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Nerve growth factor (NGF) plays an important role in regulating the hypothalamus-pituitary-gonadal (HPG) axis. However, the effects of NGF on spermatogenesis remain unclear. This study aimed to assess the potential application of NGF with nasal delivery on spermatogenesis in azoospermic mice. We established a model with azoospermia induced by a single intraperitoneal (i.p.) injection of busulfan. NGF pre-encapsulated with liposomes (25, 50, and 100 μg/kg) was delivered via internasal administration. Three weeks after busulfan injection, NGF treatments were performed twice a week for 8 weeks; the change of sperm quality, testis and epididymis histopathology, and androgenic hormone were analyzed to evaluate sperm regeneration. Furthermore, 30 mg/kg busulfan injection caused severe testicular atrophy of the seminiferous tubules, characterized by a loss of spermatogenic elements and sperms. NGF with nasal administration could significantly upregulate the markers expressing meiotic spermatogonia (Stra8) and spermatocytes (SYCP3), restore spermatogenesis, and improve sperm quality in busulfan-treated mice by increasing the secretion of sexual hormones. The convenient and noninvasive nasal delivery of NGF may be a new potential therapy for spermatogenesis via activating the HPG axis and elevating androgenic hormones. This study opened a new horizon for NGF application in reproductive endocrine.

A predominant trigger and driver of sporadic Alzheimer’s disease (AD) is the synergy of brain oxidative stress and glucose hypometabolism starting at early preclinical stages. Oxidative stress damages macromolecules, while glucose hypometabolism impairs cellular energy supply and antioxidant defense. However, the exact cause of AD-associated glucose hypometabolism and its network consequences has remained unknown. Here we report NADPH oxidase 2 (NOX2) activation as the main initiating mechanism behind Aβ1-42-related glucose hypometabolism and network dysfunction. We utilize a combination of electrophysiology with real-time recordings of metabolic transients both ex- and in-vivo to show that Aβ1-42 induces oxidative stress and acutely reduces cellular glucose consumption followed by long-lasting network hyperactivity and abnormalities in the animal behavioral profile. Critically, all of these pathological changes were prevented by the novel bioavailable NOX2 antagonist GSK2795039. Our data provide the first direct experimental evidence for causes and consequences of AD-related brain glucose hypometabolism, and suggest that targeting NOX2-mediated oxidative stress is a promising approach to both the prevention and treatment of AD.Single sentence summaryBeta-amyloid induces brain hypometabolism, network hyperactivity, and behavioral changes via NADPH oxidase-mediated oxidative stress, suggesting a novel therapeutic target for Alzheimer’s disease treatment.

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the United States. In spite of evidence of females having a greater lifetime risk of developing Alzheimer’s Disease (AD) and greater apolipoprotein E4-related (APOE ε4) AD risk compared to males, molecular signatures underlying these differences remain elusive.Methods: We took a meta-analysis approach to study gene expression in the brains of 1,084 AD patients and age-matched controls and whole blood from 645 AD patients and age-matched controls in seven independent datasets. Sex-specific gene expression patterns were investigated through use of gene-based, pathway-based and network-based approaches. The ability of a sex-specific AD gene expression signature to distinguish Alzheimer’s disease from healthy controls was assessed using a linear support vector machine model. Cell type deconvolution from whole blood gene expression data was performed to identify differentially regulated cells in males and females with AD.Results: Strikingly gene-expression, network-based analysis and cell type deconvolution approaches revealed a consistent immune signature in the brain and blood of female AD patients that was absent in males. In females, network-based analysis revealed a coordinated program of gene expression involving several zinc finger nuclease genes related to Herpes simplex viral infection whose expression was modulated by the presence of the APOE ε4 allele. Interestingly, this gene expression program was missing in the brains of male AD patients. Cell type deconvolution identified an increase in neutrophils and naïve B cells and a decrease in M2 macrophages, memory B cells, and CD8+ T cells in AD samples compared to controls in females. Interestingly, among males with AD, no significant differences in immune cell proportions compared to controls were observed. Machine learning-based classification of AD using gene expression from whole blood in addition to clinical features produced an improvement in classification accuracy upon stratifying by sex, achieving an AUROC of 0.91 for females and 0.80 for males.Conclusion: These results help identify sex and APOE ε4 genotype-specific transcriptomic signatures of AD and underscore the importance of considering sex in the development of biomarkers and therapeutic strategies for AD.

In steroidogenic cells, steroids are synthesized de novo from cholesterol stored in lipid droplets (LDs). The size of LDs regulated by adipose differentiation-related protein (ADRP) is closely related to cholesterol ester hydrolysis. Many studies reported that cadmium (Cd) had dual effects on steroidogenesis in granulosa cells (GCs). However, the role of LD and its regulation in abnormal steroidogenesis caused by Cd exposure remain unknown. In current study, female rats were exposed to CdCl2 during gestation and lactation, and influence of such exposure was investigated in ovarian GCs of female offspring. The size of LDs was found much smaller than normal in GCs; ADRP was down-regulated and hormone-sensitive lipase (HSL) phosphorylation was increased, followed by up-regulation of steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (CYP11A1); the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 (PLCβ2) and protein kinase C alpha type (PKCα) were both decreased accompanying the ADRP down-regulation. This series of events resulted in a high level of progesterone in serum. Similar results were demonstrated in GCs treated with 20 μM CdCl2 for 24 h in vitro. The protein level of ADRP was decreased after gene silencing of PLCβ2/PKCα, and the knockdown of PLCβ2/PKCα/ADRP led to micro-sized LD formation. We found that Cd exposure down-regulated ADRP by inhibiting the PLCβ2-PKCα signaling pathway, reduced the size of LDs, and promoted HSL phosphorylation. StAR and CYP11A1 were both up-regulated following the hydrolysis of cholesterol ester, which led to a high production of progesterone. LD thereby is a target subcellular organelle for Cd to affect steroid hormone synthesis in ovarian GCs. These findings might help to uncover the mechanism of ovarian dysfunction and precocious puberty caused by Cd pollution.

Understanding why adult hippocampal neurogenesis (AHN) is impaired in Alzheimer's disease (AD) is essential for unravelling its role in pathogenesis. In this issue of Cell Stem Cell, Zheng et al. (2020) report that human tau accumulation in dentate gyrus GABAergic interneurons disrupts AHN and strengthening GABAergic signaling restores AHN and improves cognition in an AD mouse model.

