Free-electron lasing at 27 nanometres based on a laser wakefield accelerator.

X-ray free-electron lasers can generate intense and coherent radiation at wavelengths down to the sub-ångström region1-5, and have become indispensable tools for applications in structural biology and chemistry, among other disciplines6. Several X-ray free-electron laser facilities are in operation2-5; however, their requirement for large, high-cost, state-of-the-art radio-frequency accelerators has led to great interest in the development of compact and economical accelerators. Laser wakefield accelerators can sustain accelerating gradients more than three orders of magnitude higher than those of radio-frequency accelerators7-10, and are regarded as an attractive option for driving compact X-ray free-electron lasers11. However, the realization of such devices remains a challenge owing to the relatively poor quality of electron beams that are based on a laser wakefield accelerator. Here we present an experimental demonstration of undulator radiation amplification in the exponential-gain regime by using electron beams based on a laser wakefield accelerator. The amplified undulator radiation, which is typically centred at 27 nanometres and has a maximum photon number of around 1010 per shot, yields a maximum radiation energy of about 150 nanojoules. In the third of three undulators in the device, the maximum gain of the radiation power is approximately 100-fold, confirming a successful operation in the exponential-gain regime. Our results constitute a proof-of-principle demonstration of free-electron lasing using a laser wakefield accelerator, and pave the way towards the development of compact X-ray free-electron lasers based on this technology with broad applications.

Attenuation of relapsing fever neuroborreliosis in mice by IL-17A blockade.

Relapsing fever due to Borrelia hermsii is characterized by recurrent bacteremia episodes. However, infection of B. hermsii, if not treated early, can spread to various organs including the central nervous system (CNS). CNS disease manifestations are commonly referred to as relapsing fever neuroborreliosis (RFNB). In the mouse model of B. hermsii infection, we have previously shown that the development of RFNB requires innate immune cells as well as T cells. Here, we found that prior to the onset of RFNB, an increase in the systemic proinflammatory cytokine response followed by sustained levels of IP-10 concurrent with the CNS disease phase. RNA sequencing analysis of the spinal cord tissue during the disease phase revealed an association of the interleukin (IL)-17 signaling pathway in RFNB. To test a possible role for IL-17 in RFNB, we compared B. hermsii infection in wild-type and IL-17A-/- mice. Although the onset of bacteremia and protective anti-B. hermsii antibody responses occurred similarly, the blood-brain barrier permeability, proinflammatory cytokine levels, immune cell infiltration in the spinal cord, and RFNB manifestations were significantly diminished in IL-17A-/- mice compared to wild-type mice. Treatment of B. hermsii-infected wild-type mice with anti-IL-17A antibody ameliorated the severity of spinal cord inflammation, microglial cell activation, and RFNB. These data suggest that the IL-17 signaling pathway plays a major role in the pathogenesis of RFNB, and IL-17A blockade may be a therapeutic modality for controlling neuroborreliosis.

Coxsackievirus B: The important agent of hand, foot, and mouth disease.

Hand, foot, and mouth disease (HFMD) is a common pediatric infectious illness caused by enteroviruses (EVs). EV-A serotypes are the main pathogens associated with HFMD. In this study, 213 stool samples from 213 children with severe HFMD in Yunnan, China in 2013, 2015, and 2016 were further analyzed retrospectively for EV-B infection. A total of 70.0% of the specimens tested positive for EV.20 EV serotypes were detected. The predominant serotype was enterovirus A71 (EV-A71, 27.7%), followed by coxsackievirus B4 (CV-B4, 16.4%), CV-A16 (9.9%), CV-B5 (6.6%), and Echovirus 9 (E-9,4.7%). EV-A and EV-B accounted for 45.1% and 41.3%, respectively. Among the positive specimens, 28.6% were CV-Bs. Co-infection was present in 19.3% of these cases. In the study, CV-B5 and the majority of CV-B4 isolates belonged to genotypes VI and C3, respectively. This result indicates that EV-B, especially CV-Bs, might be the important agents associated with HFMD and this knowledge will contribute to the prevention and treatment of the disease.

