Alzheimer's disease and other neurodegenerative disorders of aging are characterized by clinical and pathological features that are relatively specific to humans. To obtain greater insight into how brain aging has evolved, we compared age-related gene expression changes in the cortex of humans, rhesus macaques, and mice on a genome-wide scale. A small subset of gene expression changes are conserved in all three species, including robust age-dependent upregulation of the neuroprotective gene apolipoprotein D (APOD) and downregulation of the synaptic cAMP signaling gene calcium/calmodulin-dependent protein kinase IV (CAMK4). However, analysis of gene ontology and cell type localization shows that humans and rhesus macaques have diverged from mice due to a dramatic increase in age-dependent repression of neuronal genes. Many of these age-regulated neuronal genes are associated with synaptic function. Notably, genes associated with GABA-ergic inhibitory function are robustly age-downregulated in humans but not in mice at the level of both mRNA and protein. Gene downregulation was not associated with overall neuronal or synaptic loss. Thus, repression of neuronal gene expression is a prominent and recently evolved feature of brain aging in humans and rhesus macaques that may alter neural networks and contribute to age-related cognitive changes.

Expression of neutrophil gelatinase-associated lipocalin (NGAL)/lipocalin2, a recently recognized iron regulatory protein that binds to matrix metalloproteinase-9 (MMP9), is increased in a spectrum of cancers, including those of the colorectum. Using colon carcinoma cell lines stably transfected with NGAL or antisense NGAL, we showed that NGAL overexpression altered subcellular localization of E-cadherin and catenins, decreased E-cadherin-mediated cell-cell adhesion, enhanced cell-matrix attachment, and increased cell motility and in vitro invasion. Conversely, a decrease in NGAL enhanced more aggregated growth pattern and decreased in vitro invasion. We further showed that NGAL exerted these effects through the alteration of the subcellular localization of Rac1 in an extracellular matrix-dependent, but MMP9-independent, manner. Furthermore, we observed that the NGAL-overexpressing cells tolerated increased iron levels in the culture environment, whereas the NGAL-underexpressing cells showed significant cell death after prolonged incubation in high-iron condition. Thus, overexpressing NGAL in colon carcinomas is an important regulatory molecule that integrates extracellular environment cues, iron metabolism, and intracellular small GTPase signaling in cancer migration and invasion. NGAL may therefore be a new target for therapeutic intervention in colorectal carcinoma.

Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer's disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer's disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.

RNA silencing is a process triggered by 21-24 small RNAs to repress gene expression. Many organisms including plants use RNA silencing to regulate development and physiology, and to maintain genome stability. Plants possess two classes of small RNAs: microRNAs (miRNAs) and small interfering RNAs (siRNAs). The frameworks of miRNA and siRNA pathways have been established in the model plant, Arabidopsis thaliana (Arabidopsis).

Transcription factors have been studied intensively because they play an important role in gene expression regulation. However, the transcription factors in the CPP family (cystein-rich polycomb-like protein), compared with other transcription factor families, have not received sufficient attention, despite their wide prevalence in a broad spectrum of species, from plants to animals. The total number of known CPP transcription factors in plants is 111 from 16 plants, but only 2 of them have been studied so far, namely TSO1 and CPP1 in Arabidopsis thaliana and soybean, respectively.

Several studies have revealed that adipose-derived mesenchymal stem cells (ADSCs) can be used as seed cells for the treatment of spinal cord injury (SCI). Chondroitinase ABC (ChABC) decomposes chondroitin sulfate proteoglycans in the glial scar that forms following SCI, allowing stem cells to penetrate through the scar and promote recovery of nerve function. This study aimed to establish ADSCs that stably express ChABC (ChABC-ADSCs) and evaluate the migratory capability of ChABC-ADSCs in vitro.

The identification of V-raf murine sarcoma viral oncogene homolog B1 (BRAF)V600E mutations has been recommended in patients with Langerhans cell histiocytosis (LCH) with difficult diagnosis and failure of first-line treatment. The reported frequencies of BRAFV600E mutations vary in Chinese patients with LCH.

Tropical rainforests play important roles in carbon sequestration and are hot spots for biodiversity. Tropical forests are being replaced by rubber (Hevea brasiliensis) plantations, causing widespread concern of a crash in biodiversity. Such changes in aboveground vegetation might have stronger impacts on belowground biodiversity. We studied tropical rainforest fragments and derived rubber plantations at a network of sites in Xishuangbanna, China, hypothesizing a major decrease in diversity with conversion to plantations. We used metabarcoding of the 18S rRNA gene and recovered 2313 OTUs, with a total of 449 OTUs shared between the two land-use types. The most abundant phyla detected were Annelida (66.4% reads) followed by arthropods (15.5% reads) and nematodes (8.9% reads). Of these, only annelids were significantly more abundant in rubber plantation. Taken together, α- and β-diversity were significantly higher in forest than rubber plantation. Soil pH and spatial distance explained a significant portion of the variability in phylogenetic community structure for both land-use types. Community assembly was primarily influenced by stochastic processes. Overall it appears that forest replacement by rubber plantation results in an overall loss and extensive replacement of soil micro- and mesofaunal biodiversity, which should be regarded as an additional aspect of the impact of forest conversion.

