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To screen the key genes in the development of gastric cancer and their influence on prognosis. The GEO database was used to screen gastric cancer-related gene chips as a training set, and the R packages limma tool was used to analyze the differential genes expressed in gastric cancer tissues compared to normal tissues, and then the selected genes were verified in the validation set. The String database was used to calculate their Protein–protein interaction (PPI) network, using Cytoscape software's Centiscape and other plug-ins to analyze key genes in the PPI network. The DAVID database was used to enrich and annotate gene functions of differential genes and PPI key module genes, and further explore correlation between expression level and clinical stage and prognosis. Based on clinical data and patient samples, differential expression of key node genes was verified by immunohistochemistry. The 63 characteristic differential genes screened had good discrimination between gastric cancer and normal tissues, and are mainly involved in regulating extracellular matrix receptor interactions and the PI3k-AKT signaling pathway. Key nodes in the PPI network regulate tumor proliferation and metastasis. Analysis of the expression levels of key node genes found that relative to normal tissues, the expression of ITGB1 and COL1A2 was significantly increased in gastric cancer tissues, and patients with late clinical stages of tumors had higher expression of ITGB1 and COL1A2 in tumor tissues, and their survival time was longer (P

Maintaining and manipulating sequences online is essential for daily activities such as scheduling a day. In Parkinson's disease (PD), sequential working memory deficits have been associated with altered regional activation and functional connectivity in the basal ganglia. This study demonstrates that the substantia nigra (SN) integrity correlated with basal ganglia function and sequencing performance in 29 patients with PD (17 women) and 29 healthy controls (HCs; 18 women). In neuromelanin-sensitive structural magnetic resonance imaging (MRI), PD patients showed smaller SNs than HCs. In a digit-ordering task with functional MRI (fMRI), participants either recalled sequential digits in the original order (pure recall) or rearranged the digits and recalled the new sequence (reorder and recall). PD patients performed less accurately than HCs, accompanied by the caudate and pallidal hypoactivation, subthalamic hyperactivation, and weakened functional connectivity between the bilateral SN and all three basal ganglia regions. PD patients with larger SNs tended to exhibit smaller ordering-related accuracy costs (reorder and recall vs pure recall). This effect was fully mediated by the ordering-related caudate activation. Unlike HCs, the ordering-related accuracy cost correlated with the ordering-related caudate activation but not subthalamic activation in PD patients. Moreover, the ordering-related caudate activation correlated with the SN area but not with the daily dose of D2/3 receptor agonists. In PD patients, the daily dose of D2/3 receptor agonists correlated with the ordering-related subthalamic activation, which was not related to the accuracy cost. The findings suggest that damage to the SN may lead to sequential working memory deficits in PD patients, mediated by basal ganglia dysfunction. SIGNIFICANCE STATEMENT We demonstrate that damage to the SN correlates with basal ganglia dysfunction and poor sequencing performance in PD patients. In neuromelanin-sensitive MRI, PD patients showed smaller SNs than healthy controls. In a digit-ordering task with fMRI, PD patients' lower task accuracy was accompanied by the caudate and pallidal hypoactivation, subthalamic hyperactivation, and weakened functional connectivity between the SN and basal ganglia. PD patients with larger SNs exhibited greater ordering-related caudate activation and lower ordering-related accuracy cost when sequencing digits. PD patients with more daily exposure to D2/3 receptor agonists exhibited greater ordering-related subthalamic activation, which did not reduce accuracy cost. It suggests that the SN may affect sequencing performance by regulating the task-dependent caudate activation in PD patients.

The synthesis of a chlorin e6-nevirapine conjugate is reported, in which the nevirapine moiety is attached to the 131-position of chlorin e6 via a diethylene glycol linker. This conjugate was found to be nontoxic in the dark (IC[Formula: see text] > 200 [Formula: see text]M), but highly phototoxic (IC[Formula: see text] = 0.21 [Formula: see text]M at 1.5 J/cm[Formula: see text] toward human HEp2 cells. The chlorin e6-nevirapine conjugate accumulated within cells in multiple organelles, including the Golgi, lysosomes and mitochondria. On the other hand, nevirapine was found to be nontoxic to HEp2 cells.

