RESUMEN

The symptoms of fragile X syndrome (FXS), caused by a single gene mutation to Fmr1, have been increasingly linked to disordered astrocyte signalling within the cerebral cortex. We have recently demonstrated that the purinergic signalling pathway, which utilizes nucleoside triphosphates and their metabolites to facilitate bidirectional glial and glial-neuronal interactions, is upregulated in cortical astrocytes derived from the Fmr1 knockout (KO) mouse model of FXS. Heightened Fmr1 KO P2Y purinergic receptor levels were correlated with prolonged intracellular calcium release, elevated synaptogenic protein secretion, and hyperactivity of developing circuits. However, due to the relative lack of sensitive and reproducible quantification methods available for measuring purines and pyrimidines, determining the abundance of these factors in Fmr1 KO astrocytes was limited. We therefore developed a hydrophilic interaction liquid chromatography protocol coupled with mass spectrometry to compare the abundance of intracellular and extracellular purinergic molecules between wildtype and Fmr1 KO mouse astrocytes. Significant differences in the concentrations of UDP, ATP, AMP, and adenosine intracellular stores were found within Fmr1 KO astrocytes relative to WT. The extracellular level of adenosine was also significantly elevated in Fmr1 KO astrocyte-conditioned media in comparison to media collected from WT astrocytes. Glycosylation of the astrocyte membrane-bound CD39 ectonucleotidase, which facilitates ligand breakdown following synaptic release, was also elevated in Fmr1 KO astrocyte cultures. Together, these differences demonstrated further dysregulation of the purinergic signalling system within Fmr1 KO cortical astrocytes, potentially leading to significant alterations in FXS purinergic receptor activation and cellular pathology.

Asunto(s)

RESUMEN

We analyzed multidimensional biodiversity (including species diversity, functional diversity, and phylogenetic diversity) of needle-broadleaf mixed forests of Abies fargesii var. faxoniana-Betula spp. and needleleaf forests of A. fargesii var. faxoniana in the subalpine regions of eastern edge of Qinghai-Tibet Plateau. We measured leaf functional traits including leaf area, leaf thickness, leaf dry matter content, and specific leaf area. The results showed that leaf thickness (0.28 mm) and leaf dry matter content (319.86 mg·g-1) in the needle-broadleaf mixed forests were significantly lower than in the needleleaf forest (0.39 mm and 371.33 mg·g-1, respectively), while specific leaf area (192.74 cm2·g-1) was significantly higher (100.91 cm2·g-1). Leaf area showed no significant difference between the two forest communities (27.88 and 26.63 cm2, respectively). The phylogenetic signals of all leaf functional traits were significant, except for leaf thickness. The phylogenetic structure of the needle-broadleaf mixed forests and needleleaf forest communities tended toward divergence. Shannon diversity index, Simpson diversity index, species richness, functional richness, functional dispersion, Rao's quadratic entropy, and phylogenetic diversity in the needle-broadleaf mixed forests were all significantly higher than in the needleleaf forest, and these indices were significantly positively correlated. Competitive exclusion played a major role in the assembly of subalpine forest communities, and species diversity, functional diversity, and phylogenetic diversity exhibited synchrony.

Asunto(s)

RESUMEN

The recurrence of glioma after treatment has remained an intractable problem for many years. Recently, numerous studies have explored the pivotal role of the mouse double minute 2 (MDM2)/p53 pathway in cancer treatment. Lysine phosphate phosphohistidine inorganic pyrophosphate phosphatase (LHPP), a newly discovered tumor suppressor, has been confirmed in numerous studies on tumors, but its role in glioma remains poorly understood. Expression matrices in The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases were analyzed using gene set enrichment analysis (GSEA), revealing significant alterations in the p53 pathway among glioma patients with high LHPP expression. The overexpression of LHPP in glioma cells resulted in a reduction in cell proliferation, migration, and invasive ability, as well as an increase in apoptosis and alterations to the cell cycle. The present study has identified a novel inhibitory mechanism of LHPP against glioma, both in vivo and in vitro. The results demonstrate that LHPP exerts anti-glioma effects via the MDM2/p53 pathway. These findings may offer a new perspective for the treatment of glioma in the clinic.

