The synergistic anti-nociceptive effects of nefopam and gabapentinoids in inflammatory, osteoarthritis, and neuropathic pain mouse models.

Pain is a common public health problem and remains as an unmet medical need. Currently available analgesics usually have limited efficacy or are accompanied by many adverse side effects. To achieve satisfactory pain relief by multimodal analgesia, new combinations of nefopam and gabapentinoids (pregabalin/gabapentin) were designed and assessed in inflammatory, osteoarthritis and neuropathic pain. Isobolographic analysis was performed to analyze the interactions between nefopam and gabapentinoids in carrageenan-induced inflammatory pain, mono-iodoacetate-induced osteoarthritis pain and paclitaxel-induced peripheral neuropathic pain in mice. The anti-inflammatory effect and motor performance of monotherapy or their combinations were evaluated in the carrageenan-induced inflammatory responses and rotarod test, respectively. Nefopam (1, 3, 5, 10, 30 mg/kg, p.o.), pregabalin (3, 6, 12, 24 mg/kg, p.o.) or gabapentin (25, 50, 75, 100 mg/kg, p.o.) dose-dependently reversed mechanical allodynia in three pain models. Isobolographic analysis indicated that the combinations of nefopam and gabapentinoids exerted synergistic anti-nociceptive effects in inflammatory, osteoarthritis, and neuropathic pain mouse models, as evidenced by the experimental ED50 (median effective dose) falling below the predicted additive line. Moreover, the combination of nefopam-pregabalin/gabapentin alleviated carrageenan-induced inflammation and edema, and also prevented gabapentinoids-related sedation or ataxia by lowering their effective doses. Collectively, the co-administration of nefopam and gabapentinoids showed synergistic analgesic effects and may result in improved therapeutic benefits for treating pain.

Study on the interaction between agglutinin and chondroitin sulfate and dermatan sulfate using multiple methods.

In this work, the interaction of chondroitin sulfate (CS) and dermatan sulfate (DS) with plant lectins was studied by affinity capillary electrophoresis (ACE), surface plasmon resonance (SPR) technology, molecular docking simulation, and circular dichroism spectroscopy. The ACE method was used for the first time to study the interaction of Ricinus Communis Agglutinin I (RCA I), Wisteria Floribunda Lectin (WFA), and Soybean Agglutinin (SBA) with CS and DS, and the results were in good agreement with those of the SPR method. The results of experiments indicate that RCA I has a strong binding affinity with CS, and the sulfated position does not affect the relationship, but the degree of sulfation can affect the combination of RCA I with CS to some extent. However, the binding affinity with DS is very weak. This study lays the foundation for developing more specialized analysis methods for CS and DS based on RCA I.

Physical-Entanglements-Supported Polymeric Form Stable Phase Change Materials with Ultrahigh Melting Enthalpy.

With the rapid development of new energy and the upgrading of electronic devices, structurally stable phase change materials (PCMs) have attracted widespread attentions from both academia and industries. Traditional cross-linking, composites, or microencapsulation methods for preparation of form stable PCMs usually sacrifice part of the phase change enthalpy and recyclability. Based on the basic polymer viscoelasticity and crystallization theories, here, a kind of novel recyclable polymeric PCM is developed by simple solution mixing ultrahigh molecular weight of polyethylene oxide (UHMWPEO) with its chemical identical oligomer polyethylene glycol (PEG). Rheological and leakage-proof experiments confirm that, even containing 90% of phase change fraction PEG oligomers, long-term of structure stability of PCMs can be achieved when the molecular weight of UHMWPEO is higher than 7000 kg mol-1 due to their ultralong terminal relaxation time and large number of entanglements per chain. Furthermore, because of the reduced overall entanglement concentration, phase change enthalpy of PCMs can be greatly promoted, even reaching to ≈185 J g-1, which is larger than any PEG-based form stable PCMs in literatures. This work provides a new strategy and mechanism for designing physical-entanglements-supported form stable PCMs with ultrahigh phase change enthalpies.

