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The transcriptional repressor B cell lymphoma 6 (BCL6) plays a critical role in driving tumorigenesis of diffuse large B-cell lymphoma (DLBCL). However, the therapeutic potential of inhibiting or degrading BCL6 for DLBCL has not been thoroughly understood. Herein, we reported the discovery of a series of novel BCL6-targeting PROTACs based on our previously reported N-phenyl-4-pyrimidinamine BCL6 inhibitors. The optimal compound DZ-837 degraded BCL6 with DC 50 values around 600 nM and effectively inhibited the proliferation of several DLBCL cell lines. Further study indicated that DZ-837 induced significant G1 phase arrest and exhibited sustained reactivation of BCL6 downstream genes. In the SU-DHL-4 xenograft model, DZ-837 significantly inhibited tumor growth with TGI of 71.8 % at 40 mg/kg once daily. Furthermore, the combination of DZ-837 with BTK inhibitor Ibrutinib showed synergistic effects and overcame acquired resistance against DLBCL cells. Overall, our findings demonstrate that DZ-837 is an effective BCL6 degrader for DLBCL treatment as a monotherapy or in combination with Ibrutinib., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Multilayer dense myelin tissue provides insulating space and nutritional support for axons in healthy spinal cord tissue. Oligodendrocyte precursor cells (OPCs) are the main glial cells that complement myelin loss in the central nervous system and play an important role in the repair of spinal cord injury (SCI). However, the regulation of axonal remyelination after SCI is still insufficient. In this study, we focused on the changes in genes related to myelin repair after rat hemisection SCI by gene set enrichment analysis (GSEA). Key genes proteolipid protein 1 (Plp1), hexosaminidase subunit alpha (Hexa), and hexosaminidase subunit beta (Hexb) during remyelination after SCI were found. Through quantitative real-time polymerase chain reaction (qPCR) experiments, we confirmed that within 28 days after rat hemisection SCI, the mRNA expression of gene Plp1 gradually decreased, while the expressions of gene Hexa and Hexb gradually increased, which was consistent with RNA sequencing results. In vitro, we performed EdU proliferation assays on OPC cell line OLN-93 and primary rat OPCs. We found that interference of Plp1 promoted OPC proliferation, while interference of Hexa and Hexb inhibited OPC proliferation. In addition, we performed in vitro differentiation experiments on primary rat OPCs. By measuring myelin sheath branch outgrowth and the fluorescence intensity of the mature myelin sheath marker myelin basic protein (MBP), we found that interference of Hexa or Hexb promoted OPC differentiation and maturation, but interference of Plp1 inhibited this process. Finally, we injected Hexb siRNA in vivo and found that interfering Hexb could improve motor movements and myelin regeneration after SCI in rats. Our results provide new target genes that can selectively regulate the proliferation and differentiation of endogenous OPCs, providing new ideas for promoting remyelination and functional recovery after SCI., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Triplostegia glandulifera Wall (T. glandulifera) is an ethnomedicine commonly used by ethnic minorities in Yunnan, China, to treat kidney disease. However, there are few reports on the renoprotective effects of this substance, and the active ingredients remain unclear. In this study, we extracted the polysaccharide fractions TGB and TGC using the water extraction-alcohol precipitation method and determined their molecular weight (Mw) and monosaccharide composition. The study investigated the protective effects of TGB and TGC fractions against diabetic nephropathy (DN) using an in vitro high glucose-induced HRMCs model and an in vivo STZ-induced diabetic mouse model. HPLC analysis revealed that TGB contained D-galacturonic acid, D-glucose, D-galactose, and D-arabinose, and had a lower Mw than TGC. In vitro, TGB showed concentration-dependent antioxidant activity and effectively reduced abnormal proliferation and while attenuating oxidative stress in HRMCs. In mice with diabetes, TGB corrected the dysregulation of glucose-lipid metabolism and alleviated oxidative stress in the kidneys. Additionally, it improved renal function and reduced renal tissue damage. The study suggests that the low Mw polysaccharides (TGB) have better activity against DN through the antioxidative stress mechanism., (© 2024. The Author(s).)

Microgravity, as a unique hazardous factor encountered in space, can induce a series of harmful effects on living organisms. The impact of microgravity on the pivotal functional gene modules stemming from gene enrichment analysis via the regulation of miRNAs is not fully illustrated. To explore the microgravity-induced alterations in critical functional gene modules via the regulation of miRNAs, in the present study, we proposed a novel bioinformatics algorithm for the integrated analysis of miRNAome and transcriptome from short-term space-flown C. elegans. The samples of C. elegans were exposed to two space conditions, namely spaceflight (SF) and spaceflight control (SC) onboard the International Space Station for 4 days. Additionally, the samples of ground control (GC) were included for comparative analysis. Using the present algorithm, we constructed regulatory networks of functional gene modules annotated from differentially expressed genes (DEGs) and their associated regulatory differentially expressed miRNAs (DEmiRNAs). The results showed that functional gene modules of molting cycle, defense response, fatty acid metabolism, lysosome, and longevity regulating pathway were facilitated by 25 down-regulated DEmiRNAs (e.g., cel-miR-792, cel-miR-65, cel-miR-70, cel-lsy-6, cel-miR-796, etc.) in the SC vs. GC groups, whereas these modules were inhibited by 13 up-regulated DEmiRNAs (e.g., cel-miR-74, cel-miR-229, cel-miR-70, cel-miR-249, cel-miR-85, etc.) in the SF vs. GC groups. These findings indicated that microgravity could significantly alter gene expression patterns and their associated functional gene modules in short-term space-flown C. elegans. Additionally, we identified 34 miRNAs as post-transcriptional regulators that modulated these functional gene modules under microgravity conditions. Through the experimental verification, our results demonstrated that microgravity could induce the down-regulation of five critical functional gene modules (i.e., molting cycle, defense response, fatty acid metabolism, lysosome, and longevity regulating pathways) via the regulation of miRNAs in short-term space-flown C. elegans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Committee on Space Research (COSPAR). Published by Elsevier B.V. All rights reserved.)

Background: Hyperglycemia is associated with worse stroke outcomes, but it is uncertain whether tight glycemic control during the acute stroke period is associated with a better outcome. We conducted a meta-analysis to compare the effect of tight glycemic control versus loose glycemic control in the acute phase of stroke patients., Methods: A literature search was performed to identify randomized controlled trials comparing the safety and efficacy of tight glycemic control with a relatively loose control of blood glucose of acute stroke (ischemic or hemorrhagic) patients within 24 h after stroke onset. We required that the blood glucose level of the patients should not be lower than 6.11 mmol/L at the time of enrollment, and for the intensive blood glucose control range, we defined the blood glucose level as lower than that of the control group. The primary efficacy outcome measure was deaths from any cause at 90 days. Secondary efficacy outcomes comprised the number of participants with modified Rankin score (mRS). We define mRS scores 0-2 as favorable scores, recurrent stroke, and the National Institute of Health Stroke Scale or the European Stroke Scale scores. We defined the number of participants with hypoglycemia as our primary safety outcome. Subgroup analysis was performed according to age, the variety of interventions, maintained glucose level, and status of hypoglycemia on National Institute of Health Stroke Scale (NIHSS) scores or European Stroke Scale (ESS) scores., Results: Fifteen randomized controlled trials (RCTs) with 2957 participants meeting the including criteria were identified and included in this meta-analysis, although not all included data on every outcome measure. Data on the primary efficacy endpoint, mortality at 90 days, was available in 11 RCTs, a total of 2575 participants. There was no significant difference between the intervention and control groups (odds ratio (OR): 1.00; 95% confidence interval (CI): 0.81-1.23; P = 0.99). For secondary endpoints, there was no difference between intervention and control groups for a mRS from 0 to 2 (OR: 0.96; 95% CI: 0.80-1.15; P = 0.69; data from 9 RCTs available), or recurrent stroke (OR: 1.34; 95% CI: 0.92-1.96; P = 0.13; data from 3 RCTs available). For NIHSS scores or ESS scores, there was a small difference in favor of intensive controls (standardized mean difference: -0.29; 95% CI: -0.54 to -0.04; P = 0.02). There was a marked increase in hypoglycemia with tight control: (OR of 9.46 (95% CI: 4.59-19.50; P < 0.00001; data from 9 RCTs available)., Conclusion: There was no difference between tight and loose glycemic control on mortality, independence, or recurrent stroke outcome in acute stroke, but an increase in hypoglycemia. There was a small effect improvement on neurological scales, but the relevance of this needs to be confirmed in future adequately powered studies., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