RESUMEN

In this study, four machine learning (ML) prediction models were developed to predict and optimize the production performance of caproic acid based on substrates, products, and process parameters. The XGBoost outperformed others, with a high R2 of 0.998 on the training set and 0.885 on the test set. Feature importance analysis revealed hydraulic retention time (HRT) and butyric acid concentration are decisive. The SHAP method offered profound insights into the interplay and cumulative effects of substrate composition, identified the synergistic effects between butyric acid and lactic acid, and emphasized adding glucose can benefit caproic with lactic acid co-fermentation. By integrating the Adaptive Variation Particle Swarm Optimization (AVPSO) algorithm, the optimal process conditions to achieve a maximum caproic acid production of 8.64 g/L was obtained. This study not only advances caproic acid production but contributes a versatile ML-driven strategy applicable to bioprocess optimizations, potentially transformative for sustainable and economically viable bioproduction.

Asunto(s)

RESUMEN

The use of highly tensile and self-healing conductive composites has gained considerable interest due to their wide range of applications in healthcare, sensors, and robotics. Epoxidized natural rubber (ENR), known for its ability to undergo highly reversible deformation, can be utilized in strain sensors to effectively transmit a broader range of signal changes. In this study, we introduced a self-healing ENR composite specifically designed for high-strain sensors. The rubber molecular chains were enhanced with hydrogen bonds and metal coordination bonds, allowing the matrix material to autonomously repair itself through these interactions. Following a repair period of 12 h at 45 °C, the composites achieve a repair efficiency exceeding 90%. Furthermore, by incorporating conductive fillers into the matrix using multistage layering, the resulting composite has good electrical conductivity, thermal conductivity, and hydrophobicity. In addition, this composite presents good sensitivity even at large strain (strain in the range of 50-200%, GF = 7.65). In conclusion, this self-healing nanocomposite, characterized by its high strain sensitivity, holds immense potential for various strain sensor applications.

RESUMEN

Spin-mechanical coupling is vital in diverse fields including spintronics, sensing, and quantum transduction. Two-dimensional (2D) magnetic materials provide a unique platform for investigating spin-mechanical coupling, attributed to their mechanical flexibility and novel spin orderings. However, studying their spin-mechanical coupling presents challenges in probing mechanical deformation and thermodynamic property changes at the nanoscale. Here we use nano-optoelectromechanical interferometry to mechanically detect the phase transition and magnetostriction effect in multilayer CrSBr, an air-stable antiferromagnet with large magnon-exciton coupling. The transitions among antiferromagnetism, spin-canted ferromagnetism, and paramagnetism are visualized. Nontrivial magnetostriction coefficient 2.3 × 10-5 and magnetoelastic coupling strength on the order of 106 J/m3 have been found. Moreover, we demonstrate the substantial tunability of the magnetoelastic constant by nearly 50% via gate-induced strain. Our findings demonstrate the strong spin-mechanical coupling in CrSBr and pave the way for developing sensitive magnetic sensing and efficient quantum transduction at the atomically thin limit.

RESUMEN

Given the growing interest in the metabolic heterogeneity of hepatocellular carcinoma (HCC) and portal vein tumour thrombus (PVTT). This study comprehensively analysed the metabolic heterogeneity of HCC, PVTT, and normal liver samples using multi-omics combinations. A single-cell RNA sequencing dataset encompassing six major cell types was obtained for integrated analysis. The optimal subtypes were identified using cluster stratification and validated using spatial transcriptomics and fluorescent multiplex immunohistochemistry. Then, a combined index based meta-cluster was calculated to verify its prognostic significance using multi-omics data from public cohorts. Our study first depicted the metabolic heterogeneity landscape of non-malignant cells in HCC and PVTT at multiomics levels. The optimal subtypes interpret the metabolic characteristics of PVTT formation and development. The combined index provided effective predictions of prognosis and immunotherapy responses. Patients with a higher combined index had a relatively poor prognosis (p <0.001). We also found metabolism of polyamines was a key metabolic pathway involved in conversion of metabolic heterogeneity in HCC and PVTT, and identified ODC1 was significantly higher expressed in PVTT compared to normal tissue (p =0.03). Our findings revealed both consistency and heterogeneity in the metabolism of non-malignant cells in HCC and PVTT. The risk stratification based on cancer-associated fibroblasts and myeloid cells conduce to predict prognosis and guide treatment. This offers new directions for understanding disease development and immunotherapy responses.

