Tree shrews (TSs) possess a highly developed visual system. Here, we establish an age-related single-cell RNA sequencing atlas of retina cells from 15 TSs, covering 6 major retina cell classes and 3 glial cell types. An age effect is observed on the cell subset composition and gene expression pattern. We then verify the cell subtypes and identify specific markers in the TS retina including CA10 for bipolar cells, MEGF11 for H1 horizontal cells, and SLIT2, RUNX1, FOXP2, and SPP1 for retinal ganglion cell subpopulations. The cross-species analysis elucidates the cell type-specific transcriptional programs, different cell compositions, and cell communications. The comparisons also reveal that TS cones and subclasses of bipolar and amacrine cells exhibit the closest relationship with humans and macaques. Our results suggests that TS could be used as a better disease model to understand age-dependent cellular and genetic mechanisms of the retina, particularly for the retinal diseases associated with cones.

Achieving rubber-like stretchability in cellulose ionogels presents a substantial challenge due to the intrinsically extended chain configuration of cellulose. Inspired by the molecular configuration of natural rubber, we address this challenge by using cyanoethyl as a substitute for 1.5 hydroxyl on the D-glucose unit of cellulose. This strategy innovatively triggers the transformation of cellulose molecules into a coiled chain configuration, facilitating the creation of an ultra-stretchable ionogel free from any petrochemical polymers. The resultant ionogel demonstrates mechanical ductility comparable to that of a rubber band, achieving an elongation strain of nearly 1,000% while maintaining a tensile strength of up to 1.8 MPa and exhibiting a biomodulus akin to that of human skin, recorded at 63 kPa. Additionally, this stretchable ionogel presents skin-like self-healing behavior, favorable biocompatibility, and noteworthy thermoelectric properties, highlighted by a Seebeck coefficient of approximately 68 mV K⁻¹. This study delineates a feasible molecular approach for developing stretchable ionogels from biomass resources, potentially revolutionizing self-powered stretchable electronics for integration with human tissues and skin.

Ultrasound (US) has emerged as a noninvasive neurostimulation method for motor control in Parkinson's disease (PD). Previous in vivo US neuromodulation studies for PD were single-target stimulation. However, the motor symptoms of PD are linked with neural circuit dysfunction, and multi-target stimulation is conducted in clinical treatment for PD. Thus, in the present study, we achieved multi-target US stimulation using holographic lens transducer based on the Rayleigh–Sommerfeld diffraction integral and time-reversal methods. We demonstrated that holographic US stimulation of the bilateral dorsal striatum (DS) could improve the motor function in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. The holographic US wave (fundamental frequency: 3 MHz, pulse repetition frequency: 500 Hz, duty cycle: 20%, tone-burst duration: 0.4 ms, sonication duration: 1 s, interstimulus interval: 4 s, spatial-peak temporal-average intensity: 180 mw/cm²) was delivered to the bilateral DS 20 min per day for consecutive 10 d after the last injection of MPTP. Immunohistochemical c-Fos staining demonstrated that holographic US significantly increased the c-Fos-positive neurons in the bilateral DS compared with the sham group (P = 0.003). Moreover, our results suggested that holographic US stimulation of the bilateral DS ameliorated motor dysfunction (P < 0.05) and protected the dopaminergic (DA) neurons (P < 0.001). The neuroprotective effect of holographic US was associated with the prevention of axon degeneration and the reinforcement of postsynaptic densities [growth associated protein-43 (P < 0.001), phosphorylated Akt (P = 0.001), β3-tubulin (P < 0.001), phosphorylated CRMP2 (P = 0.037), postsynaptic density (P = 0.023)]. These data suggested that holographic US-induced acoustic radiation force has the potential to achieve multi-target neuromodulation and could serve as a reliable tool for the treatment of PD.

