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Osteoid plays a crucial role in directing cell behavior and osteogenesis through its unique characteristics, including viscoelasticity and liquid crystal (LC) state. Thus, integrating osteoid-like features into 3D printing scaffolds proves to be a promising approach for personalized bone repair. Despite extensive research on viscoelasticity, the role of LC state in bone repair has been largely overlooked due to the scarcity of suitable LC materials. Moreover, the intricate interplay between LC state and viscoelasticity in osteogenesis remains poorly understood. Here, we developed innovative hydrogel scaffolds with osteoid-like LC state and viscoelasticity using digital light processing with a custom LC ink. By utilizing these LC scaffolds as 3D research models, we discovered that LC state mediates high protein clustering to expose accessible RGD motifs to trigger cell-protein interactions and osteogenic differentiation, while viscoelasticity operates via mechanotransduction pathways. Additionally, our investigation revealed a synergistic effect between LC state and viscoelasticity, amplifying cell-protein interactions and osteogenic mechanotransduction processes. Furthermore, the interesting mechanochromic response observed in the LC hydrogel scaffolds suggests their potential application in mechanosensing. Our findings shed light on the mechanisms and synergistic effects of LC state and viscoelasticity in osteoid on osteogenesis, offering valuable insights for the biomimetic design of bone repair scaffolds.

Abstract Synchronous excitatory discharges from the entorhinal cortex (EC) to the dentate gyrus (DG) generate fast and prominent patterns in the hilar local field potential (LFP), called dentate spikes (DSs). As sharp-wave ripples in CA1, DSs are more likely to occur in quiet behavioral states, when memory consolidation is thought to take place. However, their functions in mnemonic processes are yet to be elucidated. The classification of DSs into types 1 or 2 is determined by their origin in the lateral or medial EC, as revealed by current source density (CSD) analysis, which requires recordings from linear probes with multiple electrodes spanning the DG layers. To allow the investigation of the functional role of each DS type in recordings obtained from single electrodes and tetrodes, which are abundant in the field, we developed an unsupervised method using Gaussian mixture models to classify such events based on their waveforms. Our classification approach achieved high accuracies (> 80%) when validated in 8 mice with DG laminar profiles. The average CSDs, waveforms, rates, and widths of the DS types obtained through our method closely resembled those derived from the CSD-based classification. As an example of application, we used the technique to analyze single-electrode LFPs from apolipoprotein (apo) E3 and apoE4 knock-in mice. We observed that the latter group, which is a model for Alzheimer’s disease, exhibited wider DSs of both types from a young age, with a larger effect size for DS type 2, likely reflecting early pathophysiological alterations in the EC-DG network, such as hyperactivity. In addition to the applicability of the method in expanding the study of DS types, our results show that their waveforms carry information about their origins, suggesting different underlying network dynamics and roles in memory processing.

ABSTRACT Polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) is a traditional non-culture technique that can provide a fingerprint of the microbial community. In the field of gut microbiota analysis, PCR-DGGE still holds potential for development. In the present study, we utilized an improved nested PCR-DGGE approach targeting the V3 region of 16S ribosomal DNA to investigate the impact of whole grain highland hull-less barley (WHLB), a cereal known for its significant hypocholesterolemic effect, on the gut microbiota profiles of high-fat diet rats. Seventy-two male Sprague–Dawley rats were divided into four groups and fed a normal control diet, a high-fat diet, or a high-fat diet supplemented with a low or high dose of WHLB for 4 or 8 weeks. The results revealed that the dominant bands varied among different dose groups and further changed with different treatment times. The compositions of bacterial communities in feces and cecal content were similar, but the dominant bacterial bands differed. After performing double DGGE, extracting the bands, sequencing the DNA, and aligning the sequences, a total of 19 bands were classified under the Firmicutes and Bacteroidetes phyla, while two bands were identified as unclassified uncultured bacteria. The relative abundance of Lactobacillus gasseri, Uncultured Prevotella sp., and Clostridium sp. increased following the administration of WHLB. Illumina-based sequencing was employed to assess the reliability of DGGE, demonstrating its reliability in analyzing the dominant taxonomic composition, although it may have limitations in accurately detecting the alpha diversity of bacterial species.IMPORTANCEWhile next-generation sequencing has overshadowed polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE), the latter still holds promise for advancing gut microbiota analysis due to its unique advantages. In this study, we used optimized nested PCR-DGGE to investigate the gut microbiota profile of high-fat diet rats after administering whole grain highland hull-less barley. High-throughput sequencing was employed to validate the DGGE results. Our results proved the reliability of PCR-DGGE for analyzing the dominant taxonomic composition while also providing visual evidence of a notable relationship between the composition of cecal and fecal microbial communities, highlighting substantial differences in both richness and abundance.

The epidermal barrier is vital for protecting the skin from environmental stressors and ultraviolet (UV) radiation. Filaggrin-2 (FLG2), a critical protein in the stratum corneum, plays a significant role in maintaining skin barrier homeostasis. However, the precise role of FLG2 in mitigating the adverse effects of UV-induced barrier disruption and photoaging remains poorly understood. In this study, we revealed that UVB exposure resulted in a decreased expression of FLG2 in HaCaT keratinocytes, which correlated with a compromised barrier function. The administration of recombinant filaggrin-2 (rFLG2) enhanced keratinocyte differentiation, bolstered barrier integrity, and offered protection against apoptosis and oxidative stress induced by UVB irradiation. Furthermore, in a UV-induced photodamage murine model, the dermal injection of rFLG2 facilitated the enhanced restoration of the epidermal barrier, decreased oxidative stress and inflammation, and mitigated the collagen degradation that is typical of photoaging. Collectively, our findings suggested that targeting FLG2 could be a strategic approach to prevent and treat skin barrier dysfunction and combat the aging effects associated with photoaging. rFLG2 emerges as a potentially viable therapy for maintaining skin health and preventing skin aging processes amplified by photodamage.