RESUMEN

Cataract patients look forwards to fewer postoperative complications and higher vision quality after surgery. However, the current intraocular lens (IOL) implanted after cataract surgery neither can adjust focal length in response to ciliary muscle contraction as natural lens nor have the ability to prevent postoperative complications. Herein, a thermosensitve Poloxamer based hybrid hydrogel with antibacterial anti-inflammatory and photothermal functional elements doping was designed and used as injectable, in situ curable, and adjustable IOL (FHTAB IOL). The FHTAB IOL was composed of thermosensitve triblock-polymer F127DA and a small amount of HAMA, combined with BP NS, TA, and Ag NPs. FHTAB IOL can be injected into the empty lens capsule after cataract surgery via an injectable thermos-gel under NIR illumination and then be rapidly cured to form a full-size IOL under short-time blue light irradiation. The designed injectable FHTAB IOL possesses high transparency and transmittance, with a refractive index similar to the natural lens and adjustable properties. It was stabilized as a refractive medium without any leakage in the eye. In addition, the TA and Ag NPs loaded in the FHTAB IOL displayed significant antibacterial and anti-inflammatory effects in vitro and vivo. This study presents a potentially effective new strategy for the development of multifunctional adjustable IOLs.

RESUMEN

Fungi have historically been the source of numerous important medicinal compounds, but full exploitation of their genetic potential for drug development has been hampered in traditional discovery paradigms. Here we describe a radically different approach, top-down drug discovery (TD3), starting with a massive digital search through a database of over 100,000 fully genomicized fungi to identify loci encoding molecules with a predetermined human target. We exemplify TD3 by the selection of cyclin-dependent kinases (CDKs) as targets and the discovery of two molecules, 1 and 2, which inhibit therapeutically important human CDKs. 1 and 2 exhibit a remarkable mechanism, forming a site-selective covalent bond to the CDK active site Lys. We explored the structure-activity relationship via semi- and total synthesis, generating an analog, 43, with improved kinase selectivity, bioavailability, and efficacy. This work highlights the power of TD3 to identify mechanistically and structurally novel molecules for the development of new medicines.

Asunto(s)

RESUMEN

Lipid nanoparticles encapsulating mRNA (LNP-mRNA) revolutionized medicine over the past several years. While clinically approved indications currently focus on infectious disease vaccination, LNP-mRNA based treatments also hold promise for cancer immunotherapy. However, the route of dosing may impact treatment efficacy, safety, and dose. To minimize adverse effects, it is hypothesized that LNP-mRNA can be used to activate and engineer dendritic cells (DC) ex vivo before re-administration of these cells. Here, it is shown that LNP-mRNA engineered DCs can indeed vaccinate recipient mice. Vaccinated mice showed strong anti-tumor T cell responses, rejected tumor challenge, and displayed no evidence of toxicity. Further, it is found that DC specific ablation of the immune activating kinase NFkB inducing kinase (NIK) abrogated vaccination efficacy, demonstrating that adoptively transferred DCs can be functionally modified in addition to their antigen presentation capacity. Collectively, these studies show that ex vivo LNP-mRNA engineering of DCs is a feasible and robust therapeutic strategy for cancer.