As an acute inflammatory response, sepsis may cause septic shock and multiple organ failure. Rapid and reliable detection of pathogens from blood samples can promote early diagnosis and treatment of sepsis. However, traditional pathogen detection methods rely on bacterial blood culture, which is complex and time-consuming. Although pre-separation of bacteria from blood can help with the identification of pathogens for diagnosis, the required low-velocity fluid environment of most separation techniques greatly limits the processing capacity for blood samples. Here, we present an acoustofluidic device for high-throughput bacterial separation from human blood cells. Our device utilizes a serpentine microfluidic design and standing surface acoustic waves (SSAWs), and separates bacteria from blood cells effectively based on their size difference. The serpentine microstructure allows the operating distance of the acoustic field to be multiplied in a limited chip size via the "spatial multiplexing" and "pressure node matching" of SSAW field. Microscopic observation and flow cytometry analysis shows that the device is helpful in improving the flow rate (2.6 μL min-1 for blood samples; the corresponding velocity is ∼3 cm s-1) without losing separation purity or cell recovery. The serpentine microfluidic design provides a compatible solution for high-throughput separation, which can synergize with other functional designs to improve device performance. Further, its advantages such as low cost, high biocompatibility, label-free separation and ability to integrate with on-chip biosensors are promising for clinical utility in point-of-care diagnostic platforms.

Indomethacin is a potent non-steroidal anti-inflammatory drug (NSAID) with a strong selective inhibitor activity towards cyclooxygenase-2 (COX-2), an enzyme that is highly overexpressed in various tumour cells, being involved in tumourigenesis. Concomitantly, porphyrins have gained much attention as promising photosensitizers (PSs) for the non-invasive photodynamic therapy (PDT) of cancer. Herein, we report the design, and determine the singlet oxygen generation capacity and in vitro cellular toxicity of porphyrin- and chlorin-indomethacin conjugates (P2-Ind and C2-Ind). Both the conjugates were obtained in high yields and were characterized by 1H, 19F and 13C NMR as well as by high resolution mass spectrometry. The singlet oxygen generation properties were assessed by the 1,3-diphenylisobenzofuran singlet oxygen trap method, which showed that C2 and C2-Ind are the best singlet oxygen photosensitizers. In addition, it was found that the presence of indomethacin did not influence the singlet oxygen generation of porphyrin or chlorin. Cytotoxicity studies of the conjugate in human HEp2 cells revealed that the porphyrin- and chlorin-indomethacin conjugates have similar dark cytotoxicities, while chlorin C2 was shown to be the most phototoxic. Despite having lower cellular uptake than C2-Ind after 24 hours, chlorin C2 had a broad localization in HEp2 cells while the chlorin-indomethacin conjugate C2-Ind could be detected in the form of small aggregates. DFT calculations were performed to shed light on the reaction energy involved in the formation of the indomethacin conjugates and to compare the relative stability of selected isomers in solution. Moreover, the calculated energy of their first excited triplet state structures confirmed their use as suitable photosensitizers to generate singlet oxygen for PDT.