Despite its clear impact on Alzheimer’s Disease (AD) risk, apolipoprotein (apo) E4’s contributions to AD etiology remain poorly understood. Progress in answering this and other questions in AD research has been limited by an inability to model human-specific phenotypes in an in vivo environment. Here we transplanted human induced pluripotent stem cell derived neurons carrying normal apoE3 or pathogenic apoE4 into human apoE3 or apoE4 knock-in mouse hippocampus, enabling us to disentangle the effects of apoE4 produced in human neurons and in the brain environment. Using single nucleus RNA-sequencing, we identified key transcriptomic differences between human and mouse neurons, as well as transcriptional changes specific to human neuron subtypes, in response to apoE4 . We also found A β from transplanted human neurons formed plaque-like aggregates, with differences in localization and interaction with microglia depending on the transplant and host apoE genotype, again highlighting the power of chimeric modeling for studying AD.

Background Nerve growth factor (NGF) plays essential roles in regulating the development and maintenance of central sympathetic and sensory neurons. However, the effects of NGF on hypogonadism remain unexplored. Methods To assess the effects of NGF on hypogonadism, we established a convenient and noninvasive way to deliver NGF to the hypothalamus by spraying liposome-encapsulated NGF into the nasal cavity. The ten-month-old aging male senescence accelerate mouse P8 (SAMP8) mice with age-related hypogonadotrophic hypogonadism were used to study the role of NGF in hypogonadism. The age-matched accelerated senescence-resistant mouse R1 (SAMR1) served as a control. The ten-month-old SAMP8 mice were treated with NGF twice per week for 12 weeks. Sexual hormones, sexual behaviors, and fertility were analyzed after NGF treatment. And the mechanisms of NGF in sex hormones sexual function were also studied. Findings NGF could enhance the sexual function, improve the quality of the sperm, and restore the fertility of aging male SAMP8 mice with age-related hypogonadism by activating gonadotropin-releasing hormone (GnRH) neuron and regulating secretion of GnRH. And NGF regulated the GnRH release through the PKC/p-ERK1/2/p-CREB signal pathway. Interpretation These results suggest that NGF treatment could alleviate various age-related hypogonadism symptoms in male SAMP8 and may be usefulness for age-related hypogonadotrophic hypogonadism and its related subfertility. Fund National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, the Science and Technology Plan Project of Guangzhou, Wenzhou Science & Technology Bureau, Guangdong Province Pearl River Scholar Fund, Guangdong province science and technology innovation leading Scholar Fund.

The current production of agricultural products has some problems, such as poor customized service, difficulty in quality control and high wastage in production process. Based on the technology of Internet of Things (IoT), artificial intelligence and blockchains, this paper designs an smart precision agricultural system called Agricultural Computer, which can realize the holographic, automatic and intelligent production of agricultural products. The system can solve the separation of information collection, processing and application in agricultural production, so it can supplement corresponding nutrients according to the physiological needs of plants. The system realizes the standardization, precision and intelligence of agricultural production, improves the quality of agricultural products, promotes the greening and high quality of agricultural production, and meets the needs of consumers for personalized and healthy consumption.

Cavitation characteristics in the wake of a circular cylinder, which contains multiscale vortices, are numerically investigated via Large Eddy Simulation (LES) in this paper. The Reynolds number is 9500 based on the inlet velocity, the cylinder diameter and the kinematic viscosity of the noncavitation liquid. The Schneer–Sauer (SS) model is applied to cavitation simulation because it is more sensitive to vapor–liquid two-phase volume fraction than the Zwart–Gerber–Belamri (ZGB) model, according to theoretical analyses. The wake is quasiperiodic, with an approximate frequency of 0.2. It is found that the cavitation of vortices could inhibit the vortex shedding. Besides, the mutual aggregation of small-scale vortices in the vortex system or the continuous stripping of small-scale vortices at the edge of large-scale vortices could induce the merging or splitting of cavities in the wake.

Back-layering length and critical velocity are important parameters in longitudinally ventilated tunnel fires. The present study explored the effects of tunnel aspect ratios on smoke back flow by scale model tests and theoretical analyses. Results show that the increase of the tunnel width will enhance the heat transfer between the smoke and the tunnel boundaries and decrease the smoke layer thickness, reducing the back-layering length and critical velocity. New correlations to predict back-layering length and critical velocity with more comprehensive physical significance were proposed by improving the aspect ratio correction coefficient. The prediction results of the model are in good agreement with the experimental data. The new model indicates that under small fire conditions, non-dimensional critical velocity gradually decreases as the aspect ratio increases and eventually approaches a limiting value, which is the critical velocity without sidewall constraints. The determination of the fire scale relies on the aspect ratio when non-dimensional heat release rate Q* is lower than 0.44. In contrast, the fire is always a large one when Q* is larger than 0.44.

Specific classes of GABAergic neurons play specific roles in regulating information processing in the brain. In the hippocampus, two major classes – parvalbumin-expressing (PV(+)) and somatostatin-expressing (SST(+)) – differentially regulate endogenous firing patterns and target subcellular compartments of principal cells. How these classes regulate the flow of information throughout the hippocampus is poorly understood. We hypothesize that PV(+) and SST(+) interneurons in the dentate gyrus (DG) and CA3 differentially modulate CA3 patterns of output, thereby altering the influence of CA3 on CA1. We find that while suppressing either interneuron class increases DG and CA3 output, the effects on CA1 were very different. Suppressing PV(+) interneurons increases local field potential signatures of coupling from CA3 to CA1 and decreases signatures of coupling from entorhinal cortex to CA1; suppressing SST(+) interneurons has the opposite effect. Thus, DG and CA3 PV(+) and SST(+) interneurons bidirectionally modulate the flow of information through the hippocampal circuit.