The Gastrointestinal Tract Is an Alternative Route for SARS-CoV-2 Infection in a Nonhuman Primate Model.

BACKGROUND & AIMS: Gastrointestinal (GI) manifestations have been increasingly reported in patients with coronavirus disease 2019 (COVID-19). However, the roles of the GI tract in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are not fully understood. We investigated how the GI tract is involved in SARS-CoV-2 infection to elucidate the pathogenesis of COVID-19. METHODS: Our previously established nonhuman primate (NHP) model of COVID-19 was modified in this study to test our hypothesis. Rhesus monkeys were infected with an intragastric or intranasal challenge with SARS-CoV-2. Clinical signs were recorded after infection. Viral genomic RNA was quantified by quantitative reverse transcription polymerase chain reaction. Host responses to SARS-CoV-2 infection were evaluated by examining inflammatory cytokines, macrophages, histopathology, and mucin barrier integrity. RESULTS: Intranasal inoculation with SARS-CoV-2 led to infections and pathologic changes not only in respiratory tissues but also in digestive tissues. Expectedly, intragastric inoculation with SARS-CoV-2 resulted in the productive infection of digestive tissues and inflammation in both the lung and digestive tissues. Inflammatory cytokines were induced by both types of inoculation with SARS-CoV-2, consistent with the increased expression of CD68. Immunohistochemistry and Alcian blue/periodic acid-Schiff staining showed decreased Ki67, increased cleaved caspase 3, and decreased numbers of mucin-containing goblet cells, suggesting that the inflammation induced by these 2 types of inoculation with SARS-CoV-2 impaired the GI barrier and caused severe infections. CONCLUSIONS: Both intranasal and intragastric inoculation with SARS-CoV-2 caused pneumonia and GI dysfunction in our rhesus monkey model. Inflammatory cytokines are possible connections for the pathogenesis of SARS-CoV-2 between the respiratory and digestive systems.

Effects of hypercaloric diet-induced hyperinsulinemia and hyperlipidemia on the ovarian follicular development in mice.

Long-term hypercaloric diets may adversely affect the development of ovarian follicles. We investigated the effects of high sugar (HS), high fat low sugar (HFLS), and high fat normal sugar (HFNS) diets on the ovarian follicle development in mice fed with these diets as compared to those fed with normal diet (control) for 180 days. Body weight, gonadal fat, glucose, lipid, insulin, estrous cycle, sex hormones and ovarian tissues were examined, and metabolism-related protein expression in the ovaries was evaluated by immunoblotting. The mice fed with hypercaloric diets showed hyperinsulinemia and hyperlipidemia, and exhibited heavier body and gonadal fat weights, longer estrous cycles, and fewer preantral and antral follicles than mice fed with normal diet. The sex hormone levels in the blood were similar to those in controls, except for significantly elevated estradiol levels in the HS diet group. The AMPKα phosphorylation was reduced, while AKT phosphorylation and caspase-3 levels were increased in the ovarian tissues of mice in all three hypercaloric diet groups than those in control. Taken together, the results suggest hyperinsulinemia and hyperlipidemia as possible mechanisms that impair the development of ovarian follicles in response to long-term exposure to unhealthy hypercaloric diets.

Signal transducer and activator of transcription 3 mediates apoptosis inhibition through reducing mitochondrial ROS and activating Bcl-2 in gemcitabine-resistant lung cancer A549 cells.

Lung cancer is a leading cause of cancer-related death worldwide. In this study, we used lung adenocarcinoma cells as a model, as lung adenocarcinoma has the highest mortality rate among all lung cancers. For the past few years, medical treatments or lung cancer have been limited because of chemotherapy resistance. Therefore, understanding the pathogenesis of the development of drug resistance in lung cancer is urgent. Gemcitabine is widely prescribed in the chemotherapeutic treatment of lung cancers. In this study, we developed gemcitabine-resistant lung adenocarcinoma cells (A549-GR) from the A549 cell line. The results showed that apoptotic protein expression and reactive oxygen species (ROS) generation were reduced in A549-GR cells compared to A549 cells. Interestingly, we found that signal transducer and activator of transcription 3 (STAT3) translocated to the nucleus and mitochondria to affect the apoptotic pathway and ROS generation, respectively. Furthermore, treatment with STAT3 small interfering RNA diminished the increase in ROS production, proliferation and antiapoptotic proteins in A549-GR cells. Taken together, the study demonstrated that STAT3 acts as an essential regulator and moderates apoptosis through two major mechanisms to induce gemcitabine resistance in cells; and these findings provide a potential target for the treatment of gemcitabine-resistant lung cancer.

