ZSCAN10 deficiency causes a neurodevelopmental disorder with characteristic oto-facial malformations.

Neurodevelopmental disorders are major indications for genetic referral and have been linked to more than 1,500 loci including genes encoding transcriptional regulators. The dysfunction of transcription factors often results in characteristic syndromic presentations, however, at least half of these patients lack a genetic diagnosis. The implementation of machine learning approaches has the potential to aid in the identification of new disease genes and delineate associated phenotypes. Next generation sequencing was performed in seven affected individuals with neurodevelopmental delay and dysmorphic features. Clinical characterization included reanalysis of available neuroimaging datasets and 2D portrait image analysis with GestaltMatcher. The functional consequences of ZSCAN10 loss were modelled in mouse embryonic stem cells (mESC), including a knock-out and a representative ZSCAN10 protein truncating variant. These models were characterized by gene expression and Western blot analyses, chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR), and immunofluorescence staining. Zscan10 knockout mouse embryos were generated and phenotyped. We prioritized bi-allelic ZSCAN10 loss-of-function variants in seven affected individuals from five unrelated families as the underlying molecular cause. RNA-Seq analyses in Zscan10-/- mESCs indicated dysregulation of genes related to stem cell pluripotency. In addition, we established in mESCs the loss-of-function mechanism for a representative human ZSCAN10 protein truncating variant by showing alteration of its expression levels and subcellular localization, interfering with its binding to DNA enhancer targets. Deep phenotyping revealed global developmental delay, facial asymmetry, and malformations of the outer ear as consistent clinical features. Cerebral MRI showed dysplasia of the semicircular canals as an anatomical correlate of sensorineural hearing loss. Facial asymmetry was confirmed as a clinical feature by GestaltMatcher and was recapitulated in the Zscan10 mouse model along with inner and outer ear malformations. Our findings provide evidence of a novel syndromic neurodevelopmental disorder caused by bi-allelic loss-of-function variants in ZSCAN10.

TRPP2 is located in the primary cilia of human non-pigmented ciliary epithelial cells.

PURPOSE: Mechanosensitive channels (MSCs) and primary cilium possess a possible relevance for the sensation of intraocular pressure (IOP). However, there is only limited data on their expression and localization in the ciliary body epithelium (CBE). The purpose of this study was to characterize the expression and localization of TRPP2 in a human non-pigmented ciliary epithelial cell (HNPCE) line. METHODS: The expression of the TRPP2 was studied by quantitative (q)RT-PCR and in situ hybridization in rat and human tissue. Protein expression and distribution were studied by western blot analysis, immunohistochemistry, and immunoelectron microscopy. Cellular location of TRPP2 was determined in rat and human CBE by immunofluorescence and immunoblot analysis. Electron microscopy studies were conducted to evaluate where and with substructure TRPP2 is localized in the HNPCE cell line. RESULTS: The expression of TRPP2 in rat and human non-pigmented ciliary epithelium was detected. TRPP2 was mainly located in nuclei, but also showed a punctate distribution pattern in the cytoplasm of HNPCE of the tissue and the cell line. In HNPCE cell culture, primary cilia did exhibit different length following serum starvation and hydrostatic pressure. TRPP2 was found to be colocalized with these cilia in HNPCE cells. CONCLUSION: The expression of TRPP2 and the primary cilium in the CB may indicate a possible role, such as the sensing of hydrostatic pressure, for the regulation of IOP. Functional studies via patch clamp or pharmacological intervention have yet to clarify the relevance for the physiological situation or aqueous humor regulation.

Assessment of the Binding of Pseudallecin A to Human Serum Albumin with Multi-Spectroscopic Analysis, Molecular Docking and Molecular Dynamic Simulation.