JOURNAL/nrgr/04.03/01300535-202408000-00035/figure1/v/2023-12-16T180322Z/r/image-tiff Exosomes exhibit complex biological functions and mediate a variety of biological processes, such as promoting axonal regeneration and functional recovery after injury. Long non-coding RNAs (lncRNAs) have been reported to play a crucial role in axonal regeneration. However, the role of the lncRNA-microRNA-messenger RNA (mRNA)-competitive endogenous RNA (ceRNA) network in exosome-mediated axonal regeneration remains unclear. In this study, we performed RNA transcriptome sequencing analysis to assess mRNA expression patterns in exosomes produced by cultured fibroblasts (FC-EXOs) and Schwann cells (SC-EXOs). Differential gene expression analysis, Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis, and protein-protein interaction network analysis were used to explore the functions and related pathways of RNAs isolated from FC-EXOs and SC-EXOs. We found that the ribosome-related central gene Rps5 was enriched in FC-EXOs and SC-EXOs, which suggests that it may promote axonal regeneration. In addition, using the miRWalk and Starbase prediction databases, we constructed a regulatory network of ceRNAs targeting Rps5, including 27 microRNAs and five lncRNAs. The ceRNA regulatory network, which included Ftx and Miat, revealed that exsosome-derived Rps5 inhibits scar formation and promotes axonal regeneration and functional recovery after nerve injury. Our findings suggest that exosomes derived from fibroblast and Schwann cells could be used to treat injuries of peripheral nervous system., (Copyright © 2024 Copyright: © 2024 Neural Regeneration Research.)

Fused Deposition Modeling (FDM), a widely-utilized additive manufacturing (AM) technology, has found significant favor among automotive manufacturers. Polypropylene (PP) compound is extensively employed in the production of automotive parts due to its superior mechanical properties and formability. However, aiming at the problem of poor dimensional accuracy of pure PP parts, the quality of products can be enhanced by optimizing the combination of processing parameters. In this paper, the dimensional accuracy of 3D-printed components made from pure PP material is investigated. Key influencing factors such as infill percentage, infill pattern, layer thickness, and extrusion temperature are considered. To gain a deeper understanding, fluid simulation is conducted, and mathematical models are established to correlate processing parameters with dimensional accuracy. Furthermore, the Taguchi's experiments are designed and the experimental data are subjected to rigorous Signal-to-Noise ratio and ANOVA analyses. Within the experimental range, the lower extrusion temperature, infill percentage and layer thickness yield the best dimensional accuracy. Considering the influence factors of X, Y and Z directions, the optimal processing parameters for PP prints using screw extrusion 3D printers are determined as follows: an extrusion temperature of 210 °C, an infill percentage of 40 %, a layer thickness of 0.3 mm, and a concentric circle infill pattern. This study provides reference value for the subsequent improvement of the dimensional accuracy of the printed parts., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objective: Sleep-related hypermotor epilepsy (SHE) is a focal epilepsy syndrome characterized by seizures that predominantly occur during sleep. The pathogenesis of these seizures remains unclear. We previously detected rare variants in GABRG2, which encodes the γ 2 subunit of γ-aminobutyric acid type A receptor (GABA A R), in patients with SHE and demonstrated that these variants impaired GABA A R function in vitro. However, the mechanisms by which GABRG2 variants contribute to seizure attacks during sleep remain unclear., Methods: In this study, we designed a knock-in (KI) mouse expressing the mouse Gabrg2 T316N variant, corresponding to human GABRG2 T317N variant, using CRISPR/Cas9. Continuous video-electroencephalogram monitoring and in vivo multichannel electrophysiological recordings were performed to explore seizure susceptibility to pentylenetetrazol (PTZ), alterations in the sleep-wake cycle, spontaneous seizure patterns, and synchronized activity in the motor thalamic nuclei (MoTN) and secondary motor cortex (M2). Circadian variations in the expression of total, membrane-bound, and synaptic GABA A R subunits were also investigated., Results: No obvious changes in gross morphology were detected in Gabrg2 T316N/+ mice compared to their wild-type (Gabrg2 +/+ ) littermates. Gabrg2 T316N/+ mice share key phenotypes with patients, including sleep fragmentation and spontaneous seizures during sleep. Gabrg2 T316N/+ mice showed increased susceptibility to PTZ-induced seizures and higher mortality after seizures. Synchronization of the local field potentials between the MoTN and M2 was abnormally enhanced in Gabrg2 T316N/+ mice during light phase, when sleep dominates, accompanied by increased local activities in the MoTN and M2. Interestingly, in Gabrg2 +/+ mice, GABA A R γ2 subunits showed a circadian increase on the neuronal membrane and synaptosomes in the transition from dark phase to light phase, which was absent in Gabrg2 T316N/+ mice., Conclusion: We generated a new SHE mouse model and provided in vivo evidence that rare variants of GABRG2 contribute to seizure attacks during sleep in SHE., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

The enhanced permeability and retention (EPR) effect has become the guiding principle for nanomedicine against cancer for a long time. However, several biological barriers severely resist therapeutic agents' penetration and retention into the deep tumor tissues, resulting in poor EPR effect and high tumor mortality. Inspired by lava, we proposed a proteolytic enzyme therapy to improve the tumor distribution and penetration of nanomedicine. A trypsin-crosslinked hydrogel (Trypsin@PSA Gel) was developed to maintain trypsin's activity. The hydrogel postponed trypsin's self-degradation and sustained the release. Trypsin promoted the cellular uptake of nanoformulations in breast cancer cells, enhanced the penetration through endothelial cells, and degraded total and membrane proteins. Proteomic analysis reveals that trypsin affected ECM components and down-regulated multiple pathways associated with cancer progression. Intratumoral injection of Trypsin@PSA Gel significantly increased the distribution of liposomes in tumors and reduced tumor vasculature. Combination treatment with intravenous injection of gambogic acid-loaded liposomes and intratumoral injection of Trypsin@PSA Gel inhibited tumor growth. The current study provides one of the first investigations into the enhanced tumor distribution of liposomes induced by a novel proteolytic enzyme therapy., (© 2024. The Author(s).)