Recent Advances in Nanobiotechnology for the Treatment of Non-Hodgkin's Lymphoma.

Lymphoma is the eighth most common type of cancer worldwide. Currently, lymphoma is mainly classified into two main groups: Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL), with NHL accounting for 80% to 90% of the cases. NHL is primarily divided into B, T, and natural killer (NK) cell lymphoma. Nanotechnology is developing rapidly and has made significant contributions to the field of medicine. This review summarizes the advancements of nanobiotechnology in recent years and its applications in the treatment of NHL, especially in diffuse large B cell lymphoma (DLBCL), central nerve cell lymphoma, and follicular lymphoma. The technologies discussed include clinical imaging, targeted drug delivery, photodynamic therapy (PDT), and thermodynamic therapy for lymphoma. This review aims to provide a better understanding of the use of nanotechnology in the treatment of non-Hodgkin's lymphoma.

Lyoprotectant Formulation and Optimization of the J-Aggregates Astaxanthin/BSA/Chitosan Nanosuspension.

Astaxanthin is a carotenoid with excellent antioxidant activity. However, this small lipid-soluble molecule is insoluble in water and has low stability. Although this situation can be improved when astaxanthin is prepared as a nanosuspension, the aqueous form is still not as convenient and safe as the dry powder form for storage, transport, and use. The lyophilization process provides better protection for thermosensitive materials, but this leads to collapse and agglomeration between nanoparticles. To improve this situation, appropriate lyophilization protectants are needed to offer support between the nanoparticles, such as sugars, amino acids, and hydroxy alcohols. The purpose of this work is to screen lyophilization protectants by single-factor experiments and response surface optimization experiments and then explore the optimal ratio of compound lyophilization protectants, and finally, make excellent astaxanthin/BSA/chitosan nanosuspension (ABC-NPs) lyophilized powder. The work shows that the optimal ratio of the compounding lyophilization protectant is 0.46% oligomeric mannose, 0.44% maltose, and 0.05% sorbitol (w/v). The ABC-NPs lyophilized powder prepared under the above conditions had a re-soluble particle size of 472 nm, with a ratio of 1.32 to the particle size of the sample before lyophilization. The lyophilized powder was all in the form of a pink layer. The sample was fluffy and dissolved entirely within 10 s by shaking with water. Consequently, it is expected to solve the problem of inconvenient storage and transportation of aqueous drugs and to expand the application of nanomedicine powders and tablets.

Design, synthesis and evaluation of heterocyclic 2-phenylacetate derivatives as water-soluble rapid recovery hypnotics.

In this work, a series of novel heterocyclic 2-phenylacetate derivatives were designed and synthesized as water-soluble and rapid recovery hypnotic agents. After introducing heterocyclic ring to the amide group of propanidid, the obtained propanidid derivatives showed greatly improved hydrophilicity and good anesthetic activity. In three animal experiments (mice, rats, and rabbits), compounds 13-15 showed potent hypnotic potency (HD50 = 7.6, 6.5, 7.4 mg/kg in rabbits, respectively) and higher therapeutic indexes (TI = 17.3, 16.6, 15.2 in rabbits, respectively) than propanidid (TI = 14.7 in rabbits) or propofol (TI = 5.4 in rabbits). Moreover, the recovery time of compounds 13-15 (time to walk, 96.6, 79.6, 81.4 s in rabbits, respectively) were shorter than that of propanidid (124.5 s in rabbits) or propofol (425.3 s in rabbits). The experimental results suggested the potential of compounds 13-15 as water-soluble anesthetics with rapid recovery profile.

[Genotype and Phenotype of α-Thalassemia Fusion Gene in Huadu District of Guangzhou, Guangdong Province of China].