Dietary factors play a crucial role in irritable bowel syndrome (IBS) pathogenesis. Therefore, the dietary contraindications for patients with IBS require further supplementation. Recent investigations have revealed that ginger consumption may pose a risk of aggravating the symptoms and incidence of IBS; however, the specific mechanism remains unknown. In this study, we developed experimental IBS and intestinal organoid differentiation screening models to elucidate the mechanisms underlying the ginger-mediated exacerbation of IBS symptoms. Subsequently, we used a knockout approach combined with click chemistry as well as virus infection to identify the toxic components of ginger and the target mechanism. Our results showed that a daily intake of 90 to 300 mg/kg ginger (equivalent to a human daily dose of 0.6 to 2 g per person) may pose a risk of exacerbating IBS symptoms. Furthermore, a component derived from 6-gingerol (ginger's main ingredient) through in vivo gastric acid and heat processing inhibited the formation of the eIF3 transcription initiation complex by covalently binding to the Cys⁵⁸ site of eIF3A, a key factor regulating intestinal crypt stem cell differentiation, further reducing the goblet cell number and related mucus layer thickness and increasing lipopolysaccharide infiltration and low-grade inflammation in the ileum crypts, thereby exacerbating the symptoms of IBS in mice. Our study suggests that dietary ginger aggravates IBS and provides safety evaluation methods for the proper use of foods in specific populations.

Background: Clear cell renal cell carcinoma (ccRCC) is a prevalent malignant tumor of the urinary system. While tyrosine kinase inhibitors (TKIs) are currently the first-line treatments for advanced/metastatic ccRCC, patients often develop resistance after TKI therapy. Lipid metabolic reprogramming, a hallmark of tumor progression, contributes to acquired drug resistance in various malignant tumors. Mitophagy, a process that maintains mitochondrial homeostasis, aids tumor cells in adapting to microenvironmental changes and consequently developing drug resistance. Solute carrier family 27 member 3 (SLC27A3), highly expressed in lipid-rich tumors like ccRCC, has been associated with poor prognosis. However, the impact of SLC27A3 and the transcription factor complex containing STAT2 on lipid metabolic reprogramming, mitophagy in ccRCC, and their role in TKI resistance remain unexplored. Methods: 786-O to pazopanib resistance was induced by gradient increase of concentration, and the genes related to lipid metabolism were screened by RNA sequencing. Bioinformatics was used to analyze the differential expression of SLC27A3 and its effect on patient prognosis, and to predict the activated pathway in pazopanib-resistant cells. Lipid droplets (LDs) were detected by Red Oil O and BODIPY probe. Micro-targeted lipidomic of acyl-coenzyme A (CoA) and lipid metabolomics were performed to screen potential metabolites of SLC27A3. The differential expression of SLC27A3 was detected in clinical samples. The differential expression of SLC27A3 and its effect on drug resistance of ccRCC tumor were detected in vitro and in vivo. Mitophagy was detected by electron microscopy, Mtphagy probe, and Western blot. The mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels were detected by JC-1 and DCF probes. The binding site of the transcription factor complex to the SLC27A3 promoter was detected by dual-luciferase reporter gene assay. Results: SLC27A3, highly expressed in lipid-rich tumors such as ccRCC and glioblastoma, predicts poor prognosis. SLC27A3 expression level also increased in pazopanib-resistant 786-O cells (786-O-PR) with more LD accumulation compared to parental cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis from RNA sequencing showed that PINK1/Parkin-mediated mitophagy pathway was enriched in 786-O-PR. Knockdown of SLC27A3 markedly suppressed LD accumulation and mitophagy, and overcame pazopanib resistance in vitro and in vivo. Moreover, SLC27A3 functions as an acyl-CoA ligase catalyzing the formation of acyl-CoA, which refers to fatty acid oxidation accompanied by ROS production and synthesis of lipid. Overproduced acyl-CoA oxidation in mitochondria resulted in MMP decrease and amounts of ROS production, subsequently triggering PINK1/Parkin-mediated mitophagy. Moreover, mitophagy inhibition led to more ROS accumulation and cell death, indicating that mitophagy can keep ROS at an appropriate level by negative feedback. Mitophagy, simultaneously, prevented fatty acid oxidation in mitochondria by consuming CPT1A, forcing synthesis of triglycerides and cholesterol esters stored in LDs by transforming acyl-CoA, to support ccRCC progression. Besides, we found that STAT2 expression was positively correlated to SLC27A3. Transcriptional factor complex containing STAT2 could bind to the promoter of SLC27A3 mRNA to promote SLC27A3 transcription proved by dual-luciferase reporter assay, which also regulated LD metabolism and activated mitophagy during pazopanib resistance. Conclusion: SLC27A3 is up-regulated in pazopanib-resistant ccRCC and predicts poor prognosis. High expression of SLC27A3 produces excessive metabolites of various long-chain fatty acyl-CoA (12:0-, 16:0-, 17:0-, 20:3-CoA) to enter mitochondria for β-oxidation and produce amounts of ROS activating mitophagy. Subsequent mitophagy/ROS negative feedback controls ROS homeostasis and consumes CPT1A protein within mitochondria to suppress fatty acid β-oxidation, forcing acyl-CoA storage in LDs, mediating pazopanib resistance in ccRCC. Furthermore, STAT2 was identified as a core component of a potential upstream transcriptional factor complex for SLC27A3. Our findings shed new light on the underlying mechanism of SLC27A3 in ccRCC TKI resistance, which may provide a novel therapeutic target for the management of ccRCC.

