A d-peptide ligand of the nicotine acetylcholine receptors (nAChRs), termed DCDX, enables drug delivery to the brain when incorporated into liposomes and has shown promise as a nanocarrier for treating brain diseases. However, few reports have described the mechanisms whereby DCDX-modified liposomes traverse the blood-brain barrier (BBB). Here, we studied the molecular mechanisms enabling DCDX (and its associated liposomes) to cross an in vitro BBB using a simulated cerebral endothelium monolayer formed by brain capillary endothelial cells (bEnd.3 cells). We also examined the mechanisms whereby DCDX-modified liposomes cross the BBB in vivo using the brain efflux-index method. Transport of DCDX and its modified liposomes was dominantly mediated via the lipid raft/caveolae endocytic pathway. Both the endoplasmic reticulum (ER) and Golgi complex participated in delivering DCDX-modified liposomes to the plasma membrane (PM). DCDX-modified liposomes also participated in the endosome/lysosome pathway (with high-efficiency BBB crossing observed in vitro), while competing for the ER/Golgi/PM pathway. In addition, nAChR α7 did not promote the transportation of DCDX-modified liposomes in vivo or in vitro, as assessed with α7-knockout mice and by performing α-bungarotoxin (α-Bgt) binding-competition experiments. P-glycoprotein (P-gp) was identified as the main efflux transporter across the BBB, in vivo and in vitro. Using a xenograft nude mouse model of human glioblastoma multiforme, blocking the efflux function of P-gp with verapamil enhanced the therapeutic efficiency of DCDX-modified liposomes that were formulated with doxorubicin against glioblastoma. The findings of this study reveal novel mechanisms underlying crossing of the BBB by DCDX-modified liposomes, suggesting that DCDX-modified liposomes can potentially serve as a powerful therapeutic tool for treating glioma.

To explore the association between three-dimensional (3D) cardiac magnetic resonance (CMR) feature tracking (FT) right ventricular peak global longitudinal strain (RVpGLS) and major adverse cardiovascular events (MACEs) in patients with stage C or D heart failure (HF) with non-ischaemic dilated cardiomyopathy (NIDCM) but without atrial fibrillation (AF).

Cassiae semen are dried and ripe seeds of Cassia obtusifolia L. or Cassia tora L. (Fabaceae) and have been made into roasted tea or used as a traditional medicine in Asian countries. However, it was reported to result in liver and renal toxicity. The components of Cassiae semen that induce hepatotoxicity or nephrotoxicity remain unknown. In the present study, we evaluate the potential toxicity of 26 newly isolated compounds from Cassiae semen using quantitative structure-activity relationship (QSAR) methods and co-culture of hepatic and renal cell approaches, and we aim to illustrate the relationship between the structural characteristics and cytotoxicity by general linear models (GLMs). Both the QSAR models and co-culture of hepatic and renal cell systems predicted that 6 compounds were potentially hepatotoxic, 10 compounds were potentially nephrotoxic, and specific anthraquinones and anthraquinone-glucosides were potential toxicants in Cassiae semen. Specific groups such as -OH and -OCH3 at the R1, R2, R3, and R7 positions influenced the cytotoxicity.

Sanghuangporus vaninii, called "Sanghuang," is orally used for health care, tumor, and inflammation treatment in Asia. However, the safety of S. vaninii has not been evaluated. The major compounds analysis showed that aqueous extracts of S. vaninii fruiting body were rich in polysaccharides, nucleotides, and polyphenols. Then, the aqueous was given orally to Sprague-Dawley rats for toxical test. In acute toxicity study, the maximum tolerated dose was 21 g/kg. In 17-week repeated dose toxicity experiment, all rats had no abnormal reaction among control group, low dose group (0.15 g/kg) and middle dose group (1.00 g/kg). At high dose group (6.00 g/kg), the feces began to darken on 16th day (D16), and turned to drug stained stool on D21, all rats recovered on the 3rd day (D92) of recovery period. During the whole experiment, there were no animal death and no treatment-related changes in any of the parameters under the all doses. These results indicated the No-Observed Adverse Effect Level of aqueous extract of S. vaninii fruiting body was 1.0 g/kg.