OBJECTIVE: To explore the carrier rate, genotype and phenotype of α-thalassemia fusion gene in Huadu district of Guangzhou, Guangdong province of China, and provide data reference for the prevention and control of thalassemia. METHODS: A total of 10 769 samples who were screened for thalassemia in Maternal and Child Health Hospital of Huadu District from July 2019 to November 2020 were analyzed retrospectively. Blood cell analysis and hemoglobin (Hb) electrophoresis were performed. Thalassemia genes were analyzed by gap-PCR and PCR-reverse dot blot hybridization (PCR-RDB). RESULTS: A total of 9 cases with α-thalassemia fusion gene were detected in 10 769 samples (0.08%). There were 7 cases with fusion gene heterozygote, 1 case with compound of α-thalassemia fusion gene and Hb G-Honolulu, 1 case with compound of α-thalassemia fusion gene and Hb QS. The MCV results of 4 samples of blood cell analysis were within the reference range, the Hb A2 value of 1 case was decreased, and there were no other abnormalities found. CONCLUSION: The α-thalassemia fusion gene is common in Huadu district of Guangzhou, and heterozygotes are more common, and current screening methods easily lead to misdiagnosis.

Vimentin as a potential target for diverse nervous system diseases.

Vimentin is a major type III intermediate filament protein that plays important roles in several basic cellular functions including cell migration, proliferation, and division. Although vimentin is a cytoplasmic protein, it also exists in the extracellular matrix and at the cell surface. Previous studies have shown that vimentin may exert multiple physiological effects in different nervous system injuries and diseases. For example, the studies of vimentin in spinal cord injury and stroke mainly focus on the formation of reactive astrocytes. Reduced glial scar, increased axonal regeneration, and improved motor function have been noted after spinal cord injury in vimentin and glial fibrillary acidic protein knockout (GFAP-/-VIM-/-) mice. However, attenuated glial scar formation in post-stroke in GFAP-/- VIM-/- mice resulted in abnormal neuronal network restoration and worse neurological recovery. These opposite results have been attributed to the multiple roles of glial scar in different temporal and spatial conditions. In addition, extracellular vimentin may be a neurotrophic factor that promotes axonal extension by interaction with the insulin-like growth factor 1 receptor. In the pathogenesis of bacterial meningitis, cell surface vimentin is a meningitis facilitator, acting as a receptor of multiple pathogenic bacteria, including E. coli K1, Listeria monocytogenes, and group B streptococcus. Compared with wild type mice, VIM-/- mice are less susceptible to bacterial infection and exhibit a reduced inflammatory response, suggesting that vimentin is necessary to induce the pathogenesis of meningitis. Recently published literature showed that vimentin serves as a double-edged sword in the nervous system, regulating axonal regrowth, myelination, apoptosis, and neuroinflammation. This review aims to provide an overview of vimentin in spinal cord injury, stroke, bacterial meningitis, gliomas, and peripheral nerve injury and to discuss the potential therapeutic methods involving vimentin manipulation in improving axonal regeneration, alleviating infection, inhibiting brain tumor progression, and enhancing nerve myelination.

Hb Huadu [α124(H7)Ser→Thr (TCC>ACC), HBA2: c.373T>A]: A Novel Variant of the α-Globin Gene.

Here, we report a novel α chain hemoglobin (Hb) variant found during routine thalassemia screening. This Hb variant can be detected by capillary electrophoresis (CE) but cannot be recognized by high performance liquid chromatography (HPLC). Sanger sequencing revealed a heterozygous missense substitution at nucleotide 373 on the HBA2 gene, which results in the replacement of serine by threonine at codon 124 [α124(H7)Ser→Thr (TCC>ACC), HBA2: c.373T>A]. It is the first report of this variant, named Hb Huadu for the birthplace of the proband. In addition, the proband coinherited the heterozygous codons 41/42 (-TTCT) (HBB: c126_129delCTTT) on the ß-globin gene.

COVIDX-LwNet: A Lightweight Network Ensemble Model for the Detection of COVID-19 Based on Chest X-ray Images.