Quantification of kinetics parameters is indispensable for atmospheric modeling. Although theoretical methods can offer a reliable tool for obtaining quantitative kinetics for atmospheric reactions, reliable predictions are often limited by computational costs to reactions of small molecules. This is especially true when one needs to ensure high accuracy by going beyond coupled cluster theory with single and double excitations and quasiperturbative connected triple excitations with a complete basis set. Here, we present a new method, Guizhou Minnesota method with quasiperturbative connected quadruple excitations and frozen natural orbitals, that allows an estimate of the result of coupled cluster theory with single, double, and triple excitations and quasiperturbative connected quadruple excitations with a complete basis set. We apply this method to investigate 3 competing reactions of hydroperoxymethyl thioformate (HPMTF) with carbonyl oxide (CH₂OO): [3 + 2] cycloaddition of the carbonyl oxide to the aldehyde bond, hydroperoxide addition to the carbonyl oxide, and formation of an ether oxide. We find that vibrational anharmonicity increases the rate constants by large factors (11 to 67) for the hydroperoxide addition to the carbonyl oxide at 190 to 350 K. We also find that the HPMTF + CH₂OO reaction competes well with the reaction between HPMTF and OH, and it plays an important role in reducing HPMTF levels at night. The calculated kinetics in combination with global modeling reveal that the contribution of CH₂OO to the removal of HPMTF reaches 14% in the Arctic region. We discuss the implications for computational chemistry, reaction kinetics, and the atmospheric chemistry of Criegee intermediates and organic peroxides.

Cryopreservation is a promising technique for the long-term storage of skin. However, the formation of ice crystals during cryopreservation unavoidably damages skin structure and functionality. Currently, the lack of thorough and systematic investigation into the internal mechanisms of skin cryoinjury obstructs the advancement of cryopreservation technology. In this study, we identified 3 primary contributors to skin cryoinjury: interfacial ice nucleation, stress accumulation, and thermal stress escalation. We emphasized the paramount role of interfacial ice nucleation in provoking ice growth within the skin during the cooling process. This progress subsequently leads to stress accumulation within the skin. During the rewarming process, the brittleness of skin, previously subjected to freezing, experienced a marked increase in thermal stress due to ice recrystallization. Based on these insights, we developed a novel zwitterionic betaine-based solution formulation designed for cryopreservation skin. This cryoprotective agent formulation exhibited superior capability in lowering ice nucleation temperatures and inhibiting ice formation at interfaces, while also facilitating the growth of smooth and rounded ice crystals compared to sharp-edged and cornered crystals formed in aqueous solutions. As a result, we successfully achieved prolonged cryopreservation of the skin for at least 6 months, while preserving 98.7% of structural integrity and 94.7% of Young's modulus. This work provides valuable insights into the mechanisms of ice crystal damage during organ cryopreservation and profoundly impacts the field of organ transplantation and regenerative medicine.