During space exploration, space radiation is widely recognized as an inescapable perilous stressor, owing to its capacity to induce genomic DNA damage and escalate the likelihood of detrimental health outcomes. Rapid and reliable estimation of space radiation dose holds paramount significance in accurately assessing the health risks associated with spaceflight. However, the identification of space radiation-responsive genes, with their potential to serve as early indicators for diagnosing radiation dose associated with spaceflight, continues to pose a significant challenge. In this study, based on the evolutionarily conserved mechanism of radiation response, an in silico analysis method of homologous comparison was performed to identify the Caenorhabditis elegans orthologues of human radiation-responsive genes with possible roles in the major processes of response to radiation, and thereby to explore the potential C. elegans radiation-responsive genes for evaluating the levels of space radiation exposure. The results showed that there were 60 known C. elegans radiation-responsive genes and 211 C. elegans orthologues of human radiation-responsive genes implicated in the major processes of response to radiation. Through an investigation of all available transcriptomic datasets obtained from space-flown C. elegans, it was observed that the expression levels of the majority of these putative C. elegans radiation-responsive genes identified in this study were notably changed across various spaceflight conditions. Furthermore, this study indicated that within the identified genes, 19 known C. elegans radiation-responsive genes and 40 newly identified C. elegans orthologues of human radiation-responsive genes exhibited a remarkable positive correlation with the duration of spaceflight. Moreover, a noteworthy presence of substantial multi-collinearity among the majority of these identified genes was observed. This observation lends support to the possibility of treating each identified gene as an independent indicator of radiation dose in space. Ultimately, a subset of 15 potential radiation-responsive genes was identified, presenting the most promising indicators for estimation of radiation dose associated with spaceflight in C. elegans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Iron is essential for all the lives and mitochondria integrate iron into heme and Fe-S clusters for diverse use as cofactors. Here, we screened mitochondrial proteins in KU812 human chronic myelogenous leukemia cells by glutathione S- transferase pulldown assay with PCBP2 to identify mitochondrial receptors for PCBP2, a major cytosolic Fe(II) chaperone. LC-MS analyses identified TOM20, sideroflexin-3 (SFXN3), SFXN1 and TOM70 in the affinity-score sequence. Stimulated emission depletion microscopy and proteinase-K digestion of mitochondria in HeLa cells revealed that TOM20 is located in the outer membrane of mitochondria whereas SFXN3 is located in the inner membrane. Although direct association was not observed between PCBP2 and SFXN3 with co-immunoprecipitation, proximity ligation assay demonstrated proximal localization of PCBP2 with TOM20 and there was a direct binding between TOM20 and SFXN3. Single knockdown either of PCBP2 and SFXN3 in K562 leukemia cells significantly decreased mitochondrial catalytic Fe(II) and mitochondrial maximal respiration. SFXN3 but not MFRN1 knockout (KO) in mouse embryonic fibroblasts decreased FBXL5 and heme oxygenase-1 (HO-1) but increased transferrin uptake and induced ferritin, indicating that mitochondrial iron entry through SFXN3 is distinct. MFRN1 KO revealed more intense mitochondrial Fe(II) deficiency than SFXN3 KO. Insufficient mitochondrial heme synthesis was evident under iron overload both with SFXN3 and MFRN KO, which was partially reversed by HO-1 inhibitor. Conversely, SFXN3 overexpression caused cytosolic iron deficiency with mitochondrial excess Fe(II), which further sensitized HeLa cells to RSL3-induced ferroptosis. In conclusion, we discovered a novel pathway of iron entry into mitochondria from cytosol through PCBP2-TOM20-SFXN3 axis.

Human cerebellum encompasses numerous neurons, exhibiting a distinct developmental paradigm from cerebrum. Here we conducted scRNA-seq, scATAC-seq and spatial transcriptomic analyses of fetal samples from gestational week (GW) 13 to 18 to explore the emergence of cellular diversity and developmental programs in the developing human cerebellum. We identified transitory granule cell progenitors that are conserved across species. Special patterns in both granule cells and Purkinje cells were dissected multidimensionally. Species-specific gene expression patterns of cerebellar lobes were characterized and we found that PARM1 exhibited inconsistent distribution in human and mouse granule cells. A novel cluster of potential neuroepithelium at the rhombic lip was identified. We also resolved various subtypes of Purkinje cells and unipolar brush cells and revealed gene regulatory networks controlling their diversification. Therefore, our study offers a valuable multi-omics landscape of human fetal cerebellum and advances our understanding of development and spatial organization of human cerebellum., (© 2024. The Author(s).)

Bird sex chromosomes play a unique role in sex-determination, and affect the sexual morphology and behavior of bird species. Core waterbirds, a major clade of birds, share the common characteristics of being sexually monomorphic and having lower levels of inter-sexual conflict, yet their sex chromosome evolution remains poorly understood. Here, by we analyse of a chromosome-level assembly of a female crested ibis (Nipponia nippon), a typical core waterbird. We identify neo-sex chromosomes resulting from fusion of microchromosomes with ancient sex chromosomes. These fusion events likely occurred following the divergence of Threskiornithidae and Ardeidae. The neo-W chromosome of the crested ibis exhibits the characteristics of slow degradation, which is reflected in its retention of abundant gametologous genes. Neo-W chromosome genes display an apparent ovary-biased gene expression, which is largely driven by genes that are retained on the crested ibis W chromosome but lost in other bird species. These results provide new insights into the evolutionary history and expression patterns for the sex chromosomes of bird species., (© 2024. The Author(s).)

The mammalian cerebral cortex contains an extraordinary diversity of cell types that emerge by implementing different developmental programs. Delineating when and how cellular diversification occurs is particularly challenging for cortical inhibitory neurons because they represent a small proportion of all cortical cells and have a protracted development. Here, we combine single-cell RNA sequencing and spatial transcriptomics to characterize the emergence of neuronal diversity among somatostatin-expressing (SST+) cells in mice. We found that SST+ inhibitory neurons segregate during embryonic stages into long-range projection (LRP) neurons and two types of interneurons, Martinotti cells and non-Martinotti cells, following distinct developmental trajectories. Two main subtypes of LRP neurons and several subtypes of interneurons are readily distinguishable in the embryo, although interneuron diversity is likely refined during early postnatal life. Our results suggest that the timing for cellular diversification is unique for different subtypes of SST+ neurons and particularly divergent for LRP neurons and interneurons., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Peripheral nerve injuries, especially those involving long-distance deficits, pose significant challenges in clinical repair. This study explores the potential of continuous microcurrent electrical nerve stimulation (cMENS) as an adjunctive strategy to promote regeneration and repair in such cases., Methods: The study initially optimized cMENS parameters and assessed its impact on Schwann cell activity, neurotrophic factor secretion, and the nerve regeneration microenvironment. Subsequently, a rat sciatic nerve defect-bridge repair model was employed to evaluate the reparative effects of cMENS as an adjuvant treatment. Functional recovery was assessed through gait analysis, motor function tests, and nerve conduction assessments. Additionally, nerve regeneration and denervated muscle atrophy were observed through histological examination., Results: The study identified a 10-day regimen of 100uA microcurrent stimulation as optimal. Evaluation focused on Schwann cell activity and the microenvironment, revealing the positive impact of cMENS on maintaining denervated Schwann cell proliferation and enhancing neurotrophic factor secretion. In the rat model of sciatic nerve defect-bridge repair, cMENS demonstrated superior effects compared to control groups, promoting motor function recovery, nerve conduction, and sensory and motor neuron regeneration. Histological examinations revealed enhanced maturation of regenerated nerve fibers and reduced denervated muscle atrophy., Discussion: While cMENS shows promise as an adjuvant treatment for long-distance nerve defects, future research should explore extended stimulation durations and potential synergies with tissue engineering grafts to improve outcomes. This study contributes comprehensive evidence supporting the efficacy of cMENS in enhancing peripheral nerve regeneration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kong, Teng, Liu, Wang, Zhou, Zong, Wan, Qin, Yu, Mi and Wang.)

Island endemic birds account for the majority of extinct vertebrates in the past few centuries. To date, the evolutionary characteristics of island endemic bird's is poorly known. In this research, we de novo assembled a high-quality chromosome-level reference genome for the Swinhoe's pheasant, which is a typical endemic island bird. Results of collinearity tests suggest rapid ancient chromosome rearrangement that may have contributed to the initial species radiation within Phasianidae, and a role for the insertions of CR1 transposable elements in rearranging chromosomes in Phasianidae. During the evolution of the Swinhoe's pheasant, natural selection positively selected genes involved in fecundity and body size functions, at both the species and population levels, which reflect genetic variation associated with island adaptation. We further tested for variation in population genomic traits between the Swinhoe's pheasant and its phylogenetically closely related mainland relative the silver pheasant, and found higher levels of genetic drift and inbreeding in the Swinhoe's pheasant genome. Divergent demographic histories of insular and mainland bird species during the last glacial period may reflect the differing impact of insular and continental climates on the evolution of species. Our research interprets the natural history and population genetic characteristics of the insular endemic bird the Swinhoe's pheasant, at a genome-wide scale, provides a broader perspective on insular speciation, and adaptive evolution and contributes to the genetic conservation of island endemic birds., (© 2023 John Wiley & Sons Ltd.)