The binding of pseudallecin A (PA), a potential antibiotic with strong inhibitory activities against Gram-positive Escherichia coli and Gram-negative Staphylococcus aureus, to human serum albumin (HSA) was explored. The interaction between them was assessed by multi-spectroscopic analysis, binding site competitive analysis, molecular docking and molecular dynamic simulation, showing the results as follows: PA effectively quenched the innate fluorescence of HSA by a static quenching process, formed a complex at a molar ratio of approximately 1 : 1 and performed an effective non-radiative energy transfer; the binding of PA to HSA was a spontaneous exothermic reaction driven by enthalpy with strong affinity and had a slight effect on the conformation of HSA; PA bound at site III of HSA and hydrogen bonds were the major binding forces to maintain the stability of the PA-HSA complex. Molecular dynamic simulation was performed to calculate the root mean square deviation (RMSD), root mean square fluctuation (RMSF) and radius of gyration (Rg) for this complex and effectively supported the spectroscopic outcome. These results meant that the delivery and distribution of PA as a water-insoluble molecule can be efficiently accomplished via HSA in human blood and, it has a good potential for future drug application and pharmacological development.

"Sandwich-like" structure electrostatic spun micro/nanofiber polylactic acid-polyvinyl alcohol-polylactic acid film dressing with metformin hydrochloride and puerarin for enhanced diabetic wound healing.

A diabetic wound is a typical chronic wound with a long repair process and poor healing effects. It is an effective way to promote diabetic wound healing to design electrospinning nanofiber films with drug-assisted therapy, good air permeability and, a multilayer functional structure. In this paper, a diabetic wound dressing with a "sandwich-like" structure was designed. Metformin hydrochloride, loaded in the hydrophilic PVA inner layer, could effectively promote diabetic wound healing. The drug release was slowed down by osmosis. The laminate film dressing had good mechanical properties, with tensile strength and elongation at break reaching 5.91 MPa and 90.47 %, respectively, which was close to human skin. The laminate film loaded with erythromycin and puerarin in the hydrophobic PLA outer layer had good antibacterial properties. In addition, due to the high specific surface of the electrostatic spun film, it exhibited high water vapor permeability. It facilitates the gas exchange between the wound and the outside world. The cell experiments proved that the laminate film dressing had good biocompatibility. There was no toxic side effect on cell proliferation. In the diabetic animal wound model, it was shown that the closure rate of diabetic wound repair by laminate film reached 91.11 % in the second week. Our results suggest that the "sandwich-like" nanofiber film dressing could effectively promote the healing process and meet the various requirements of diabetic wound dressing as a promising candidate for future clinical application of chronic wound dressings.

Inflammatory regulation by restraining M2 microglial polarization: Neurodestructive effects of Kallikrein-related peptidase 8 activation in intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a cerebrovascular disease. Kallikrein-related peptidase 8 (KLK8) is a serine peptidase, while its role in ICH remains unclarified. Western blot (WB) showed that KLK8 was upregulated in rat perihematomal tissues 24 h following autologous blood injection. KLK8 overexpression aggravated behavioral deficits and increased water content and Fluoro-Jade B (FJB)-positive neuron numbers in brain tissue of rats. Immunofluorescence (IF) assay showed that overexpressed-KLK8 promoted Iba-1 and iNOS expression in perihematomal tissue of rats. Overexpressed-KLK8 increased COX-2, iNOS, and Arg-1 expression and the content of IL-6, IL-1ß, and TNF-α in perihematomal tissue of rats, confirmed by WB and ELISA. IF staining confirmed the expression of CCR5 was co-expressed with Iba-1, and the WB results shown increased CCR5 expression and decreased p-PKA and p-CREB expression in perihematomal tissue. Maraviroc (MVC, CCR5 inhibitor) administration rescued KLK8-induced behavioral deficits and brain injury (decreased water content and FJB-positive neuron numbers) in rats. Additionally, MVC suppressed p-PKA and p-CREB expression and the content of IL-6, IL-1ß, and TNF-α in perihematomal tissue, induced by overexpressed-KLK8. Co-IP confirmed the binding of CCR5 and CCL14 in HMC3 cells. Transwell assay shown that KLK8 plus CCL4 promoted the chemotactic activity of cells, which was rescued by MVC. The biological function of KLK8/CCL14/CCR5 axis in ICH injury was also proved by MVC administration in HMC3 cells. Overall, our work revealed that KLK8 overexpression aggravated ICH process and involved in microglial activation. KLK8 might activate CCL14 thereby turning on downstream CCR5/PKA/CREB pathway, providing a theoretical basis for future therapy.

