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• This paper presents a new dynamic model for a spur gear system cosidering time-varying behaviors of pressure angle and baclash, together with the effecs of other factors. • The time-varying gear mesh stiffness is calculated by an improved potential energy method. • The differential equations of motion of the gear system are strictly derived using Lagrange's equation. • The proposed model can more accurately estimate the dynamic responses in comparison to the traditional models. In the previous nonlinear dynamic models of spur gear system, when considering bearing deformation, the pressure angle and gear backlash are usually considered as constants to facilitate the modelling. In fact, bearing deformation will cause the gear translation motion, and then lead to the changes of a series of gear mesh parameters. In view of this, this paper presents a new nonlinear dynamic model for a spur gear system considering the time-varying behaviors of pressure angle and gear backlash, together with the effects of gear gravity, unbalance mass, and internal/external excitations, etc. The equations of motion of the system are strictly derived using Lagrange method and solved by the numerical integral method. The time-varying mesh stiffness is calculated by the potential energy method based on an improved mesh stiffness model. Afterwards, the new model is compared with the previous model and some dynamic characteristic differences between the two models are demonstrated using the rotating speed and backlash as control parameters. This results shows that due to the effects of the time-varying pressure angle and backlash, the system may enter into chaotic motion in advance and the tooth impact state will also alter. This research can provide a useful source of reference for dynamic design of gear transmission system and the further study of spur gear system. [ABSTRACT FROM AUTHOR]

This study aimed to improve the flavor of fermented soybean foods and to investigate the molecular mechanisms of this flavor improvement phenomenon. Three fermented soybean foods (Bv, BvLp and Lp) were obtained using Bacillus velezensis SDL1 and Lactiplantibacillus plantarum Ly8 as starter cultures. Organoleptic evaluation showed that BvLp had the best flavor, followed by Bv and Lp. Next, some flavor-related physicochemical properties were investigated. Acid production level was ranked as Lp > BvLp > Bv, in which acetic acid and lactic acid were the main contributors to the variation in sample acid content, and BvLp contained the most lactic acid and isovaleric acid, 3.72−49.62 and 3.61−37.75 times those of Lp and Bv, respectively. Free amino acid analysis showed that the concentration trends of branched-chain amino acids and threonine were consistent with the sensory evaluation. Volatile metabolomics analysis indicated that acetoin and pyrazines were the key compounds for the superior flavor of BvLp. Finally, transcriptomic analysis, combined with the above data, revealed that under a parasitic-like interaction in microbial mixed culture, BvLp had significantly more flavor than Bv and Lp by reducing the acid content and increasing the concentration of some esters, acetoin and pyrazines. [Display omitted] • Mix-fermented soybean products taste better than single bacterial fermentation. • Acetoin and pyrazines are the main flavor compounds of fermented soybean foods. • B. velezensis and Lb. plantarum show a parasite-like interaction in co-fermentation. [ABSTRACT FROM AUTHOR]

Kringle 5, derived from plasminogen, is highly capable of inhibiting angiogenesis. Here, we have designed and synthesized 10 tetrapeptides, based on the amino acid properties of the core tetrapeptide Lys-Leu-Tyr-Asp (KLYD) originating from anti-angiogenic kringle 5 of human plasminogen. Of these, Arg-Leu-Tyr-Glu (RLYE) effectively inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation, migration and tube formation, with an IC 50 of 0.06–0.08 nM, which was about ten-fold lower than that of the control peptide KLYD (0.79 nM), as well as suppressed developmental angiogenesis in a zebrafish model. Furthermore, this peptide effectively inhibited the cellular events that precede angiogenesis, such as ERK and eNOS phosphorylation and nitric oxide production, in endothelial cells stimulated with VEGF. Collectively, these data demonstrate that RLYE is a potent anti-angiogenic peptide that targets the VEGF signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract: Mg2+ is one of the most important cations in cells, affecting the structures and functions of the proteins and nucleic acids. It should be noted that Mg2+ is indispensable in DNA transcription, where G-quadruplex is believed to be actively involved. Therefore, it is important to investigate the influence of Mg2+ on G-quadruplex. Here we studied the effect of Mg2+ on G-quadruplex DNA with CD, FRET, EMSA, and PCR-stop assay. We found that various G-quadruplexes could be differentiated through simultaneous addition of both K+ and Mg2+, which could be used for selective identification of G-quadruplexes in promoter oncogene but not in telomere. Mg2+ at physiological relevant concentration not only greatly enhanced the thermostability of oncogene G-quadruplexes but also efficiently protected them from unfolding by their complementary strands, which revealed the great impact of Mg2+ on the equilibrium between promoter G-quadruplex and duplex DNA. The PCR-stop assay further confirmed that Mg2+ could affect gene transcription by stabilizing promoter G-quadruplex. The above studies were carried out for various G-quadruplexes of varying sequences in promoter oncogenes and telomeric region. Our results suggest that Mg2+ may be a key regulator for G-quadruplexes of oncogene promoter, which can subsequently affect the expression of related genes. [ABSTRACT FROM AUTHOR]