Background: Gorals Naemorhedus resemble both goats and antelopes, which prompts much debate about the intragenus species delimitation and phylogenetic status of the genus Naemorhedus within the subfamily Caprinae. Their evolution is believed to be linked to the uplift of the Qinghai-Tibet Plateau (QTP). To better understand its phylogenetics, the genetic information is worth being resolved., Results: Based on a sample from the eastern margin of QTP, we constructed the first reference genome for Himalayan goral Naemorhedus goral, using PacBio long-read sequencing and Hi-C technology. The 2.59 Gb assembled genome had a contig N50 of 3.70 Mb and scaffold N50 of 106.66 Mb, which anchored onto 28 pseudo chromosomes. A total of 20,145 protein-coding genes were predicted in the assembled genome, of which 99.93% were functionally annotated. Phylogenetically, the goral was closely related to muskox on the mitochondrial genome level and nested into the takin-muskox clade on the genome tree, rather than other so-called goat-antelopes. The cladogenetic event among muskox, takin and goral occurred sequentially during the late Miocene (~ 11 - 5 Mya), when the QTP experienced a third dramatic uplift with consequent profound changes in climate and environment. Several chromosome fusions and translocations were observed between goral and takin/muskox. The expanded gene families in the goral genome were mainly related to the metabolism of drugs and diseases, so as the positive selected genes. The Ne of goral continued to decrease since ~ 1 Mya during the Pleistocene with active glaciations., Conclusion: The high-quality goral genome provides insights into the evolution and valuable information for the conservation of this threatened group., (© 2024. The Author(s).)

Introduction: Current clinical computed tomography arteriography (cCTA) and clinical computed tomography venography (cCTV) images often display restricted cerebrovascular profiles, incomplete brain tissue segmentation, and incomplete artery-vein segmentation. Especially for vessels associated with diseases, capturing their complete profiles proves challenging., Methods: In this work, we developed a Task-driven Cerebral Angiographic Imaging (TDCAI) technique using computed tomography perfusion (CTP) images of stroke patients. A evaluation on intracranial hemorrhagic stroke (IHS) and acute ischemic stroke (AIS) cases was performed with CT perfusion imaging. The TDCAI technique processed the CTP images, resulting in supplementary diagnostic images, including CTA, CTV, centerline images of the vessels-of-interest [internal carotid artery (ICA) for AIS patients, Labbé vein for IHS patients], and straightened images of the vessels-of-interest., Results: We conducted a comparison between the obtained CTA/CTV images and the cCTA/cCTV images in terms of overall image quality and visibility of the vessels-of-interest. By constructing a virtual vascular phantom, we extracted its centerline and compared it with the actual centerline to calculate maximum and average deviations. This allowed us to evaluate both the accuracy of the centerline extraction algorithm and its capability to resist the influence of side branches. We assessed whether vascular stenosis and dilatation could be expressed in straightened vessel images, conducting statistical analyses to establish the superiority of TDCAI technique., Discussion: This study proposes a TDCAI technique to eliminate bone and soft tissue interference, effectively segregate the comprehensive cerebral venous and arterial systems, and extract centerlines and straighten the vessels-of-interest, which would aid doctors in assessing the outflow profiles of vessels after a stroke and seeking imaging biomarkers correlated with clinical outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Chen and Mi.)

Habitat degradation and loss of genetic diversity are common threats faced by almost all of today's wild cats. Big cats, such as tigers and lions, are of great concern and have received considerable conservation attention through policies and international actions. However, knowledge of and conservation actions for small wild cats are lagging considerably behind. The black-footed cat, Felis nigripes , one of the smallest felid species, is experiencing increasing threats with a rapid reduction in population size. However, there is a lack of genetic information to assist in developing effective conservation actions. A de novo assembly of a high-quality chromosome-level reference genome of the black-footed cat was made, and comparative genomics and population genomics analyses were carried out. These analyses revealed that the most significant genetic changes in the evolution of the black-footed cat are the rapid evolution of sensory and metabolic-related genes, reflecting genetic adaptations to its characteristic nocturnal hunting and a high metabolic rate. Genomes of the black-footed cat exhibit a high level of inbreeding, especially for signals of recent inbreeding events, which suggest that they may have experienced severe genetic isolation caused by habitat fragmentation. More importantly, inbreeding associated with two deleterious mutated genes may exacerbate the risk of amyloidosis, the dominant disease that causes mortality of about 70% of captive individuals. Our research provides comprehensive documentation of the evolutionary history of the black-footed cat and suggests that there is an urgent need to investigate genomic variations of small felids worldwide to support effective conservation actions., Competing Interests: Competing interests statement:The authors declare no competing interest.

Myoferlin (MYOF) mediates the growth and metastasis of various cancers as an emerging therapeutic target by regulating exocytosis and endocytosis. However, the previously reported MYOF inhibitor, 6y , failed to be a favorable candidate agent due to its poor physicochemical properties, such as water solubility, in preclinical studies. Naturally, a novel range of MYOF inhibitors was synthesized and optimized based on the lead compound 6y . The optimal compound HJ445A potently repressed the proliferation of gastric cancer cells with IC 50 values of 0.16 and 0.14 μM in MGC803 and MKN45, respectively. Moreover, HJ445A bound to the MYOF-C2D domain with a K D of 0.17 μM, and HJ445A prevented the migration of gastric cancer cells by reversing the epithelial-mesenchymal transition (EMT) process and inhibited the colony formation of the MKN45 cells in a concentration-dependent manner. Notably, the water solubility of HJ445A was significantly improved compared to 6y , with about 170-fold enhancement. Additionally, HJ445A also demonstrated superior antitumor efficacy in vivo .

This article introduces a one-step extrusion-based fused deposition modeling (FDM) approach for the challenging separation of polypropylene (PP) and polyethylene terephthalate (PET) during recycling. A shear screw printer (SSP) with shear elements was designed, and it was compared to a conventional single-screw printer (CSP) to investigate the differences in print stability, degradation levels, tensile performance, molecular orientation, and crystallization when preparing recycled PP and recycled PET blends. Although the retention effect of the SSP screw slightly increases the degradation of the blended rPP/rPET, the strong shear (2.6 × 10 4 s -1 ) applied near the extrusion exit improves the blending efficiency. The SSP also enhances molecular orientation, modulus of the parts, and reduces performance fluctuations. Additionally, the SSP has the potential to simplify the recycling process, enabling the transformation of blended recycled materials into products with just one melt process.