Sanghuangporus vaninii, also called 'Sanghuang' mushroom in Chinese, has various medicinal uses, but its effects on human melanoma cells have not been reported. The present study investigated the inhibitory ability and potential anticancer mechanism of the aqueous extracts of S. vaninii (SH). The results revealed that SH inhibited the proliferation of A375 human melanoma cells in a dose-dependent manner, and flow cytometry analysis suggested that SH induced A375 cell cycle arrest at S phase and apoptosis. Reverse transcription-quantitative PCR, western blotting and immunofluorescence analyses indicated that SH induced S-phase arrest by upregulating p21 expression, and p21 inhibited the expression of cyclin-cyclin-dependent kinases complexes at both the RNA and protein levels. In addition, SH induced apoptosis of A375 cells by inhibiting the expression levels of the anti-apoptosis gene Bcl-2. Therefore, the results suggested that SH may be a potential candidate for the treatment of human melanoma, thus providing new ideas for developing drugs that target melanoma.

Hyperuricemia is the second most prevalent metabolic disease to human health after diabetes. Only a few clinical drugs are available, and most of them have serious side effects. The human body does not have urate oxidase, and uric acid is secreted via the kidney or the intestine. Reduction through kidney secretion is often the cause of hyperuricemia. We hypothesized that the intestine secretion could be enhanced when a recombinant urate-degrading bacterium was introduced into the gut. We engineered an Escherichia coli Nissle 1917 strain with a plasmid containing a gene cassette that encoded two proteins PucL and PucM for urate metabolism from Bacillus subtilis, the urate importer YgfU and catalase KatG from E. coli, and the bacterial hemoglobin Vhb from Vitreoscilla sp. The recombinant E. coli strain effectively degraded uric acid under hypoxic conditions. A new method to induce hyperuricemia in mice was developed by intravenously injecting uric acid. The engineered Escherichia coli strain significantly lowered the serum uric acid when introduced into the gut or directly injected into the blood vessel. The results support the use of urate-degrading bacteria in the gut to treat hyperuricemia. Direct injecting bacteria into blood vessels to treat metabolic diseases is proof of concept, and it has been tried to treat solid tumors.

Aberrant expression of HOXA9 is a prominent feature of acute leukemia driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid and B progenitor cells leads to significant enhancer reorganizations with prominent emergence of leukemia-specific de novo enhancers. Alterations in the enhancer landscape lead to activation of an ectopic embryonic gene program. We show that HOXA9 functions as a pioneer factor at de novo enhancers and recruits CEBPα and the MLL3/MLL4 complex. Genetic deletion of MLL3/MLL4 blocks histone H3K4 methylation at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis in vivo. These results suggest that therapeutic targeting of HOXA9-dependent enhancer reorganization can be an effective therapeutic strategy in acute leukemia with HOXA9 overexpression.

MLL rearrangements occur in myeloid and lymphoid leukemias and are generally associated with a poor prognosis, however this varies depending on the fusion partner. We modeled acute myeloid leukemia (AML) in mice using various MLL fusion proteins (MLL-FPs) and observed significantly different survival outcomes. To better understand the differences between these leukemias, we examined the genome wide expression profiles of leukemic cells transformed with different MLL-FPs. RNA-sequencing and pathway analysis identified the c-Myc transcriptional program as one of the top distinguishing features. c-Myc protein levels were highly correlative with AML disease latency in mice. Functionally, overexpression of c-Myc resulted in a more aggressive proliferation rate in MLL-FP cell lines. While all MLL-FP transformed cells displayed sensitivity to BET inhibitors, high c-Myc expressing cells showed greater resistance to Brd4 inhibition. The Myc target Lin28B was also differentially expressed in MLL-FP cell lines in agreement with c-Myc expression. Examination of Lin28B miRNAs targets revealed that let-7g was significantly increased in leukemic cells associated with the longest disease latency and forced let-7g expression induced differentiation of leukemic blasts. Thus, differential regulation of the c-Myc/Lin28/let-7g program by different MLL-FPs is functionally related to disease latency and BET inhibitor resistance in MLL leukemias.