Advanced glycation end product (AGE) accumulation due to diabetes causes vascular and neurological lesions, delaying healing. The use of stem cells could overcome these problems. Although many studies have shown the potential beneficial effects of stem cell therapies in the treatment of chronic and refractory skin ulcers, their delivery methods are still under investigation. Human periodontal ligament stem cells (hPDLSCs) can spontaneously differentiate into myofibroblasts in specific cultures; therefore, they have the potential to effectively treat diabetic wounds and may also have applications in the field of medical cosmetics. The myofibroblastic differentiation ability of hPDLSCs in the presence of AGEs was evaluated by the expression of α-SMA and COL1A1 using RT-qPCR and WB technology. Wound healing in diabetic mice, induced by streptozotocin (STZ) and assessed using H&E staining, Masson staining, and immunohistochemical (IHC) and immunofluorescence (IF) staining, was used to validate the effects of hPDLSCs. In the wound tissues, the expression of α-SMA, COL1A1, CD31, CD206, iNOS, and vimentin was detected. The findings indicated that in H-DMEM, the expression of COL1A1 exhibited a significant decrease, while α-SMA demonstrated an increase in P7 cells, ignoring the damage from AGEs (p < 0.05). In an STZ-induced diabetic C57BL/6J mice whole-skin defect model, the healing rate of the hPDLSCs treatment group was significantly higher than that in the models (on the 7th day, the rate was 65.247% vs. 48.938%, p < 0.05). hPDLSCs have been shown to spontaneously differentiate into myofibroblasts in H-DMEM and resist damage from AGEs in both in vivo and in vitro models, suggesting their potential in the field of cosmetic dermatology.

The testes serve as the primary source of androgens and the site of spermatogenesis, with their development and function governed by hormonal actions via endocrine and paracrine pathways. Male fertility hinges on the availability of testosterone, a cornerstone of spermatogenesis, while follicle-stimulating hormone (FSH) signaling is indispensable for the proliferation, differentiation, and proper functioning of Sertoli and germ cells. This review covers the research on how androgens, FSH, and other hormones support processes crucial for male fertility in the testis and reproductive tract. These hormones are regulated by the hypothalamic–pituitary–gonad (HPG) axis, which is either quiescent or activated at different stages of the life course, and the regulation of the axis is crucial for the development and normal function of the male reproductive system. Hormonal imbalances, whether due to genetic predispositions or environmental influences, leading to hypogonadism or hypergonadism, can precipitate reproductive disorders. Investigating the regulatory network and molecular mechanisms involved in testicular development and spermatogenesis is instrumental in developing new therapeutic methods, drugs, and male hormonal contraceptives.

Coral atolls are widely recognized as oases of remarkable biodiversity and productivity within the oligotrophic open ocean. However, considerable debate surrounds the net carbon metabolism of planktonic communities in oceanic coral atolls and their contribution to the overall carbon budget of the ocean. Zhongsha Atoll, situated in the central South China Sea, represents one of the largest submerged reef atolls globally. Despite its significance, the ecological environment and characteristics of community production and metabolism at Zhongsha Atoll have been scarcely studied, and it remains uncertain whether these features differ from those observed in barrier-type reefs. In this study, we examined the gross primary production (GPP), community respiration (CR), and net community production (NCP) of the planktonic community in Zhongsha Atoll and its surrounding waters from 22 June to 6 July 2020. We also analyzed the potential influences of their distribution patterns. Our findings revealed that CR did not vary significantly with depth and it was considerably higher than GPP. As a result, the waters at the euphotic depth of Zhongsha Atoll were found to be heterotrophic, with negative NCP. Additionally, the correlation analysis demonstrated a negative relationship between NCP and CR. The NCP values were -35.28 ± 26.73 and -53.18 ± 31.77 mg C m-3 d-1 for the surface and chlorophyll maximum (DCM) layers, respectively. The NCP for the upper water column was -3023 mg C m-2 d-1. The waters above the reef flat (FL) exhibited higher primary productivity, with GPP in the surface and DCM layer being 1.61 and 2.71 times greater, respectively, than in the surrounding oceanic regions. However, the FL displayed a greater level of heterotrophy due to its stronger CR. In conclusion, the carbon metabolism of the planktonic community in submerged Zhongsha Atoll acts as a source of atmospheric CO2, and the distribution of coral reefs considerably contributes to the efficiency of carbon cycling within the atoll.

Due to the increasing trend of delayed childbirth, the age-related decline in male reproductive function has become a widely recognized issue. Sertoli cells (SCs) play a vital role in creating the necessary microenvironment for spermatogenesis in the testis. However, the mechanism underlying Sertoli cell aging is still unclear. In this study, senescent Sertoli cells showed a substantial upregulation of miR-143-3p expression. miR-143-3p was found to limit Sertoli cell proliferation, promote cellular senescence, and cause blood–testis barrier (BTB) dysfunction by targeting ubiquitin-conjugating enzyme E2 E3 (UBE2E3). Additionally, the TGF-β receptor inhibitor SB431542 showed potential in alleviating age-related BTB dysfunction, rescuing testicular atrophy, and reversing the reduction in germ cell numbers by negatively regulating miR-143-3p. These findings clarified the regulatory pathways underlying Sertoli cell senescence and suggested a promising therapeutic approach to restore BTB function, alleviate Sertoli cell senescence, and improve reproductive outcomes for individuals facing fertility challenges.

Abstract Background The direct application of umbilical cord‐derived mesenchymal stem cells (UCMSCs) for promoting skin wound healing and regeneration is challenging due to strict maintenance requirements and unpredictable differentiation results. Methods We developed dead but functional liquid nitrogen‐treated UCMSCs (LNT‐MSCs) by rapidly immersing live UCMSCs (live‐MSCs) in liquid nitrogen. Results The LNT‐MSCs maintained similar cellular structures and surface markers to those of live‐MSCs. We evaluated the therapeutic effects of both live‐MSCs and LNT‐MSCs on full‐thickness skin wound healing in rats. Our results showed that the LNT‐MSCs accelerated wound closure by enhancing the proliferation and migration of skin cells, promoting angiogenesis, and inducing a favourable macrophage phenotype shift. The regenerative healing effect of LNT‐MSCs was comparable to that of live‐MSCs, making them a potential alternative strategy for accelerating wound closure that avoids unpredictable differentiation results and creates a ready‐to‐use cell bank for clinical applications.