Background and Purpose: Current clinical computed tomography venographic (cCTV) images present limited cerebral venous profiles. Therefore, this study aimed to develop an automatic cerebral CTV imaging technique using computed tomographic perfusion (CTP) images in a cohort of patients with stroke., Materials and Methods: We retrospectively evaluated 10 (intracerebral hemorrhage) and 2 (acute ischemic stroke) patients who underwent institutional CTP imaging. CTV images were processed with the proposed CTV (pCTV) technique, and pCTV and cCTV images were then independently evaluated by two experienced neuroradiologists blinded to all clinical information using a novel scoring method that considered overall image quality, venous visibility, and arterial mis-segmentation. Venous visibility was separately evaluated for the dural sinus, superficial vein, and deep vein. Then, statistical analysis was performed to determine whether the pCTV technique was superior to the cCTV technique., Results: In total, 14 sets of pCTV images were generated and compared with cCTV images. The overall image quality and venous visibility scores of pCTV images were significantly higher than those of cCTV images (all values of p<0.05), especially for the dural sinus (median [25th, 75th percentiles], 14.00 [13.63, 15.50] vs. 7.50 [7.00, 10.88]), and superficial vein (9.00 [8.88, 10.00] vs. 3.25 [1.63, 8.25]), while the difference in arterial mis-segmentation was not statistically significant (p= 0.164)., Conclusions: This study proposed an automatic cerebral CTV imaging technique to eliminate residual bone and soft tissues, minimize the impact of the cerebral arterial system, and present a relatively comprehensive cerebral venous system, which would help physicians assess cerebral venous outflow profiles after stroke and seek imaging markers associated with clinical outcomes., Competing Interests: Declaration of Competing Interest We have no conflicts of interest., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: Stroke is a major cause of acute neurological symptoms in children with significant long-term neurological sequelae. However, data of diseases burden on stroke among children was lack. We aimed to be dedicated to analyze and compare global trends as well as regional and sociodemographic differences in stroke prevalence, incidence, mortality and disability-adjusted life-years (DALYs) among children aged 0 ~ 14 years., Method: We obtained data on annual number of incident strokes, prevalent strokes, deaths, and DALYs, age-standardized incidence rates (ASIRs), prevalence rates (ASPRs), mortality rates (ASMRs) and DALY rates (ASDRs) of stroke among individuals aged 14 years and younger during 1990-2019 from the 2019 Global Burden of Disease Study. To quantify the temporal trends, we calculated changes (%) in number, and used joinpoint regression analysis to identify the average annual percentage changes (AAPCs) of age standardized rates., Result: Globally, the incident strokes and prevalent strokes increased by 18.51% and 31.97%, respectively, but DALYs due to stroke and deaths due to stroke decreased by 60.18% and 65.03%, respectively, from 1990 to 2019. During the same period, ASIR increased by 0.21% (95%CI: 0.17, 0.24) from 18.02 to 100,000 population in 1990 to 19.11 per 100,000 in 2019; ASPR increased by 0.66% (95%CI: 0.36, 0.96) from 68.88 to 100,000 population in 1990 to 81.35 per 100,000 in 2019; while ASMR (AAPC= -3.94; 95%CI: -4.07, -3.81) and ASDR (AAPC= -3.50; 95%CI: -3.64, -3.36) both decreased. In 2019, the highest age standardized incidence, prevalence, mortality, and DALY rates all occurred in low sociodemographic index (SDI) regions. The greatest increase of age standardized incidence rate (AAPC = 0.21; 95%CI: 0.18, 0.25) and prevalence rate (AAPC = 1.15; 95%CI: 0.34, 1.96) both were in high SDI regions. Eastern Sub-Saharan Africa had the highest ASIR and ASPR in 2019, and Oceania had the highest ASMR and ASDR in 2019 across 21 GBD regions. High-income North America had the largest increase in ASIR (AAPC = 0.63; 95%CI: 0.59, 0.66) and ASPR (AAPC = 1.58; 95%CI: 0.54, 2.63). Against the overall decreasing trend of ASMR, an increasing trend of ASMR was found in Zimbabwe (AAPC = 0.91; 95%CI: 0.44, 1.37) and Botswana (AAPC = 0.74; 95%CI: 0.02, 1.47)., Conclusion: The overall increasing stroke incidence and prevalence indicated that prevention and management of stroke among younger population should be critical in the future. Despite stroke mortality with falling trend worldwide, specific countries or territories present worrying increase in stroke mortality. Without urgent implementation of effective primary prevention strategies, the stroke burden of children will probably continue to grow across the world, particularly in high-SDI countries., (© 2023. The Author(s).)

We demonstrated direct conversion of benzene into pyridine and aniline, assisted through exact mass measurements ( m / z 80.0494, 93.0574, and 94.0651, respectively), through the interaction of benzene with water/nitrogen vapor plasma produced by corona discharge. Systematic analysis using a series of isotopic standards indicated that formation of pyridine and aniline occurred through the reaction between neutral benzene and reactive N + (OH 2 ) 2 in water/nitrogen plasma; exact mass measurements of products and intermediates supported this hypothesis. As the proportion of water vapor in plasma increased over time, the reaction proceeded from exclusive formation of protonated pyridine to formation of protonated aniline as the main product; theoretical simulations indicated that the presence of water vapor promoted proton migration to elicit formation of protonated aniline. The reactions we discovered suggest a new mechanism for direct nitrogen fixation.

Background: Angelica polysaccharides (AP) have numerous benefits in relieving type 2 diabetes (T2D). However, the underlying mechanisms have yet to be fully understood. Recent many reports have suggested that altering gut microbiota can have adverse effects on the host metabolism and contribute to the development of T2D. Here, we successfully established the T2D model using the male KKAy mice with high-fat and high-sugar feed. Meanwhile, the male C57BL/6 mice were fed with a normal feed. T2D KKAy mice were fed either with or without AP supplementation. In each group, we measured the mice's fasting blood glucose, weight, and fasting serum insulin levels. We collected the cecum content of mice, the gut microbiota was analyzed by targeted full-length 16S rRNA metagenomic sequencing and metabolites were analyzed by untargeted-metabolomics., Results: We found AP effectively alleviated glycemic disorders of T2D KKAy mice, with the changes in gut microbiota composition and function. Many bacteria species and metabolites were markedly changed in T2D KKAy mice and reversed by AP. Additionally, 16 altered metabolic pathways affected by AP were figured out by combining metagenomic pathway enrichment analysis and metabolic pathway enrichment analysis. The key metabolites in 16 metabolic pathways were significantly associated with the gut microbial alteration. Together, our findings showed that AP supplementation could attenuate the diabetic phenotype. Significant gut microbiota and gut metabolite changes were observed in the T2D KKAy mice and AP intervention., Conclusions: Administration of AP has been shown to improve the composition of intestinal microbiota in T2D KKAy mice, thus providing further evidence for the potential therapeutic application of AP in the treatment of T2D., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: We aimed to obtain more precise estimates of stroke to address the wide variation of stroke burden among people with HIV (PWH) in different clinical settings., Design: Systematic review and meta-analysis., Methods: We systematically searched PubMed, EMBASE, and Web of Science for original articles reporting the prevalence and incidence of stroke among PWH up to November 23, 2022. Der Simonian-Laird random effects were used to obtain pooled estimates and 95% confidence intervals (CIs)., Results: We included 17 observational studies covering 1 749 003 PWH on estimation of prevalence, and 17 cohort studies covering 249 606 PWH on estimation of incidence. The pooled prevalence of stroke was 1.30% (95% CI: 1.01%, 1.59%) for PWH aged at least 15 years, and 3.98% (95% CI: 2.45%, 5.51%) for PWH aged at least 50 years. The pooled incidence of stroke was 17.86 per 10 000 person-years (95% CI: 15.96, 19.76), meanwhile, the pooled incidence of ischemic stroke (31.50 per 10 000 person-years; 95% CI: 11.11, 51.89) was higher than hemorrhagic stroke (4.43 per 10 000 person-years; 95% CI: 1.95, 6.91) among PWH aged at least 15 years., Conclusion: The prevalence of stroke was nearly one per hundred among PWH aged ≥15 years, and reached four per hundred for those aged ≥50 years. The occurrence of stroke is common during HIV progression, particularly ischemic stroke. Therefore, more efforts should be made on implementing policies, strategies, and programs aimed at identifying the risk factors, improving treatment, and facilitating rehabilitation for stroke to reduce the disease burden among PWH., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To address the challenges posed by the COVID-19 pandemic, our hospital developed an intelligent hospital management mode specifically tailored to COVID-19 patients., Methods: This study included patients with confirmed diagnosis of COVID-19 admitted to our hospital between January 2020 to December 2022. We sought to explore intelligent hospital management mode based on artificial intelligence (AI) and new technologies such as 5G, Internet of Things (IoT), wearable devices, robots, and small programs., Results: Intelligent hospital management mode can help improve the quality of life of patients, while also improving the management ability of the hospital, as it can automatically deliver timely patient reminders, maintain environmental cleanliness, and help in the transportation of medical equipment without any manual labor. This can help in conserving time and reducing the workload of medical staff. Moreover, itcan help intellectualize patient admission, patient discharge, and hospital management, thereby helping in providing efficient medical and patient humanistic care., Conclusions: The development of intelligent management mode can reduce the burden of medical personnel and the probability of developing infection and bring about timely and better patient care. Intelligent management can play a pivotal role in control of the epidemic, treating patients, allocation of resources, tracing the root cause of the virus, and monitoring., Competing Interests: CH was employed by Shanghai Shenkang Health Capital Construction Administration Co., Ltd. JZ was employed by Luban Software Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mi, Li, Zhang, Huang, Shan and Zhang.)