Recently, the COVID-19 pandemic coronavirus has put a lot of pressure on health systems around the world. One of the most common ways to detect COVID-19 is to use chest X-ray images, which have the advantage of being cheap and fast. However, in the early days of the COVID-19 outbreak, most studies applied pretrained convolutional neural network (CNN) models, and the features produced by the last convolutional layer were directly passed into the classification head. In this study, the proposed ensemble model consists of three lightweight networks, Xception, MobileNetV2 and NasNetMobile as three original feature extractors, and then three base classifiers are obtained by adding the coordinated attention module, LSTM and a new classification head to the original feature extractors. The classification results from the three base classifiers are then fused by a confidence fusion method. Three publicly available chest X-ray datasets for COVID-19 testing were considered, with ternary (COVID-19, normal and other pneumonia) and quaternary (COVID-19, normal) analyses performed on the first two datasets, bacterial pneumonia and viral pneumonia classification, and achieved high accuracy rates of 95.56% and 91.20%, respectively. The third dataset was used to compare the performance of the model compared to other models and the generalization ability on different datasets. We performed a thorough ablation study on the first dataset to understand the impact of each proposed component. Finally, we also performed visualizations. These saliency maps not only explain key prediction decisions of the model, but also help radiologists locate areas of infection. Through extensive experiments, it was finally found that the results obtained by the proposed method are comparable to the state-of-the-art methods.

Moral distress experienced by online suicide prevention volunteers: qualitative research / La angustia moral experimentada por los voluntarios de la prevención del suicidio en línea: investigación cualitativa / Stress moral experimentado por voluntários de prevenção de suicídio online

Abstract: Background: With the increasing number of internet users, it becomes feasible to identify individuals at high risk of suicide and then carry out online suicide prevention. At the same time, online suicide prevention volunteers may encounter moral distress, which requires more attention. Purpose: This study aimed to explore the experience of moral distress in online suicide prevention. Method: The study was carried out as a qualitative study following the method of phenomenology. 11 interviewers were recruited through the purposive sampling method. Data were collected through semi-structured, in-depth face-to-face interviews. Colaizzi's phenomenological framework was used for data analysis. Results: All participants reported they encountered moral distress during online suicide prevention. Four themes were condensed, including: "constraints from the surrounding," "be cruel to be kind," "baby spoiled by free milk," and "when face death and depression" Participants also described their emotional experiences and response when they encountered moral distress. Conclusion: Moral distress in the process of online suicide prevention exists. More attention should be paid to the moral distress and ethical issues in online suicide prevention as the internet gradually becomes a brand-new way to prevent suicide.

Resumen: Antecedentes: Con el creciente número de usuarios de Internet, es posible identificar a las personas con alto riesgo de suicidio y llevar a cabo la prevención del suicidio en línea. Al mismo tiempo, los voluntarios de esta prevención pueden encontrarse con angustia moral, lo que requiere más atención. Objetivo: Este estudio tiene como objetivo explorar la experiencia de la angustia moral en la prevención del suicidio en línea. Método: El estudio se llevó a cabo como un estudio cualitativo siguiendo el método de la fenomenología. Se reclutó a 11 entrevistadores mediante el método de muestreo intencional. Los datos se recogieron mediante entrevistas semiestructuradas y en profundidad, cara a cara. Se utilizó el marco fenomenológico de Colaizzi para el análisis de los datos. Resultados: Todos los participantes informaron que habían encontrado angustia moral durante la prevención del suicidio en línea. Se condensaron cuatro temas, a saber: "limitaciones del entorno", "ser cruel para ser amable", "bebé mimado por la leche gratis" y "cuando se enfrenta a la muerte y la depresión". Los participantes también describieron sus experiencias emocionales y su respuesta cuando se encontraron con la angustia moral. Conclusión: La angustia moral en este proceso existe. Hay que prestar más atención a la angustia moral y a las cuestiones éticas en la prevención del suicidio en línea, ya que Internet se convierte gradualmente en una nueva forma de prevenir el suicidio.