Therapeutics discovery and development for Alzheimer’s disease (AD) has been an area of intense research to alleviate memory loss and the underlying pathogenic processes. Recent drug discovery approaches have utilized in silico computational strategies for drug candidate selection which has opened the door to repurposing drugs for AD. Computational analysis of gene expression signatures of patients stratified by the APOE4 risk allele of AD led to the discovery of the FDA-approved drug bumetanide as a top candidate agent that reverses APOE4 transcriptomic brain signatures and improves memory deficits in APOE4 animal models of AD. Bumetanide is a loop diuretic which inhibits the kidney Na+-K+-2Cl− cotransporter isoform, NKCC2, for the treatment of hypertension and edema in cardiovascular, liver, and renal disease. Electronic health record data revealed that patients exposed to bumetanide have lower incidences of AD by 35%–70%. In the brain, bumetanide has been proposed to antagonize the NKCC1 isoform which mediates cellular uptake of chloride ions. Blocking neuronal NKCC1 leads to a decrease in intracellular chloride and thus promotes GABAergic receptor mediated hyperpolarization, which may ameliorate disease conditions associated with GABAergic-mediated depolarization. NKCC1 is expressed in neurons and in all brain cells including glia (oligodendrocytes, microglia, and astrocytes) and the vasculature. In consideration of bumetanide as a repurposed drug for AD, this review evaluates its pharmaceutical properties with respect to its estimated brain levels across doses that can improve neurologic disease deficits of animal models to distinguish between NKCC1 and non-NKCC1 mechanisms. The available data indicate that bumetanide efficacy may occur at brain drug levels that are below those required for inhibition of the NKCC1 transporter which implicates non-NKCC1 brain mechansims for improvement of brain dysfunctions and memory deficits. Alternatively, peripheral bumetanide mechanisms may involve cells outside the central nervous system (e.g., in epithelia and the immune system). Clinical bumetanide doses for improved neurological deficits are reviewed. Regardless of mechanism, the efficacy of bumetanide to improve memory deficits in the APOE4 model of AD and its potential to reduce the incidence of AD provide support for clinical investigation of bumetanide as a repurposed AD therapeutic agent.

The micro-arc oxidation coatings (MAO) coatings formed on the magnesium (Mg) matrix usually have various porosity in the cross-section due to the uneven thermal stress, resulting in the non-consistent compact density in the external and inner layer. However, the consistency of the compact density in the cross-section is less concerned, and its effect on the surficial anti-corrosion and mechanical properties is still unclear. Herein, we employed the Zirconium Oxide particles as a heat-absorbing agent to tune the temperature gradient and achieved the in situ growth of MAO coatings on Mg alloy with a tunable compact density in the external layer and inner layer separately. It is found that compact density plays a key role in corrosion resistance, while the consistency of compact density along the cross-section is very crucial for the mechanical properties. Increasing the compact density and reducing its gradual difference could significantly enhance both the anti-corrosion and mechanical properties. The effect of the inconsistent compact density on the anti-corrosion property could be weakened by reducing the porosity on the external layer, but the simulation results demonstrate its effect on the mechanical properties would be strengthened due to the stress concentration. MAO coatings with homogeneous and compact structures in the cross-section present superior anti-corrosion properties and excellent mechanical properties.

Approximately 59.4–100% of head and neck cancer patients receiving radiotherapy or radio chemotherapy suffer from aphthous ulcers (AUs), which seriously affect the subsequent treatment. At the same time, AUs are a common oral mucosal disease with a high incidence rate among the population, often accompanied by severe pain, and affect both physical and mental health. Strategies to increase the ulcer healing rate and relieve pain symptoms quickly is a long-term clinical objective. Oral mucosal discontinuity is the main histological hallmark of AUs. So, covering the inner mucosal defect with an in vitro engineered oral mucosal equivalent shows good prospects for AU alleviation. Fibronectin (FN) is a glycopeptide in the extracellular matrix and exhibits opsonic properties, aiding the phagocytosis and clearance of foreign pathogens through all stages of ulcer healing. But native FN comes from animal blood, which has potential health risks. rhFN3C was designed with multi-domains of native FN, whose core functions are the recruitment of cells and growth factors to accelerate AU healing. rhFN3C is a peptide-fused recombinant protein. The peptides are derived from the positions of 1444–1545 (FNIII10) and 1632–1901 (FNIII12–14) in human native FN. We optimized the fermentation conditions of rhFN3C in E. coli BL21 to enable high expression levels. rhFN3C is thermally stable and nontoxic for L929, strongly promotes the migration and adhesion of HaCaT, decreases the incidence of wound infection, and shortens the mean healing time by about 2 days compared to others (p < 0.01). rhFN3C may have great potential for use in the treatment of AUs. The specific methods and mechanisms of rhFN3C are yet to be investigated.

Resorption and loss of alveolar bone leads to oral dysfunction and loss of natural or implant teeth. Biomimetic delivery of growth factors based on stem cell recruitment and osteogenic differentiation, as the key steps in natural alveolar bone regenerative process, has been an area of intense research in recent years. A mesoporous self-healing hydrogel (DFH) with basic fibroblast growth factor (bFGF) entrapment and transforming growth factor β3 (TGFβ3) - loaded chitosan microspheres (CMs) was developed. The formulation was optimized by multiple tests of self-healing, in-bottle inversion, SEM, rheological, swelling rate and in vitro degradation. In vitro tubule formation assays, cell migration assays, and osteogenic differentiation assays confirmed the ability of DFH to promote blood vessels, recruit stem cells, and promote osteogenic differentiation. The optimum DFH formula is 0.05 ml 4Arm-PEG-DF (20%) added to 1 ml CsGlu (2%) containing bFGF (80 ng) and TGFβ3-microspheres (5 mg). The results of in vitro release studied by Elisa kit, indicated an 95% release of bFGF in 7 d and long-term sustained release of TGFβ3. For alveolar defects rat models, the expression levels of CD29 and CD45, the bone volume fraction, trabecular number, and trabecular thickness of new bone monitored by Micro-CT in DFH treatment groups were significantly higher than others (*P < 0.05, vs Model). HE and Masson staining show the same results. In conclusion, DFH is a design of bionic alveolar remodelling microenvironment, that is in early time microvessels formed by bFGF provide nutritious to recruited endogenous stem cells, then TGFβ3 slowly released speed up the process of new bones formation to common facilitate rat alveolar defect repair. The DFH with higher regenerative efficiency dovetails nicely with great demand due to the requirement of complicated biological processes.

Summary: Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cycle metabolites. To investigate the requirement for glycolysis, we generated mice with postnatal deletion of either the dominant neuronal glucose transporter (GLUT3cKO) or the neuronal-enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons. GLUT3cKO and PKM1cKO mice show age-dependent learning and memory deficits. Hyperpolarized magnetic resonance spectroscopic (MRS) imaging shows that female PKM1cKO mice have increased pyruvate-to-lactate conversion, whereas female GLUT3cKO mice have decreased conversion, body weight, and brain volume. GLUT3KO neurons also have decreased cytosolic glucose and ATP at nerve terminals, with spatial genomics and metabolomics revealing compensatory changes in mitochondrial bioenergetics and galactose metabolism. Therefore, neurons metabolize glucose through glycolysis in vivo and require glycolysis for normal function.