Proteolysis-targeting chimeras (PROTACs) as an emerging drug discovery modality has been extensively concerned in recent years. Over 20 years development, accumulated studies have demonstrated that PROTACs show unique advantages over traditional therapy in operable target scope, efficacy, and overcoming drug resistance. However, only limited E3 ligases, the essential elements of PROTACs, have been harnessed for PROTACs design. The optimization of novel ligands for well-established E3 ligases and the employment of additional E3 ligases remain urgent challenges for investigators. Here, we systematically summarize the current status of E3 ligases and corresponding ligands for PROTACs design with a focus on their discovery history, design principles, application benefits, and potential defects. Meanwhile, the prospects and future directions for this field are briefly discussed., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Hepatocellular carcinoma (HCC) remains a worldwide health problem. Mounting evidence indicates that exhausted T cells play a critical role in the progress and treatment of HCC. Therefore, a detailed characterisation of exhausted T cells and their clinical significance warrants further investigation in HCC. Based on the GSE146115, we presented a comprehensive single-cell Atlas in HCC. Pseudo-time analysis revealed that tumour heterogeneity progressively increased, and the exhausted T cells gradually appeared during tumour progression. Functional enrichment analysis revealed that the evolutionary process of exhausted T cells mainly contained the pathway of cadherin binding, proteasome, cell cycle, and T cell receptor regulation of apoptosis. In the International Cancer Genome Consortium database, we divided patients into three clusters with the T cell evolution-associated genes. We found that the exhausted T cells are significantly related to poor outcomes through immunity and survival analysis. In The Cancer Genome Atlas database, the authors enrolled weighted gene co-expression network analysis, univariate Cox analysis, and Lasso Cox analysis, then screened the 19 core genes in T cells evolution and built a robust prognostic model. This study offers a fresh view on evaluating the patients' outcomes from an exhausted T cells perspective and might help clinicians develop therapeutic systems., (© 2023 The Authors. IET Systems Biology published by John Wiley & Sons Ltd on behalf of The Institution of Engineering and Technology.)

There has been some controversy over the use of radiobiological models when modeling the dose-response curves of ionizing radiation (IR)-induced chromosome aberration and tumor prevalence, as those curves usually show obvious non-targeted effects (NTEs) at low doses of high linear energy transfer (LET) radiation. The lack of understanding the contribution of NTEs to IR-induced carcinogenesis can lead to distinct deviations of relative biological effectiveness (RBE) estimations of carcinogenic potential, which are widely used in radiation risk assessment and radiation protection. In this work, based on the initial pattern of two classes of IR-induced DNA double-strand breaks (DSBs) clustering in chromatin domains and the subsequent incorrect repair processes, we proposed a novel radiobiological model to describe the dose-response curves of two carcinogenic-related endpoints within the same theoretical framework. The representative experimental data was used to verify the consistency and validity of the present model. The fitting results indicated that, compared with targeted effect (TE) and NTE models, the current model has better fitting ability when dealing with the experimental data of chromosome aberration and tumor prevalence induced by multiple types of IR with different LETs. Notably, the present model without introducing an NTE term was adequate to describe the dose-response curves of IR-induced chromosome aberration and tumor prevalence with NTEs in low-dose regions. Based on the fitting parameters, the LET-dependent RBE values were calculated for three given low doses. Our results showed that the RBE values predicted by the current model gradually decrease with the increase of doses for the endpoints of chromosome aberration and tumor prevalence. In addition, the calculated RBE was also compared with those evaluated from other models. These analyses show that the proposed model can be used as an alternative tool to well describe dose-response curves of multiple carcinogenic-related endpoints and effectively estimate RBE in low-dose regions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Water dimer radical cations are regarded as key intermediates in many aqueous reactions and biochemical processes. However, the structure of the water dimer radical cations, and particularly the inter-conversion between their isomers, remain difficult to investigate experimentally due to their short lifetime and low abundance under ambient conditions. Furthermore, the isomers cannot be distinguished in a full mass spectra. In this study, we report the experimental evidence for the hemi-bonded and proton-transferred isomers of gas-phase water dimer radical cations, and the inter-conversion process between them in a linear ion trap at low pressure and near room temperature. Multiple collisions of isolated water dimer radical cations with He inside the ion trap were systematically investigated; first, under different trapping times (i.e., reaction times) ranging from 0.03 to 800 ms, and then at a very low collision energies ranging from 0.1% to 10% normalized collision energy. The proton-transferred isomers were dominant at shorter trapping times (≤250 ms), while the hemi-bonded isomers were dominant at longer trapping times (250-800 ms). Moreover, the difference in symmetry of the shapes of the H 2 O •+ signal profiles and the H 3 O + signal profiles implied the existence of two kinds of isomers and there were small potential differences between them. Our results also suggested that by tuning the experimental parameters the hemi-bonded isomers would become dominant, which could allow the study of novel chemical reactions involving the hemi-bonded two-center-three-electron (2c-3e) structure in a linear ion trap., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors.)

As an essential nutrient, copper's redox properties are both beneficial and toxic to cells. Therefore, leveraging the characteristics of copper-dependent diseases or using copper toxicity to treat copper-sensitive diseases may offer new strategies for specific disease treatments. In particular, copper concentration is typically higher in cancer cells, making copper a critical limiting nutrient for cancer cell growth and proliferation. Hence, intervening in copper metabolism specific to cancer cells may become a potential tumor treatment strategy, directly impacting tumor growth and metastasis. In this review, we discuss the metabolism of copper in the body and summarize research progress on the role of copper in promoting tumor cell growth or inducing programmed cell death in tumor cells. Additionally, we elucidate the role of copper-related drugs in cancer treatment, intending to provide new perspectives for cancer treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tang, Yan, Miao, Ha, Li, Yang and Mi.)

Triple-negative breast cancer (TNBC) is a leading malignancy among women that currently lack effective targeted therapeutic agents, and the limitations of treatment have prompted the emergence of new strategies. Methuosis is a novel vacuole-presenting cell death modality that promotes tumor cell death. Hence, a series of pyrimidinediamine derivatives were designed and synthesized through evaluation of their abilities that inhibit proliferation as well as induce methuosis against TNBC cells. Among them, JH530 showed excellent anti-proliferative activities and vacuolization capacity in TNBC. The mechanism research indicated that JH530 caused cell death through inducing methuosis of cancer cells. Furthermore, JH530 inhibited tumor growth remarkably in the HCC1806 xenograft model without an apparent decrease in body weight. Overall, JH530 is a methuosis inducer that displayed remarkable suppression of TNBC growth in vitro and in vivo , which provides a basis for the future progress of more small molecules for TNBC treatment.

Shear and thermal processing can greatly influence nanoparticles' orientation and dispersion, affecting the nanocomposites' conductivity and mechanical properties. The synergistic effects of shear flow and Carbon nanotubes (CNTs) nucleating ability on the crystallization mechanisms have been proven. In this study, Polylactic acid/Carbon nanotubes (PLA/CNTs) nanocomposites were produced by three different molding methods: compression molding (CM), conventional injection molding (IM), and interval injection molding (IntM). Solid annealing at 80 °C for 4 h and pre-melt annealing at 120 °C for 3 h was applied to research the CNTs' nucleation effect and the crystallized volume exclusion effect on the electrical conductivity and mechanical properties. The volume exclusion effect only significantly impacts the oriented CNTs, causing the conductivity along the transverse direction to rise by about seven orders of magnitude. In addition, the tensile modulus of the nanocomposites decreases with the increased crystallinity, while the tensile strength and modulus decrease.