The temperature distribution characteristics in tunnel fire scenarios are not only crucial for evaluating the hot damage of tunnel structure, but also pivotal fundation to study the smoke kinetic characteristics. In the present work, the scaled-model tests and the CFD simulations were adopted to investigate the effects of aspect ratio, longitudinal ventilation velocity and fire heat release rate on smoke temperature decay characteristics at both transverse and longitudinal directions in tunnel fires. Results indicate that: Tunnel aspect ratio has a significant influence on smoke temperature rate at both transverse and longitudinal directions. The increase of aspect ratio will increase the contact area between the smoke layer and the ceiling, enhancing the heat loss of the smoke backflow layer. As a result, smoke temperature decays faster in a wide-shallow cross-section tunnel. The longitudinal temperature decay rate in the wide-shallow tunnel (AR = 9.3) is almost eight times as large as that in the normal tunnel (AR = 1.1). The increase of fire heat release rate will reduce the smoke temperature decay rate at both transverse and longitudinal direction; As the ventilation velocity increases, the longitudinal temperature decay rate increases while the transverse temperature decay rate decreases. The definition of smoke backflow ratio was proposed to establish the fire smoke temperature decay model of the smoke backflow layer, which considers the effects of aspect ratio, longitudinal ventilation velocity and fire heat release rate. By comparing the test results in previous research work, the new model shows relatively good applicability in the full-scaled tunnel and is valid for a wide range of testing conditions.

Timely and proper backfilling of open-pits in strip coal-mines has been an effective measurement for the recovery of the hydrothermal regimes and ecological environment in permafrost regions. In this study, numerical simulations and statistical regressions were applied for analyzing the recovery processes of the backfill and its major influencing factors for the thermal equilibrium in recently backfilled open pits at the Gulian strip coalmine in Mo'he, Northeast China. Results show that the thermal recovery time of backfilled areas is positively correlated to the backfill depth (BD) of the soils, the backfilled soil temperature (BST), and the mean annual ground surface temperature (MAGST); meanwhile, climate warming can impact on thermal regimes of the backfill area. The impact of climate warming on ground temperature of the backfill will show up significantly in about 50 years after backfilling (BD at 10.0 and 20.0 m, BST at 20.0°C) under the climate warming scenario (CWS) of 0.025°C·year−1. Grey-relation analyses show that the sensitivity of the backfill recovery time declines in the order of the BD, BST and MAGST. On the basis of the abovementioned studies, the layer-by-layer backfilling in cold seasons is advised for more effective and more rapid recovery of thermal regimes of the backfilled open-pits in cold regions.

Study of climatic evolution in the source area of the Yellow River (SAYR) and its mechanisms is of significance for understanding and predicting the climate and environmental changes and permafrost evolution on the northeastern Tibetan Plateau (TP). This study reconstructed the Asian monsoon and climatic evolution in SAYR since 6.1 cal (cal = the calendar year, as below) ka BP in the mid-late Holocene using geochemical parameters (i.e., SiO2/[RO+R2O], SiO2/Al2O3, SiO2/TiO2, SiO2/[Al2O3 + Fe2O3], chemical index of alteration (Al2O3/[Al2O3 + CaO* + Na2O + K2O]), chemical index of weathering (Al2O3/[Al2O3 + CaO* + Na2O]), [CaO + K2O + Na2O]/Al2O3 and K/Na ratios) of peat deposits and AMS 14C chronology. The climate was warm and humid between 6.1 and 5.4 cal ka BP, with weak winter monsoon intensity and strong summer monsoon intensity, and accompanied by strong chemical weathering and leaching. From 5.4 to 1.5 cal ka BP, the climate was relatively cold and dry with enhanced winter monsoon and weakened summer monsoon intensities. During 1.5 and 0.8 cal ka BP, with the winter and summer monsoon changing rapidly, lower winter monsoon intensity, higher summer monsoon intensity, and higher chemical weathering and leaching since 6.1 cal ka BP indicated a warm and humid regional climate. It has been relatively cold and dry as a whole, with a trend of being warm and wet, since 0.8 cal ka BP, accompanied by gradually weakened winter monsoon intensity, gradually enhanced summer monsoon intensity, and gradually enhanced chemical weathering and leaching. The Asian monsoon and climatic evolution process in SAYR is highly unstable and has undergone centennial–millennial scale oscillations since 6.1 cal ka BP. Also, six phases at 6.1–5.9, 4.5–4.2, 2.7–2.4, 1.9–1.7, 1.5–1.4, and 0.6–0.4 cal ka BP correspond with cold events recorded by peat and lacustrine deposits and ice cores on the northeastern and eastern TP and with deep-sea sediments in high-latitude regions in the Northern Hemisphere. The results show that climate change in SAYR on the northeastern TP has been consistent with global climate change since the mid-late Holocene.

The food contaminant acrylamide (AA) is usually recognized as a probable human carcinogen. In addition, AA has also been found able to induce male infertility in animals. Interestingly, resent research work revealed that the toxic effect of AA on the ability of male reproduction in vivo may due to glycidamide (GA) which is the metabolite of AA. In this study, R2C Leydig cells was used to investigate the toxic effects of GA on progesterone production. GA caused dose-dependent inhibition on the cell growth, with IC25, IC50, and IC75 values found at 0.635, 0.872, and 1.198 mM, respectively. The results of single cell gel/Comet assay showed that GA significantly induced early-phase cell apoptosis, reduced progesterone production, as well as decreasing the protein expression of steroidogenic acute regulatory (StAR) in R2C cells. Furthermore, GA induced overproduction of intracellular reactive oxygen species (ROS), upregulated Bax expression, decreased mitochondrial membrane potential, and triggered mitochondria-mediated cell apoptosis. Consequently, the downstream effector caspase-3 was activated, resulting in Leydig cells apoptosis. Overall, our results showed that GA could damage R2C Leydig cells by the lesion of the ability of progesterone genesis and inducing cells apoptosis.

Purpose Material conscious and information network (MCIN) is a kind of cyber physics social system. This paper aims to study the MCIN modeling method and design the MCIN-based architecture of smart agriculture (MCIN-ASA) which is different from current vertical architecture and involves production, management and commerce. Architecture is composed of three MCIN-ASA participants which are MCIN-ASA enterprises, individuals and commodity. Design/methodology/approach Architecture uses enterprises and individuals personalized portals as the carriers which are linked precisely with each other through a peer-to-peer network called six-degrees-of-separation block-chain. The authors want to establish a self-organization, open and ecological operational system which includes active, personalized consumption, direct, centralized distribution, distributed and smart production. Findings The paper models three main MCIN-ASA participants, namely, design the smart supply, demand and management functions, which show the feasibility innovation and high efficiency of implementing MCIN on agriculture. At the same time, the paper presents a prototype system based on the architecture. Originality/value The authors think that MCIN-ASA improves current agriculture greatly and inspires a lot in production-marketing-combined electronic commerce.