RESUMEN

With the widespread application of anaerobic digestion technology, biogas slurry become the main source of organic amendments in practice. Comprehensive studies into the inhibitory effects of low molecular weight (LMW) organic acids, essential components in biogas slurry, on the sulfide minerals biooxidation and its bioleaching (AMD) have been lacking. In this study, acetic acid (AA) served as a representative of LMW organic acids in biogas slurry to investigate its impact on the inhibition of chalcopyrite biooxidation by Acidithiobacillus ferrooxidans (A. ferrooxidans). It was shown that AA could slow down the chalcopyrite biooxidation and inhibit the jarosite formation on the mineral surface. Compared with the control group (0 ppm AA), the sulfate increment in the leachate of the 50 ppm, 100 ppm, and 200 ppm AA-treated groups decreased by 36.4%, 66.8%, and 69.0%, respectively. AA treatment (≥50 ppm) could reduce the oxidation of ferrous ions in the leachate by one order of magnitude. At the same time, the bacterial concentration of the leachate in the 50 ppm, 100 ppm, and 200 ppm AA-treated groups decreased by 70%, 93%, and 94%, respectively. These findings provide a scientific basis for new strategies to utilize biogas slurry for mine remediation and contribute to an enhanced comprehension of organic amendments to prevent AMD in situ in mining soil remediation.

Asunto(s)

RESUMEN

Globally, streptococcal disease caused by Streptococcus agalactiae is known for its high mortality rate, which severely limits the development of the tilapia breeding industry. As a third-generation vaccine, DNA vaccines have shown great application prospects in the prevention and control of aquatic diseases, but their low immunogenicity limits their development. The combination of DNA vaccines and molecular adjuvants proved to be an effective method for inducing protective immunity. This study constructed recombinant plasmids encoding tilapia HSP70 and IL-1ß genes (pcHSP70 and pcIL-1ß) to verify their effectiveness as molecular adjuvants for S. agalactiae DNA vaccine (pcSIP) in the immunized tilapia model. The results revealed that serum-specific IgM production, enzyme activities, and immune-related gene expression in tilapia immunized with pcSIP plus pcHSP70 or pcIL-1ß were significantly higher than those in tilapia immunized with pcSIP alone. It is worth noting that combination with molecular adjuvants improved the immune protection of DNA vaccines, with a relative percentage survival (RPS) of 51.72% (pcSIP plus pcHSP70) and 44.83% (pcSIP plus pcIL-1ß), respectively, compared with that of pcSIP alone (24.14%). Thus, our study indicated that HSP70 and IL-1ß in tilapia are promising molecular adjuvants of the DNA vaccine in controlling S. agalactiae infection.

RESUMEN

Activatable probes with a higher signal-to-background ratio and accuracy are essential for monitoring liver cancer as well as intraoperative fluorescence navigation. However, the presence of only one biomarker is usually not sufficient to meet the high requirement of a signal-to-background ratio in cancer surveillance, leading to the risk of misdiagnosis. In this work, a dual-locked activation response probe, Si-NTR-LAP, for nitroreductase and leucine aminopeptidase was reported. This dual-locked probe provides better tumor recognition and a higher signal-to-noise ratio than that of single-locked probes (Si-LAP and Si-NTR). In both the subcutaneous tumor model and the more complex orthotopic hepatocellular carcinoma model, the probe was able to identify tumor tissue with high specificity and accurately differentiate the boundaries between tumor tissue and normal tissue. Therefore, the dual-locked probe may provide a new and practical strategy for applying to real patient tumor tissue samples.

Asunto(s)

RESUMEN

The natural abundance of stable carbon and nitrogen isotopes (δ13C and δ15N) in leaves can provide comprehensive information on the physiological and ecological processes of plants and has been widely used in ecological research. However, recent studies on leaf δ13C and δ15N have focused mainly on woody species, few studies have been conducted on herbs in different vegetation types, and their differences and driving factors are still unclear. In this study, we focused on the herbs in subalpine coniferous forests, alpine shrublands, and alpine mea-dows on the eastern Qinghai-Tibet Plateau, and investigated the differences in leaf δ13C and δ15N of herbs and the driving factors. The results showed that there were significant differences in leaf δ13C and δ15N values of herbs among different vegetation types, with the highest δ13C and δ15N values in alpine meadows, followed by alpine shrublands, and the lowest in subalpine coniferous forests. Using variation partitioning analysis, we revealed that differences in leaf δ13C and δ15N of herbs among various vegetation types were driven by both leaf functional traits and climate factors, with the contribution of leaf functional traits being relatively higher than that of climate factors. Hierarchical partitioning results indicated that mean annual temperature (MAT), chlorophyll content index, leaf nitrogen content per unit area (Narea), and leaf mass per area were the main drivers of leaf δ13C variations of herbs across different vegetation types, while the relative importance of Narea and MAT for variation in leaf δ15N of herbs was much higher than those other variables. There was a strong coupling relationship between leaf δ13C and δ15N as indicated by the result of the ordinary least squares regression. Our findings could provide new insights into understanding the key drivers of leaf δ13C and δ15N variations in herbs across different vegetation types.