In this paper, we have obtained a series of large-area and different diameters nanosphere lithography (NSL) to obtain the required silicon nanowires (SiNWs) arrays. The single-crystalline SiNWs have been presented by combining nanosphere lithography (NSL) and metal-assisted chemical etching (MACE). The period of SiNW arrays can be controlled by adjusting the original diameter of polystyrene nanosphere (PSs) and the etching time during the NSL process. The special SiNWs structure obtained can be demonstrated to be significant for improving the antireflection properties of silicon substrate. The results show that SiNW arrays with various parameters, such as diameter, distance and height can be obtained by controlling the key etching parameter during the MACE process, which are important to obtain the structures of different parameters to adapt an appropriate value to decrease the light scattering. For a wide wavelength range of 300–1200 nm, the reflectance is below 10% or less, which is due to an ultra-high surface area. Especially, the reflectance of antireflection structure (ARS) surface reduces below 1% over a wavelength range of 300–400 nm. Furthermore, the silicon nanowire (SiNW) arrays with highly efficient antireflection obtained by MACE exhibit different surface roughness from the bottom to the top part of SiNWs by high resolution images, which is benefit for further improving the ARS of SiNWs. [ABSTRACT FROM AUTHOR]

Objectives: To determine cohorts of women diagnosed with cervical and endometrial cancers in Louisiana, meeting national NCORP clinical trial eligibility criteria based on cancer histology and stage. Then, to determine if there is a disparate rate of disqualification among these cohorts for potential trial participation based on comorbid conditions according to age, race, and socioeconomic markers. Methods: The baseline population for this study was all women with either endometrial or cervical malignancies from the Louisiana Tumor Registry (LTR) between January-December 2019. Based on the eligibility criteria of cooperative group clinical trials open at NCORP sites in Louisiana, a cohort of 'potentially eligible' trial patients was defined based on cancer stage and histology. This cohort was then further filtered according to registry reported, potentially excluding comorbid conditions (renal and/or hepatic disease, Charlson comorbidity index >6, HIV/AIDs and secondary malignancy) to define those who were 'eligible and included' versus those who were 'eligible but excluded.' Summary and comparative statistical analyses were used to determine differences between these groups based on demographic and socioeconomic factors. Results: From the baseline population, 152 (68%) patients were defined as potentially eligible for cervix clinical trials. Comparing women who did and did not meet inclusion criteria, women who were excluded were older (p=0.008) and of lower socioeconomic status (n =8, 38%) (p=0.038). Among those with endometrial cancer, 326 (55%) patients were potentially eligible for endometrial cancer trials. Patients eligible and included were more likely to be younger (p=0.028), of the White race (86%) than Black race (55%) (p=0.002) and privately insured (43%) than publicly insured (54%) (p=0.001). Those eligible and included were more likely to be alive at the time of reporting than those eligible but excluded. Conclusions: Age, race, underinsurance, and lower SES are associated with the exclusion of eligible patients from endometrial and cervical cancer trial enrollment. Critical efforts to address barriers to enrollment into clinical cancer trials, especially for underrepre-sented groups, are required in order to reconsider and tailor eligibility criteria to be more equitable and inclusive. [ABSTRACT FROM AUTHOR]