The development of biological macromolecule hydrogel dressings with fatigue resistance, sufficient mechanical strength, and versatility in clinical treatment is critical for accelerating full-thickness healing of skin wounds. Therefore, in this study, multifunctional, biological macromolecule hydrogels based on a recombinant type I collagen/chitosan scaffold incorporated with a metal–polyphenol structure were fabricated to accelerate wound healing. The resulting biological macromolecule hydrogel possesses sufficient mechanical strength, fatigue resistance, and healing properties, including antibacterial, antioxygenic, self-healing, vascularization, hemostatic, and adhesive abilities. Chitosan and recombinant type I collagen formed the scaffold network, which was the first covalent crosslinking network of the hydrogel. The second physical crosslinking network comprised the coordination of a metal–polyphenol structure, i.e., Cu2+ with the catechol group of dopamine methacrylamide (DMA) and stacking of DMA benzene rings. Double-crosslinked networks are interspersed and intertwined in the hydrogel to reduce the mechanical strength and increase its fatigue resistance, making it more suitable for clinical applications. Moreover, the biological macromolecule hydrogel can continuously release Cu2+, which provides strong antibacterial and vascularization properties. An in vivo full-thickness skin defect model confirmed that multifunctional, biological macromolecule hydrogels based on a recombinant type I collagen/chitosan scaffold incorporated with a metal–polyphenol structure can facilitate the formation of granulation tissue and collagen deposition for a short period to promote wound healing. This study highlights that this biological macromolecule hydrogel is a promising acute wound-healing dressing for biomedical applications.

The ovary is a highly susceptible organ to senescence, and granulosa cells (GCs) have a crucial role in oocyte development promotion and overall ovarian function maintenance. As age advances, GCs apoptosis and dysfunction escalate, leading to ovarian aging. However, the molecular mechanisms underpinning ovarian aging remain poorly understood. In this study, we observed a correlation between the age-related decline of fertility and elevated expression levels of miR-143-3p in female mice. Moreover, miR-143-3p was highly expressed in senescent ovarian GCs. The overexpression of miR-143-3p in GCs not only hindered their proliferation and induced senescence-associated secretory phenotype (SASP) but also impeded steroid hormone synthesis by targeting ubiquitin-conjugating enzyme E2 E3 (Ube2e3) and luteinizing hormone and human chorionic gonadotropin receptor (Lhcgr). These findings suggest that miR-143-3p plays a substantial role in senescence and steroid hormone synthesis in GCs, indicating its potential as a therapeutic target for interventions in the ovarian aging process.

Collagen is the functional protein of the skin, tendons, ligaments, cartilage, bone, and connective tissue. Due to its extraordinary properties, collagen has a wide range of applications in biomedicine, tissue engineering, food, and cosmetics. In this study, we designed a functional fragment of human type I collagen (rhLCOL-I) and expressed it in Escherichia coli (E. coli) BL21(DE3) PlysS containing a thermal-induced plasmid, pBV-rhLCOL-I. The results indicated that the optimal expression level of the rhLCOL-I reached 36.3% of the total protein at 42 °C, and expressed in soluble form. In a 7 L fermentation, the yield of purified rhLCOL-I was 1.88 g/L. Interestingly, the plasmid, pBV220-rhLCOL-I, was excellently stable during the fermentation process, even in the absence of antibiotics. Functional analyses indicated that rhLCOL-I had the capacity to promote skin cell migration and adhesion in vitro and in vivo. Taken together, we developed a high-level and low-cost approach to produce collagen fragments suitable for medical applications in E. coli.

Polygala japonica Houtt. (PJ), a member of the Polygala L. family that is suggested to exhibit detoxification properties in traditional Chinese medicine, is often used to treat upper respiratory tract infections. The anti-inflammatory effects of four main components of PJ (POL, PS-XLIX, PS-E, and PS-F) were examined using the LPS(0.3 μg·mL−1)-stimulated RAW264.7 macrophage model. The levels of NO, ROS, and iNOS were examined to analyze the anti-inflammatory activity of POL. Additionally, the levels of extracellular inflammation-related cytokines and chemokines were measured using quantibody array. The KEGG pathway analysis was performed to examine the anti-inflammatory mechanism of POL. The levels of NO in the POL-pretreated group were significantly downregulated when compared with those in the PS-E-pretreated, PS-F-pretreated, and PS-XLIX-pretreated groups. POL significantly inhibited the changes of iNOS, ROS, and inflammatory factors caused by LPS stimulation (p

Anton Malkov, Irina Popova et al. demonstrate that beta-amyloid application induces oxidative stress and reduces glucose consumption in the mouse brain, leading to network hyperactivity and behavioral changes—pathologies similar to those observed early on in Alzheimer’s disease patients. Inhibition of NADPH oxidase 2 (NOX2) rescued these phenotypes, suggesting that NOX2 may represent an important therapeutic target for Alzheimer’s disease.

Awareness of epidemics can influence people’s behavior and further trigger changes in epidemic spreading. Previous studies concentrating on the coupled awareness-epidemic dynamics usually ignore the multi-type information and the heterogeneity of individuals. However, the real-world cases can be more complicated, and the interaction between information diffusion and epidemic spreading needs further study. In this article, we propose an individual-based epidemics and multi-type information spreading (IEMIS) model on two-layered multiplex networks considering positive and negative preventive information and two types of heterogeneity: 1) heterogeneity of aware individual’s state which leads to differences in aware transmission capacity and 2) heterogeneity of individual’s node degree which affects the epidemic infection rate. Based on Micro-Markov Chain approach (MMCA), we derive the theoretical epidemic threshold for the proposed model and validate the results by those obtained with Monto Carlo (MC) simulations. Through extensive simulations, we demonstrate that for epidemics with low infectivity, promoting the diffusion of positive preventive information, enhancing the importance ratio of neighbors who are aware of positive information, and increasing social distance among individuals can effectively suppress epidemic spreading. However, for highly infectious diseases, the influence of these factors becomes limited.