MicroRNA-210 repression facilitates advanced glycation end-product (AGE)-induced cardiac mitochondrial dysfunction and apoptosis via JNK activation.

Hyperglycemia results in the formation of reactive oxygen species which in turn causes advanced glycation end products (AGEs) formation, leading to diabetic cardiomyopathy. Our previous study showed that AGE-induced reactive oxygen species-dependent apoptosis is mediated via protein kinase C delta (PKCδ)-enhanced mitochondrial damage in cardiomyocytes. By using microRNA (miRNA) database, miRNA-210 was predicted to target c-Jun N-terminal kinase (JNK), which were previously identified as downstream of PKCδ in regulating mitochondrial function. Therefore, we hypothesized that miR-210 mediates PKCδ-dependent upregulation of JNK to cause cardiac mitochondrial damage and apoptosis following AGE exposure. AGE-exposed cells showed activated cardiac JNK, PKCδ, and apoptosis, which were reversed by treatment with a JNK inhibitor and PKCδ-KD (deficient kinase). Cardiac miR-210 and mitochondrial function were downregulated following AGE exposure. Furthermore, JNK was upregulated and involved in AGE-induced mitochondrial damage. Interestingly, luciferase activity of the miR-210 mimic plus JNK WT-3'-untranslated region overexpressed group was significantly lower than that of miR-210 mimic plus JNK MT-3'UTR group, indicating that JNK is a target of miR-210. Moreover, JNK activation induced by AGEs was reduced by treatment with the miR-210 mimic and reversed by treatment with the miR-210 inhibitor, indicating the regulatory function of miR-210 in JNK activation following AGE exposure. Additionally, JNK-dependent mitochondrial dysfunction and apoptosis were reversed following treatment with the miR-210 mimic, while the miR-210 inhibitor showed no effect on JNK-induced mitochondrial dysfunction and apoptosis in AGE-exposed cardiac cells. Taken together, our study showed that PKCδ-enhanced JNK-dependent mitochondrial damage is mediated through the reduction of miR-210 in cardiomyocytes following AGE exposure.

Erythropoietin-producing hepatocellular receptor A7 restrains estrogen negative feedback of luteinizing hormone via ephrin A5 in the hypothalamus of female rats.

We have previously shown that systemic injection of erythropoietin-producing hepatocellular receptor A7 (EPHA7)-Fc raises serum luteinizing hormone (LH) levels before ovulation in female rats, indicating the induction of EPHA7 in ovulation. In this study, we aimed to identify the mechanism and hypothalamus-pituitary-ovary (HPO) axis level underlying the promotion of LH secretion by EPHA7. Using an ovariectomized (OVX) rat model, in conjunction with low-dose 17ß-estradiol (E2) treatment, we investigated the association between EPHA7-ephrin (EFN)A5 signaling and E2 negative feedback. Various rat models (OVX, E2-treated OVX, and abarelix treated) were injected with the recombinant EPHA7-Fc protein through the caudal vein to investigate the molecular mechanism underlying the promotion of LH secretion by EPHA7. Efna5 was observed strongly expressed in the arcuate nucleus of the female rat by using RNAscope in situ hybridization. Our results indicated that E2, combined with estrogen receptor (ER)α, but not ERß, inhibited Efna5 and gonadotropin-releasing hormone 1 (Gnrh1) expressions in the hypothalamus. In addition, the systemic administration of EPHA7-Fc restrained the inhibition of Efna5 and Gnrh1 by E2, resulting in increased Efna5 and Gnrh1 expressions in the hypothalamus as well as increased serum LH levels. Collectively, our findings demonstrated the involvement of EPHA7-EFNA5 signaling in the regulation of LH and the E2 negative feedback pathway in the hypothalamus, highlighting the functional role of EPHA7 in female reproduction.