Carbon monoxide (CO), derived by the enzymatic reaction of heme oxygenase (HO), is a cellular regulator of energy metabolism and cytoprotection; however, its underlying mechanism has not been clearly elucidated. Astrocytes pre-exposed to the CO-releasing compound CORM-2 increased mitochondrial biogenesis, mitochondrial electron transport components (cytochrome c, Cyt c ; cytochrome c oxidase subunit 2, COX2), and ATP synthesis. The increased mitochondrial function was correlated with activation of AMP-activated protein kinase α and upregulation of HO-1, peroxisome proliferators-activated receptor γ-coactivator-1α (PGC-1α), and estrogen-related receptor α (ERRα). These events elicited by CORM-2 were suppressed by Ca 2+ chelators, a HO inhibitor, and an L-type Ca 2+ channel blocker, but not other Ca 2+ channel inhibitors. Among the HO byproducts, combined CORM-2 and bilirubin treatment effectively increased PGC-1α, Cyt c and COX2 expression, mitochondrial biogenesis, and ATP synthesis, and these increases were blocked by Ca 2+ chelators. Moreover, cerebral ischemia significantly increased HO-1, PGC-1α, and ERRα levels, subsequently increasing Cyt c and COX2 expression, in wild-type mice, compared with HO-1 +/− mice. These results suggest that HO-1-derived CO enhances mitochondrial biogenesis in astrocytes by activating L-type Ca 2+ channel-mediated PGC-1α/ERRα axis, leading to maintenance of astrocyte function and neuroprotection/recovery against damage of brain function. [ABSTRACT FROM AUTHOR]

Abstract: The tumor suppressor p53 is pivotal in cell growth arrest and apoptosis upon cellular stresses including DNA damage. Mounting evidence indicates that p63 proteins, which are homologs of p53, are also involved in apoptosis under certain circumstances. In this study, we found that treatment with DNA damage agents leads to down-regulation of ΔNp63α and induces apoptosis in FaDu and HaCat cells carrying mutant p53. Further study shows that DNA damage reduces steady-state mRNA level of ΔNp63α, but has little effect on its protein stability. In addition, knockdown of endogenous ΔNp63α directly induces apoptosis and sensitizes cells to DNA damage, while exogenous expression of ΔNp63α partially confers cellular resistance to DNA damage. Together, these data suggest that DNA damage down-regulates ΔNp63α, which may directly contribute to DNA damage-induced apoptosis. [Copyright &y& Elsevier]

Abstract: Autism is a pervasive developmental disorder that frequently co-occurs with epilepsy. Dravet syndrome is a severe epileptic encephalopathy associated with psychomotor developmental delay. Autism in Dravet syndrome, however, has rarely been studied. In this study, the prevalence and features of autism in patients with Dravet syndrome, their potential association with mental retardation, and the clinical characteristics of epilepsy were investigated. Clinical data of 37 patients with Dravet syndrome were collected, and evaluations of autism and mental retardation were performed. Nine patients (24.3%) met the criteria for autism. All patients with autism showed speech delay, no emotional reciprocity, and narrow interests, whereas 89.3, 46.4, and 39.9% of patients without autism had speech delay, short temper, and narrow interests, respectively. Mental retardation was observed in 94.6% of patients with Dravet syndrome, with more frequent severe or profound mental retardation in those with autism. The clinical features of epilepsy did not statistically differ between the patients with autism and the patients without autism. [Copyright &y& Elsevier]

Abstract: The effect of fusaric acid (FA) on the activity of leaf nitrogen (N) metabolism enzymes in watermelon seedlings supplied with different N forms was studied. The results showed that FA inhibited nitrogen uptake and caused decreased leaf amide and protein but increased the content of ammonium and amino acids. When treated with FA the activities of enzymes in the pathway for the synthesis of amino acid in leaves (GS, GOGAT, and GDH) were decreased by 15–23%, 13–40%, and 71–86%, respectively. The activity of asparagine synthetase was decreased by 34–57%. The proteinase activity was initially increased by 37–125% at 12h after treatment of FA but then subsequently decreased. The activity of glutamate-pyruvate aminotransferase was increased by 280–400%, though the activity of glutamate-oxaloacetate aminotransferase was decreased by 30–63%. It was suggested that FA inhibited the uptake of ammonium in seedlings and suppressed the activities of amino acid and amide synthases, while stimulating proteinase activity. A new pathogenic mechanism of watermelon infection by Fusarium spp. was found as FA caused the complete disorder and collapse of the host plant''s nitrogen metabolism. This work provides a new insight into the progression of watermelon wilting caused by Fusarium oxysporum f.sp. niveum. [Copyright &y& Elsevier]