Arbuscular mycorrhizal fungi (AMF), ubiquitous symbiotic fungi associated with the majority of terrestrial plants, were demonstrated to play important roles in arsenic (As) translocation and transformation in the plant-soil continuum, and substantially influence plant As tolerance. However, the direct involvement of AMF in As methylation and volatilization and their molecular mechanisms remain unsolved. Here, an arsenite methyltransferase gene RiMT-11 was identified and characterized from AM fungus Rhizophagus irregularis. Heterologous expression of RiMT-11 enhanced arsenite resistance of E. coli (Δars) through methylating As into monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) and ultimately volatile trimethyl arsine (TMAs). In a two-compartment in vitro monoxenic cultivation system, methylated and volatile As were also detected from AM symbioses with arsenate addition, accompanied by strong up-regulation of RiMT-11 expression in extraradical hyphae. The present study provided direct evidence and illustrated an underlying mechanism of As methylation and volatilization by AMF, leading to a deeper insight into the role of AMF in As biogeochemical cycling.

Doxorubicin entrapped carbon dots (DOX-CDs) were prepared for bioimaging and enhanced intracellular drug delivery. The CDs were synthesized via the hydrothermal method using citrate and urea under 200 °C for 1 h. Then, DOX was successfully conjugated on the CDs via physicochemical interactions. The DOX-CDs exhibited good crystal structure, remarkable aqueous stability, excellent photoluminescence property, and a high quantum yield of 93%. The fluorescent images revealed that the DOX-CDs could be readily taken up by the cancer cells for cell labeling. Furthermore, endo-lysosomal pH-assisted DOX release behavior was observed from DOX-CDs, and the cytotoxicity of DOX-CDs was confirmed by the MTS assay against H0-8910 ovarian cancer cells. In addition, the CDs indicated bright fluorescent signal in the animal imaging test and demonstrated low toxicity after administration for 7 and 21 days. Therefore, the prepared CDs could be a promising imaging probe for biomedical imaging and intracellular drug delivery.

Individuals with mild cognitive impairment (MCI) of different subtypes show distinct alterations in network patterns. The first aim of this study is to identify the subtypes of MCI by employing a regional radiomics similarity network (R2SN). The second aim is to characterize the abnormality patterns associated with the clinical manifestations of each subtype. An individual-level R2SN is constructed for N = 605 normal controls (NCs), N = 766 MCI patients, and N = 283 Alzheimer's disease (AD) patients. MCI patients' R2SN profiles are clustered into two subtypes using nonnegative matrix factorization. The patterns of brain alterations, gene expression, and the risk of cognitive decline in each subtype are evaluated. MCI patients are clustered into "similar to the pattern of NCs" (N-CI, N = 252) and "similar to the pattern of AD" (A-CI, N = 514) subgroups. Significant differences are observed between the subtypes with respect to the following: 1) clinical measures; 2) multimodal neuroimaging; 3) the proportion of progression to dementia (61.54% for A-CI and 21.77% for N-CI) within three years; 4) enriched genes for potassium-ion transport and synaptic transmission. Stratification into the two subtypes provides new insight for risk assessment and precise early intervention for MCI patients.

An enzyme activity is influenced by the external environment. It is important to have an enzyme remain high activity in a specific condition. A usual way is to first determine the optimal condition of an enzyme by either the gradient test or by tertiary structure, and then to use protein engineering to mutate a wild type enzyme for a higher activity in an expected condition.