Generation and observation of ultrafast spectro-temporal dynamics of different pulsating solitons from a fiber laser.

As a universal phenomenon in nonlinear optical systems, pulsating behaviors of solitons have attracted increasingly more investigations. While pulsating solitons and their likely generation conditions had been widely theoretical studied, their detailed spectro-temporal dynamics had been hardly reported in experiments. Here, three types of pulsating solitons are experimentally generated and observed in a dispersion-managed, hybrid mode-locked fiber laser. By controllably generating such states through intracavity tuning and leveraging the dispersive Fourier transform technique that maps spectral information into the time domain, real-time ultrafast spectro-temporal evolutions of the pulsating behaviors are revealed. The numerical results further show the generation of the pulsating soliton could be caused by the intracavity spectral filtering effect, consistent with the experimental configurations. Our findings could provide further insights into the complex nonlinear dynamics in lasers and potential ways to the design such systems to deliver targeted soliton outputs for potential applications.

Guiding and emission of milijoule single-cycle THz pulse from laser-driven wire-like targets.

The miscellaneous applications of terahertz have called for an urgent demand of a super intense terahertz source. Here, we demonstrate the capability of femtosecond laser-driven wires as an efficient ultra-intense terahertz source using 700 mJ laser pulses. When focused onto a wire target, coherent THz generation took place in the miniaturized gyrotron-like undulator where emitted electrons move in the radial electric field spontaneously created on wire surface. The single-cycle terahertz pulse generated from the target is measured to be radially polarized with a pulse energy of a few milijoule. By further applying this scheme to a wire-tip target, we show the near field of the 500 nm radius apex could reach up to 90 GV/m. This efficient THz energy generation and intense THz electric field mark a substantial improvement toward ultra-intense terahertz sources.

Decreased brain and muscle ARNT-like protein 1 expression mediated the contribution of hyperandrogenism to insulin resistance in polycystic ovary syndrome.

BACKGROUND: The interface between environmental risk factors and genetic factors could contribute to the pathogenesis of hyperandrogenism and insulin resistance in polycystic ovary syndrome (PCOS); however, the underlying complex mechanism remains to be elucidated. METHODS: We used dehydroepiandrosterone (DHEA)-induced PCOS-like rat model to measure circadian clock genes and insulin resistance-related genes. Additionally, we performed in vitro experiments in mature adipocytes to verify the molecular mechanisms. RESULTS: DHEA-induced PCOS-like rats exhibited insulin resistance and arrhythmic expression of circadian clock genes in the liver and adipose tissues, particularly showing decreased brain and muscle ARNT-like protein 1 (BMAL1) expression. In addition, hyperandrogenism gave rise to negative regulation of BMAL1 expression to nicotinamide phosphoribosyltransferase and sirtuin 1, which further inhibited downstream glucose transporter type 4, leading to insulin resistance in mature adipocytes, which was consistent with our previous results in HepG2 cells. CONCLUSIONS: Decreased BMAL1 expression in the liver and adipose played a potentially novel role in the contribution of hyperandrogenism to insulin resistance, which might be a possible mechanism accounting for the pathogenesis of PCOS.

Clinical characteristics of 276 hospitalized patients with coronavirus disease 2019 in Zengdu District, Hubei Province: a single-center descriptive study.