The exacerbation of climate change has made the development of alternative and sustainable technologies to achieve carbon neutrality an urgent matter. The intricate preparation and arduous recovery of conventionally prepared CO 2 solid adsorbents make their large-scale application a significant challenge, which significantly limits the application of the adsorbent. To address this problem, we have innovatively adopted a novel strategy of electrospinning and one-step carbonization to fabricate microporous carbon aerogel fibers (CAFs) as solid adsorbents for CO 2. This method offers the advantages of a simple process, cost-effectiveness, and stable performance. The designed CAFs possess a high specific surface area (1188.628 m2/g), an appropriate distribution of pore size (0.54–0.64 nm), and about 15 at% oxygen-containing functional groups without activation or doping. At 0 °C, the CAFs-800 (800 is the carbonization temperature) exhibit a maximum capture capacity of 4.25 mmol/g, and after 5 times cycles, the adsorption capacity remains above 97%; at 25 °C, the maximum capture capacity reaches 3.57 mmol/g of CAFs-800, surpassing similar materials by more than 20%, demonstrating excellent adsorption capacity and stability towards CO 2. These results indicate that the CAFs hold great promise for CO 2 capture and storage with exceptional advantages. [Display omitted] • A simple preparation and easy recovery strategy without activation or doping. • Rich pore structure and oxygen groups with CO 2 capture capacity of 4.25 mmol/g. • The adsorption capacity of CO 2 remains above 95% after 5 cycles. [ABSTRACT FROM AUTHOR]

Maize is an important food crop in the world, but the yield and quality of maize have been significantly reduced due to the impact of insect pests. In order to address this issue, the cry1Ah gene was subjected to error-prone PCR for mutagenesis, and subsequently, the mutant cry1Ah-1 gene was introduced into maize inbred line GSH9901 callus using the Agrobacterium -mediated method. The T2 generation transformed plants were obtained by subculture, and 9 transgenic positive plants were obtained by molecular detection which was carried out by PCR, qRT-PCR, Bt gold-labeled immunoassay test strips, Western blot and ELISA. It was found that the Cry1Ah-1 gene could be transcribed normally in maize leaves, of which OE1 and OE3 had higher relative expression levels and could successfully express proteins of 71.94 KD size. They were expressed in different tissues at the 6-leaf stage, heading stage and grain-filling stage, and could ensure the protection of maize from corn borer throughout the growth period. The biological activities of OE1 and OE3 were tested indoors and in the field, and the results showed that in indoors, the corn borer that fed on OE1 and OE3 corn leaves had a mortality rate of 100 % after 3 days; in the field, OE1 and OE3 had strong insecticidal activity against corn borer , reaching a high resistance level. In conclusion, the transgenic cry1Ah-1 maize has a strong insecticidal effect on corn borer , and has a good prospect of commercialization. • cry1Ah-1 mutant gene was introduced into maize callus by Agrobacterium-mediated method. • This gene is expressed in different tissues at different times, which can ensure the protection of maize from corn borer. [ABSTRACT FROM AUTHOR]

The combination of antiangiogenic agents and immune checkpoint inhibitors is more efficient than monotherapy in the management of hepatocellular carcinoma (HCC). Lenvatinib plus anti-PD1 antibodies have become the mainstay in HCC treatment. However, more than half the patients with HCC are non-responsive, and the mechanisms underlying drug resistance are unknown. To address this issue, we performed single-cell sequencing on samples from six HCC patients, aiming to explore cellular signals and molecular pathways related to the effect of lenvatinib plus anti-PD1 antibody treatment. GSVA analysis revealed that treatment with lenvatinib plus anti-PD1 antibody led to an increase in the TNF-NFKB pathway across all immune cell types, as compared to the non-treatment group. Mucosal-associated invariant T (MAIT) cells were found to secrete TNF, which activates TNFRSF1B on regulatory T cells, thereby promoting immunosuppression. Additionally, TNFSF9 was highly expressed in anticancer immune cells, including CD8+ effector T cells, MAIT, and γδ T cells in the treatment group. We also detected CD3+ macrophages in both HCC and pan-cancer tissues. Overall, our findings shed light on the potential mechanisms behind the effectiveness of lenvatinib plus anti-PD1 antibody treatment in HCC patients. By understanding these mechanisms better, we may be able to develop more effective treatment strategies for patients who do not respond to current therapies. [ABSTRACT FROM AUTHOR]