Non-pharmaceutical interventions (NPIs) are essential for the effective prevention and control of the COVID-19 pandemic. However, the scenarios for disease transmission are complicated and varied, and it remains unclear how real-world networks respond to the changes in NPIs. Here, we propose a multi-layer network combining structurally fixed social contact networks with a time-varying mobility network, select the COVID-19 outbreak in two metropolitans in China as case studies, and assess the effectiveness of NPIs. Human mobility, both in relatively fixed places and in urban commuting, is considered. Enclosed places are simulated by three different types of social contact networks, while urban commuting is represented by a time-varying commute network. We provide a composite framework that captures the heterogeneity and time variation of the real world and enables us to simulate large populations with low computational costs. We give out a thorough evaluation of the effectiveness of NPIs (i.e., work from home, school closure, close-off management, public transit limitation, quarantine, and mask use) under certain vaccine coverage varying with implementation timing and intensity. Our results highlight the strong correlation between the NPI pattern and the epidemic mitigation effect and suggest important operational strategies for epidemic control.

Background and aims:Spinal serum 25-hydroxyvitamin D [25[OH]D] status plays an important role in mediating innate immune responses by acting as a cofactor for induction of antimycobacterial activity and is thus involved in the development of Tuberculosis (TB). Results reported regarding the association of vitamin D with TB remained controversial. We aimed to identify any common association between 25[OH]D status and TB in the Chinese Han population.Methods280 subjects (70 TB patients and 210 matched controls) were recruited. TB cases were diagnosed based on the presence of acid-fast bacilli on smears from sputum and MTB isolation. Healthy controls were randomly selected from four local community-based populations. 25[OH]D was detected by electrochemiluminescence immunoassay (ECLIA) on Roche Elecsys before the initial treatment. Multivariable logistic regression analysis was used to examine the association of Vitamin D with TB.ResultsThere was no significant difference in the serum vitamin D level between total cases and controls, but we found a strong tendency toward a higher serum vitamin D level in male population (P < 0.05) with TB but not in females. High serum vitamin D increased the risk of TB in the Chinese Han population (OR = 1.035, 95%CI: 1.001–1.070, P < 0.05). The serum vitamin D level was significantly decreased with age increasing in cases and controls (all P < 0.001).ConclusionsHigh serum vitamin D may be an independent risk factor for TB in the Chinese Han population.

Dissolved organic carbon (DOC) is the main participant in carbon cycles through water pathways. Recent studies have highlighted the roles of aquatic systems in landscape and watershed carbon budgets. This study is based on 261 samples collected between 2016 and 2017, from individual water types (e.g., river/stream, lake/pond, icing/spring, snow/rain, groundwater/ice, and others) in the source area of the Yellow River (SAYR). These samples were analyzed for examining the distributive features of DOC in aquatic systems, especially in relation to environmental factors. It shows that: 1) DOC concentrations in permafrost-related waters (7.2–234.4 mg C·L−1) were often the highest among all aquatic DOC sources (lakes/ponds: 21.3 ± 34.1 mg C·L−1, rivers/streams: 4.3 ± 3.7 mg C·L−1, and groundwater: 1.8 ± 1.4 mg C·L−1); 2) the seasonality of riverine DOC showed declining features in 2016 and high in summer/autumn, followed by a spring freshet in 2017, and a close association with intra-annual precipitation modes; 3) the main controls of aquatic DOC are permafrost presence, precipitation, and NDVI, and they contribute to 38% of variances of environmental variables in affecting variations in aquatic DOC in the SAYR; and 4) a literature review on biodegradable DOC (BDOC) of varied aquatic DOC pools indicates the highest DOC concentrations (48–1,548 mg C·L−1) and BDOC (23–71%) of ground-ice meltwater. Thus, we suggest that in the SAYR, permafrost dynamics dominate aquatic DOC distribution, and permafrost thaw may alter aquatic DOC budgets, eventually becoming an additional source for atmospheric carbon emissions.

Metabolisms of field plankton community, including gross primary production (GPP), community respiration (CR), and net community production (NCP), usually indicate the status of the health, resource production, and carbon budget of marine ecosystems. In this study, we explored the regional variance and driving forces of plankton metabolism in coastal waters of the Guangdong-Hong Kong-Macao Greater Bay Area (GGBA), a fast-developed area with complex hydrological and environmental states. The results showed that the maximum GPP and CR occurred in the estuarine plume of the GGBA in summer, while in winter the more active metabolisms of plankton community occurred in the Daya Bay, with the GPP and CR being respectively mediated by the nutrient level and temperature. Moreover, four regional zones were divided on the base of the environments and biological factors in surface water of the GGBA i.e., the river-runoff zone, river-plume zone, nearshore and far-offshore zones. The metabolic states in these zones varied significantly due to the regional and seasonal variations of, for example, the nutrient level, temperature, and turbidity driven by multiple factors including land-derived runoffs, anthropogenic activities, the Yuedong Coastal Current, and offshore seawater-intrusions. On the whole, the GGBA areas exhibited the weak heterotrophic processes in both summer (NCP = -24.9 ± 26.7 mg C m-3 d-1) and winter (NCP = -51.2 ± 8.51 mg C m -3 d-1). In addition, we found that the higher CR occurred to the bottom layers of the river plume and nearshore zones wherein hypoxia happened, indicating a possible attribution of plankton community respiration to the hypoxia in the GGBA.

Periodontal bone tissue defects and bone shortages are the most familiar and troublesome clinical problems in the oral cavity. Stem cell-derived extracellular vesicles (SC-EVs) have biological properties similar to their sources, and they could be a promising acellular therapy to assist with periodontal osteogenesis. In the course of alveolar bone remodeling, the RANKL/RANK/OPG signaling pathway is an important pathway involved in bone metabolism. This article summarizes the experimental studies of SC-EVs applied for the therapy of periodontal osteogenesis recently and explores the role of the RANKL/RANK/OPG pathway in their mechanism of action. Their unique patterns will open a new field of vision for people, and they will help to advance a possible future clinical treatment.