Resumo: Antecedentes: Com o crescente número de usuário de internet, torna-se viável identificar indivíduos com alto risco de suicídio e então conduzir prevenção de suicídio online. Ao mesmo tempo, voluntários de prevenção de suicídio online podem enfrentar stress moral, o qual requer mais atenção. Proposta: Esse estudo objetiva explorar a experiência de stress moral em prevenção de suicídio online. Método: O estudo foi conduzido como um estudo qualitativo seguindo o método da fenomenologia. Foram recrutados 11 entrevistados do método de amostragem intencional. Foram coletados dados através de entrevistas face a face, semiestruturadas e em profundidade. O referencial fenomenológico de Colaizzi foi utilizado para análise dos dados. Resultados: Todos os participantes relataram terem experimentado stress moral durante a prevenção de suicídio online. Quatro temas foram condensados: "limitações do ambiente", "ser cruel para ser gentil", "bebê mimado com leite gratuito" e "quando encarando a morte e a depressão". Os participantes também descreveram suas experiências emocionais e respostas quando enfrentaram stress moral. Conclusão: Stress moral no processo de prevenção de suicídio online existe. Mais atenção deve ser dada ao stress moral e aspectos éticos em prevenção de suicídio online na medida em que a internet se torna gradualmente uma maneira totalmente nova de prevenção de suicídio.

[Molecular Epidemiological Characteristics and Differential Diagnosis of Common 뫧-Thalassemia/HPFH].

OBJECTIVE: To investigate the molecular epidemiological characteristics of common δß-thalassemia/hereditary persistence of fetal hemoglobin(HPFH) in the prepregnant population in Huadu, and to provide a laboratory basis for prevention and control of thalassemia. METHODS: Blood samples of childbearing age people in Huadu District of Guangzhou who participated in free thalassemia testing from January 2016 to July 2021 were collected for hematological parameters analysis and hemoglobin electrophoresis. Chinese Gγ+(Aγδß)0-thalassemia, SEA-HPFH and Taiwanese deletion ß-thalassemia were detected by Gap-PCR in the samples with higher HbF(≥5%). Primers were designed for the proximal HBG1 and HBG2 promoter, and the point mutations in the proximal promoter region were detected by Sanger sequencing. Hematology parameters data were statistically analyzed. RESULTS: Among 27 088 samples, Thirteen cases of Chinese Gγ+(Aγδß)0-thalassemia and thirty-three cases of SEA-HPFH were detected, which including 3 cases of Chinese Gγ+(Aγδß)0/ßN compounded with --SEA/αα and three cases of SEA-HPFH/ßN compounded with --SEA/αα. 6 carriers with Aγ-196 C>T were also detected; No Taiwanese thalassemia genetype was detected. The total detection rate of common δß-thalassemia/HPFH was 0.19% (52/27 088). There were significant differences in the levels of MCV, MCH, HbA2, and HbF among Chinese Gγ+(Aγδß)0-thalassemia, SEA-HPFH, Aγ-196 C>T (P<0.001). The hematological parameters of Aγ-196C>T combined with α0-thalassemia were similar to those of Chinese Gγ+(Aγδß)0-thalassemia carriers, and only HbA2 was significantly lower than that of the latter, which was helpful for clinical identification. CONCLUSION: δß-thalassemia/HPFH should be included in the scope of thalassemia prevention program in the prepregnant population in Huadu District, and hematological parameters can provide some basis for identifying different types of δß-thalassemia/HPFH.

FABNet: Fusion Attention Block and Transfer Learning for Laryngeal Cancer Tumor Grading in P63 IHC Histopathology Images.

