 6 weeks, for a total of 12 sessions. The primary outcome was change in the Brief Fatigue Inventory (BFI) score from baseline to week 6 with follow-up until week 18 assessed in the intention-to-treat population. RESULTS: Between June 2018 and July 2021, 273 patients were assessed for eligibility, and 140 patients were finally enrolled and included in the intention-to-treat analysis. Compared with WLC, ILM reduced the average BFI score by 0.9 points (95% CI, 0.3 to 1.6, P = .007) from baseline to week 6, with a difference between the groups of 1.1 points (95% CI, 0.4 to 1.8, P = .002) at week 18. Compared with SILM, ILM treatment resulted in a non-significant reduction in the BFI score (0.4; 95% CI, -0.2 to 0.9, P = .206) from baseline to week 6, while the between-group difference was significant at week 18 (0.7; 95% CI, 0.2 to 1.3, P = .014). No serious adverse events were reported. CONCLUSION: While ILM was found to be safe and to significantly reduce fatigue compared with WLC, its promising efficacy against the sham control needs to be verified in future adequately powered trials. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04144309. Registered 12 June 2018.

One-Shot Dual-Detection-Based Single-Molecule Super-Resolution Imaging Method for Real-Time Observation of Spatiotemporal Catalytic Activity Variations on the Plasmonic Gold Nanoparticle Surface.

Understanding the relationship between the surface properties of a single plasmonic nanoparticle and its catalytic performance is critical for developing highly efficient nanocatalysts. In this study, a one-shot dual-detection-based single-molecule super-resolution imaging method in the evanescent field was developed to observe real-time spatiotemporal catalytic activity on a single plasmonic gold nanoparticle (AuNP) surface. The scattering intensity of AuNPs and the fluorescence of resorufin molecules produced on the AuNP surface were obtained simultaneously to investigate the relationship between nanoparticles and catalytic reactions at a single-molecule level. Chemisorbed adsorbates (i.e., catalytic product and resorufin) changed the electron density of individual AuNPs throughout the catalytic cycle, resulting in the fluctuation of the scattering intensity of individual AuNPs, which was attributed to the electron transfer between reactant resazurin molecules and AuNPs. The increase in the electron density of individual AuNPs affected the catalytic reaction rate. Furthermore, sequential mapping of individual catalytic events at the subdiffraction limit resolution was completed for real-time surface dynamics and spatiotemporal activity variations on the single AuNP surface. The developed method can aid in understanding surface-property-dependent catalytic kinetics and facilitate the development of nanoparticle-based heterogeneous catalysts at subdiffraction limit resolution.

Climatic niche evolution and niche conservatism of Nymphaea species in Africa, South America, and Australia.

BACKGROUND: Interest in the evolution of climatic niches, particularly in understanding the potential adaptive responses of species under climate change, has increased both theoretically and within macroecological studies. These studies have provided valuable insights into how climatic traits of species influence their niche evolution. In this study, we aim to investigate whether niche conservatism plays a role in the species diversification of Nymphaea, a group of aquatic plants with a cosmopolitan distribution that is facing severe habitat loss. We will use climatic models and phylogenetic data for 23 species to reconstruct Nymphaea's niche evolution, measure niche overlap, and assess disparity through time while testing for evolutionary models. RESULTS: There was a lot of overlap in niches both within and between groups, especially for species that can be found in many places. The breadth and peaks of the niche profile varied depending on the bioclimatic variables, which suggested that the species evolved differently to cope with changes in climate. The analysis also showed that evolutionary changes happened across the phylogeny, with weak to moderate signals. The morphological disparity index (MDI) values indicated that there were disparities within subclades over time but not between or among them. Niche reconstruction and evolution analysis revealed both convergent and divergent evolution among various variables. For example, N. immutabilis, N. atrans, N. violancea, and N. nouchali evolved towards intermediate temperatures for bio2 and bio3 (isothermity) while moving towards extreme temperatures for bio8 and bio9 (wettest and driest average quarterly temperatures). CONCLUSION: Our study will improve our understanding of how changes in climatic niches are potentially driving the evolution of Nymphaea. It has significant scientific implications for the limits, assemblages, evolution, and diversification of species. This information is crucial for the ongoing efforts of conservation and management, particularly considering the inevitable effects of climate change.

Gravity-Oriented Microfluidic Device for Biocompatible End-to-End Fabrication of Cell-Laden Microgels.

Droplet microfluidics are extensively utilized to generate monodisperse cell-laden microgels in biomedical applications. However, maintaining cell viability is still challenging due to overexposure to harsh conditions in subsequent procedures that recover the microgels from the oil phase. Here, a gravity-oriented microfluidic device for end-to-end fabrication of cell-laden microgels is reported, which integrates dispersion, gelation, and extraction into a continuous workflow. This innovative on-chip extraction, driven by native buoyancy and kinetically facilitated by pseudosurfactant, exhibits 100% retrieval efficiency for microgels with a wide range of sizes and stiffnesses. The viability of encapsulated cells is perfectly maintained at ≈98% with minimal variations within and between batches. The end-to-end fabrication remarkably enhances the biocompatibility and practicality of microfluidics-based cell encapsulation and is promising to be compatible with various applications ranging from single-cell analysis to clinical therapy.