Electrospun polylactic acid nanofiber film modified by silver oxide deposited on hemp fibers for antibacterial fruit packaging.

Bacterial and fungal contamination have become major factors in fruit spoilage and damage, posing a potential risk to human health. In this work, polylactic acid (PLA) nanofibers combined with Ag2O-hemp fibers for a good antimicrobial effect were developed and applied to antimicrobial fruit fresh-keeping packages. The results of molecular simulation calculations showed that the strength of hydrogen bonds between Ag2O and hemp fibers reached 45.522 kJ·mol-1, which proved that Ag2O and with hemp fibers formed a stable deposition. The Ag2O-hemp fibers modified electrospun polylactic acid nanofibrous composite film exhibited favorable mechanical properties. The tensile strength reached 5.23 ± 0.05 MPa and the elongation at break reached 105.56 ± 3.95 %. The obtained nanofibrous composite film has good antibacterial activity against E. coli, S. aureus, A. niger, and Penicillium, which indicated that they could effectively inhibit the growth of bacteria and fungi. The cell experiments proved that the nanofibrous composite film had good biocompatibility with a cell survival rate of 100 %. The experimental results on the fresh-keeping of red grapes showed that the PLA nanofibrous composite film modified by the Ag2O-hemp fibers could effectively prolong the spoilage time of red grapes at room temperature. Compared with the blank group, the freshness period of PLA nanofiber film modified by Ag2O-hemp fibers could be extended for more than 5 days. The hardness of 15 days (1.94 ± 0.19 × 105 Pa) was basically the same as that of 1 day (2.05 ± 0.06 × 105 Pa). The results were superior to commercially available PE preservation films. The above research results indicated that the Ag2O-hemp fibers modified PLA nanofibrous composite film had potential application prospects in the field of fruit fresh-keeping package.

Genetic polymorphisms of pri-let-7f, gene-environment and gene-gene interactions, and associations with ischemic stroke risk in Liaoning Province.

OBJECTIVE: The incidence of stroke has been rising annually and investigations into traditional risk factors have led to increased attention on genetic factors. In this study, we focused on the pri-let-7f gene, and investigated the association between pri-let-7f gene polymorphisms and ischemic stroke (IS). METHODS: This case-control study included 1803 patients and 1456 healthy controls of Han ethnicity living in Liaoning Province. We carried out genotyping analysis of two loci, pri-let-7f-1 rs10739971 and pri-let-7f-2 rs17276588, and performed statistical analysis controlling for confounding factors by logistic regression. RESULTS: The A alleles and AA genotypes of both loci were significantly associated with an increased risk of IS. Variant genotypes of rs17276588 may also increase the risk of IS in females with alcohol intake. Gene-gene interaction analysis showed combined effects of mutations in both these single nucleotide polymorphisms (SNPs). CONCLUSIONS: This study demonstrated an association between pri-let-7f SNPs and IS, providing potential latent biomarkers for the risk of IS. However, more detailed studies are needed to clarify these results.

A combined experimental and computational study on the interfacial distribution behavior in colloidal particle-surfactant co-stabilized Pickering emulsions.

Recently, co-stabilized Pickering emulsion (CPE) that stabilized by colloidal particles and surfactant has received increased research attention, owing to its improved stability and fluid properties comparing with conventional emulsions stabilized by particles or surfactants alone. Herein, the dynamic distribution behavior at multi-scale and the synergistic-competitive interfacial absorption in CPE co-stabilized by Tween20 (Tw20) and zein particles (Zp) were studied by experiment combined simulation method. The experimental studies identified the delicate synergistic-competitive stabilization phenomenon tuned by the molar ratio of Zp and Tw20. Meanwhile, dissipative particle dynamic (DPD) simulation was utilized to reveal the distribution and kinetic motion. Based on the two- and three-dimensional simulation on the formation of CPE, simulation revealed that Zp - Tw20 aggregates were formed when anchoring at the interface. The interfacial adsorption efficiency of Zp was improved at low Tw 20 concentration (0-1.0%wt), Tw20 inhibited the Brownian motion of Zp at the interface and competed them out at high concentrations (1.5-2.0%wt). Zp was departured from the interface 4.5 Å to 10 Å, as Tw20 increased from 1.06% to 5%. The study offers a novel approach to reveal the dynamic distribution behavior of surface active substances during the dynamic formation process of CEP, which will expand our current strategies for interface engineering of emulsions.