BACKGROUND: We aimed to report the epidemiological and clinical characteristics of hospitalized patients with coronavirus disease-19 (COVID-19) in Zengdu District, Hubei Province, China. METHODS: Clinical data on COVID-19 inpatients in Zengdu Hospital from January 27 to March 11, 2020 were collected; this is a community hospital in an area surrounding Wuhan and supported by volunteer doctors. All hospitalized patients with COVID-19 were included in this study. The epidemiological findings, clinical features, laboratory findings, radiologic manifestations, and clinical outcomes of these patients were analyzed. The patients were followed up for clinical outcomes until March 22, 2020. Severe COVID-19 cases include severe and critical cases diagnosed according to the seventh edition of China's COVID-19 diagnostic guidelines. Severe and critical COVID-19 cases were diagnosed according to the seventh edition of China's COVID-19 diagnostic guidelines. RESULTS: All hospitalized COVID-19 patients, 276 (median age: 51.0 years), were enrolled, including 262 non-severe and 14 severe patients. The proportion of patients aged over 60 years was higher in the severe group (78.6%) than in the non-severe group (18.7%, p < 0.01). Approximately a quarter of the patients (24.6%) had at least one comorbidity, such as hypertension, diabetes, or cancer, and the proportion of patients with comorbidities was higher in the severe group (85.7%) than in the non-severe group (21.4%, p < 0.01). Common symptoms included fever (82.2% [227/276]) and cough (78.0% [218/276]). 38.4% (106/276) of the patients had a fever at the time of admission. Most patients (94.9% [204/276]) were cured and discharged; 3.6% (10/276) deteriorated to a critical condition and were transferred to another hospital. The median COVID-19 treatment duration and hospital stay were 14.0 and 18.0 days, respectively. CONCLUSIONS: Most of the COVID-19 patients in Zengdu had mild disease. Older patients with underlying diseases were at a higher risk of progression to severe disease. The length of hospital-stay and antiviral treatment duration for COVID-19 were slightly longer than those in Wuhan. This work will contribute toward an understanding of COVID-19 characteristics in the areas around the core COVID-19 outbreak region and serve as a reference for decision-making for epidemic prevention and control in similar areas.

Dissociation mechanism of GDP from Cdc42 via DOCK9 revealed by molecular dynamics simulations.

Cell division control protein 42 homolog (Cdc42) influences a variety of cellular responses such as cell migration and polarity. Deregulation of Cdc42 has been associated with several human diseases and developmental disorders. Over-activation of Cdc42 through guanine nucleotide exchange factor (GEF) is a critical event for Cdc42 involved cancer metastasis. Members of DOCK family of GEF are important activators of Cdc42. However, this activation mechanism is still unknown. Molecular dynamics (MD) simulations and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) calculations were employed to investigate the central step of the activation of Cdc42: the dissociation mechanism of GDP from Cdc42 via DOCK9. Simulation results show that Mg2+ ion has a remarkable influence on the conformational change of switch I of Cdc42 through residue Pro34 which functions as a "clasp" to control the flexibility of switch I. In the GDP dissociation process, the Mg2+ ion leave first to result in a suitable conformation of Cdc42 for following DOCK9 binding to. When DOCK9 binds to Cdc42, it changes the orientations of residues Lys16, Thr17, Cys18 and Phe28 of Cdc42 to weaken the interactions between Cdc42 and GDP to release GDP. This study first elucidates the dissociation mechanism of GDP from Cdc42 via DOCK9 and identifies the essential residues of Cdc42 in this process. These simulation results are consistent with the recent findings of biochemical and amino acid mutational studies, and the observations are beneficial to understand the activation mechanism of Cdc42 and to provide insights for designing compounds targeting on Cdc42 related cancer metastasis.

Generation of ultrashort coherent radiation based on a laser plasma accelerator.

A laser plasma accelerator (LPA) has the potential to realize compact free-electron laser (FEL) radiation at the regular laboratory scale. However, large initial angular divergence and energy spread dramatically hinder ways to transport the beam and realize FEL radiation. Although methods have been proposed to solve these problems, the relatively large jitter, including transverse position jitter and energy jitter, still limits the advance of these experiments. In this paper a simple method to realize coherent harmonic generation based on a LPA beam is proposed. The scheme is very compact, adopting a high-power laser split from the driver laser, a short modulator and a short radiator which has a great tolerance to these typical types of jitter. Numerical simulations indicate that coherent third-harmonic radiation with gigawatt-level power and single spike spectra can be obtained, verifying the feasibility of the scheme and indicating the capability to generate ultrashort fully coherent radiation.