Early life stress usually causes the abnormal brain development and results in the onset of cognitive and emotional disorders in later childhood. Neonatal hypoxic ischemia (HI) causes dramatic brain damage in early life and resulted in serious impairment to brain development. Hippocampal neurogenesis, as one of the key structural plasticity to mediate animal behaviors, can be impact by neonatal HI until child stage. In our study, we identified the natural product resveratrol (RES) as the potential alternative therapy to improve brain functions of childhood mice after underwent neonatal HI. Treatment of RES improved the spatial learning and memory in morris water maze and increased the recognize ability in objective recognition task. Moreover, RES also attenuate the depressive and anxiety like mood in child mice after experiencing neonatal HI. Brain morphological study showed RES promote the proliferation of neural stem cells and increase the neuronal differentiation in hippocampal dentate gyrus (DG) region. Our in vitro study in C17.2 neural stem cell line demonstrated RES could prevent the mitochondrial fragmentation induced by hypoxia. Moreover, same effect was also observed in primary cultural neurons. To summarize, RES could prevent the cognitive deficit and depressive/anxiety mood in childhood with experience of neonatal HI via promoting hippocampal neurogenesis. Improving mitochondrial dynamics could be one of the key biological mechanisms underlying such effects of RES.

Sappanone A (SA) is a homoisoflavonoid compound isolated from Caesalpinia sappan L. that selectively binds to inosine monophosphate dehydrogenase 2, a protein involved in aging. It is unknown if SA has an anti-aging effect and what is it mechanism. This study aimed to investigate the lifespan-extending and health-enhancing effects of SA, and the potential pharmacological mechanism in Caenorhabditis elegans (C. elegans). The worms were exposed to 0-50 μM SA. The effect on the lifespan was observed, and health status was evaluated by detecting motility, feeding, reproduction, thermotolerance, lipofuscin and ROS accumulation. To explore a possible mechanism, the transcription of the genes of the insulin/insulin-like growth factor-1 signalling pathway and heat stress response was detected by RT-qPCR. Moreover, subcellular distribution of green fluorescent protein-labeled DAF-16 was determined, and the interaction between SA and HSP-90 protein was simulated by molecular docking. We found that SA prolonged lifespan in C. elegans and enhanced motility and thermotolerance. The feeding and reproduction were not impacted. The ROS and lipofuscin accumulation was declined. Mechanistic study revealed that the gene expression levels of daf-16 and hsp-90 were up-regulated. Moreover, DAF-16 was translocated into the nucleus. SA was docked into the active pocket of HSP-90 in the simulation. SA (50 μM) can extend lifespan in C. elegans and decelerate aging by regulating the IIS pathway, and daf-16 is specifically important for the regulation of longevity. HSP-90 was involved in the enhancement of thermotolerance. Thus, SA may act as a promising candidate for the development of an anti-aging agent.

Epilepsy is a chronic neurological disorder characterized by spontaneous recurrent seizures (SRS) and comorbidities. Kindling through repetitive brief stimulation of a limbic structure is a commonly used model of temporal lobe epilepsy. Particularly, extended kindling over a period up to a few months can induce SRS, which may simulate slowly evolving epileptogenesis of temporal lobe epilepsy. Currently, electroencephalographic (EEG) features of SRS in rodent models of extended kindling remain to be detailed. We explored this using a mouse model of extended hippocampal kindling. Intracranial EEG recordings were made from the kindled hippocampus and unstimulated hippocampal, neocortical, piriform, entorhinal, or thalamic area in individual mice. Spontaneous EEG discharges with concurrent low-voltage fast onsets were observed from the two corresponding areas in nearly all SRS detected, irrespective of associated motor seizures. Examined in brain slices, epileptiform discharges were induced by alkaline artificial cerebrospinal fluid in the hippocampal CA3, piriform and entorhinal cortical areas of extended kindled mice but not control mice. Together, these in vivo and in vitro observations suggest that the epileptic activity involving a macroscopic network may generate concurrent discharges in forebrain areas and initiate SRS in hippocampally kindled mice.