Fabrication and Performance of Bubble-Containing Multicompartmental Particles: Novel Self-Orienting Carriers.

In this work, a class of bubble-containing multicompartmental particles with self-orienting capability is developed, where a single bubble is enclosed at the top of the super-segmented architecture. Such bubbles, driven by potential energy minimization, cause the particles to have a bubble-upward preferred orientation in liquid, enabling efficient decoding of their high-density signals in an interference-resistant manner. The particle preparation involves bubble encapsulation via the impact of a multicompartmental droplet on the liquid surface and overall stabilization via rational crosslinking. The conditions for obtaining these particles are systematically investigated. Methodological compatibility with materials is demonstrated by different hydrogel particles. Finally, by encapsulating cargoes of interest, these particles have found broad applications in actuators, multiplexed detection, barcodes, and multicellular systems.

Magnetic detection under high pressures using designed silicon vacancy centres in silicon carbide.

Pressure-induced magnetic phase transitions are attracting interest as a means to detect superconducting behaviour at high pressures in diamond anvil cells, but determining the local magnetic properties of samples is a challenge due to the small volumes of sample chambers. Optically detected magnetic resonance of nitrogen vacancy centres in diamond has recently been used for the in situ detection of pressure-induced phase transitions. However, owing to their four orientation axes and temperature-dependent zero-field splitting, interpreting these optically detected magnetic resonance spectra remains challenging. Here we study the optical and spin properties of implanted silicon vacancy defects in 4H-silicon carbide that exhibit single-axis and temperature-independent zero-field splitting. Using this technique, we observe the magnetic phase transition of Nd2Fe14B at about 7 GPa and map the critical temperature-pressure phase diagram of the superconductor YBa2Cu3O6.6. These results highlight the potential of silicon vacancy-based quantum sensors for in situ magnetic detection at high pressures.

Arc discharge method to fabricate large concave structures for open-access fiber Fabry-Pérot cavities.

We present a novel micro-fabrication technique for creating concave surfaces on the endfacets of photonic crystal fibers. A fiber fusion splicer is used to generate arc discharges to melt and reshape the fiber endfacet. This technique can produce large spherical concave surfaces with roughness as low as 0.12 nm in various types of photonic crystal fibers. The deviation of fabricated surface and a spherical profile in the region of 70 µm in diameter is less than 50 nm. The center of the concave surface and the fiber mode field are highly coincident with a deviation less than 500 nm. Finesse measurements have shown that a Fabry-Pérot cavity composed of the fiber fabricated using this method and a plane mirror maintains finesse of 20000. This method is easy to replicate, making it a practical and efficient approach to fabricate concave surface on fibers for open-access fiber Fabry-Pérot cavities.

Activation of ß2-adrenergic receptors prevents AD-type synaptotoxicity via epigenetic mechanisms.

We previously reported that prolonged exposure to an enriched environment (EE) enhances hippocampal synaptic plasticity, with one of the significant mechanistic pathways being activation of ß2-adrenergic receptor (ß2-AR) signaling, thereby mitigating the synaptotoxic effects of soluble oligomers of amyloid ß-protein (oAß). However, the detailed mechanism remained elusive. In this work, we recorded field excitatory postsynaptic potentials (fEPSP) in the CA1 region of mouse hippocampal slices treated with or without toxic Aß-species. We found that pharmacological activation of ß2-AR, but not ß1-AR, selectively mimicked the effects of EE in enhancing LTP and preventing oAß-induced synaptic dysfunction. Mechanistic analyses showed that certain histone deacetylase (HDAC) inhibitors mimicked the benefits of EE, but this was not seen in ß2-AR knockout mice, suggesting that activating ß2-AR prevents oAß-mediated synaptic dysfunction via changes in histone acetylation. EE or activation of ß-ARs each decreased HDAC2, whereas Aß oligomers increased HDAC2 levels in the hippocampus. Further, oAß-induced inflammatory effects and neurite degeneration were prevented by either ß2-AR agonists or certain specific HDAC inhibitors. These preclinical results suggest that activation of ß2-AR is a novel potential therapeutic strategy to mitigate oAß-mediated features of AD.

A H2O2 Oxidation Approach to Ti3C2/TiO2 for Efficient Photocatalytic Removal of Distinct Organic Pollutants in Water.