Alzheimer’s Disease (AD) is a complex neurodegenerative disease that gravely affects patients and imposes an immense burden on caregivers. Apolipoprotein E4 (APOE4) has been identified as the most common genetic risk factor for AD, yet the molecular mechanisms connecting APOE4 to AD are not well understood. Past transcriptomic analyses in AD have revealed APOE genotype-specific transcriptomic differences; however, these differences have not been explored at a single-cell level. To elucidate more complex APOE genotype-specific disease-relevant changes masked by the bulk analysis, we leverage the first two single-nucleus RNA sequencing AD datasets from human brain samples, including nearly 55,000 cells from the prefrontal and entorhinal cortices. In each brain region, we performed a case versus control APOE genotype-stratified differential gene expression analysis and pathway network enrichment in astrocytes, microglia, neurons, oligodendrocytes, and oligodendrocyte progenitor cells. We observed more global transcriptomic changes in APOE4 positive AD cells and identified differences across APOE genotypes primarily in glial cell types. Our findings highlight the differential transcriptomic perturbations of APOE isoforms at a single-cell level in AD pathogenesis and have implications for precision medicine development in the diagnosis and treatment of AD.

Cadmium (Cd) is one of the most common environmental pollutants, which has a long biological half-life. Maternal Cd-exposure in the natural environment causes steroidogenesis defects resulting in spermatogenesis disorder in male offspring. For better understanding its underlying mechanism, we have employed iTRAQ to screen the differentially expressed protein and found that the expression of CORO1A and Cofilin 1 was up-regulated approximately 2 fold in Leydig cells of maternal Cd-exposure offspring. As the major source of steroid hormone, cholesterol is transported to cells via receptor-mediated endocytosis which relies on the remodel of cytoskeleton, then stores in lipid droplets (LDs). However, few studies have focused on the role of cytoskeleton in abnormal steroidogenesis. This study was performed to explore the role of CORO1A in androgen deficiency caused by Cd exposure and its involvement of low-density lipoprotein (LDL) uptake and effects on LDs. We found that Cd resulted in the up-regulation of CORO1A and Cofilin 1, and down-regulation of Profilin 1 in the testis of male offspring with maternal exposure. The structure of filamentous actin was broken, disordered and even crumpled up in Cd-treated R2C cells. F-actin disassembly led to a low uptake of LDL with a reduced number of LDs, followed by decreased total cholesterol and low progesterone production. When CORO1A was silenced, the expression of Cofilin 1 was down-regulated and Profilin 1 was up-regulated in Cd-treated R2C cells. The filamentous actin was rescued and the integrated cytoskeleton prompted LDL uptake, which resulted in the increased total cholesterol and high progesterone production. These findings highlight the crucial role of CORO1A as a cytoskeleton regulatory protein in steroidogenesis, which may help to better understand Cd-induced steroid hormone deficiency in children.

Abstract Impressive clinical benefit is seen in clinic with PD‐1 inhibitors on portion of cancer patients. Yet, there remains an urgent need to develop effective synergizers to expand their clinical application. Tumor‐associated macrophage (TAM), a type of M2‐polarized macrophage, eliminates or suppresses T‐cell‐mediated anti‐tumor responses. Transforming TAMs into M1 macrophages is an attractive strategy of anti‐tumor therapy. Here, we conducted a high‐throughput screening and found that Carfilzomib potently drove M2 macrophages to express M1 cytokines, phagocytose tumor cells, and present antigens to T cells. Mechanistically, Carfilzomib elicited unfolded protein response (UPR), activated IRE1α to recruit TRAF2, and activated NF‐κB to transcribe genes encoding M1 markers in M2 macrophages. In vivo, Carfilzomib effectively rewired tumor microenvironment through reprogramming TAMs into M1‐like macrophages and shrank autochthonous lung cancers in transgenic mouse model. More importantly, Carfilzomib synergized with PD‐1 antibody to almost completely regress autochthonous lung cancers. Given the safety profiles of Carfilzomib in clinic, our work suggested a potentially immediate application of combinational treatment with Carfilzomib and PD‐1 inhibitors for patients with solid tumors.

In the northern Da Xing’anling Mountains in Northeast China on the southern margin of the Eastern Asia permafrost body, the ground thermal state and boreal ecological environment are sensitive to climate change and human activities. Since the 1980s, the Hola Basin here has been continuously and extensively developed. In particular, open pits and later backfilling in strip coal mining alters land–atmospheric hydrothermal exchanges in permafrost regions, leading to serious damages to the permafrost environment and boreal forest. After mining, pits need to be backfilled timely and properly for hydrothermal recovery of Xing’an permafrost and the boreal ecological environment. In this study, based on the comparative analysis of monitored ground temperatures in backfilled and undisturbed areas, influencing factors of thermal recovery after backfilling were analyzed through numerical simulations. Results show that the thermal recovery of permafrost in the backfilled area is closely related to temperature, depth, material, and soil moisture content of backfill. The warmer, finer, and thicker the backfill soils, the longer the permafrost recovery. Thermal recovery of permafrost also depends on the moisture content of backfill; the shortest recovery occurs at 15–25% in the backfilled soil moisture content. Based on numerical simulations and combined with enlightenments from features of the ecosystem-protected Xing’an permafrost in Northeast China, a composite configuration of organic soil, crush-rock layer, and proper re-vegetation measures is advised. Based on prudent regulation of heat transfer modes, this composite backfilling method can effectively cool the backfilled ground and can even possibly offset the climate warming.

Summary: Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies. : In this article, Karch, Temple and colleagues describe a resource of fibroblasts, patient-derived induced pluripotent stem cells, and genome engineered stem cells with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for primary tauopathies. Keywords: tau, MAPT, fibroblasts, induced pluripotent stem cells, neural progenitor cells, tauopathy, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, CRISPR/Cas9

In males, Leydig cells are the primary source of testosterone, which is necessary for testis development, masculinization, and spermatogenesis. Leydig cells are a valuable cellular model for basic research; thus, it is important to develop an improved method for isolation and purification of Leydig cells from testes. The available methods for Leydig cell isolation have some drawbacks, including the need for sophisticated instruments, high cost, tediousness, and time consumption. Here, we describe an improved protocol for isolation of primary Leydig cells from testicular tissue by digestion with collagenase IV.

Cyclobutane pyrimidine dimers (CPDs) are the main mutagenic DNA photoproducts caused by ultraviolet B (UVB) radiation and represent the major cause of photoaging and skin carcinogenesis. CPD photolyase can efficiently and rapidly repair CPD products. Therefore, they are candidates for the prevention of photodamage. However, these photolyases are not present in placental mammals. In this study, we produced a recombinant photolyase-thymine (rPHO) from Thermus thermophilus (T. thermophilus). The rPHO displayed CPD photorepair activity. It prevented UVB-induced DNA damage by repairing CPD photoproducts to pyrimidine monomers. Furthermore, it inhibited UVB-induced ROS production, lipid peroxidation, inflammatory responses, and apoptosis. UVB-induced wrinkle formation, epidermal hyperplasia, and collagen degradation in mice skin was significantly inhibited when the photolyase was applied topically to the skin. These results demonstrated that rPHO has promising protective effects against UVB-induced photodamage and may contribute to the development of anti-UVB skin photodamage drugs and cosmetic products.