Background Deficits in maintaining and manipulating sequential information online can occur even in patients with mild Parkinson's disease. The subthalamic nucleus may play a modulatory role in the neural system for sequential working memory, which also includes the lateral prefrontal cortex. Objectives The objective of this study was to investigate neural markers of sequential working memory deficits in patients with de novo Parkinson's disease. Methods A total of 50 patients with de novo Parkinson's disease and 50 healthy controls completed a digit ordering task during functional magnetic resonance imaging scanning. The task separated the maintenance ("pure recall") and manipulation of sequences ("reorder & recall" vs "pure recall"). Results In healthy controls, individual participants' task accuracy was predicted by the regional activation and functional connectivity of the subthalamic nucleus. Healthy participants who showed lower subthalamic nucleus activation and stronger subthalamic nucleus connectivity with the putamen performed more accurately in maintaining sequences ("pure recall"). Healthy participants who showed greater ordering-related subthalamic nucleus activation change exhibited smaller accuracy costs in manipulating sequences ("reorder & recall" vs "pure recall"). Patients performed less accurately than healthy controls, especially in "reorder & recall" trials, accompanied by an overactivation in the subthalamic nucleus and a loss of synchrony between the subthalamic nucleus and putamen. Individual patients' task accuracy was predicted only by the subthalamic nucleus connectivity. The contribution of the subthalamic nucleus activation or activation change was absent. We observed no change in the lateral prefrontal cortex. Conclusions The overactivation and weakened functional connectivity of the subthalamic nucleus are the neural markers of sequential working memory deficits in de novo Parkinson's disease. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Osteosarcoma (OS) is the most common primary malignant tumor of the skeletal system in the clinic. It mainly occurs in adolescent patients and the pathogenesis of the disease is very complicated. The distant metastasis may occur in the early stage, and the prognosis is poor. MicroRNAs (miRNAs) are non-coding RNAs of about 18–25 nt in length that are involved in post-transcriptional regulation of genes. miRNAs can regulate target gene expression by promoting the degradation of target mRNAs or inhibiting the translation process, thereby the proliferation of OS cells can be inhibited and the apoptosis can be promoted; in this way, miRNAs can affect the metabolism of OS cells and can also participate in the occurrence, invasion, metastasis, and recurrence of OS. Some miRNAs have already been found to be closely related to the prognosis of patients with OS. Unlike other reviews, this review summarizes the miRNA molecules closely related to the development, diagnosis, prognosis, and treatment of OS in recent years. The expression and influence of miRNA molecule on OS were discussed in detail, and the related research progress was summarized to provide a new research direction for early diagnosis and treatment of OS.

Summary: Hepatocytes are the primary functional cells of the liver, performing its metabolic, detoxification, and endocrine functions. Functional hepatocytes are extremely valuable in drug discovery and evaluation, as well as in cell therapy for liver diseases. However, it has been a long-standing challenge to maintain the functions of hepatocytes in vitro. Even freshly isolated hepatocytes lose essential functions after short-term culture for reasons that are still not well understood. In the present study, we find that mechanical tension-induced yes-associated protein activation triggers hepatocyte dedifferentiation. Alleviation of mechanical tension by confining cell spreading is sufficient to inhibit hepatocyte dedifferentiation. Based on this finding, we identify a small molecular cocktail through reiterative chemical screening that can maintain hepatocyte functions over the long term and in vivo repopulation capacity by targeting actin polymerization and actomyosin contraction. Our work reveals the mechanisms underlying hepatocyte dedifferentiation and establishes feasible approaches to maintain hepatocyte functions. : It has been a long-standing challenge to maintain the functions of hepatocytes in vitro. Sun et al. find that mechanical tension-induced Yap activation triggers hepatocyte dedifferentiation. Alleviation of mechanical tension by confining cell spreading or treatment with a small molecule cocktail targeting actin/actomyosin dynamics could maintain hepatocyte functions. Keywords: hepatocytes, dedifferentiation, small molecules, mechanical tension

Previous studies have shown that cold exposure can cause disturbance of estrus cycle in female rats. However, whether cold exposure can cause organic pathological damage to the reproductive system of female rats was undefined. Meanwhile there are few reports on the mechanism of decompensation in rat reproductive function after cold exposure. This study aims to further discuss how cold exposure impact female ovarian reserve function in rats. Female rats were randomly divided into control group and cold exposure group. Ovarian reserve function, differential genes in hypothalamus reproductive regulation center or peripheral were evaluated. After cold exposure, ovarian reserve function was impaired, follicle development was abnormal, the number of mature follicles decreased significantly, the key hypothalamic reproductive regulation molecule GnRH decreased significantly, the response of its regulatory receptor NPY-5R was down-regulated, and the peripheral hormone serum leptin, which is closely related to it, decreased significantly. Our results indicate that cold exposure can lead to impaired ovarian function in female rats, resulting from decrease in serum leptin cause by WAT leptin depletion, which can release the inhibitory of NPY in the hypothalamus, and further lead to the down-regulation of GnRH expression, resulting in the whole HPO axis.