Laryngeal cancer tumor (LCT) grading is a challenging task in P63 Immunohistochemical (IHC) histopathology images due to small differences between LCT levels in pathology images, the lack of precision in lesion regions of interest (LROIs) and the paucity of LCT pathology image samples. The key to solving the LCT grading problem is to transfer knowledge from other images and to identify more accurate LROIs, but the following problems occur: 1) transferring knowledge without a priori experience often causes negative transfer and creates a heavy workload due to the abundance of image types, and 2) convolutional neural networks (CNNs) constructing deep models by stacking cannot sufficiently identify LROIs, often deviate significantly from the LROIs focused on by experienced pathologists, and are prone to providing misleading second opinions. So we propose a novel fusion attention block network (FABNet) to address these problems. First, we propose a model transfer method based on clinical a priori experience and sample analysis (CPESA) that analyzes the transfer ability by integrating clinical a priori experience using indicators such as the relationship between the cancer onset location and morphology and the texture and staining degree of cell nuclei in histopathology images; our method further validates these indicators by the probability distribution of cancer image samples. Then, we propose a fusion attention block (FAB) structure, which can both provide an advanced non-uniform sparse representation of images and extract spatial relationship information between nuclei; consequently, the LROI can be more accurate and more relevant to pathologists. We conducted extensive experiments, compared with the best Baseline model, the classification accuracy is improved 25%, and It is demonstrated that FABNet performs better on different cancer pathology image datasets and outperforms other state of the art (SOTA) models.

MiR-615 Agomir Encapsulated in Pluronic F-127 Alleviates Neuron Damage and Facilitates Function Recovery After Brachial Plexus Avulsion.

Brachial plexus avulsion (BPA) is a devastating traumatic peripheral nerve injury complicated with paralysis of the upper extremity. We previously reported that leucine-rich repeat and immunoglobulin-like domain-containing NOGO receptor-interacting protein 1 (LINGO-1) has a potent role in inhibiting neuron survival and axonal regeneration after the central nervous system (CNS) damage and miR-615 is a potential microRNA (miRNA) negatively regulated LINGO-1. However, the effect of miR-615 in BPA remains to be elucidated. Accumulating evidence indicates that pluronic F-127 (PF-127) hydrogel could serve as a promising vehicle for miRNA encapsulation. Thus, to further explore the potential role of hydrogel-miR-615 in BPA-reimplantation, the present study established the BPA rat model and injected miR-615 agomir encapsulated by PF-127 hydrogel into the reimplantation site using a microsyringe. In this study, results indicated that hydrogel-miR-615 agomir effectively alleviated motoneuron loss by LINGO-1 inhibition, promoted musculocutaneous nerve regeneration and myelination, reduced astrocytes activation, promoted angiogenesis and attenuated peripheral amyotrophy, leading to improved motor functional rehabilitation of the upper extremity. In conclusion, our findings demonstrate that miR-615-loaded PF-127 hydrogel may represent a novel therapeutic strategy for BPA treatment.

Selective Interaction of Sugarcane eIF4E with VPgs from Sugarcane Mosaic Pathogens.

Eukaryotic translation initiation factor 4E (eIF4E) plays a key role in the infection of potyviruses in susceptible plants by interacting with viral genome-linked protein (VPg). Sugarcane (Saccharum spp.) production is threatened by mosaic disease caused by Sugarcane mosaic virus (SCMV), Sorghum mosaic virus (SrMV), and Sugarcane streak mosaic virus (SCSMV). In this study, two eIF4Es and their isoform eIF(iso)4E and 4E-binding protein coding genes were cloned from sugarcane cultivar ROC22 and designated SceIF4Ea, SceIF4Eb, SceIF(iso)4E, and ScnCBP, respectively. Real-time quantitative PCR analysis showed different expression profiles of these four genes upon SCMV challenge. A subcellular localization assay showed that SceIF4Ea, SceIF4Eb, SceIF(iso)4E, and ScnCBP were distributed in the nucleus and cytoplasm. Yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays showed that SceIF4Ea/b and SceIF(iso)4E were selectively employed by different sugarcane mosaic pathogens, i.e., SCMV-VPg interacted with SceIF4Ea/b and SceIF(iso)4E, SrMV-VPg interacted with both SceIF4Eb and SceIF(iso)4E, and SCSMV-VPg interacted only with SceIF(iso)4E. Intriguingly, the BiFC assays, but not the Y2H assays, showed that ScnCBP interacted with the VPgs of SCMV, SrMV, and SCSMV. Competitive interaction assays showed that SCMV-VPg, SrMV-VPg, and SCMV-VPg did not compete with each other to interact with SceIF(iso)4E, and SceIF(iso)4E competed with SceIF4Eb to interact with SrMV-VPg but not SCMV-VPg. This study sheds light on the molecular mechanism of sugarcane mosaic pathogen infection of sugarcane plants and benefits sugarcane breeding against the sugarcane mosaic disease.