Acid fibroblast growth factor (aFGF) has shown neuroprotection in Alzheimer’s disease (AD) models in previous studies, yet its mechanism is still uncertain. Here we report that the efficacy of Tat-haFGF14–154 is markedly increased when loaded cationic liposomes for intranasal delivery are intranasally administered to APP/PS1 mice. Our results demonstrated that liposomal Tat-haFGF14–154 treatment significantly ameliorated behavioral deficits, relieved brain Aβ burden, and increased the expression and activity of disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in the brain. Tat-haFGF14–154 antagonized Aβ1–42-induced cell death and structural damage in rat primary neurons in an ADAM10-dependent manner, which, in turn, was promoted by the activation of XBP1 splicing and modulated by the PI3K-CREB pathway. Both knockdown of ADAM10 and inhibition of PI3K (LY294002) negated Tat-haFGF14–154 rescue. Thus, Tat-haFGF14–154 activates the IRE1α/XBP1 pathway of the unfolded protein response (UPR) against the endoplasmic reticulum (ER) stress induced by Aβ, and, subsequently, the nuclear translocation of spliced XBP1 (XBP1s) promotes transcription of ADAM10. These results highlight the important role of ADAM10 and its activation through the PI3K-CREB-IRE1α/XBP1 pathway as a key factor in the mechanism of neuroprotection for Tat-haFGF14–154.

Purpose The purpose of this paper is to study the architecture of holographic personalized portal, user modeling, commodity modeling and intelligent interaction. Design/methodology/approach In this paper, the authors propose crowd-science industrial ecological system based on holographic personalized portal and its interaction. The holographic personality portal is based on holographic enterprises, commodities and consumers, and the personalized portal consists of accurate ontology, reliable supply, intelligent demand and smart cyberspace. Findings The personalized portal can realize the information acquisition, characteristic analysis and holographic presentation. Then, the intelligent interaction, e.g. demand decomposition, personalized search, personalized presentation and demand prediction, will be implemented within the personalized portal. Originality/value The authors believe that their work on intelligent interaction based on holographic personalized portal, which has been first proposed in this paper, is innovation focusing on the interaction between intelligence and convenience.

Highlight Barley HvUGT13248 catalyzes conversion of nivalenol (NIV) to its non-toxic form 3-O-glucoside, and in transgenic wheat confers resistance to NIV-producing Fusarium graminearum, Fusarium Head Blight is a disease of cereal crops that causes severe yield losses and mycotoxin contamination of grain. The main causal pathogen, Fusarium graminearum, produces the trichothecene toxins deoxynivalenol or nivalenol as virulence factors. Nivalenol-producing isolates are most prevalent in Asia but co-exist with deoxynivalenol producers in lower frequency in North America and Europe. Previous studies identified a barley UDP-glucosyltransferase, HvUGT13248, that efficiently detoxifies deoxynivalenol, and when expressed in transgenic wheat results in high levels of type II resistance against deoxynivalenol-producing F. graminearum. Here we show that HvUGT13248 is also capable of converting nivalenol into the non-toxic nivalenol-3-O-β-d-glucoside. We describe the enzymatic preparation of a nivalenol-glucoside standard and its use in development of an analytical method to detect the nivalenol-glucoside conjugate. Recombinant Escherichia coli expressing HvUGT13248 glycosylates nivalenol more efficiently than deoxynivalenol. Overexpression in yeast, Arabidopsis thaliana, and wheat leads to increased nivalenol resistance. Increased ability to convert nivalenol to nivalenol-glucoside was observed in transgenic wheat, which also exhibits type II resistance to a nivalenol-producing F. graminearum strain. Our results demonstrate the HvUGT13248 can act to detoxify deoxynivalenol and nivalenol and provide resistance to deoxynivalenol- and nivalenol-producing Fusarium.

Apoptosis and autophagy play crucial roles during Bombyx mori metamorphosis and in response to various adverse conditions, including starvation. Recently, calpain, one of the major intracellular proteases, has been reported to be involved in apoptosis and autophagy in mammals. BmATG5 and BmATG6 have been identified to mediate apoptosis following autophagy induced by 20-hydroxyecdysone and starvation in B. mori. However, B. mori calpains and their functions remain unclear. In this study, phylogenetic analysis of calpains from B. mori, Drosophila melanogaster and Homo sapiens were performed and the results showed distinct close relationships of BmCalpain-A/B with DmCalpain-A/B, BmCalpain-C with DmCalpain-C, and BmCalpain-7 with HsCalpain-7. Then, the expression profiles of BmCalpains were analyzed by quantitative real-time polymerase chain reaction, and results showed that expression of BmCalpain-A/B, BmCalpain-C and BmCalpain-7 was significantly increased during B. mori metamorphosis and induced in the fat body and midgut of starved larvae, which is consistent with the expression profiles of BmAtg5, BmAtg6 and BmCaspase-1. Moreover, the apoptosis-associated cleavage of BmATG6 in Bm-12 cells was significantly enhanced when BmCalpain-A/B and BmCalpain-7 were induced by starvation, and was partially inhibited by the inhibitor of either calpain or caspase, but completely inhibited when both types of inhibitors were applied together. Our results indicated that BmCalpains, including BmCalpain-A/B, -C and -7, may be involved in autophagy and apoptosis during B. mori metamorphosis and after starvation, and may also contribute to the apoptosis-associated cleavage of BmATG6.

In the last decade, as an emerging transaction measure driven by computer and internet technology, e-commerce experienced explosive growth in many areas. It has greatly broken down the limitations of space and time to economic activities, thus changing the rules of business fundamentally. Significant work has been done to understand the laws of e-commerce from multiple dimensions, but the question of how e-commerce shapes firms' specialization and market structure from the perspective of spatial factors remains obscure. In this paper, we propose a simple and symmetric firm resource allocation model with a specialized-economy production function and market size constraint, to investigate how individual firms adjust resource allocation with reachable transaction scope expanded. It is shown that with the expansion of reachable transaction scope, individual firms discretely take back one unit resource from a low-investment direction and, instead, channel it to a “specialized direction”. Meanwhile, at the macro level, an optimal division network evolves from a static self-sufficient stage to a diverse semi-specialized stage, and finally to a highly integrated completely specialized stage. Ergo, a Complex Adaptive System (CAS) based simulation framework is constructed. Designed simulation experiments are carried out and confirm to the analysis result of our proposed model.