The orientation and dispersion of nanoparticles can greatly influence the conductivity and mechanical properties of nanocomposites. In this study, the Polypropylene/ Carbon Nanotubes (PP/CNTs) nanocomposites were produced using three different molding methods, i.e., compression molding (CM), conventional injection molding (IM), and interval injection molding (IntM). Various CNTs content and shear conditions give CNTs different dispersion and orientation states. Then, three electrical percolation thresholds (4 wt.% CM, 6 wt.% IM, and 9 wt.% IntM) were obtained by various CNTs dispersion and orientations. Agglomerate dispersion (Adis), agglomerate orientation (Aori), and molecular orientation (Mori) are used to quantify the CNTs dispersion and orientation degree. IntM uses high shear to break the agglomerates and promote the Aori, Mori, and Adis. Large Aori and Mori can create a path along the flow direction, which lead to an electrical anisotropy of nearly six orders of magnitude in the flow and transverse direction. On the other hand, when CM and IM samples already build the conductive network, IntM can triple the Adis and destroy the network. Moreover, mechanical properties are also been discussed, such as the increase in tensile strength with Aori and Mori but showing independence with Adis. This paper proves that the high dispersion of CNTs agglomerate goes against forming a conductivity network. At the same time, the increased orientation of CNTs causes the electric current to flow only in the orientation direction. It helps to prepare PP/CNTs nanocomposites on demand by understanding the influence of CNTs dispersion and orientation on mechanical and electrical properties.

Refractory status epilepticus (RSE) is a neurological emergency where sustaining seizure causes severe neuronal death. Currently, there is no available neuroprotectant effective in RSE. Aminoprocalcitonin (NPCT) is a conserved peptide cleaved from procalcitonin, but its distribution and function in the brain remain enigmatic. Survival of neurons relies on sufficient energy supply. Recently, we found that NPCT was extensively distributed in the brain and had potent modulations on neuronal oxidative phosphorylation (OXPHOS), suggesting that NPCT might be involved in neuronal death by regulating energy status. In the present study, combining biochemical and histological methods, high-throughput RNA-sequence, Seahorse XFe analyser, an array of mitochondria function assays, and behavior-electroencephalogram (EEG) monitoring, we investigated the roles and translational values of NPCT in neuronal death after RSE. We found that NPCT was extensively distributed throughout gray matters in rat brain while RSE triggered NPCT overexpression in hippocampal CA3 pyramidal neurons. High-throughput RNA-sequence demonstrated that the influences of NPCT on primary hippocampal neurons were enriched in OXPHOS. Further function assays verified that NPCT facilitated ATP production, enhanced the activities of mitochondrial respiratory chain complexes I, IV, V, and increased neuronal maximal respiration capacity. NPCT exerted multiple neurotrophic effects including facilitating synaptogenesis, neuritogenesis, spinogenesis, and suppression of caspase-3. A polyclonal NPCT immunoneutralization antibody was developed to antagonize NPCT. In the in vitro 0-Mg 2+ seizure model, immunoneutralization of NPCT caused more neuronal death, while exogenous NPCT supplementation, though did not reverse death outcomes, preserved mitochondrial membrane potential. In rat RSE model, both peripheral and intracerebroventricular immunoneutralization of NPCT exacerbated hippocampal neuronal death and peripheral immunoneutralization increased mortality. Intracerebroventricular immunoneutralization of NPCT further led to more serious hippocampal ATP depletion, and significant EEG power exhaustion. We conclude that NPCT is a neuropeptide regulating neuronal OXPHOS. During RSE, NPCT was overexpressed to protect hippocampal neuronal survival via facilitating energy supply., (© 2023. The Author(s).)

Kir6.2/SUR1 is an ATP-regulated potassium channel that acts as an intracellular metabolic sensor, controlling insulin and appetite-stimulatory neuropeptides secretion. In this Letter, we present the SAR around a novel Kir6.2/SUR1 channel opener scaffold derived from an HTS screening campaign. New series of compounds with tractable SAR trends and favorable potencies are reported., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

During spaceflight, multiple unique hazardous factors, particularly microgravity and space radiation, can induce different types of DNA damage, which pose a constant threat to genomic integrity and stability of living organisms. Although organisms have evolved different kinds of conserved DNA repair pathways to eliminate this DNA damage on Earth, the impact of space microgravity on the expressions of these DNA repair genes and their regulatory miRNAs has not been fully explored. In this study, we integrated all existing datasets, including both transcriptional and miRNA microarrays in wild-type (WT) Caenorhabditis elegans that were exposed to the treatments of spaceflight (SF), spaceflight control with a 1g centrifugal device (SC), and ground control (GC) in three space experiments with the periods of 4, 8 and 16.5 days. The results of principal component analysis showed the gene expression patterns for five major DNA repair pathways (i.e., non-homologous end joining (NHEJ), homologous recombination (HR), mismatch repair (MMR), nucleotide excision repair (NER), and base excision repair (BER)) were well separated and clustered between SF/GC and SC/GC treatments after three spaceflights. In the 16.5-days space experiment, we also selected the datasets of dys-1 mutant and ced-1 mutant of C. elegans, which respectively presented microgravity-insensitivity and radiosensitivity. Compared to the WT C. elegans flown in the 16.5-days spaceflight, the separation distances between SF and SC samples were significantly reduced in the dys-1 mutant, while greatly enhanced in the ced-1 mutant for five DNA repair pathways. By comparing the results of differential expression analysis in SF/GC versus SC/GC samples, we found the DNA repair genes annotated in the pathways of BER and NER were prominently down-regulated under microgravity during both the 4- and 8-days spaceflights. While, under microgravity, the genes annotated in MMR were dominatingly up-regulated during the 4-days spaceflight, and those annotated in HR were mainly up-regulated during the 8-days spaceflight. And, most of the DNA repair genes annotated in the pathways of BER, NER, MMR, and HR were up-regulated under microgravity during the 16.5-days spaceflight. Using miRNA-mRNA integrated analysis, we determined the regulatory networks of differentially expressed DNA repair genes and their regulatory miRNAs in WT C. elegans after three spaceflights. Compared to GC conditions, the differentially expressed miRNAs were analyzed under SF and SC treatments of three spaceflights, and some altered miRNAs that responded to SF and SC could regulate the expressions of corresponding DNA repair genes annotated in different DNA repair pathways. In summary, these findings indicate that microgravity can significantly alter the expression patterns of DNA repair genes and their regulatory miRNAs in space-flown C. elegans. The alterations of the expressions of DNA repair genes and the dominating DNA repair pathways under microgravity are possibly related to the spaceflight period. In addition, the key miRNAs are identified as the post-transcriptional regulators to regulate the expressions of various DNA repair genes under microgravity. These altered miRNAs that responded to microgravity can be implicated in regulating diverse DNA repair processes in space-flown C. elegans., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests regarding the publication of this paper., (Copyright © 2023 The Committee on Space Research (COSPAR). Published by Elsevier B.V. All rights reserved.)

