Lysinuric protein intolerance with novel mutations in solute carrier family 7A member 7 in a Chinese family.

Introduction: Lysinuric protein intolerance (LPI) is a rare genetic disorder caused by mutations in the solute carrier family 7A member 7 (SLC7A7) gene. Case presentation: We presented two siblings with LPI, carrying novel mutations of c.776delT (p.L259Rfs*18) and c.155G>T (p.G52V) in SLC7A7. The younger sibling, preferring protein-rich foods, showed severe symptoms, including alveolar proteinosis, macrophage activation syndrome, severe diarrhea, and disturbance of consciousness with involuntary movements. In contrast, the elder sibling only had mild symptoms, likely due to aversion to protein-rich food since toddler age. Conclusion: LPI is a congenital genetic metabolic disease with multi-system involvement. Initiating appropriate protein-restricted diet therapy as soon as possible could help prevent the progression of LPI.

Improvement of Thick Coal Seam Gas Drainage Efficiency Using Highly Pressurized Multidischarge CO2 Gas Fracturing Technique.

Thick coal seam fracture stimulations were conducted to enhance pre-gas drainage efficiency through the use of a highly pressurized multidischarge carbon dioxide gas fracturing technique. This method also offers potential as a strategy for carbon dioxide sequestration, aiding in the reduction of atmospheric carbon dioxide levels and thereby contributing to the fight against climate change. This paper discusses findings from both field experiments and numerical simulations. Data from the field show that the multidischarge fracturing approach significantly improves permeability in thick coal seams, thereby boosting gas drainage effectiveness. Additionally, the impact of increasing the number of fracturing devices is more pronounced at distances of 2.5 or 7.5 m from the borehole but becomes more complex at 12.5 m or further. The numerical simulations reveal that this technique primarily enhances coal seam gas drainage by improving the seam permeability and establishing a gas pressure gradient within the seam. It is noted that the radius of failure around the borehole wall expands with higher discharge pressures, while the radius of effective drainage narrows as the gap between discharge heads increases. Moreover, adding more discharge sets significantly influences the deformation and permeability of the coal seam within a 5 m radius of the fracturing borehole, but the influence is not obvious after 10 m from the fracturing borehole.

Consumer brand and category switching behaviors after food safety incidents: Factors and mechanisms.

The excessive mold found in Three Squirrels' nuts and the clenbuterol abuse of Shuanghui are two infamous food safety incidents in China. We adopted push-pull-mooring theory to conduct a model and examined the factors influencing consumer short-term or long-term brand-switching or category-switching behaviors following the two food safety incidents. We employed multinomial logistic regression and structural equation modeling as tools to analyze 1027 valid questionnaires. The results, for the first time, revealed that perceived risk, alternative selectivity, alternative attractiveness, controllability attribution, and habits were key push, pull and mooring factors influencing Chinese consumers' brand and category switching from food brands under food safety crisis, and most importantly, that their influential paths differed greatly under the two food safety incidents, suggesting a different influential mechanism across two product categories (i.e., utilitarian food and hedonic food). These findings throw light on the predictors and mechanisms that affect consumer brand and category switching from food brands under food safety crisis and help associated food businesses develop more targeted and powerful crisis management and public relations strategies.

Recurrent infection triggered encephalopathy syndrome in a pediatric patient with RANBP2 mutation and severe acute respiratory syndrome coronavirus 2 infection.

Introduction: Acute necrotizing encephalopathy (ANE), a fatal subtype of infection-triggered encephalopathy syndrome (ITES), can be triggered by many systemic infections. RANBP2 gene mutations were associated with recurrent ANE. Case presentation: Here we report a 1-year-old girl with recurrent ITES and RANBP2 mutation. She was diagnosed with influenza-associated encephalopathy and made a full recovery on the first episode. After severe acute respiratory syndrome coronavirus 2 infection, the patient presented with seizures and deteriorating mental status. Brain magnetic resonance imaging revealed necrotic lesions in bilateral thalami and pons. Methylprednisolone, immunoglobulin, and interleukin 6 inhibitors were administered. Her consciousness level was improved at discharge. Nineteen cases of 2019 coronavirus disease-related ANE have been reported, of which 22.2% of patients died and 61.1% had neurologic disabilities. RANBP2 gene mutation was found in five patients, two of whom developed recurrent ITES. Conclusion: Patients with RANBP2 mutations are at risk for recurrent ITES, may develop ANE, and have a poor prognosis after relapse.

Feasibility of applying a noninvasive method for sleep monitoring based on mouse behaviors.