Simulating and Predicting the Part Warping in Fused Deposition Modeling by Thermal-Structural Coupling Analysis.

As the most commonly used additive manufacturing technology, fused deposition modeling (FDM) still faces some technical issues caused by temperature change-induced unsteady thermal stress and warping. These issues can further lead to the deformation of printed parts and even terminate the printing process. In response to these issues, this article established a numerical model of temperature field and thermal stress field for FDM by finite element modeling and "birth-death element" technique to predict the deformation of the part. What makes sense in this process is that the logic of elements sort based on ANSYS Parametric Design Language (APDL) was proposed to sort the meshed elements, which was aimed to perform FDM simulation quickly on the model. In this work, the effects of the sheets shape and infill line directions (ILDs) on the distortion during FDM were simulated and verified. From the analysis of stress field and deformation nephogram, the simulation results indicated that ILD had greater effects on the distortion. Moreover, the sheet warping became most serious when the ILD was aligned with the diagonal of the sheet. The simulation results matched well with the experimental results. Thus, the proposed method in this work can be used to optimize the printing parameters for FDM process.

Ozanimod-Dependent Activation of SIRT3/NF-κB/AIM2 Pathway Attenuates Secondary Injury After Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is characterized by poor prognosis and high mortality rates. To date, satisfactory therapeutic approaches for ICH remain limited, so it is urgently needed to develop a safer and more effective prescription. Secondary inflammatory response has been acknowledged as an aggravating factor to neurological deterioration after ICH. As a component of inflammasome sensors, absent in melanoma 2 (AIM2) plays an important role in the neuroinflammation process. Here, ozanimod, a novel selective sphingosine 1-phosphate receptor modulator, has gained much attention, which alleviates the resultant neuroinflammation and improves functional recovery derived from ICH. In this study, ozanimod improved neurological functions of ICH mice via reduction of hematoma size. Furthermore, both microglial and AIM2 inflammasome activations were reversed by ozanimod, which are confirmed by the downregulation of related inflammatory proteins and cytokines (IL-1ß, IL-6, and TNF-α), coupled with the upregulation of SIRT3, by leveraging the Western blot and enzyme-linked immunosorbent assay. Additionally, we find that ozanimod decreases nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression. Notably, in vitro cell experiments induced by lipopolysaccharide confirms that the anti-inflammatory effect of ozanimod could be abolished by the SIRT3 inhibitor. In conclusion, these results indicate that ozanimod mitigates ICH-induced secondary inflammatory responses by modulating AIM2 inflammasome mediated by SIRT3/NF-κB/AIM2 pathway. This demonstrates ozanimod orchestrates ICH-induced neuroinflammation and could be a targeted therapy for improving prognosis of ICH.

Recycling of waste crab shells into reinforced poly (lactic acid) biocomposites for 3D printing.

To promote natural waste resource utilization, a novel biocomposite, composed of waste crab shells and poly (lactic acid) matrix, was developed by combining chemical treatment and 3D printing. A crab shell powder (ISCSP) with an abundant porous structure and a high specific surface area was obtained by treatment with hydrochloric acid and sodium hydroxide. Importantly, under the optimal printing parameters determined by the finite element analysis, test samples, and porous bones were successfully printed using CSP/PLA composites by a commercial fused deposition modeling (FDM) 3D printer. The morphology, mechanical and thermal properties, antibacterial properties, and biocompatibility of the CSP/PLA composites were then assessed. Our results revealed that the tensile strength and flexural strength of the ISCSP/PLA composites reached 58.71 and 90.11 MPa, which were 28.6 % and 28.8 % higher than that of pure PLA, respectively. The glass transition and melting temperatures of the composites remained similar to those of pure PLA. Interestingly, the addition of CSP increased PLA crystallinity, which could be attributed to the nucleation effect of CSP in the system. The antibacterial activity of the PLA-1.5ESCSP composite samples against Escherichia coli (E. coli) was greater than 99 %. More importantly, the live/dead assay showed that the CSP/PLA composites possessed excellent biocompatibility. Therefore, the developed CSP/PLA biocomposites are potential feedstocks for 3D printing in bone tissue engineering and may be used as graft substitutes in reparative and reconstructive surgery. They are especially beneficial due to their superior mechanical and thermal properties, excellent antibacterial activities, and significant biocompatibility.