Recombinant human keratinocyte growth factor-2 (rhKGF-2), an effective agent for the regeneration of epithelial tissue, was found to have great potential for use in treatments of corneal diseases that involve corneal epithelial defects. Furthermore, the safety of long-term and high-dose external use of KGF-2 eye drops in rabbits has been well established previously. The aim of this study is to determine the safe dose range and target organs for toxicity of rhKGF-2 eye drops in Macaca fascicularis (M. fascicularis). The M. fascicularis animals were administered with different doses of rhKGF-2 eye drops (125, 500, and 2000 μg/ml) for four consecutive weeks, followed by a 2 week recovery period. No significant differences in weight, electrocardiogram characteristics, blood and urine indexes, pathology, and bone marrow cells were detected among the animals in different groups. The corneas of some animals in the middle- and high-dose groups showed fluorescence when stained with sodium fluorescein, and then the staining disappeared on days 28 and 42. Anti-rhKGF-2 antibodies were detected in a small number of animals in the high-dose group, and their level decreased after rhKGF-2 withdrawal. No neutralizing antibodies were detected. The result demonstrated that there was no obvious adverse reaction when topical application of rhKGF-2 eye drops at the dosage of 125 or 500 μg/ml on the M. fascicularis. This study is of great significance for the future clinical transformation of rhKGF-2 eye drops.

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.

Injury to the peripheral nerves can result in temporary or life-long neuronal dysfunction and subsequent economic or social disability. Acidic fibroblast growth factor (aFGF) promotes the growth and survival of neurons and is a possible treatment for peripheral nerve injury. Yet, the actual therapeutic utility of aFGF is limited by its short half-life and instability in vivo. In the present study, we prepared sulfated chitooligosaccharides (SCOS), which have heparin-like properties, to improve the bioactivity of aFGF. We investigated the protective effects of SCOS with or without aFGF on RSC96 cells exposed to Na2S2O4 hypoxia/reoxygenation injury. Cell viability was measured by MTT assay and cytotoxicity induced by Na2S2O4 was assessed by lactate dehydrogenase (LDH) release into the culture medium. Pretreatment with aFGF and SCOS dramatically decreased LDH release after injury compared to pretreatment with aFGF or SCOS alone. We subsequently prepared an aFGF/SCOS thermo-sensitive hydrogel with poloxamer and examined its effects in vivo. Paw withdrawal thresholds and thermal withdrawal latencies were measured in rats with sciatic nerve injury. Local injection of the aFGF/SCOS hydrogels (aFGF: 40, 80 µg/kg) increased the efficiency of sciatic nerve repair compared to aFGF (80 µg/kg) hydrogel alone. Especially aFGF/SCOS thermo-sensitive hydrogel decreased paw withdrawal thresholds from 117.75 ± 8.38 (g, 4 d) to 65.74 ± 3.39 (g, 10 d), but aFGF alone group were 140.58 ± 27.54 (g, 4 d) to 89.12 ± 5.60 (g, 10 d) (aFGF dose was 80 µg/kg, P

Abstract 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.

Patients with a skull defect are at risk of developing cerebrospinal fluid leakage and ascending bacterial meningitis at >10% per year. However, treatment with stem cells has brought great hope to large-area cranial defects. Having found that transforming growth factor (TGF)-β3 can promote the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs), we designed a hybrid TGF-β3/recombinant human-like collagen recombinant human collagen/chitosan (CS) freeze-dried sponge (TRFS) loading hPDLSCs (TRFS-h) to repair skull defects in rats. CFS with 2% CS was selected based on the swelling degree, water absorption, and moisture retention. The CS freeze-dried sponge (CFS) formed a porous three-dimensional structure, as observed by scanning electron microscopy. In addition, cytotoxicity experiments and calcein-AM/PI staining showed that TRFS had a good cellular compatibility and could be degraded completely at 90 days in the implantation site. Furthermore, bone healing was evaluated using micro-computed tomography in rat skull defect models. The bone volume and bone volume fraction were higher in TRFS loaded with hPDLSCs (TRFS-h) group than in the controls (p < 0.01, vs. CFS or TRFS alone). The immunohistochemical results indicated that the expression of Runx2, BMP-2, and collagen-1 (COL Ⅰ) in cells surrounding bone defects in the experimental group was higher than those in the other groups (p < 0.01, vs. CFS or TRFS alone). Taken together, hPDLSCs could proliferate and undergo osteogenic differentiation in TRFS (p < 0.05), and TRFS-h accelerated bone repair in calvarial defect rats. Our research revealed that hPDLSCs could function as seeded cells for skull injury, and their osteogenic differentiation could be accelerated by TGF-β3. This represents an effective therapeutic strategy for restoring traumatic defects of the skull.

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.

Epidermal growth factor (EGF) is important for promoting skin repair and remodeling. Native collagen is also widely used as a scaffold for skin tissue engineering. The limitations of EGF include easy decomposition or inactivation, whereas native collagen is immunogenic and has poor solubility. Therefore, we constructed a freeze-dried dressing based on the recombinant human-like collagen (RHC) to act as a carrier for EGF (RHC/EGF freeze-dried dressing) and promote skin wound closure. Here, the freeze-dried dressing that combined EGF and RHC significantly enhanced the proliferation, adhesion, and spreading of NIH/3T3 fibroblasts and migration of HaCaT keratinocytes at the wound site. The physicochemical characteristics of the RHC/EGF freeze-dried dressing investigated using scanning electron microscopy, Fourier transform infrared (FTIR) spectroscopy, and differential scanning calorimetry revealed that it was a loose and porous cake that redissolved quickly. The molecular mechanisms involved in cell proliferation and angiogenesis were also assessed. The expression levels of the markers Ki-67, proliferating cell nuclear antigen, vascular endothelial growth factor, and cluster of differentiation 31 were significantly increased after treatment with the RHC/EGF freeze-dried dressing (P < 0.01, vs. RHC or EGF alone). This increase indicated that the RHC/EGF freeze-dried dressing significantly accelerated wound closure, re-epithelialization, and the orderly arrangement and deposition of collagen in the Sprague–Dawley rats with full-thickness skin defects. This work describes a significant step toward the development of wound environments conducive to healing, and the RHC/EGF freeze-dried dressing is a potential therapeutic strategy in wound management.