Dual-comb spectroscopy of methane based on a free-running Erbium-doped fiber laser.

Dual-comb spectroscopy has been developed into a high-precision technique that is capable of sensing many important species of samples, such as methane. Recent studies on single-cavity, dual-comb light sources further reduce the system complexity of such schemes. In contrast to the previous demonstrations around the lasing spectrum, this work significantly expands the spectral coverage of a dual-comb spectroscopy setup using one free-running laser to a region far beyond the laser's emission wavelengths. Nonlinear wavelength conversion based on soliton self-frequency shift is adopted to convert and tune the wavelengths of both dual-comb pulses to ~1650nm. It is shown that this process has introduced little additional intensity noise. The 2ν3 absorption band of methane from 1647 nm to 1663nm is measured with very good agreement with HITRAN, and the standard deviation of the residual is < ~0.006 after averaging ~1.96 seconds of data. Our results further elucidate the potential of dual-comb spectroscopy using one laser, and could pave the way for the development of low-cost, power-efficient, and compact dual-comb instrument targeting more spectral regions.

IL-18 induced IL-23/IL-17 expression impairs Aß clearance in cultured THP-1 and BV2 cells.

Recent studies have provided overwhelming evidence of the involvement of microglia-related molecular networks in the pathogenesis of Alzheimer's diseases (AD). The potential involvement of pro-inflammatory cytokines interleukin (IL)-18, IL-23 and IL-17 on amyloid (Aß) clearance is still unclear. In this study, we addressed that there might be a net relationship among IL-18, IL-23, and IL-17 and they can affect Aß clearance in cultured macrophage/microglia cells. In human macrophage cell line THP-1, Aß42 incubation could increase the expression of IL-18, IL-23 and IL-17 in a concentration dependent manner. THP-1 cell could clear Aß42 in the culture medium time-dependently, but its capacity of Aß clearance was impaired by IL-18, IL-23 or IL-17 treatment. Similarly, the capacity of the microglia cell line BV2 to clear Aß42 was impaired by IL-18, IL-23 or IL-17 treatment. In co-cultures of BV2 with APP/PS1 neuron, Aß was efficiently cleared by BV2 cell, but Aß clearance was impaired by IL-18, IL-23 or IL-17 treatment. The effects of IL-18, IL-23 and IL-17 could be blocked by their corresponding neutralizing antibodies. In addition, the inhibitory effects of IL-18 were blocked by IL-23 or IL-17 neutralizing antibodies while the inhibitory effects of IL-23 were blocked by IL-17 neutralizing antibodies. Our study provides evidences showing that amyloid induced IL-18/IL-23/IL-17 axis could impair macrophage and microglia-mediated Aß clearance. Thus, IL-18/IL-23/IL-17 axis might be a therapeutic target in AD.

Identification of a new recombinant strain of echovirus 33 from children with hand, foot, and mouth disease complicated by meningitis in Yunnan, China.

BACKGROUND: Hand, foot, and mouth disease (HFMD) is a common childhood disease, which is usually caused by enterovirus A (EV-A) serotypes. Enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16) are the main etiologic agents. Multiple serotypes of enterovirus B serotypes (EV-B) have been detected in outbreaks or sporadic cases of HFMD. RESULTS: During HFMD surveillance in Yunnan, China in 2013, two echovirus 33 (E-33) isolates were recovered in cell culture and typed by molecular methods from the cerebrospinal fluid (CSF) and feces of two sporadic cases of HFMD complicated by meningitis. Sequence analysis indicated that the study isolates, YNK35 and YNA12, formed an independent branch, and belonged to E-33 genotype H. Recombination analysis indicated multiple recombination events in the genomic sequence of isolate YNK35. The recombination mainly occurred in the non-structural coding region of P2 and P3, and involved intra-species recombination of species B. CONCLUSION: In this study, the complete sequences of two E-33 isolates were determined. This is the first report of severe HFMD associated with E-33 in Yunnan China, and it enriches the number of full-length genome sequences of E-33 in the GenBank database.