To develop versatile photocatalysts for efficient degradation of distinct organic pollutants in water is a continuous pursuit in environment remediation. Herein, we directly oxidize Ti3C2 MXene with hydrogen peroxide to produce C-doped anatase TiO2 nanowires with aggregates maintaining a layered architecture of the MXene. The Ti3C2 MXene provides a titanium source for TiO2, a carbon source for in situ C-doping, and templates for nanowire aggregates. Under UV light illumination, the optimized Ti3C2/TiO2 exhibits a reaction rate constant 1.5 times that of the benchmark P25 TiO2 nanoparticles, toward photocatalytic degradations of trace phenol in water. The mechanism study suggests that photogenerated holes play key roles on the phenol degradation, either directly oxidizing phenol molecules or in an indirect way through oxidizing first the surface hydroxyl groups. The unreacted Ti3C2 MXene, although with trace amounts, is supposed to facilitate electron transfer, which inhibits charge recombination. The unique nanostructure of layered aggregates of nanowires, abundant surface oxygen vacancies arising from the carbon doping, and probably the Ti3C2/TiO2 heterojunction guarantee the high photocatalytic efficiency toward removals of organic pollutants in water. The photocatalyst also exhibits an activity superior to, or at least comparable to, the benchmark P25 TiO2 toward photodegradations for typical persistent organic pollutants of phenol, dye molecule of rhodamine B, antibiotic of tetracycline, pharmaceutical wastewater of ofloxacin, and pesticide of N,N-dimethylformamide, when evaluated in total organic carbon removal.

Inubritantrimers A-D: Trimerized Sesquiterpenoid [4 + 2] Adducts Featuring a Distinctive Spiro-Polycyclic Scaffold from Inula britannica.

Inubritantrimer A (1), a trace trimerized sesquiterpenoid [4 + 2] adduct featuring an unusual exo-exo type spiro-polycyclic scaffold, together with three new endo-exo [4 + 2] adducts, inubritantrimers B-D (2-4), were discovered from the flowers of Inula britannica. Their structures were elucidated using 1D/2D NMR, X-ray diffraction, and ECD approaches. 1 is characterized as a novel exo-exo trimer, synthesized biogenetically from three sesquiterpenoid monomers, featuring a unique linkage of C-11/C-1', C-13/C-3' and C-13'/C-3″, C-11'/C-1″ through a two-step exo [4 + 2] cycloaddition process. Compounds 1-4 exhibited modest cytotoxicity against breast cancer cells with IC50 values in the range of 5.84-12.01 µM.

Robust Crystal Phase Separation with Distinct Charge, Orbital, and Spin Orders in AgMn7O12.

An AA'3B4O12-type A-site-ordered quadruple perovskite oxide AgMn7O12 was prepared by high-pressure and high-temperature methods. At room temperature, the compound crystallizes into a cubic Im3̅ symmetry with a charge distribution of AgMn33+Mn43.5+O12. With the temperature decreasing to TCO,OO ≈ 180 K, the compound undergoes a structural phase transition toward a monoclinic C2/m symmetry, giving rise to a B-site charge- and orbital-ordered AgMn33+Mn23+Mn24+O12 phase. Moreover, this charge-/orbital-ordered main phase coexists with the initial cubic AgMn33+Mn43.5+O12 phase in the wide temperature range we measured. The charge-/orbital-ordered phase shows two antiferromagnetic phase transitions near 125 and 90 K, respectively. Short-range ferromagnetic correlations are found to occur for the initial B-site mixed cubic phase around 35 K. Because of the robust phase separation, considerable magnetoresistance effects are observed below TCO,OO in AgMn7O12.

Triethyl amine as an effective reducing agent for sulfoxide deoxygenation.

Enabled by triethyl amine (Et3N) and thionyl chloride (SOCl2), an efficient and practical protocol for deoxygenation of sulfoxide to sulfide was developed. This new method features a wide range of substrate scope, including diaryl, dialkyl and aryl alkyl substituted sulfoxides. Detailed mechanistic investigations reveal the crucial role played by Et3N as an electron-donating reductant rather than a hydrogen-atom donor.

Lipid Metabolites as Potential Regulators of the Antibiotic Resistome in Tetramorium caespitum.

Antibiotic resistance genes (ARGs) are ancient but have become a modern critical threat to health. Gut microbiota, a dynamic reservoir for ARGs, transfer resistance between individuals. Surveillance of the antibiotic resistome in the gut during different host growth phases is critical to understanding the dynamics of the resistome in this ecosystem. Herein, we disentangled the ARG profiles and the dynamic mechanism of ARGs in the egg and adult phases of Tetramorium caespitum. Experimental results showed a remarkable difference in both gut microbiota and gut resistome with the development of T. caespitum. Meta-based metagenomic results of gut microbiota indicated the generalizability of gut antibiotic resistome dynamics during host development. By using Raman spectroscopy and metabolomics, the metabolic phenotype and metabolites indicated that the biotic phase significantly changed lipid metabolism as T. caespitum aged. Lipid metabolites were demonstrated as the main factor driving the enrichment of ARGs in T. caespitum. Cuminaldehyde, the antibacterial lipid metabolite that displayed a remarkable increase in the adult phase, was demonstrated to strongly induce ARG abundance. Our findings show that the gut resistome is host developmental stage-dependent and likely modulated by metabolites, offering novel insights into possible steps to reduce ARG dissemination in the soil food chain.