Fertility preservation and assisted reproductive medicine require effective culture systems for the successful proliferation and differentiation of spermatogonial stem cells (SSCs). Many SSC culture systems require the addition of feeder cells at each subculture, which is tedious and inefficient. Here, we prepared decellularized testicular matrix (DTM) from testicular tissue, which preserved essential structural proteins of testis. The DTM was then solubilized and induced to form a porous hydrogel scaffold with randomly oriented fibrillar structures that exhibited good cytocompatibility. The viability of SSCs inoculated onto DTM hydrogel scaffolds was significantly higher than those inoculated on Matrigel or laminin, and intracellular gene expression and DNA imprinting patterns were similar to that of native SSCs. Additionally, DTM promoted SSC differentiation into round spermatids. More importantly, the DTM hydrogel supported SSC proliferation and differentiation without requiring additional somatic cells. The DTM hydrogel scaffold culture system provided an alternative and simple method for culturing SSCs that eliminates potential variability and contamination caused by feeder cells. It might be a valuable tool for reproductive medicine.

Under a warming climate, permafrost degradation has resulted in profound hydrogeological consequences. Here, we mainly review 240 recent relevant papers. Permafrost degradation has boosted groundwater storage and discharge to surface runoffs through improving hydraulic connectivity and reactivation of groundwater flow systems, resulting in reduced summer peaks, delayed autumn flow peaks, flattened annual hydrographs, and deepening and elongating flow paths. As a result of permafrost degradation, lowlands underlain by more continuous, colder, and thicker permafrost are getting wetter and uplands and mountain slopes, drier. However, additional contribution of melting ground ice to groundwater and stream-flows seems limited in most permafrost basins. As a result of permafrost degradation, the permafrost table and supra-permafrost water table are lowering; subaerial supra-permafrost taliks are forming; taliks are connecting and expanding; thermokarst activities are intensifying. These processes may profoundly impact on ecosystem structures and functions, terrestrial processes, surface and subsurface coupled flow systems, engineered infrastructures, and socioeconomic development. During the last 20 years, substantial and rapid progress has been made in many aspects in cryo-hydrogeology. However, these studies are still inadequate in desired spatiotemporal resolutions, multi-source data assimilation and integration, as well as cryo-hydrogeological modeling, particularly over rugged terrains in ice-rich, warm (>−1 °C) permafrost zones. Future research should be prioritized to the following aspects. First, we should better understand the concordant changes in processes, mechanisms, and trends for terrestrial processes, hydrometeorology, geocryology, hydrogeology, and ecohydrology in warm and thin permafrost regions. Second, we should aim towards revealing the physical and chemical mechanisms for the coupled processes of heat transfer and moisture migration in the vadose zone and expanding supra-permafrost taliks, towards the coupling of the hydrothermal dynamics of supra-, intra- and sub-permafrost waters, as well as that of water-resource changes and of hydrochemical and biogeochemical mechanisms for the coupled movements of solutes and pollutants in surface and subsurface waters as induced by warming and thawing permafrost. Third, we urgently need to establish and improve coupled predictive distributed cryo-hydrogeology models with optimized parameterization. In addition, we should also emphasize automatically, intelligently, and systematically monitoring, predicting, evaluating, and adapting to hydrogeological impacts from degrading permafrost at desired spatiotemporal scales. Systematic, in-depth, and predictive studies on and abilities for the hydrogeological impacts from degrading permafrost can greatly advance geocryology, cryo-hydrogeology, and cryo-ecohydrology and help better manage water, ecosystems, and land resources in permafrost regions in an adaptive and sustainable manner.

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. Keywords: NGF, GnRH, Testosterone, Hypogonadism, Fertility

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. : 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. Keywords: biomarker, sharp-wave ripple, slow gamma, apolipoprotein E4, Alzheimer’s disease, hippocampus, CA3, learning, memory

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.

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.

Purpose – This paper aims to study the node modeling, multi-agent architecture and addressing method for the material conscious information network (MCIN), which is a large-scaled, open-styled, self-organized and ecological intelligent network of supply–demand relationships. Design/methodology/approach – This study models the MCIN by node model definition, multi-agent architecture design and addressing method presentation. Findings – The prototype of novel E-commerce platform based on the MCIN shows the effectiveness and soundness of the MCIN modeling. By comparing to current internet, the authors also find that the MCIN has the advantages of socialization, information integration, collective intelligence, traceability, high robustness, unification of producing and consuming, high scalability and decentralization. Research limitations/implications – Leveraging the dimensions of structure, character, knowledge and experience, a modeling approach of the basic information can fit all kinds of the MCIN nodes. With the double chain structure for both basic and supply–demand information, the MCIN nodes can be modeled comprehensively. The anima-desire-intention-based multi-agent architecture makes the federated agents of the MCIN nodes self-organized and intelligent. The MCIN nodes can be efficiently addressed by the supply–demand-oriented method. However, the implementation of the MCIN is still in process. Practical implications – This paper lays the theoretical foundation for the future networked system of supply–demand relationship and the novel E-commerce platform. Originality/value – The authors believe that the MCIN, first proposed in this paper, is a transformational innovation which facilitates the infrastructure of the future networked system of supply–demand relationship.

Frontotemporal dementia (FTD) and other tauopathies characterized by focal brain neurodegeneration and pathological accumulation of proteins are commonly associated with tau mutations. However, the mechanism of neuronal loss is not fully understood. To identify molecular events associated with tauopathy, we studied induced pluripotent stem cell (iPSC)-derived neurons from individuals carrying the tau-A152T variant. We highlight the potential of in-depth phenotyping of human neuronal cell models for pre-clinical studies and identification of modulators of endogenous tau toxicity. Through a panel of biochemical and cellular assays, A152T neurons showed accumulation, redistribution, and decreased solubility of tau. Upregulation of tau was coupled to enhanced stress-inducible markers and cell vulnerability to proteotoxic, excitotoxic, and mitochondrial stressors, which was rescued upon CRISPR/Cas9-mediated targeting of tau or by pharmacological activation of autophagy. Our findings unmask tau-mediated perturbations of specific pathways associated with neuronal vulnerability, revealing potential early disease biomarkers and therapeutic targets for FTD and other tauopathies.