Triple-negative breast cancer (TNBC) has a poor prognosis due to the lack of specific and highly effective therapeutic agents. Cancer stem cells (CSCs) are one of the main factors contributing to TNBC relapse and metastasis. Therefore, targeting CSCs selectively with small molecules is a novel strategy for drug development. In this study, the natural product harmine (HM) was identified as a hit compound from 2632 natural product monomers based on phenotypic screening of a 2D assay and patient-derived organoid (PDO) model that was established from a patient who had multiple drug resistance and various visceral and contralateral breast metastases. Next, harmine was further modified and optimized to obtain a lead compound (YH677) with a tetrahydro-β-carboline scaffold. YH677 showed potent antiproliferative and antimigratory activities against several TNBC cell lines in vitro. In addition, YH677 inhibited epithelial mesenchymal transition (EMT) and stem cell marker expression in a dose-dependent manner. More importantly, YH677 suppressed breast cancer growth and metastasis in orthotopic, metastatic xenograft and patient-derived xenograft (PDX) models in vivo. Mechanistic studies showed that YH677 inhibits the expansion of CSCs by regulating the TGFβ/Smad signaling pathway. These preclinical data provide a basis for the development of YH677 as a lead compound for TNBC treatment., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Hepatocellular carcinoma (HCC) remains a challenging medical problem. Cuproptosis is a novel form of cell death that plays a crucial role in tumorigenesis, angiogenesis, and metastasis. However, it remains unclear whether cuproptosis-related genes (CRGs) influence the outcomes and immune microenvironment of HCC patients., Method: From The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases, we obtained the mRNA expression file and related clinical information of HCC patients. We selected 19 CRGs as candidate genes for this study according to previous literature. We performed a differential expression analysis of the 19 CRGs between malignant and precancerous tissue. Based on the 19 CRGs, we enrolled cluster analysis to identify cuproptosis-related subtypes of HCC patients. A prognostic risk signature was created utilizing univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses. We employed independent and stratification survival analyses to investigate the predictive value of this model. The functional enrichment features, mutation signatures, immune profile, and response to immunotherapy of HCC patients were also investigated according to the two molecular subtypes and the prognostic signature., Results: We found that 17 CRGs significantly differed in HCC versus normal samples. Cluster analysis showed two distinct molecular subtypes of cuproptosis. Cluster 1 is preferentially related to poor prognosis, high activity of immune response signaling, high mutant frequency of TP53 , and distinct immune cell infiltration versus cluster 2. Through univariate and LASSO Cox regression analyses, we created a cuproptosis-related prognostic risk signature containing LIPT1 , DLAT , MTF1 , GLS , and CDKN2A . High-risk HCC patients were shown to have a worse prognosis. The risk signature was proved to be an independent predictor of prognosis in both the TCGA and ICGC datasets, according to multivariate analysis. The signature also performed well in different stratification of clinical features. The immune cells, which included regulatory T cells (Treg), B cells, macrophages, mast cells, NK cells, and aDCs, as well as immune functions containing cytolytic activity, MHC class I, and type II IFN response, were remarkably distinct between the high-risk and low-risk groups. The tumor immune dysfunction and exclusion (TIDE) score suggested that high-risk patients had a higher response rate to immune checkpoint inhibitors than low-risk patients., Conclusion: This research discovered the potential prognostic and immunological significance of cuproptosis in HCC, improved the understanding of cuproptosis, and may deliver new directions for developing more efficacious therapeutic techniques for HCC patients., Competing Interests: No potential conflicts of interest were disclosed., (Copyright © 2023 Xiaolong Tang et al.)

Surgical removal remains the predominant treatment strategy for triple-negative breast cancer (TNBC). However, risks that include high locoregional recurrence and remote metastasis threaten patient survival and quality of life after surgery. In this study, a hydrogel based on poly (ethylene glycol) dimethacrylate and sericin methacryloyl was fabricated by photopolymerization to fill the resection cavity and prevent recurrence. The obtained hydrogel exhibited mechanical properties compatible with breast tissue and facilitated postsurgical wound management by promoting tissue regeneration. The DNA methylation inhibitor decitabine (DEC) and poly (lactic-co-glycolic acid)-encapsulated phytochemical gambogic acid (GA) were loaded into the hydrogel. The as-prepared hydrogel promoted fast release of DEC and sustained release of GA, leading to gasdermin E-mediated tumor cell pyroptosis and activating antitumor immune responses. Inducing postsurgical tumor cell pyroptosis inhibited local tumor recurrence and lung metastasis. While the dual-drug-loaded hydrogel system cured less than half of tumor-bearing mice, the cured mice survived for over half a year. These findings indicate that our hydrogel system is an excellent biocompatible platform for postsurgical TNBC therapy., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Triple-negative breast cancer (TNBC) is one of the most malignant tumors with poor prognosis. Methuosis is a new type of nonapoptotic cell death characterized by the accumulation of cytoplasmic vacuoles. In this study, we synthesized and screened a series of N-phenyl-4-pyrimidinediamine derivatives in TNBC cells, finding that DZ-514 was the best compound with high toxicity independent of the inhibition of BCL6. DZ-514 decreased cell viability, inhibited cell cycle progression, and induced caspase-independent cell death in TNBC cells. Interestingly, DZ-514 induced cytoplasm vacuolation, which could be blocked by Baf A1, the V-ATPase inhibitor. Furthermore, we found that DZ-514-induced vacuoles were derived from macropinosomes rather than autophagosomes. Most importantly, methuosis induced by DZ-514 was partially mediated by activating the ROS-MKK4-p38 axis. Finally, we demonstrated that DZ-514 significantly inhibited tumor growth in an HCC1806 xenograft mouse model. These findings revealed that the novel methuosis inducer DZ-514 could be developed for TNBC treatment., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Interneurons are fundamental cells for maintaining the excitation-inhibition balance in the brain in health and disease. While interneurons have been shown to play a key role in the pathophysiology of autism spectrum disorder (ASD) in adult mice, little is known about how their maturation is altered in the developing striatum in ASD. Here, we aimed to track striatal developing interneurons and elucidate the molecular and physiological alterations in the Cntnap2 knockout mouse model. Using Stereo-seq and single-cell RNA sequencing data, we first characterized the pattern of expression of Cntnap2 in the adult brain and at embryonic stages in the medial ganglionic eminence (MGE), a transitory structure producing most cortical and striatal interneurons. We found that Cntnap2 is enriched in the striatum, compared to the cortex, particularly in the developing striatal cholinergic interneurons. We then revealed enhanced MGE-derived cell proliferation, followed by increased cell loss during the canonical window of developmental cell death in the Cntnap2 knockout mice. We uncovered specific cellular and molecular alterations in the developing Lhx6-expressing cholinergic interneurons of the striatum, which impacts interneuron firing properties during the first postnatal week. Overall, our work unveils some of the mechanisms underlying the shift in the developmental trajectory of striatal interneurons which greatly contribute to the ASD pathogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ahmed, Knowles, Liu, Yan, Li, Schumann, Wang, Sontani, Reynolds, Natoli, Wen, Del Pino, Mi and Dehorter.)

Background: While a variety of evidence supports a prenatal component in schizophrenia, there are few data regarding the cell populations involved. We sought to identify cells of the human prenatal brain mediating genetic risk for schizophrenia by integrating cell-specific gene expression measures generated through single-nuclei RNA sequencing with recent large-scale genome-wide association study (GWAS) and exome sequencing data for the condition., Methods: Single-nuclei RNA sequencing was performed on 5 brain regions (frontal cortex, ganglionic eminence, hippocampus, thalamus, and cerebellum) from 3 fetuses from the second trimester of gestation. Enrichment of schizophrenia common variant genetic liability and rare damaging coding variation was assessed in relation to gene expression specificity within each identified cell population., Results: Common risk variants were prominently enriched within genes with high expression specificity for developing neuron populations within the frontal cortex, ganglionic eminence, and hippocampus. Enrichments were largely independent of genes expressed in neuronal populations of the adult brain that have been implicated in schizophrenia through the same methods. Genes containing an excess of rare damaging variants in schizophrenia had higher expression specificity for developing glutamatergic neurons of the frontal cortex and hippocampus that were also enriched for common variant liability., Conclusions: We found evidence for a distinct contribution of prenatal neuronal development to genetic risk for schizophrenia, involving specific populations of developing neurons within the second-trimester fetal brain. Our study significantly advances the understanding of the neurodevelopmental origins of schizophrenia and provides a resource with which to investigate the prenatal antecedents of other psychiatric and neurologic disorders., (Copyright © 2022 Society of Biological Psychiatry. All rights reserved.)

Background: SHP2 is a protein tyrosine phosphatase that is extensively involved in several signaling pathways related to cancer occurrence, and thus SHP2 has been proposed as an attractive target for cancer treatment., Methods: After a brief introduction of SHP2, we provided a short overview of the structure, function and regulation mechanism of SHP2 in cancer occurrence. Then, this perspective focused on the current therapeutic strategies targeting SHP2, including SHP2 PTP inhibitors, SHP2 allosteric inhibitors and SHP2-targeting PROTACs, and discussed the benefits and defects of these strategies. Finally, the opportunities and challenges were presented., Results: SHP2 regulated RAS-ERK, PI3K-AKT, JAK-STAT and PD-1/PD-L1 signaling pathways involved in the pathogenesis of cancer via conformations conversion. Current therapeutic strategies targeting SHP2, especially SHP2 allosteric inhibitors, hold significant potency and have broad application prospects for cancer therapy., Conclusion: In summary, SHP2 is a promising therapeutic target, and strategies targeting SHP2 offer an alternative program for cancer patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)