RVG-modified exosomes derived from mesenchymal stem cells rescue memory deficits by regulating inflammatory responses in a mouse model of Alzheimer's disease.

BACKGROUND: Exosomes are lipid-bilayer enclosed nano-sized vesicles that transfer functional cellular proteins, mRNA and miRNAs. Mesenchymal stem cells (MSCs) derived exosomes have been demonstrated to prevent memory deficits in the animal model of Alzheimer's disease (AD). However, the intravenously injected exosomes could be abundantly tracked in other organs except for the targeted regions in the brain. Here, we proposed the use of central nervous system-specific rabies viral glycoprotein (RVG) peptide to target intravenously-infused exosomes derived from MSCs (MSC-Exo) to the brain of transgenic APP/PS1 mice. MSC-Exo were conjugated with RVG through a DOPE-NHS linker. RESULTS: RVG-tagged MSC-Exo exhibited improved targeting to the cortex and hippocampus after being administered intravenously. Compared with the group administered MSC-Exo, in the group administered RVG-conjugated MSC-Exo (MSC-RVG-Exo) plaque deposition and Aß levels were sharply decreased and activation of astrocytes was obviously reduced. The brain targeted exosomes derived from MSCs was better than unmodified exosomes to improve cognitive function in APP/PS1 mice according to Morris water maze test. Additionally, although MSC-Exo injected intravenously reduced the expression of pro-inflammatory mediators TNF-α, IL-ß, and IL-6, but the changes of anti-inflammatory factors IL-10 and IL-13 were not obvious. However, administration of MSC-RVG-Exo significantly reduced the levels of TNF-α, IL-ß, and IL-6 while significantly raised the levels of IL-10, IL-4 and IL-13. CONCLUSIONS: Taken together, our results demonstrated a novel method for increasing delivery of exosomes for treatment of AD. By targeting exosomes to the cortex and hippocampus of AD mouse, there was a significant improvement in learning and memory capabilities with reduced plaque deposition and Aß levels, and normalized levels of inflammatory cytokines.

Activating transcriptional factor 4 correlated with obesity and insulin resistance in polycystic ovary syndrome.

PCOS is a systemic disorder that is commonly characterized by insulin resistance (IR). ATF4 participates in the regulation of energy homeostasis and glucose metabolism, but its role in PCOS remains unclear. In this study, we found that ATF4 was highly expressed in human granulosa cells (hGCs) of PCOS patients with obesity and IR. Thus, we performed Spearman's correlation analysis to further investigate the correlation between ATF4 expression and obesity, lipometabolic disorders, or IR in PCOS. We found that increased ATF4 was an important trigger for lipid accumulation and abnormal insulin signal transduction in PCOS. In cultured KGN cells, insulin positively regulated the mRNA and protein abundance of ATF4. Overexpression of ATF4 significantly impaired insulin-stimulated phosphorylation of AKT. Collectively, our findings provided a novel insight into the molecular mechanisms underlying the occurrence and development of PCOS, implying that ATF4 may be a new molecular target for PCOS therapy.

A Tunable Optical Bragg Grating Filter Based on the Droplet Sagging Effect on a Superhydrophobic Nanopillar Array.

Nanostructures have been widely applied on superhydrophobic surfaces for controlling the wetting states of liquid microdroplets. Many modern optic devices including sensors are also integrated with micro- or nanostructures for function enhancement. However, it is rarely reported that both microfluidics and optics are compatibly integrated in the same nanostructures. In this paper, a novel microfluidic-controlled tunable filter composed of an array of periodic micro/nanopillars on top of a planar waveguide is proposed and numerically simulated, in which the periodic pillars endow both the Bragg grating and the superhydrophobic functions. The tunability of grating is achieved by controlling the sagging depth of a liquid droplet into the periodic pillars. Simulation results show that a narrow bandwidth of 0.4 nm and a wide wavelength tuning range over 25 nm can be achieved by such a microfluidic-based tunable optofluidic waveguide Bragg grating filter. Moreover, this proposed scheme can be easily modified as a refractive index sensor with a sensitivity of 103 nm per refractive index unit.