Summary Leydig cells (LCs) play crucial roles in producing testosterone, and their dysfunction leads to male hypogonadism. LC transplantation is a promising alternative therapy for male hypogonadism. However, the source of LCs limits this strategy for clinical applications. Here, we report our success in reprogramming mice fibroblasts into LCs by expressing three transcriptional factors, Dmrt1, Gata4, and Nr5a1. The induced Leydig-like cells (iLCs) expressed steroidogenic genes, had a global gene expression profile similar to that of adult LCs, and acquired androgen synthesis capabilities. When iLCs were transplanted into rats or mice testes that were selectively depleted of endogenous LCs, the transplanted cells could survive and function in the interstitium of testis, resulting in the restoration of normal levels of serum testosterone. These findings demonstrate that the fibroblasts were able to be directly converted into iLCs by few defined factors, which may facilitate future applications in regenerative medicine., Graphical Abstract, Highlights • Direct reprogramming of fibroblasts into Leydig cell fate by defined factors • Induced Leydig-like cells (iLCs) exhibit adult Leydig cell characterizations • Conversion process toward iLCs did not pass through a mitotic cell state • Transplantation of iLCs could survive and function in the interstitium of testis, In this article, Huang, Su, and colleagues show that a cocktail of transcriptional factors can drive direct lineage reprogramming of mouse fibroblasts into functional Leydig cells (iLCs) which exhibit adult Leydig cell characterizations and acquired androgen synthesis capabilities. Furthermore, iLCs could restore testosterone levels of testosterone-deficient rodents when transplanted into rats or mice testes.

Instability of a wake controlled by a streamwise Lorentz force is investigated through a Floquet stability analysis. The streamwise Lorentz force, which is a two-dimens- ional control input created by an electromagnetic actuator located on the cylinder surface, adjusts the base flow to affect the three-dimensional wake instability and achieve wake stabilization and transition delay. The instability mode at a Reynolds number Re = 300 can be transformed from B to A with N = 1.0, where N is an interaction number repre- senting the strength of the Lorentz force relative to the inertial force in the fluid. The wake flow is Floquet stable when N increases to 1.3. The spanwise perturbation wavelengths are 3.926D and 0.822D in the modes A and B, respectively, where D is the cylinder diameter. In addition, the oscillating amplitudes of drag and lift are reduced with the increase in the interaction number. Particle tracing is used to explore the essential physical mechanism for mode transformation. The path lines show that suppression of flow separation hinders the fluid deformation and rotation, leading to the decrease in elliptic and hyperbolic instability regions, which is the material cause of mode transformation. All of the results indicate that wake stabilization and transition delay can be achieved under open-loop active control via the streamwise Lorentz force.

SUMMARY Alzheimer’s disease (AD) is characterized by progressive memory loss, and there is a pressing need to identify early pathophysiological alterations that predict subsequent memory impairment. Hippocampal sharp-wave ripples (SWRs)—electrophysiological signatures of memory reactivation in the hippocampus—are a compelling candidate for this purpose. Mouse models of AD show reductions in both SWR abundance and associated slow gamma (SG) power during aging, but these alterations have yet to be directly linked to memory impairments. In aged apolipoprotein E4 knockin (apoE4-KI) mice—a model of the major genetic risk factor for AD—we find that reduced SWR abundance and associated CA3 SG power predicted spatial memory impairments measured 1–2 months later. Importantly, SWR-associated CA3 SG power reduction in young apoE4-KI mice also predicted spatial memory deficits measured 10 months later. These results establish features of SWRs as potential functional biomarkers of memory impairment in AD., Graphical Abstract, In Brief Currently, there are no functional biomarkers that can predict progression to Alzheimer’s disease before cognitive decline begins. Jones et al. demonstrate that sharp-wave ripple and associated slow gamma deficits predict memory impairments in aged apoE4 mice. Slow gamma deficits in young apoE4 mice predict memory impairment onset 10+ months later.

With the popularization and application of big data technology and artificial intelligence technology, great breakthroughs have been made in the field of e-commerce. While, there are imperfections of user demand for major e-commerce platforms, for instance, incomplete expression of demand, difficult to deal with the voice input, difficult to deal with the fuzzy demand, unsustainable acquisition of demand. In this paper, a method of acquiring accurate information from fuzzy demand is proposed. This method is suitable for scenarios with fuzzy voice input, which makes up for the shortcomings of the existing e-commerce platform. It can help to reduce the expression burden on demand of transaction subject, also it meets his/her personalized needs with accurate recognition results. Furthermore, it enhances the experience of the transaction subject with flexible and controllable interaction methods.

With the application of information technology, biotechnology, remote sensing technology, etc, great breakthroughs have been made in the field of environmental protection. While there are still problems within existing environmental protection system, such as the hardware fraud and software fraud of environmental data. In this paper, an environmental monitoring system based on blockchain is proposed, within which the environmental data of the whole network is unified and data processing, consensus and pubilcation requrie multiparty anthentication. As a result, falsification of environmental data will be prevented by adopting the proposed system. In addition, three-dimensional enviromental monitoring architecture and intelligent trusted device are propoed, which can ensure the integrety and originity of the environmental data collected by the devices.

Due to the stringent quality requirements imposed by the US malting barley industry, barley breeders have been reluctant to introduce exotic germplasm into cultivar development programs. To determine whether wild barley (Hordeum vulgare ssp. spontaneum) contains favorable alleles for yield and malting quality characteristics, we mapped quantitative trait loci (QTL) for heading date, height, lodging, yield, and nine malting parameters important to the malting and brewing industry. Traits were mapped in a wild x cultivated barley BC2-derived advanced backcross mapping population. Harrington, the recurrent parent, is a North American two-rowed malting barley cultivar, and OUH602, the donor parent, is a wild barley accession that exhibits resistance to multiple barley diseases. The 98 derived lines were grown in replicated field trials at St. Paul and Crookston, MN in 2009–2011. One to four QTL were identified for each trait, for a total of 36 QTL. Trangressive segregants for increased yield were identified and four lines had higher yield than Harrington across all environments; however, for yield QTL the OUH602 alleles decreased the trait value. Wild barley alleles had both positive and negative effects on the malting traits of diastatic power, free amino nitrogen, and soluble protein. Combined with the previously identified QTL associated with resistance to fungal diseases, this population represents a rich resource for barley breeding. To facilitate future breeding and genetics studies with this population, a set of pre-introgression lines composed of 28 BC2-derived and 6 BC3-derived lines were identified that collectively contain introgressions across the entire OUH602 genome.