A thymoma is a common cancer within the anterior mediastinum; however, the prognostic characteristics have not been established. The aim of this study was to identify the prognostic factors and develop a nomogram for the prognostic prediction of patients with thymoma based on data from the Surveillance, Epidemiology, and End Results (SEER) database.

To quantitatively evaluate the effect of preexisting diabetes mellitus (DM) on the outcomes of patients with non-small-cell lung cancer (NSCLC).

Aberrant activation of p21-activated kinase 1 (PAK1) is associated with tumour progression, and PAK1 has been recognized as a promising target for anticancer drug discovery. However, the development of potent PAK1 inhibitors with satisfactory kinase selectivity and favourable physicochemical properties remains a daunting challenge. Herein, we identified the 1H-indazole-3-carboxamide derivatives as potential PAK1 inhibitors using a fragment-based screening approach. The representative compound 30l exhibited excellent enzyme inhibition (PAK1 IC50 = 9.8 nM) and high PAK1 selectivity toward a panel of 29 kinases. The Structure-activity relationship (SAR) analysis showed that substituting of an appropriate hydrophobic ring in the deep back pocket and introducing a hydrophilic group in the bulk solvent region were critical for PAK1 inhibitory activity and selectivity. Additionally, the hERG channel activity of 30l demonstrated its low risk of hERG toxicity. Furthermore, it significantly suppressed the migration and invasion of MDA-MB-231 cells by downregulating Snail expression without affecting the tumour growth. These results provide a new type of chemical scaffolds targeting PAK1 and suggested that 1H-indazole-3-carboxamide derivatives may serve as lead compounds for the development of potential and selective PAK1 inhibitors.

The expression levels of α-enolase, also known as enolase 1 (ENO1), in liver cancer tissues and the autoantibody levels of ENO1 in the sera of patients with liver cancer were detected to investigate the function of ENO1 in the invasion and metastasis of liver cancer, as well as its clinical diagnostic value. Small interfering RNA (siRNA) was used to disrupt ENO1 gene expression in HepG2 and Huh7 liver cancer cells. The proliferation ability of liver cancer cells was assessed using Cell Counting Kit-8 (CCK-8); the migration ability of liver cancer cells was assessed using scratch tests; and the migration and invasion abilities of liver cancer cells were assessed using Transwell assays. ENO1 expression in liver cancer tissues (43.8%) was significantly higher than that in benign liver lesions (15.2%) (P=0.005). The serum anti-ENO1 antibody levels in the liver cancer group were significantly higher than those in the control and benign liver lesion groups (P<0.001). After ENO1 gene interference, the proliferation, migration and invasion abilities of HepG2 and Huh7 liver cancer cells exhibited different degrees of suppression. The results revealed that ENO1 promotes liver cancer invasion and metastasis; ENO1 plays an important role in liver cancer and can be used as a potential liver cancer-associated marker.

Due to limited immunological profiles of high-grade serous ovarian cancer (HGSOC), we aimed to characterize its molecular features to determine whether a specific subset that can respond to immunotherapy exists.

The rapid development of coronavirus disease 2019 (COVID-19) pandemic has become a great threat to global health. Its mortality is associated with inflammation-related airway mucus hypersecretion and dysfunction of expectoration, and the subsequent mucus blockage of the bronchioles at critical stage is attributed to hypoxemia, complications, and even death. Traditional Chinese medicine (TCM) has rich experience in expectorant, including treatment of COVID-19 patients with airway mucus dysfunction, yet little is known about the mechanisms. This study is aiming to explore the potential biological basis of TCM herbal expectorant for treating COVID-19.

Targeting CD40 with agonist antibodies is a promising approach to cancer immunotherapy. CD40 acts as a master regulator of immunity by mobilizing multiple arms of the immune system to initiate highly effective CD8 + T-cell-mediated responses against foreign pathogens and tumors. The clinical development of CD40 agonist antibodies requires careful optimization of the antibody to maximize therapeutic efficacy while minimizing adverse effects. Both epitope specificity and isotype are critical for CD40 agonist antibody mechanism of action and potency. We developed a novel antibody, APX005M, which binds with high affinity to the CD40 ligand-binding site on CD40 and is optimized for selective interaction with Fcγ receptors to enhance agonistic potency while limiting less desirable Fc-effector functions like antibody-dependent cellular cytotoxicity of CD40-expressing immune cells. APX005M is a highly potent inducer of innate and adaptive immune effector responses and represents a promising CD40 agonist antibody for induction of an effective anti-tumor immune response with a favorable safety profile.