Asunto(s)

RESUMEN

The human cannot detect light with a wavelength exceeding 700 nm, primarily due to limitations in the physiological structure of the human eye. However, in certain specific scenarios, the ability to detect near-infrared (NIR) light proves to be extremely valuable. To attain this desired capability, NIR up conversion nanoparticles (UCNPs) were prepared and doped in the optical lens materials, aiming to obtain a NIR light "visible" optical lens. It is demonstrated that the doping of UCNPs in the optical lens materials does not significantly impact on their mechanical properties, optical properties, surface properties and it exhibits excellent biocompatibility in cell and animal experiments. More importantly, the UCNPs doping can convert NIR light into visible light within the material effectively and stably. The eyes can "see" the NIR light after wearing such UCNPs doped optical lens. Such NIR light visible optical lens could have great potential in actual applications.

Asunto(s)

RESUMEN

The alewife (Alosa pseudoharengus) is an anadromous herring that inhabits waters of northeastern North America. This prey species is a critical forage for piscivorous birds, mammals, and fishes in estuarine and oceanic ecosystems. During a discovery project tailored to identify potentially emerging pathogens of this species, we obtained the full genome of a novel hepadnavirus (ApHBV) from clinically normal alewives collected from the Maurice River, Great Egg Harbor River, and Delaware River in New Jersey, USA during 2015-2018. This previously undescribed hepadnavirus contained a circular DNA genome of 3146 nucleotides. Phylogenetic analysis of the polymerase protein placed this virus in the clade of metahepadnaviruses (family: Hepadnaviridae; genus: Metahepadnavirus). There was no evidence of pathology in the internal organs of infected fish and virions were not observed in liver tissues by electron microscopy. We developed a Taqman-based quantitative (qPCR) assay and screened 182 individuals collected between 2015 and 2018 and detected additional qPCR positives (n = 6). An additional complete genome was obtained in 2018 and it has 99.4% genome nucleotide identity to the first virus. Single-nucleotide polymorphisms were observed between the two genomes, including 7/9 and 12/8 synonymous vs nonsynonymous mutations across the polymerase and surface proteins, respectively. While there was no evidence that this virus was associated with disease in this species, alewives are migratory interjurisdictional fishes of management concern. Identification of microbial agents using de novo sequencing and other advanced technologies is a critical aspect of understanding disease ecology for informed population management.

Asunto(s)

RESUMEN

OBJECTIVE: Deep brain stimulation (DBS) is a promising approach for the treatment of epilepsy. However, the optimal target for DBS and underlying mechanisms are still not clear. Here, we compared the therapeutic effects of DBS on distinct septal subregions, aimed to find the precise targets of septal DBS and related mechanisms for the clinical treatment. METHODS: Assisted by behavioral test, electroencephalography (EEG) recording and analyzing, selectively neuronal manipulation and immunohistochemistry, we assessed the effects of DBS on the three septal subregions in kainic acid (KA)-induced mouse seizure model. RESULTS: DBS in the medial septum (MS) not only delayed generalized seizure (GS) development, but reduced the severity; DBS in the vertical diagonal band of Broca (VDB) only reduced the severity of GS, while DBS in the horizontal diagonal band of Broca (HDB) subregion showed no anti-seizure effect. Notably, DBS in the MS much more efficiently decreased abnormal activation of hippocampal neurons. EEG spectrum analysis indicated that DBS in the MS and VDB subregions mainly increased the basal hippocampal low-frequency (delta and theta) rhythm. Furthermore, ablation of cholinergic neurons in the MS and VDB subregions blocked the anti-seizure and EEG-modulating effects of septal DBS, suggesting the seizure-alleviating effect of DBS was dependent on local cholinergic neurons. SIGNIFICANCE: DBS in the MS and VDB, rather than HDB, attenuates hippocampal seizure by activation of cholinergic neurons-augmented hippocampal delta/theta rhythm. This may be of great therapeutic significance for the clinical treatment of epilepsy with septal DBS. PLAIN LANGUAGE SUMMARY: The optical target of deep brain stimulation in the septum is still not clear. This study demonstrated that stimulation in the medial septum and vertical diagonal band of Broca subregions, but not the horizontal diagonal band of Broca, could alleviate hippocampal seizure through cholinergic neurons-augmented hippocampal delta/theta rhythm. This study may shed light on the importance of precise regulation of deep brain stimulation therapy in treating epileptic seizures.