Quorum sensing (QS) is a means of cell-to-cell communication that regulates, via small signalling molecules, expression of a series of genes and controls multicellular behaviour in many bacterial species. The enzyme S-ribosylhomocysteine lyase (LuxS) transforms S-ribosylhomocysteine (SRH) into 4, 5-dihydroxy-2, 3-pentanedione (DPD), the precursor of the interspecies QS signalling molecule autoinducer-2 (AI-2). In this study, two LuxS-coding genes, luxS1 and luxS2 , with 70% sequence identity were isolated from Lactobacillus plantarum YM-4-3, and overexpressed in Escherichia coli BL21 (DE3), and the protein products were purified successfully. After incubation of LuxS1 or LuxS2 with SRH, the reaction products were able to induce Vibrio harveyi BB170 bioluminescence, clearly demonstrating that both LuxS1 and LuxS2 synthesize AI-2 from SRH in vitro . Ellman's assay results revealed optimal temperatures for LuxS1 and LuxS2 of 45 and 37 °C, respectively, and their activities were stimulated or inhibited by several metal ions and chemical reagents. In addition, enzyme kinetics data showed that K m , V max and K cat value of LuxS1 for the substrate (SRH) were higher than that of LuxS2. These results suggest that LuxS1 and LuxS2 mediate QS in a temperature-dependent manner and may play conserved roles in AI-2 synthesis but exhibit different activities in response to external environmental stress. To our knowledge, this paper is the first report of two luxS genes present in one bacterial genome and the subsequent comparative elucidation of their functions in AI-2 production. Collectively, our study provides a solid basis for future research concerning the AI-2/LuxS QS system in L. plantarum YM-4-3. [ABSTRACT FROM AUTHOR]

Well-aligned ZnO nanorod arrays have been prepared by using seed-assisted hydrothermal method, in which the c-axis oriented ZnO films prepared by a soft-chemical were used as the seed layers on quartz glass. The epitaxial growth mechanisms and corresponding morphology effect of samples are discussed. The results show that the morphology of ZnO nanorod arrays is closely related to the hydrothermal temperature, pH value and initial concentration of Zn source in precursor solution. The as-prepared samples are characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Brunauer-Emmett-Teller (BET), Raman spectroscopy, photoluminescence (PL) spectra and UV–vis spectra. The well-aligned ZnO nanorod arrays exhibit improved photocatalytic degradation with Rhodamine 6G (R6G) solution under UV radiation, according with the UV–vis spectra investigation and photocatalytic improvement speculation. Noteworthy, the photocatalytic properties of well-aligned ZnO nanorod arrays have obviously improved comparing with other ZnO samples without proper alignment. The oxygen vacancies suppressed recombination process of photon induced electrons and holes, as the oxygen vacancy trapped the charge carriers. [ABSTRACT FROM AUTHOR]

Neuroadaptations and alterations in neuronal excitability are critical in brain maturation and many neurological diseases. Fragile X syndrome (FXS) is a pervasive neurodevelopmental disorder characterized by extensive synaptic and circuit dysfunction. It is still unclear about the alterations in intrinsic excitability of individual neurons and their link to hyperexcitable circuitry. In this study, whole cell patch-clamp recordings were employed to characterize the membrane and firing properties of layer IV cells in slices of the somatosensory cortex of Fmr-1 knockout (KO) mice. These cells generally exhibited a regular spiking (RS) pattern, while there were significant increases in the number of cells that adopted intrinsic bursting (IB) compared with age-matched wild type (WT) cells. The cells subgrouped according to their firing patterns and maturation differed significantly in membrane and discharge properties between KO and WT. The changes in the intrinsic properties were consistent with highly facilitated discharges in KO cells induced by current injection. Spontaneous activities of RS neurons driven by local network were also increased in the KO cells, especially in neonate groups. Under an epileptiform condition mimicked by omission of Mg 2 + in extracellular solution, these RS neurons from KO mice were more likely to switch to burst discharges. Analysis on bursts revealed that the KO cells tended to form burst discharges and even severe events manifested as seizure-like ictal discharges. These results suggest that alterations in intrinsic properties in individual neurons are involved in the abnormal excitability of cortical circuitry and possibly account for the pathogenesis of epilepsy in FXS. [ABSTRACT FROM AUTHOR]