Postherpetic neuralgia (PHN), the most common complication of herpes zoster, brings about a health-care burden at both the individual and societal levels. External therapy of Chinese medicine (ETCM) is an effective treatment of PHN generally available in China, yet there is incomplete evidence to evaluate the efficacy and safety of it.

Cyanobacterial blooms are a global ecological problem that directly threatens human health and crop safety. Cyanobacteria have toxic effects on aquatic microorganisms, which could drive the selection for resistance genes. The effect of cyanobacterial blooms on the dispersal and abundance of antibiotic-resistance genes (ARGs) of concern to human health remains poorly known. We herein investigated the effect of cyanobacterial blooms on ARG composition in Lake Taihu, China. The numbers and relative abundances of total ARGs increased obviously during a Planktothrix bloom. More pathogenic microorganisms were present during this bloom than during a Planktothrix bloom or during the non-bloom period. Microcosmic experiments using additional aquatic ecosystems (an urban river and Lake West) found that a coculture of Microcystis aeruginosa and Planktothrix agardhii increased the richness of the bacterial community, because its phycosphere provided a richer microniche for bacterial colonization and growth. Antibiotic-resistance bacteria were naturally in a rich position, successfully increasing the momentum for the emergence and spread of ARGs. These results demonstrate that cyanobacterial blooms are a crucial driver of ARG diffusion and enrichment in freshwater, thus providing a reference for the ecology and evolution of ARGs and ARBs and for better assessing and managing water quality.

NIK is a critical regulatory protein of the non-classical NF-kB pathway, and its dysregulated activation has been proved to be one of the pathogenic factors in a variety of autoimmune diseases and inflammatory diseases. Nevertheless, its corresponding development of inhibitors faces many obstacles, including the lack of structure types of known inhibitors, immature activity evaluation methods of compounds in vitro. In this study, a series of quinoline derivatives were obtained through rational design and chemical synthesis. Among them, the representative compounds 17c and 24c have excellent inhibitory activities on LPS-induced macrophage (J774) nitric oxide release and anti-Con A-stimulated primary T cell proliferation. This evaluation method has good universality and overcomes the obstacles mentioned above, which are faced by the current inhibitor research to a certain extent. Besides, the compound's toxicity against the growth of T cells under non-stress conditions was evaluated, for the first time, as an indicator for the investigation to avoid potential safety risks. Pharmacokinetic properties evaluation of the less toxic compound 24c confirmed its good metabolic behavior (especially oral properties, F% = 21.7%), and subsequent development value.

The multifunctional protein Y-box binding protein 1 (YBX1), is a critical regulator of transcription and translation, and is widely recognized as an oncogenic driver in several solid tumors, including colorectal cancer (CRC). However, very little is known about the upstream or downstream factors that underlie YBX1's regulation and involvement in CRC. Previously, we demonstrated that YBX1 overexpression correlated with potent activation of nuclear factor κB (NF-κB), a well-known transcription factor believed to be crucial in CRC progression. Here, we report a novel interaction between NF-κB, YBX1 and protein arginine methyltransferase 5 (PRMT5). Our findings reveal for the first time that PRMT5 catalyzes methylation of YBX1 at arginine 205 (YBX1-R205me2), an event that is critical for YBX1-mediated NF-κB activation and its downstream target gene expression. Importantly, when WT-YBX1 is overexpressed, this methylation exists under basal (unstimulated) conditions and is further augmented upon interleukin-1β (IL-1β) stimulation. Mechanistically, co-immunoprecipitation studies reveal that the R205 to alanine (A) mutant of YBX1 (YBX1-R205A) interacted less well with the p65 subunit of NF-κB and attenuated the DNA binding ability of p65. Importantly, overexpression of YBX1-R205A significantly reduced cell growth, migration and anchorage-independent growth of CRC cells. Collectively, our findings shed important light on the regulation of a novel PRMT5/YBX1/NF-κB axis through PRMT5-mediated YBX1-R205 methylation. Given the fact that PRMT5, YBX1 and NF-κB are all among top crucial factors in cancer progression, pharmacological disruption of this pivotal axis could serve as the basis for new therapeutics for CRC and other PRMT5/YBX1/NF-κB-associated cancers.

Guillain-Barré syndrome (GBS) is the most common acute paralytic neuropathy. Many clinical trials indicate acupuncture provides a good effect as a complementary therapy of Western medicine for GBS. The objective of this systematic review protocol is to provide the evidence to evaluate the effectiveness and safety of acupuncture on the treatment of GBS.