Asunto(s)

RESUMEN

All-solid-state lithium batteries with polymer electrolytes suffer from electrolyte decomposition and lithium dendrites because of the unstable electrode/electrolyte interfaces. Herein, a molecule crowding strategy is proposed to modulate the Li+ coordinated structure, thus in situ constructing the stable interfaces. Since 15-crown-5 possesses superior compatibility with polymer and electrostatic repulsion for anion of lithium salt, the anions are forced to crowd into a Li+ coordinated structure to weaken the Li+ coordination with polymer and boost the Li+ transport. The coordinated anions prior decompose to form LiF-rich, thin, and tough interfacial passivation layers for stabilizing the electrode/electrolyte interfaces. Thus, the symmetric Li-Li cell can stably operate over 4360 h, the LiFePO4||Li full battery presents 97.18% capacity retention in 700 cycles at 2 C, and the NCM811||Li full battery possesses the capacity retention of 83.17% after 300 cycles. The assembled pouch cell shows excellent flexibility (stand for folding over 2000 times) and stability (89.42% capacity retention after 400 cycles). This work provides a promising strategy to regulate interfacial chemistry by modulating the ion environment to accommodate the interfacial issues and will inspire more effective approaches to general interface issues for polymer electrolytes.

RESUMEN

Copper is a trace element required by the organism, but once the level of copper exceeds the threshold, it becomes toxic and even causes death. The underlying mechanisms of copper-induced death are inconclusive, with different studies showing different opinions on the mechanism of copper-induced death. Multiple investigations have shown that copper induces oxidative stress, endoplasmic reticulum stress, nucleolar stress, and proteasome inhibition, all of which can result in cell death. The latest research elucidates a copper-dependent death and denominates it as cuproptosis. Cuproptosis takes place through the combination of copper and lipoylated proteins of the tricarboxylic acid cycle, triggering agglomeration of lipoylated proteins and loss of iron-sulfur cluster proteins, leading to proteotoxic stress and ultimately death. Given the toxicity and necessity of copper, abnormal levels of copper lead to diseases such as neurological diseases and cancer. The development of cancer has a high demand for copper, neurological diseases involve the change of copper contents and the binding of copper to proteins. There is a close relationship between these two kinds of diseases and copper. Here, we summarize the mechanisms of copper-related death, and the association between copper and diseases, to better figure out the influence of copper in cell death and diseases, thus advancing the clinical remedy of these diseases.

Asunto(s)

RESUMEN

The repair of bone tissue damage is a complex process that is well-orchestrated in time and space, a focus and difficulty in orthopedic treatment. In recent years, the success of mesenchymal stem cells (MSCs)-mediated bone repair in clinical trials of large-area bone defects and bone necrosis has made it a candidate in bone tissue repair engineering and regenerative medicine. MSCs are closely related to macrophages. On one hand, MSCs regulate the immune regulatory function by influencing macrophages proliferation, infiltration, and phenotype polarization, while also affecting the osteoclasts differentiation of macrophages. On the other hand, macrophages activate MSCs and mediate the multilineage differentiation of MSCs by regulating the immune microenvironment. The cross-talk between MSCs and macrophages plays a crucial role in regulating the immune system and in promoting tissue regeneration. Making full use of the relationship between MSCs and macrophages will enhance the efficacy of MSCs therapy in bone tissue repair, and will also provide a reference for further application of MSCs in other diseases.