Recent advances in automated cell counters enable us to count cells more easily with consistency. However, the wide use of the traditional vital dye trypan blue (TB) raises environmental and health concerns due to its potential teratogenic effects. To avoid this chemical hazard, it is of importance to introduce an alternative non-hazardous vital dye that is compatible with automated cell counters. Erythrosin B (EB) is a vital dye that is impermeable to biological membranes and is used as a food additive. Similarly to TB, EB stains only nonviable cells with disintegrated membranes. However, EB is less popular than TB and is seldom used with automated cell counters. We found that cell counting accuracy with EB was comparable to that with TB. EB was found to be an effective dye for accurate counting of cells with different viabilities across three different automated cell counters. In contrast to TB, EB was less toxic to cultured HL-60 cells during the cell counting process. These results indicate that replacing TB with EB for use with automated cell counters will significantly reduce the hazardous risk while producing comparable results. [ABSTRACT FROM AUTHOR]

Lactobacillus plantarum is an important probiotic and is mostly isolated from fermented foods. We sequenced the genome of L. plantarum strain 5-2, which was derived from fermented soybean isolated from Yunnan province, China. The strain was determined to contain 3114 genes. Fourteen complete insertion sequence (IS) elements were found in 5-2 chromosome. There were 24 DNA replication proteins and 76 DNA repair proteins in the 5-2 genome. Consistent with the classification of L. plantarum as a facultative heterofermentative lactobacillus, the 5-2 genome encodes key enzymes required for the EMP (Embden–Meyerhof–Parnas) and phosphoketolase (PK) pathways. Several components of the secretion machinery are found in the 5-2 genome, which was compared with L. plantarum ST-III, JDM1 and WCFS1. Most of the specific proteins in the four genomes appeared to be related to their prophage elements. [ABSTRACT FROM AUTHOR]

Abstract: The C-5-methylation of cytosine in the CpG islands is an important pattern for epigenetic modification of gene, which plays a key role in regulating gene transcription. G-quadruplex is an unusual DNA secondary structure formed in G-rich regions and is identified as a transcription repressor in some oncogenes, such as c-myc and bcl-2. In the present study, the results from CD spectrum and FRET assay showed that the methylation of cytosine in the CpG islands could induce a conformational change of the G-quadruplex in the P1 promoter of bcl-2, and greatly increase the thermal-stability of this DNA oligomer. Moreover, the methylation of cytosine in the G-quadruplex could protect the structure from the disruption by the complementary strand, showing with the increasing ability to arrest the polymerase in PCR stop assay. This data indicated that the stabilization of the G-quadruplex structure in the CpG islands might be involved in the epigenetical transcriptional regulation for specific genes through the C-5-methylation modification pattern. [Copyright &y& Elsevier]

Several studies report that the therapeutic mechanism of action of mesenchymal stem/stromal cells (MSCs) is mainly mediated by paracrine factors that are released from MSCs such as exosomes. Exosomes are nano-sized extracellular vesicles that are transferred to target cells for cell-to-cell communication. Although MSC-derived exosomes (MSC-exosomes) are suggested as novel cell-free therapeutics for various human diseases, evaluation studies for the safety and toxicity of MSC-exosomes are limited. The purpose of our study was to evaluate the toxicological profile, including skin sensitization, photosensitization, eye and skin irritation, and acute oral toxicity using exosomes derived from human adipose tissue-derived MSCs (ASC-exosomes) in accordance with the OECD guidelines and the principles of Good Laboratory Practice. The ASC-exosomes were classified as a potential non-sensitizer in the skin sensitization test, UN GHS no category in the eye irritation test, and as a skin non-irritant in the skin irritation test, and did not induce any toxicity in the phototoxicity test or in acute oral toxicity testing. Our findings are the first to suggest that ASC-exosomes are safe for use as a topical treatment, with no adverse effects in toxicological testing, and have potential application as a therapeutic agent, cosmetic ingredient, or for other biological uses. • Toxicological evaluations of ASC-exosomes were performed in accordance with OECD guidelines and the principles of GLP. • Evaluations include skin sensitization, in vitro photosensitization, eye and skin irritation, and acute oral toxicity. • ASC-exosomes are safe for topical treatments on skin with no adverse effects noted in preclinical testing. [ABSTRACT FROM AUTHOR]