Exosomal miR-23b from bone marrow mesenchymal stem cells alleviates oxidative stress and pyroptosis after intracerebral hemorrhage.

Our previous studies showed that miR-23b was downregulated in patients with intracerebral hemorrhage (ICH). This indicates that miR-23b may be closely related to the patho-physiological mechanism of ICH, but this hypothesis lacks direct evidence. In this study, we established rat models of ICH by injecting collagenase VII into the right basal ganglia and treating them with an injection of bone marrow mesenchymal stem cell (BMSC)-derived exosomal miR-23b via the tail vein. We found that edema in the rat brain was markedly reduced and rat behaviors were improved after BMSC exosomal miR-23b injection compared with those in the ICH groups. Additionally, exosomal miR-23b was transported to the microglia/macrophages, thereby reducing oxidative stress and pyroptosis after ICH. We also used hemin to mimic ICH conditions in vitro. We found that phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was the downstream target gene of miR-23b, and exosomal miR-23b exhibited antioxidant effects by regulating the PTEN/Nrf2 pathway. Moreover, miR-23b reduced PTEN binding to NOD-like receptor family pyrin domain containing 3 (NLRP3) and NLRP3 inflammasome activation, thereby decreasing the NLRP3-dependent pyroptosis level. These findings suggest that BMSC-derived exosomal miR-23b exhibits antioxidant effects through inhibiting PTEN and alleviating NLRP3 inflammasome-mediated pyroptosis, thereby promoting neurologic function recovery in rats with ICH.

Ameliorating SERS Sensitivity for Pesticide Malathion Detection with Synergistic Boosting Effect by Hydrogen Cations and Chloride Anions.

Although SERS has been widely recognized as one of the highly sensitive analytical methods that can be deployed in the field with high sensitivity and short analysis time, reports regarding the fast determination of malathion at low concentrations are still scarce. Here, in this work, the solution pH and various halogen co-adsorbates were explored to promote the SERS signal of malathion using the citrate-reduced Ag NPs. It was found that chloride anions were the most efficient signal booster among the three halogen ions screened. Further examination of the SERS profile of the malathion in the presence of different halogen species found that the stretching mode of the P-S bond shifted to a lower frequency with Cl-, which may imply closer (and stronger) binding of malathion to the Ag NPs. This concurs with literature reports that halogen ions could facilitate the adsorption of a certain analyte onto the SERS substrate. In addition, hydrogen ions showed a synergistic effect on SERS signal enhancement when combined with chloride anions. At optimum conditions, the malathion could be detected with a limit of detection (LOD) of 3 ppb. Malathion-spiked cherry tomatoes and oranges were analyzed, and the recovery rates were found to be within 85-100%.

Intronic enhancers of the human SNCA gene predominantly regulate its expression in brain in vivo.

Evidence from patients with Parkinson's disease (PD) and our previously reported α-synuclein (SNCA) transgenic rat model support the idea that increased SNCA protein is a substantial risk factor of PD pathogenesis. However, little is known about the transcription control of the human SNCA gene in the brain in vivo. Here, we identified that the DYT6 gene product THAP1 (THAP domain-containing apoptosis-associated protein 1) and its interaction partner CTCF (CCCTC-binding factor) act as transcription regulators of SNCA. THAP1 controls SNCA intronic enhancers' activities, while CTCF regulates its enhancer-promoter loop formation. The SNCA intronic enhancers present neurodevelopment-dependent activities and form enhancer clusters similar to "super-enhancers" in the brain, in which the PD-associated single-nucleotide polymorphisms are enriched. Deletion of the SNCA intronic enhancer clusters prevents the release of paused RNA polymerase II from its promoter and subsequently reduces its expression drastically in the brain, which may provide new therapeutic approaches to prevent its accumulation and thus related neurodegenerative diseases defined as synucleinopathies.