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer’s disease (AD), increasing risk and decreasing age of disease onset. Many studies have demonstrated the detrimental effects of apoE4 in varying cellular contexts. However, the underlying mechanisms explaining how apoE4 leads to cognitive decline are not fully understood. Recently, the combination of human induced pluripotent stem cell (hiPSC) modeling of neurological diseases in vitro and electrophysiological studies in vivo have begun to unravel the intersection between apoE4, neuronal subtype dysfunction or loss, subsequent network deficits, and eventual cognitive decline. In this review, we provide an overview of the literature describing apoE4’s detrimental effects in the central nervous system (CNS), specifically focusing on its contribution to neuronal subtype dysfunction or loss. We focus on γ-aminobutyric acid (GABA)-expressing interneurons in the hippocampus, which are selectively vulnerable to apoE4-mediated neurotoxicity. Additionally, we discuss the importance of the GABAergic inhibitory network to proper cognitive function and how dysfunction of this network manifests in AD. Finally, we examine how apoE4-mediated GABAergic interneuron loss can lead to inhibitory network deficits and how this deficit results in cognitive decline. We propose the following working model: Aging and/or stress induces neuronal expression of apoE. GABAergic interneurons are selectively vulnerable to intracellularly produced apoE4, through a tau dependent mechanism, which leads to their dysfunction and eventual death. In turn, GABAergic interneuron loss causes hyperexcitability and dysregulation of neural networks in the hippocampus and cortex. This dysfunction results in learning, memory, and other cognitive deficits that are the central features of AD.

The flame retardancy of asphalt binders with layered double hydroxides (LDHs) was investigated using limiting oxygen index (LOI) and cone calorimeter tests. The flame-retardant mechanism of the LDHs was also studied with thermogravimetry and differential scanning calorimetry (TG&ndash, DSC), scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS). The cone calorimeter testing results indicated that 2 wt.% of the LDHs can decease the peak heat and smoke release rate of asphalt binders. Because a low dose of LDHs can be well dispersed in asphalt binder and favor the formation of polyaromatic structures during combustion, the thermal oxidation resistance and compactness of the char layer can be improved. The LOI of asphalt binder can be increased and the heat and smoke release during combustion can be decreased with 25 wt.% LDHs. The decomposition of LDHs can absorb the heat release of the initial two stages of asphalt combustion and reduce the burning rate of asphalt. Due to the loss of loosely bound water in the LDHs during the blending process and the decrease of dispersibility at a high LDH dose, the improvement of thermal stability is limited.

The aim of the present study was to identify microRNAs (miRNAs) that regulate the proliferation and differentiation of Leydig cells (LCs) of rat. Three small RNA libraries derived from progenitor LCs (PLCs), immature LCs (ILCs) and adult LCs (ALCs) were analyzed by microarrays. In total, 68 differentially expressed miRNAs (DEMs) were identified. Based on the trend of DEM expression from PLCs to ALCs, primary LCs were transfected with miRNA mimics or inhibitors. Five miRNAs (miR-30a-5p, miR-3585-5p, miR-212-3p, miR-369-5p and miR-434-3p) promoted PLC proliferation, and 3 miRNAs (miR-17-5p, miR-532-3p and miR-329-3p) activated caspase-3, which triggered LC apoptosis. For steroidogenesis, 18 miRNAs could elevate or inhibit androsterone release at the PLC stage. Eleven and 9 miRNAs inhibited the production of 5α-androstane-3α,17β-diol in ILCs and testosterone in ALCs, respectively. miR-17-5p, miR-29a-3p and miR-299a-5p decreased androgen production by LCs at all developmental stages. Furthermore, the miR-299a-5p-mediated decrease in androgen production by the LC lineage was primarily achieved by downregulating the expression of luteinizing hormone/choriogonadotropin receptor (LHCGR) and 3β-hydroxysteroid dehydrogenase 1 (HSD3B1). These findings provide insights into the regulatory roles of miRNAs during the postnatal development of LCs and suggest potential strategies for the treatment of steroid-related disorders.

Pathogenic variation in MAPT, GRN, and C9ORF72 accounts for at most only half of frontotemporal lobar degeneration (FTLD) cases with a family history of neurological disease. This suggests additional variants and genes that remain to be identified as risk factors for FTLD. We conducted a case-control genetic association study comparing pathologically diagnosed FTLD patients (n = 94) to cognitively normal older adults (n = 3541), and found suggestive evidence that gene-wide aggregate rare variant burden in MFSD8 is associated with FTLD risk. Because homozygous mutations in MFSD8 cause neuronal ceroid lipofuscinosis (NCL), similar to homozygous mutations in GRN, we assessed rare variants in MFSD8 for relevance to FTLD through experimental follow-up studies. Using post-mortem tissue from middle frontal gyrus of patients with FTLD and controls, we identified increased MFSD8 protein levels in MFSD8 rare variant carriers relative to non-variant carrier patients with sporadic FTLD and healthy controls. We also observedan increase in lysosomal and autophagy-related proteins in MFSD8 rare variant carrier and sporadic FTLD patients relative to controls. Immunohistochemical analysis revealed that MFSD8 was expressed in neurons and astrocytes across subjects, without clear evidence of abnormal localization in patients. Finally, in vitro studies identified marked disruption of lysosomal function in cells from MFSD8 rare variant carriers, and identified one rare variant that significantly increased the cell surface levels of MFSD8. Considering the growing evidence for altered autophagy in the pathogenesis of neurodegenerative disorders, our findings support a role of NCL genes in FTLD risk and suggest that MFSD8-associated lysosomal dysfunction may contribute to FTLD pathology.