Hepatocarcinogenesis is a complicated process that is affected by a variety of microenvironmental factors, such as secretory chemokines and cell-extracellular matrix (ECM). Retinoic acid receptor-related orphan receptor (ROR)-α has been shown to attenuate tumor invasiveness by inducing suppressive cell microenvironment, and its low expression was associated with a worse prognosis in HCC patients. In the present study, we attempted to investigate the role and mechanism of the dominant transcript of ROR-α, ROR-α-1, in HCC development and progression. Among the four transcripts (ROR-α-1/-2/-3/-4), overexpression of ROR-α-1 dramatically suppressed the capacity of MHCC97H cells to proliferate, migrate and invade. We analyzed the differentially expressed genes in ROR-α-1-overexpressed and non-overexpressed MHCC97H cells, performed Gene Ontology (GO) enrichment analysis on these differentially-expressed genes, and found out that factors involved in the tumor microenvironment and ECM are related to the anti-tumor effects of ROR-α-1. Among these factors, chemokine CXCL5 was significantly downregulated by ROR-α-1 overexpression. Overexpression of ROR-α-1 remarkably inhibited the capacity of HCC cells to proliferate, migrate, invade, and downregulated the protein levels of β-catenin, c-Myc, Cyclin D1, and N-cadherin, suggesting the tumor-suppressive role of ROR-α-1 in MHCC97H cells. Moreover, overexpression of CXCL5 dramatically attenuated the suppressive effects of cell proliferation, migration and invasion induced by ROR-α-1 overexpression in MHCC97H, suggesting that ROR-α-1 exerts its anti-tumor effects via downregulating CXCL5. In conclusion, we demonstrate the tumor-suppressive role of ROR-α-1 in MHCC97H cells and that ROR-α-1 might play a tumor-suppressive role via regulation of chemokine CXCL5. [ABSTRACT FROM AUTHOR]

Mutations in SLC6A1 have been associated mainly with myoclonic atonic epilepsy (MAE) and intellectual disability. We identified a novel missense mutation in a patient with Lennox-Gastaut syndrome (LGS) characterized by severe seizures and developmental delay. Exome Sequencing was performed in an epilepsy patient cohort. The impact of the mutation was evaluated by 3H γ-aminobutyric acid (GABA) uptake, structural modeling, live cell microscopy, cell surface biotinylation and a high-throughput assay flow cytometry in both neurons and non neuronal cells. We discovered a heterozygous missense mutation (c700G to A [pG234S) in the SLC6A1 encoding GABA transporter 1 (GAT-1). Structural modeling suggests the mutation destabilizes the global protein conformation. With transient expression of enhanced yellow fluorescence protein (YFP) tagged rat GAT-1 cDNAs, we demonstrated that the mutant GAT-1(G234S) transporter had reduced total protein expression in both rat cortical neurons and HEK 293 T cells. With a high-throughput flow cytometry assay and live cell surface biotinylation, we demonstrated that the mutant GAT-1(G234S) had reduced cell surface expression. 3H radioactive labeling GABA uptake assay in HeLa cells indicated a reduced function of the mutant GAT-1(G234S). This mutation caused instability of the mutant transporter protein, which resulted in reduced cell surface and total protein levels. The mutation also caused reduced GABA uptake in addition to reduced protein expression, leading to reduced GABA clearance, and altered GABAergic signaling in the brain. The impaired trafficking and reduced GABA uptake function may explain the epilepsy phenotype in the patient. • GABA transporter 1 G234S mutation is associated with Lennox-Gastaut syndrome (<85 characters). • GABA transporter 1 G234S mutation impaired protein trafficking (<85 characters). • GABA transporter 1 G234S reduced the mutant transporter protein expression (<85 characters). • GABA transporter 1 G234S impaired GABA uptake (<85 characters). • Partial loss of function underlies pathophysiology of GABA transporter 1 G234S (<85 characters). [ABSTRACT FROM AUTHOR]