Myelin sheaths are essential in maintaining the integrity of axons. Development of the platform for in vitro myelination would be especially useful for demyelinating disease modeling and drug screening. In this study, a fiber scaffold with a core–shell structure was prepared in one step by the coaxial electrospinning method. A high-molecular-weight polymer poly-L-lactic acid (PLLA) was used as the core, while the shell was a natural polymer material such as hyaluronic acid (HA), sodium alginate (SA), or chitosan (CS). The morphology, differential scanning calorimetry (DSC), Fourier transform infrared spectra (FTIR), contact angle, viability assay, and in vitro myelination by oligodendrocytes were characterized. The results showed that such fibers are bead-free and continuous, with an average size from 294 ± 53 to 390 ± 54 nm. The DSC and FTIR curves indicated no changes in the phase state of coaxial brackets. Hyaluronic acid/PLLA coaxial fibers had the minimum contact angle (53.1° ± 0.24°). Myelin sheaths were wrapped around a coaxial electrospun scaffold modified with water-soluble materials after a 14-day incubation. All results suggest that such a scaffold prepared by coaxial electrospinning potentially provides a novel platform for oligodendrocyte myelination.

The ability to sequence thoughts and actions is impaired in Parkinson’s disease (PD). In PD, a distinct error pattern has been found in the offline performance of sequential working memory. This study examined how PD’s performance of sequential working memory unfolds over time using mouse tracking techniques. Non-demented patients with mild PD (N = 40) and healthy controls (N = 40) completed a computerized digit ordering task with a computer mouse. We measured response dynamics in terms of the initiation time, ordering time, movement time, and area under the movement trajectory curve. This approach allowed us to distinguish between the cognitive processes related to sequence processing before the actual movement (initiation time and ordering time) and the execution processes of the actual movement (movement time and area under the curve). PD patients showed longer initiation times, longer movement times, and more constrained movement trajectories than healthy controls. The initiation time and ordering time negatively correlated with the daily exposure to levodopa and D2/3 receptor agonists, respectively. The movement time positively correlated with the severity of motor symptoms. We demonstrated an altered temporal profile of sequential working memory in PD. Stimulating D1 and D2/3 receptors might speed up the maintenance and manipulation of sequences, respectively.

Objective: The interaction network between coronavirus pneumonia and Shuanghuanglian was established to explore the potential therapeutic effect of the active ingredients of Shuanghuanglian on coronary virus pneumonia.Methods: Using the TCMSP database, the effective components of Shuanghuanglian were obtained by screening consistent with oral utilization，drug similarity and blood-brain barrier permeability thresholds, and the drug target prediction was performed.The SARS treatment target mining was performed through the GeneCards database, and the two data sets of therapeutic target and drug target were analyzed and the intersection was screened, and the wayne map was drawn.The intersection genes were used as potential therapeutic targets. Cytoscape 3.6 software was used to build a drug active ingredient-therapeutic target interaction network and analyze the active ingredient-therapeutic target point network Degree parameters to find important active ingredients and targets. Using DAVID and String databases to perform GO,KEGG enrichment analysis and protein interaction analysis on the intersection genes to find out the potential signal pathway of Shuanghuanglian against SARS.Results: 43 effective components against SARS were screened, includingcoptisine、Mandenol、Ethyl linolenate、phytofluene、wogonin、FORSYTHINOL、baicalein、Moslosooflavone、Panicolin, etc.A total of 115 intersection genes with coronavirus pneumonia were screened as important treatment targets: based on the protein interaction network, Shuanghuanglian's therapeutic targets for diseases were significantly enriched in 1763 GO and 133 KEGG signaling pathways; The main action pathways are: responses to steroid hormones and ketones, and development of the reproductive system, responses to lipopolysaccharides, Toxins, responses to bacteria and aging, and effects on epithelial cell proliferation.Conclusion: The active ingredients in Shuanghuanglian Chinese medicine compound can act on the disease-related target of coronavirus pneumonia and have potential therapeutic effects on coronavirus pneumonia.