Consciousness arises from the spatiotemporal neural dynamics, however, its relationship with neural flexibility and regional specialization remains elusive. We identified a consciousness-related signature marked by shifting spontaneous fluctuations along a unimodal-transmodal cortical axis. This simple signature is sensitive to altered states of consciousness in single individuals, exhibiting abnormal elevation under psychedelics and in psychosis. The hierarchical dynamic reflects brain state changes in global integration and connectome diversity under task-free conditions. Quasi-periodic pattern detection revealed that hierarchical heterogeneity as spatiotemporally propagating waves linking to arousal. A similar pattern can be observed in macaque electrocorticography. Furthermore, the spatial distribution of principal cortical gradient preferentially recapitulated the genetic transcription levels of the histaminergic system and that of the functional connectome mapping of the tuberomammillary nucleus, which promotes wakefulness. Combining behavioral, neuroimaging, electrophysiological, and transcriptomic evidence, we propose that global consciousness is supported by efficient hierarchical processing constrained along a low-dimensional macroscale gradient.

Thermal stability is one of the most important properties of enzymes, which sustains life and determines the potential for the industrial application of biocatalysts. Although traditional methods such as directed evolution and classical rational design contribute greatly to this field, the enormous sequence space of proteins implies costly and arduous experiments. The development of enzyme engineering focuses on automated and efficient strategies because of the breakthrough of high-throughput DNA sequencing and machine learning models. In this review, we propose a data-driven architecture for enzyme thermostability engineering and summarize some widely adopted datasets, as well as machine learning-driven approaches for designing the thermal stability of enzymes. In addition, we present a series of existing challenges while applying machine learning in enzyme thermostability design, such as the data dilemma, model training, and use of the proposed models. Additionally, a few promising directions for enhancing the performance of the models are discussed. We anticipate that the efficient incorporation of machine learning can provide more insights and solutions for the design of enzyme thermostability in the coming years.

Cell-free RNA (cfRNA) allows assessment of health, status, and phenotype of a variety of human organs and is a potential biomarker to non-invasively diagnose numerous diseases. Nevertheless, there is a lack of highly efficient and bias-free cfRNA isolation technologies due to the low abundance and instability of cfRNA. Here, we developed a reproducible and high-efficiency isolation technology for different types of cell-free nucleic acids (containing cfRNA and viral RNA) in serum/plasma based on the inclusion of nucleic acids by metal-organic framework (MOF) materials, which greatly improved the isolation efficiency and was able to preserve RNA integrity compared with the most widely used research kit method. Importantly, the quality of cfRNA extracted by the MOF method is about 10-fold that of the kit method, and the MOF method isolates more than three times as many different RNA types as the kit method. The whole transcriptome mapping characteristics of cfRNA in serum from patients with liver cancer was described and a cfRNA signature with six cfRNAs was identified to diagnose liver cancer with high diagnostic efficiency (area under curve = 0.905 in the independent validation cohort) using this MOF method. Thus, this new MOF isolation technique will advance the field of liquid biopsy, with the potential to diagnose liver cancer.

For lumbar degenerative diseases, cage subsidence is a serious complication and can result in the failure of indirect decompression in the oblique lumbar interbody fusion (OLIF) procedure. Whether additional lateral plate fixation was effective to improve clinical outcomes and prevent cage subsidence was still unknown. This study aimed to compare the incidence and degree of cage subsidence between stand-alone oblique lumbar interbody fusion (SA-OLIF) and OLIF combined with lateral plate fixation (OLIF + LP) for the treatment of lumbar degenerative diseases and to evaluate the effect of the lateral plate fixation.

Ulva compressa is one of the causal green macroalgae in many countries. In this study, complete chloroplast genome sequence of U. compressa was reported, and the total length of this species was 94,226 bp (GenBank accession number MT916929). The overall base composition of chloroplast genome was A (37.2%), T (37.0%), C (12.7%) and G (13.1%), and the percentage of A + T (74.2%) was higher than C + G (25.8%). U. compressa chloroplast genome encoded 90 genes, including 63 protein-coding genes, 23 transfer RNAs genes, and 4 ribosomal RNAs genes. The maximum likelihood phylogenetic analysis showed that U. compressa is the closest sister species of U. linza. This study will be helpful to understand the genetic diversity of Ulva species.