Glucocorticoids (GCs) metabolism is regulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). When GCs are present in excess, they can impair glucose-dependent insulin sensitivity. We have previously synthesized several curcumin analogues, of which four compounds were selective inhibitors of 11β-HSD1. Here, we present data supporting that the 11β-hydroxysteroid dehydrogenase type 1 inhibitor (H8) inhibits insulin resistance and ameliorates hepatic steatosis in db/db mice. We compared glucose and lipid metabolism in db/db mice with or without administration of H8, which significantly decreased fasting blood glucose levels and protected against insulin resistance and hepatic steatosis compared to when glucose and lipid metabolism were measured following curcumin administration. The hepatic enzyme was reduced significantly in the plasma samples from db/db mice which were treated with H8. Serum corticosterone (active) levels, which are regulated by 11β-HSD1 were reduced when mice received H8. H8 administration suppressed phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6-pase) expression, which are related to gluconeogenesis and enhanced glucose transporter 4 (GLUT4) protein content in liver. Treatment with H8 improved obesity and metabolic disorders, such as insulin resistance and hepatic steatosis by suppressing activity of 11β-HSD1, suggesting that H8 might be a beneficial drug for the treatment of obesity and Type-2 diabetes (T2D).

Cellular reprogramming using chemically defined conditions, without genetic manipulation, is a promising approach for generating clinically relevant cell types for regenerative medicine and drug discovery. However, small-molecule approaches for inducing lineage-specific stem cells from somatic cells across lineage boundaries have been challenging. Here, we report highly efficient reprogramming of mouse fibroblasts into induced neural stem cell-like cells (ciNSLCs) using a cocktail of nine components (M9). The resulting ciNSLCs closely resemble primary neural stem cells molecularly and functionally. Transcriptome analysis revealed that M9 induces a gradual and specific conversion of fibroblasts toward a neural fate. During reprogramming specific transcription factors such as Elk1 and Gli2 that are downstream of M9-induced signaling pathways bind and activate endogenous master neural genes to specify neural identity. Our study provides an effective chemical approach for generating neural stem cells from mouse fibroblasts and reveals mechanistic insights into underlying reprogramming processes.

Neurotoxic amyloid-β (Aβ) peptide causing cognitive function disabilities is one of the most characteristic pathological features in Alzheimer's disease (AD). A novel fusion protein, TAT-haFGF, was administrated to AβPP/PS1 transgenic mice by intravenous (IV) injection and intranasal (IN) delivery, respectively, for 5 weeks to compare the pharmacodynamics between the two routes of administration. Our results showed that IN administration of TAT-haFGF improved cognition and reduced Aβ plaques more significantly in AβPP/PS1 mice, when compared with IV injection. Our new findings suggest that TAT-haFGF might be a promising new therapy to attenuate AD pathological process.

We prepared a cholesterol-conjugated chitosan(CHCS) material and evaluated its potential application as a bone tissue repair material by in vitro cell experiments. Cell proliferation, differentiation and morphology on CHCS membrane surfaces with different graft degrees were assessed in mouse pre-osteoblasts MC3T3-E1 cells. The results indicate that CHCS materials could promote the proliferation of MC3T3-E1 cells at low graft degrees, but the CHCS material with high graft degree inhibits the proliferation of cells in contrast to the pure chitosan membrane. However, the alkaline phosphatase(ALP) activity of MC3T3-E1 cells on different CHCS membrane surface increased with increasing graft degrees of cholesterol. The area of cells stretched onto the surface of CHCS materials was larger than on the surface of CS materials, and more microfilaments and stress fibers in cells were observed on CHCS materials than on the pure chitosan material surface. After 7 d, the expression of related osteogenic marker genes, such as runt-related transcription factor 2(Runx2), osterix(OSX), osteocalcin(OCN), osteopontin(OPN), ALP and collagen I(COL-I) were all up-regulated in CHCS materials to different degrees compared to pure chitosan material, which indicated that the CHCS materials facilitated MC3T3-E1 cell differentiation and maturation. Characterizing CHCS materials is useful in designing and developing strategies for bone tissue engineering.

The Nogo-66 receptor (NgR1), a receptor for Nogo-A, contributes to the inhibition of axonal regeneration in the adult central nervous system after traumatic injuries. Thus, NgR1 has been considered a critical target in axon regeneration therapy. Here, we identified a specific NgR1 antagonist peptide (HIYTALV, named NAP2) which promotes neurite regeneration in vitro from a phage display heptapeptide library. NAP2 was co-localized with NgR1 on the surface of PC12 cells and cerebellar granule cells (CGCs) by immunofluorescence assay. Horseradish peroxidase (HRP)-streptavidin-biotin assay further showed that NAP2 binds to NgR1 and the dissociation constant (Kd) was 0.45 μM Functional analyses indicated that NAP2 could reduce the inhibitory effects of Nogo-66 on neurite outgrowth in differentiated PC12 cells and CGCs by blocking the Nogo-66-induced activation of Rho-associated coiled coil-containing protein kinase (ROCK), collapsin response mediator protein 2 (CRMP2) and myosin light chain (MLC). Taken together, the small molecule NgR1 antagonist peptide NAP2 (MW: 815.98Da) has a potential ability in crossing blood brain barrier and will be a promising therapeutic agent for the treatment of spinal cord injury and neurodegenerative diseases.

Summary Despite its clear impact on Alzheimer’s disease (AD) risk, apolipoprotein (apo) E4’s contributions to AD etiology remain poorly understood. Progress in answering this and other questions in AD research has been limited by an inability to model human-specific phenotypes in an in vivo environment. Here we transplant human induced pluripotent stem cell (hiPSC)-derived neurons carrying normal apoE3 or pathogenic apoE4 into human apoE3 or apoE4 knockin mouse hippocampi, enabling us to disentangle the effects of apoE4 produced in human neurons and in the brain environment. Using single-nucleus RNA sequencing (snRNA-seq), we identify key transcriptional changes specific to human neuron subtypes in response to endogenous or exogenous apoE4. We also find that Aβ from transplanted human neurons forms plaque-like aggregates, with differences in localization and interaction with microglia depending on the transplant and host apoE genotype. These findings highlight the power of in vivo chimeric disease modeling for studying AD.