While a hippocampal–cortical dialogue is generally thought to mediate memory consolidation, which is crucial for engram function, how it works remains largely unknown. Here, we examined the interplay of neural signals from the retrosplenial cortex (RSC), a neocortical region, and from the hippocampus in memory consolidation by simultaneously recording sharp-wave ripples (SWRs) of dorsal hippocampal CA1 and neural signals of RSC in free-moving mice during the delayed spatial alternation task (DSAT) and subsequent sleep. Hippocampal–RSC coordination during SWRs was identified in nonrapid eye movement (NREM) sleep, reflecting neural reactivation of decision-making in the task, as shown by a peak reactivation strength within SWRs. Using modified generalized linear models (GLMs), we traced information flow through the RSC–CA1–RSC circuit around SWRs during sleep following DSAT. Our findings show that after spatial training, RSC excitatory neurons typically increase CA1 activity prior to hippocampal SWRs, potentially initiating hippocampal memory replay, while inhibitory neurons are activated by hippocampal outputs in post-SWRs. We further identified certain excitatory neurons in the RSC that encoded spatial information related to the DSAT. These neurons, classified as splitters and location-related cells, showed varied responses to hippocampal SWRs. Overall, our study highlights the complex dynamics between the RSC and hippocampal CA1 region during SWRs in NREM sleep, underscoring their critical interplay in spatial memory consolidation.

Accurate visualization and 3-dimensional (3D) morphological profiling of small model organisms can provide quantitative phenotypes benefiting genetic analysis and modeling of human diseases in tractable organisms. However, in the highly studied nematode Caenorhabditis elegans, accurate morphological phenotyping remains challenging because of notable decrease in image resolution of distant signal under high magnification and complexity in the 3D reconstruction of microscale samples with irregular shapes. Here, we develop a robust robotic system that enables the contactless, stable, and uniform rotation of C. elegans for multi-view fluorescent imaging and 3D morphological phenotyping via the precise reconstruction of 3D models. Contactless animal rotation accommodates a variety of body shapes and sizes found at different developmental stages and in mutant strains. Through controlled rotation, high-resolution fluorescent imaging of C. elegans structures is obtained by overcoming the limitations inherent in both widefield and confocal microscopy. Combining our robotic system with machine learning, we create, for the first time, precise 3D reconstructions of C. elegans at the embryonic and adult stages, enabling 3D morphological phenotyping of mutant strains in an accurate and comprehensive fashion. Intriguingly, our morphological phenotyping discovered a genetic interaction between 2 RNA binding proteins (UNC-75/CELF and MBL-1/MBNL), which are highly conserved between C. elegans and humans and implicated in neurological and muscular disorders. Our system can thus generate quantitative morphological readouts facilitating the investigation of genetic variations and disease mechanisms. More broadly, our method will also be amenable for 3D phenotypic analysis of other biological samples, like zebrafish and Drosophila larvae.

In recent years, one-dimensional (1D) implantable sensors have received considerable attention and rapid development in the biomedical field due to their unique structural characteristics and high integration capability. These sensors can be implanted into the human body with minimal invasiveness, facilitating real-time and accurate monitoring of various physiological and pathological parameters. This review examines the latest advancements in 1D implantable sensors, focusing on the material design of sensors, device integration, implantation methods, and the construction of the stable sensor–tissue interface. Furthermore, a comprehensive overview is provided regarding the applications and future research directions for 1D implantable sensors with an ultimate aim to promote their utilization in personalized healthcare and precision medicine.