Quantitative acetylome analysis reveals histone modifications that may predict prognosis in hepatitis B-related hepatocellular carcinoma.

Lysine acetylation (Kac) as an important posttranslational modification of histones is essential for the regulation of gene expression in hepatocellular carcinoma (HCC). However, the atlas of whole acetylated proteins in HCC tissues and the difference in protein acetylation between normal human tissues and HCC tissues are unknown. In this report, we characterized the proteome and acetyl proteome (acetylome) profile of normal, paracancerous, and HCC liver tissues in human clinical samples by quantitative proteomics techniques. We identified 6781 acetylation sites of 2582 proteins and quantified 2492 acetylation sites of 1190 proteins in normal, paracancerous, and HCC liver tissues. Among them, 15 proteins were multiacetylated with more than 10 lysine residues. The histone acetyltransferases p300 and CBP were found to be hyperacetylated in hepatitis B virus pathway. Moreover, we found that 250 Kac sites of 214 proteins were upregulated and 662 Kac sites of 451 proteins were downregulated in HCC compared with normal liver tissues. Additionally, the acetylation levels of lysine 120 in histone H2B (H2BK120ac), lysine 18 in histone H3.3 (H3.3K18ac), and lysine 77 in histone H4 (H4K77ac) were increased in HCC. Interestingly, the higher levels of H2BK120ac, H3.3K18ac, and H4K77ac were significantly associated with worse prognosis, such as poorer survival and higher recurrence in an independent clinical cohort of HCC patients. Overall, this study lays a foundation for understanding the functions of acetylation in HCC and provides potential prognostic factors for the diagnosis and therapy of HCC.

A-kinase-interacting protein 1 promotes EMT and metastasis via PI3K/Akt/IKKß pathway in cervical cancer.

Overexpression of A-kinase-interacting protein 1 (AKIP1) has been reported in prostate and breast cancers. Nevertheless, the clinical potential of AKIP1 during the development of cervical cancer (CC) remains unclear. A series of experiments involving BdU, colony formation, wound healing and cell invasion assays were performed to determine cell proliferation, migration and invasion, respectively. Gene expression changes were validated by qRT-PCR, Western blotting and immunocytochemistry. We found that AKIP1 expression is increased in CC cell lines and tissue specimens from CC patients. The elevated AKIP1 expression in primary tumours was related to lymph node metastasis in CC patients. In addition, we observed that overexpression of AKIP1 promotes CC cell proliferation. Enhanced expression of AKIP1 facilitated the migration and invasion of CC cells by inducing NF-κB-dependent epithelial-mesenchymal transition (EMT). Moreover, mechanistic investigations revealed that AKIP1 induced nuclear translocation and phosphorylation of the p65 NF-κB subunit through the PI3K/Akt/IKKß pathway. Conversely, enhanced expression of phosphatase and tensin homologue (PTEN) inhibited this signalling pathway and restored an epithelial phenotype to CC cells in the presence of overexpressed AKIP1. Our results indicate that AKIP1 promotes the EMT and metastasis in CC by activating NF-κB signalling through the PI3K/Akt/IKKß pathway, suggesting that AKIP1 could be a pivotal regulator of an EMT axis in CC. SIGNIFICANCE OF THE STUDY: AKIP1 expression in the samples of CC patients and in in vitro tumour cell lines provides evidence that expression of AKIP1 in CC contributes to cancer progression. Our findings indicate that AKIP1 promotes the epithelial-mesenchymal transition and metastasis in CC by activating NF-κB signalling through the PI3K/Akt/IKKß pathway, suggesting that AKIP1 is a pivotal regulator of an EMT axis in CC. AKIP1 could be implicated as a potential therapeutic target as well as a valuable biomarker for evaluating prognosis for patients with CC.