In permafrost regions, forest fires actively affect physical and chemical properties of soils. Many studies have been conducted on the effects of forest fires on physical and chemical properties of topsoil, while the research on the fire-induced changes in carbon and other nutrients of soils has received much less attention, particularly that of soils in the active layer and near-surface permafrost. Here, using soil samples from two representative areas (Mangui and Alongshan), we investigated the effects of fires on soil nutrients of larch forest soils in the discontinuous permafrost zone in the northern Da Xing’anling (Hinggan) Mountains, Northeast China. The results showed that soil pH increased with fire severity due to the burning of soil organic matter by more severe fires and leaching of base elements in the residual ash into the soil, and; forest fires resulted in a weakly acidic post-fire soil environment. Soil total organic carbon, total nitrogen, and total phosphorus declined with increasing fire severity. A severe burn led to a substantial reduction of soil carbon and nitrogen, which were not recovered seven years after fire. However, there was no substantial change in the C/N ratio. For the two chosen areas, soil C/N ratios decreased with depth. In the first post-fire year, total potassium content increased and were similar at the sites affected by fires of different severity in the area burned seven years ago. There was no significant change in available phosphorus and available potassium. These changes were notable in the active layer and/or organic layers, but not so in the near-surface permafrost layer. Our results suggest that, in permafrost regions, forest fires have important effects on the distribution of soil carbon and other nutrients. This study on the feedback mechanisms between forest fires and nutrients in discontinuous permafrost regions in the northern Da Xing’anling Mountains is of importance for understanding the boreal carbon pool and cycling.

Direct exposure to cadmium (Cd) may induce persistent impairment in learning and memory. However, the outcomes of maternal exposure on the neurological development of offspring are much less clear, and the underlying mechanism leading to toxicity remains undisclosed. Following chronic exposure of female rats during gestation and lactation, low level of Cd was detectable in the cerebral cortex but not in the hippocampus of F1 male offspring. The synapses and neurites in hippocampus were destroyed by high Cd exposure level as evidenced by abnormal morphology and cognitive behavior deficit lasting from childhood to adulthood. The membrane glycoprotein M6a (GPM6A) regulates the filopodium formation, neurite outgrowth and synaptogenesis, and is a possible target which Cd acts upon. The signaling pathway Coronin-1a (CORO1A), Ras-related C3 botulinum toxin substrate 1 (RAC1) and p21-activated kinase 1 (PAK1) promotes GPM6A-induced filopodium formation. Our results showed that maternal exposure dramatically down-regulated the level of CORO1A as well as the expression of downstream effectors RAC1, PAK1 and GPM6A. CORO1A-knockdown by siRNA caused decreases in the expression of RAC1, PAK1 and GPM6A; and siRNA targeting combined with Cd insult further decreased the expression of these proteins. Following CORO1A overexpression, the neurites were lengthened with increased expression of all the effector proteins in SH-SY5Y cells exposed to Cd, confirming the significance of CORO1A in mediating the Cd neurotoxicity. These findings may help to disclose how Cd impairs the learning and cognitive development in children, and facilitate finding of potential therapeutic targets for the treatment of Cd poisoning.

Keratinocyte growth factor −2 promotes corneal repair. Its mechanism of action involves regulating regeneration and migration of corneal cells, as well as activating corneal limbal stem cells. However, KGF-2 being a carcinogenic growth factor and its potential adverse effect in over dosage long-term treatment had not yet been reported. In this study, we used New Zealand white rabbits to study possible toxic effects of ocular administration of recombinant human keratinocyte growth factor-2 eye drops. Animals in the medium- and high-dose groups had some ocular irritant reactions during the course of drug administration; however this reaction was harmless to the cornea and it ended up when administration was stopped. Serum biochemistries were largely unaffected by treatment. Pathological examinations were unremarkable. We found that over-dosed administration of these eye drops caused some ocular irritation, but this irritant reaction was harmless to the eye, and it reversed after the drug was stopped. There were no apparent systemic effects of the drug.

Background The prevalence of tuberculosis (TB) in low and middle-income countries is a significant public health and social concern. TB is a common infectious disease caused by the Mycobacterium tuberculosis infection, which has a widespread infection rate. Health care-seeking delay maybe one of the most important neglected risk factors for the spread of TB. Objectives The aim of this study was to understand the situation of health care-seeking delay among rural tuberculosis patients in Hubei Province, and explore its risk factors. Methods A total of 1408 rural tuberculosis patients were surveyed using a standard structured questionnaire in three cities of Hubei Province during the past two years. Results For the 1408cases of pulmonary tuberculosis, 39.70% of them were health care-seeking delayed. Logistic regressions indicate that the Han nationality, farming careers, the over 45 min walk to the township&rsquo, s hospital, and awareness of the national TB free treatment policy, were significantly associated with higher odds of a delay in care seeking. Conclusions The prevalence of health care-seeking delay among tuberculosis patients was high in rural areas. It is essential to take comprehensive targeted interventions to reduce care-seeking delay.

Similar1 to the economic system of the resource allocation of market and enterprise, distributed ledger technology may support an institutional form between decentralization and centralization, especially the smart contract that runs on it. The smart contract supports a more flexible, de-intermediary economic contractual relationship potentially. So distributed ledger technology can also be considered as an institutional technology [1]. According to the economic method, regarding the transaction cost as the basic unit, based on the technical and business characteristics of the distributed ledger, we analyzed economic contract innovation scenarios of distributed ledgers, and found important institutional features, including de-intermediation, intelligence and miniaturization. In addition, we made a preliminary empirical analysis through decentralized exchanges.

E-commerce1 has experienced great growth during the past two decades, which changes the consumption mode of consumers significantly. All researchers from institutions and enterprises want to identify and satisfy the personalized demand intelligently and conveniently by every possible means. In this paper, we proposed smart demand strategy based on holographic demand and model of transaction subject, which is applicable for the decentralized, disintermediated, intelligent e-commerce platform. User demands are classified from two aspects, which will improve the accuracy of demand obtaining. In addition, from standardized description of demand and full life cycle tracking of demand, the user demand will be identified comprehensively. Meanwhile, models of the user, including physical, preference, knowledge, digital label, and social attributes, are built based on his standard description and fragmented description from his interactive objects, which results in a holographic demander. Then, smart demand strategy, i.e. demand forecast and recommendation are proposed. Based on trigger point and demand attributes, the user demand will be updated in real time, which ensures the accuracy of demand accusation and recommendation. The relationship and help degree, based on the interactions within the cyberspace, are important references in filtering the recommendation.