Comprehensive analysis of immune-related biomarkers and pathways in intracerebral hemorrhage using weighted gene co-expression network analysis and competing endogenous ribonucleic acid.

The immune response is an important part of secondary brain injury following intracerebral hemorrhage (ICH), and is related to neurological deficits and prognosis. The mechanisms underlying the immune response and inflammation are of great significance for brain injury and potential functional restoration; however, the immune-related biomarkers and competing endogenous ribonucleic acid (RNA) (ceRNA) networks in the peripheral blood of ICH patients have not yet been constructed. We collected the peripheral blood from ICH patients and controls to assess their ceRNA profiles using LCHuman ceRNA microarray, and to verify their expression with qRT-PCR. Two-hundred-eleven DElncRNAs and one-hundred-one DEmRNAs were detected in the ceRNA microarray of ICH patients. The results of functional enrichment analysis showed that the immune response was an important part of the pathological process of ICH. Twelve lncRNAs, ten miRNAs, and seven mRNAs were present in our constructed immune-related ceRNA network, combining weighted gene co-expression network analysis (WGCNA). Our study was the first to establish the network of the immune-related ceRNAs derived from WGCNA, and to identify leukemia inhibitory factor (LIF) and B cell lymphoma 2-like 13 (BCL2L13) as pivotal immune-related biomarkers in the peripheral blood of ICH patients, which are likely associated with PI3K-Akt, the MAPK signaling pathway, and oxidative phosphorylation. The MOXD2P-miR-211-3p -LIF and LINC00299-miR-198-BCL2L13 axes were indicated to participate in the immune regulatory mechanism of ICH. The goal of our study was to offer innovative insights into the underlying immune regulatory mechanism and to identify possible immune intervention targets for ICH.

Electrospun nanofibrous membrane with antibacterial and antiviral properties decorated with Myoporum bontioides extract and silver-doped carbon nitride nanoparticles for medical masks application.

Public health safety issues have been plaguing the world since the pandemic outbreak of coronavirus disease (COVID-19). However, most personal protective equipments (PPE) do not have antibacterial and anti- toxicity effects. In this work, we designed and prepared a reusable, antibacterial and anti-toxicity Polyacrylonitrile (PAN) based nanofibrous membrane cooperated with Ag/g-C3N4 (Ag-CN), Myoporum.bontioides (M. bontioides) plant extracts and Ag nanoparticles (NPs) by an electrospinning-process. The SEM and TEM characterization revealed the formation of raised, creased or wrinkled areas on the fiber surface caused by the Ag nanoparticles, the rough surface prevented the aerosol particles on the fiber surface from sliding and stagnating, thus providing excellent filtration performance. The PAN/M. bontioides/Ag-CN/Ag nanofibrous membrane could be employed as a photocatalytic bactericidal material, which not only degraded 96.37% of methylene blue within 150 min, but also exhibited the superior bactericidal effect of 98.65 ± 1.49% and 97.8 ± 1.27% against E. coli and S. aureus, respectively, under 3 hs of light exposure. After 3 cycles of sterilization experiments, the PAN/M. bontioides/Ag-CN/Ag nanofibrous membrane maintained an efficient sterilization effect. Molecular docking revealed that the compounds in M. bontioides extracts interacted with neo-coronavirus targets mainly on Mpro and RdRp proteins, and these compounds had the strongest docking energy with Mpro protein, the shortest docking radius, and more binding sites for key amino acids around the viral protein targets, which influenced the replication and transcription process of neo-coronavirus. The PAN/M.bontioides/Ag-CN/Ag nanofibrous membrane also performed significant inhibition of influenza A virus H3N2. The novel nanofiber membrane is expected to be applied to medical masks, which will improve human isolation and protection against viruses.

A SERS pH sensor for highly alkaline conditions and its application for pH sensing in aerosol droplets.