Two old drugs, NVP-AEW541 and GSK-J4, repurposed against the Toxoplasma gondii RH strain.

BACKGROUND: Toxoplasma gondii is a zoonotic pathogen that causes toxoplasmosis and leads to serious public health problems in developing countries. However, current clinical therapeutic drugs have some disadvantages, such as serious side effects, a long course of treatment and the emergence of drug-resistant strains. The urgent need to identify novel anti-Toxoplasma drugs has initiated the effective strategy of repurposing well-characterized drugs. As a principled screening for the identification of effective compounds against Toxoplasma gondii, in the current study, a collection of 666 compounds were screened for their ability to significantly inhibit Toxoplasma growth. METHODS: The inhibition of parasite growth was determined using a luminescence-based ß-galactosidase activity assay. Meanwhile, the effect of compounds on the viability of host cells was measured using CCK8. To assess the inhibition of the selected compounds on discrete steps of the T. gondii lytic cycle, the invasion, intracellular proliferation and egress abilities were evaluated. Finally, a murine infection model of toxoplasmosis was used to monitor the protective efficacy of drugs against acute infection of a highly virulent RH strain. RESULTS: A total of 68 compounds demonstrated more than 70% parasite growth inhibition. After excluding compounds that impaired host cell viability, we further characterized two compounds, NVP-AEW541 and GSK-J4 HCl, which had IC50 values for parasite growth of 1.17 µM and 2.37 µM, respectively. In addition, both compounds showed low toxicity to the host cell. Furthermore, we demonstrated that NVP-AEW541 inhibits tachyzoite invasion, while GSK-J4 HCl inhibits intracellular tachyzoite proliferation by halting cell cycle progression from G1 to S phase. These findings prompted us to analyse the efficacy of the two compounds in vivo by using established mouse models of acute toxoplasmosis. In addition to prolonging the survival time of mice acutely infected with T. gondii, both compounds had a remarkable ability to reduce the parasite burden of tissues. CONCLUSIONS: Our findings suggest that both NVP-AEW541 and GSK-J4 could be potentially repurposed as candidate drugs against T. gondii infection.

Recognition of Common Non-Normal Walking Actions Based on Relief-F Feature Selection and Relief-Bagging-SVM.

Action recognition algorithms are widely used in the fields of medical health and pedestrian dead reckoning (PDR). The classification and recognition of non-normal walking actions and normal walking actions are very important for improving the accuracy of medical health indicators and PDR steps. Existing motion recognition algorithms focus on the recognition of normal walking actions, and the recognition of non-normal walking actions common to daily life is incomplete or inaccurate, resulting in a low overall recognition accuracy. This paper proposes a microelectromechanical system (MEMS) action recognition method based on Relief-F feature selection and relief-bagging-support vector machine (SVM). Feature selection using the Relief-F algorithm reduces the dimensions by 16 and reduces the optimization time by an average of 9.55 s. Experiments show that the improved algorithm for identifying non-normal walking actions has an accuracy of 96.63%; compared with Decision Tree (DT), it increased by 11.63%; compared with k-nearest neighbor (KNN), it increased by 26.62%; and compared with random forest (RF), it increased by 11.63%. The average Area Under Curve (AUC) of the improved algorithm improved by 0.1143 compared to KNN, by 0.0235 compared to DT, and by 0.04 compared to RF.

Correction to: DNMT3A reads and connects histone H3K36me2 to DNA methylation.

The author would like to add the below information in this correction. A similar study from Chao Lu group was published online on 5 September 2019 in Nature, entitled "The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape" (Weinberg et al., 2019). Although both the studies reported the preferential recognition of H3K36me2 by DNMT3A PWWP, ours in addition uncovered a stimulation function by such interaction on the activity of DNMT3A. On the disease connections, we used a NSD2 gain-of-function model which led to the discovery of potential therapeutic implication of DNA inhibitors in the related cancers, while the other study only used NSD1 and DNMT3A loss-of-function models.