Purpose: The indispensable role of long non-coding RNAs (lncRNAs) in tumorigenesis has been increasingly reported. In the present study, LINC01694 was found to regulate the proliferation, invasion, as well as apoptosis in gallbladder cancer (GBC) cells through sponging miR-340-5p. Methods: LINC01694 level in GBC cells was quantified by quantitative real-time polymerase chain reaction (qRT-PCR). The proliferation, invasion, and apoptosis were determined by Cell Counting Kit-8 (CCK-8), Transwell, and flow cytometry, respectively. The expression of Sry-related high-mobility group box 4 (Sox4) was detected by Western blot (WB). The interaction between LINC01694 and miR-340-5p was measured by dual-luciferase reporter (DLR) assay, RNA immunoprecipitation (RIP) test, and RNA pull-down. Tumor formation was examined by in vivo experiment. Results: qRT-PCR illustrated that cancerous tissues had higher LINC01694 than normal tissues. Survival analysis demonstrated that the prognosis of patients with high LINC01694 was significantly poorer than those with low LINC01694. Down-regulation of LINC01694 slowed down the proliferation and invasion in GBC cells and accelerated the apoptosis. DLR assay indicated that LINC01694 elevated Sox4 expression by regulating miR-340-5p. LINC01694 functioned as miR-340-5p sponge to inhibit Sox4 expression. Conclusion: LINC01694 level is elevated in GBC by regulating miR-340-5p/Sox4 axis, which indicates the poor prognosis of the patients.

Mitochondrial chronic progressive external ophthalmoplegia (CPEO) is a major manifestation of human mitochondrial encephalomyopathies. Previous studies have shown cognitive deficits in patients with mitochondrial diseases. However, these studies often included patients with heterogeneous subtypes of mitochondrial diseases. Here, we aimed to provide a better cognitive profile of patients with CPEO by applying a comprehensive battery of neuropsychological assessments in a pure sample of patients with CPEO. We recruited 28 patients with CPEO (19 women, age 16-62 years) and 38 age- and education-matched healthy control subjects (25 women, age 16-60 years). The neuropsychological assessments covered global cognition and five cognitive domains (executive functions, language, working memory, memory, and visuospatial functions). We found that the patients were impaired in global cognition [Montreal Cognitive Assessment (MoCA)], executive functions [Trail Making Test Part B (TMT-B)], and language [Boston Naming Test (BNT)], but not in working memory, memory or visuospatial functions. Moreover, individual patients' performances in the TMT-B (completion time) were predicted by the severity of non-ophthalmoplegia mitochondrial symptoms/signs [Newcastle Mitochondrial Disease Adult Scale (NMDAS)] and duration of the mitochondrial disease (years). Namely, patients with more severe non-ophthalmoplegia mitochondrial symptoms/signs and a longer disease duration took a longer time to complete the TMT-B. No clinical measures predicted individual patients' performances in the BNT.

Maintaining the ability to arrange thoughts and actions in an appropriate serial order is crucial for complex behavior. We aimed to investigate age differences in the fronto-striato-parietal network underlying serial ordering using functional magnetic resonance imaging. We exposed 25 young and 27 older healthy adults to a digit ordering task, where they had to reorder and recall sequential digits or simply to recall them. We detected a network comprising of the lateral and medial prefrontal, posterior parietal, and striatal regions. In young adults, the prefrontal and parietal regions were more activated and more strongly connected with the supplementary motor area for "reorder & recall" than "pure recall" trials (psychophysiological interaction, PPI). In older adults, the prefrontal and parietal activations were elevated, but the PPI was attenuated. Individual adults who had a stronger PPI performed more accurately in "reorder & recall" trials. The decreased PPI appeared to be compensated by increased physiological correlations between the prefrontal/parietal cortex and the striatum, and by that between the striatum and the supplementary motor area.