Surface-Enhanced Raman Scattering (SERS) has been widely used in pH sensing. However, SERS sensors capable of stably analysing pH under highly alkaline conditions are still scarce. In this work, a SERS pH sensor employing Alizarin Yellow R as the molecular probe was carefully developed for strong alkaline solutions. The results showed that the probe presented excellent sensing performance in the pH range of 10.04-14.04, including desirable stability and reversibility. Raman band assignments of the probe molecules with the protonated and deprotonated forms were calculated using Gaussian 09. To demonstrate the application, we measured the centroid pH of the phosphate buffer (PB) droplet and compared it to the value obtained with 4-mercaptobenzoic acid (4-MBA) as a probe.

A novel antibacterial tyroscherin derivative with a natural unprecedented morpholine-2, 3-dione structural unit from the fungus Pseudallescheria boydii.

A novel tyroscherin derivative named pseudallecin A (1) with a natural unprecedented morpholine-2, 3-dione structural unit, and a new biogenic synthesis related organic acid named pseudallecin B (2) were purified from a symbiotic fungus Pseudallescheria boydii derived from Pomacea canaliculata. Their structures were elucidated via spectroscopic analyses and ECD calculation. Pseudallecin A exhibited strong inhibitory activities against both Gram-positive Escherichia coli and Gram-negative Staphylococcus aureus.

DYT6 mutated THAP1 is a cell type dependent regulator of the SP1 family.

DYT6 dystonia is caused by mutations in the transcription factor THAP1. THAP1 knock-out or knock-in mouse models revealed complex gene expression changes, which are potentially responsible for the pathogenesis of DYT6 dystonia. However, how THAP1 mutations lead to these gene expression alterations and whether the gene expression changes are also reflected in the brain of THAP1 patients are still unclear. In this study we used epigenetic and transcriptomic approaches combined with multiple model systems [THAP1 patients' frontal cortex, THAP1 patients' induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic neurons, THAP1 heterozygous knock-out rat model, and THAP1 heterozygous knock-out SH-SY5Y cell lines] to uncover a novel function of THAP1 and the potential pathogenesis of DYT6 dystonia. We observed that THAP1 targeted only a minority of differentially expressed genes caused by its mutation. THAP1 mutations lead to dysregulation of genes mainly through regulation of SP1 family members, SP1 and SP4, in a cell type dependent manner. Comparing global differentially expressed genes detected in THAP1 patients' iPSC-derived midbrain dopaminergic neurons and THAP1 heterozygous knock-out rat striatum, we observed many common dysregulated genes and 61 of them were involved in dystonic syndrome-related pathways, like synaptic transmission, nervous system development, and locomotor behaviour. Further behavioural and electrophysiological studies confirmed the involvement of these pathways in THAP1 knock-out rats. Taken together, our study characterized the function of THAP1 and contributes to the understanding of the pathogenesis of primary dystonia in humans and rats. As SP1 family members were dysregulated in some neurodegenerative diseases, our data may link THAP1 dystonia to multiple neurological diseases and may thus provide common treatment targets.

PCL/Collagen/UA Composite Biomedical Dressing with Ordered Microfiberous Structure Fabricated by a 3D Near-Field Electrospinning Process.

In this work, a functionalized polycaprolactone (PCL) composite fiber combining calf-type I collagen (CO) and natural drug usnic acid (UA) was prepared, in which UA was used as an antibacterial agent. Through 3D near-field electrospinning, the mixed solution was prepared into PCL/CO/UA composite fibers (PCUCF), which has a well-defined perfect arrangement structure. The influence of electrospinning process parameters on fiber diameter was investigated, the optimal electrospinning parameters were determined, and the electric field simulation was conducted to verify the optimal parameters. The addition of 20% collagen made the composite fiber have good hydrophilicity and water absorption property. In the presence of PCUCF, 1% UA content significantly inhibited the growth rate of Gram-positive and negative bacteria in the plate culture. The AC-PCUCF (after crosslinking PCUCF) prepared by crosslinking collagen with genipin showed stronger mechanical properties, water absorption property, thermal stability, and drug release performance. Cell proliferation experiments showed that PCUCF and AC-PCUCF had no cytotoxicity and could promote cell proliferation and adhesion. The results show that PCL/CO/UA composite fiber has potential application prospects in biomedical dressing.