INTRODUCTION: Currently, electroencephalogram (EEG)/electromyogram (EMG) system is widely regarded as the "golden standard" for sleep monitoring. Imperfectly, its invasive monitoring may somehow interfere with the natural state of sleep. Up to now, noninvasive methods for sleep monitoring have developed, which could preserve the undisturbed and naïve sleep state of mice to the greatest extent, but the feasibility of their application under different conditions should be extensive validated. METHODS: Based on existing research, we verified the feasibility of a sleep monitoring system based on mouse behaviors under different conditions. The experimental mice were exposed to various stresses and placed into a combined device comprising noninvasive sleep monitoring equipment and an EEG/EMG system, and the sleep status was recorded under different physiological, pharmacological, and pathophysiological conditions. The consistency of the parameters obtained from the different systems was calculated using the Bland-Altman statistical method. RESULTS: The results demonstrated that the physiological sleep times determined by noninvasive sleep monitoring system were highly consistent with those obtained from the EEG/EMG system, and the coefficients were 94.4% and 95.1% in C57BL/6J and CD-1 mice, respectively. The noninvasive sleep monitoring system exhibited high sensitivity under the sleep-promoting effect of diazepam and caffeine-induced wakefulness, which was indicated by its ability to detect the effect of dosage on sleep times, and accurate determination of the sleep/wakeful status of mice under different pathophysiological conditions. After combining the data obtained from all the mice, the coefficient between the sleep times detected by behavior-based sleep monitoring system and those obtained from the EEG/EMG equipment was determined to .94. CONCLUSION: The results suggested that behavior-based sleep monitoring system could accurately evaluate the sleep/wakeful states of mice under different conditions.

Effects of gestational inflammation on age-related cognitive decline and hippocampal Gdnf-GFRα1 levels in F1 and F2 generations of CD-1 Mice.

BACKGROUND: It has been reported that age-associated cognitive decline (AACD) accelerated by maternal lipopolysaccharide (LPS) insult during late pregnancy can be transmitted to the second generation in a sex-specificity manner. In turn, recent studies indicated that glial cell line-derived neurotrophic factor (GDNF) and its cognate receptor (GFRα1) are critical for normal cognitive function. Based on this evidence, we aimed to explore whether Gdnf-GFRα1 expression contributes to cognitive decline in the F1 and F2 generations of mouse dams exposed to lipopolysaccharide (LPS) during late gestation, and to evaluate also the potential interference effect of pro-inflammatory cytokines. METHODS: During gestational days 15-17, pregnant CD-1 mice (8-10 weeks old) received a daily intraperitoneal injection of LPS (50 µg/kg) or saline (control). In utero LPS-exposed F1 generation mice were selectively mated to produce F2 generation mice. In F1 and F2 mice aged 3 and 15 months, the Morris water maze (MWM) was used to evaluated the spatial learning and memory ability, the western blotting and RT-PCR were used for analyses of hippocampal Gdnf and GFRα1 expression, and ELISA was used to analyse IL-1ß, IL-6 and TNF-α levels in serum. RESULTS: Middle-aged F1 offspring from LPS-treated mothers exhibited longer swimming latency and distance during the learning phase, lower percentage swimming time and distance in targe quadrant during memory phase, and lower hippocampal levels of Gdnf and GFRα1 gene products compared to age-matched controls. Similarly, the middle-aged F2 offspring from the Parents-LPS group had longer swimming latency and distance in the learning phase, and lower percentage swimming time and distance in memory phase than the F2-CON group. Moreover, the 3-month-old Parents-LPS and 15-month-old Parents- and Father-LPS groups had lower GDNF and GFRα1 protein and mRNAs levels compared to the age-matched F2-CON group. Furthermore, hippocampal levels of Gdnf and GFRα1 were correlated with impaired cognitive performance in the Morris water maze after controlling for circulating pro-inflammatory cytokine levels. CONCLUSIONS: Our findings indicate that accelerated AACD by maternal LPS exposure can be transmitted across at least two generations through declined Gdnf and GFRα1 expression, mainly via paternal linage.

Environmental enrichment improves declined cognition induced by prenatal inflammatory exposure in aged CD-1 mice: Role of NGPF2 and PSD-95.

Introduction: Research suggests that prenatal inflammatory exposure could accelerate age-related cognitive decline that may be resulted from neuroinflammation and synaptic dysfunction during aging. Environmental enrichment (EE) may mitigate the cognitive and synaptic deficits. Neurite growth-promoting factor 2 (NGPF2) and postsynaptic density protein 95 (PSD-95) play critical roles in neuroinflammation and synaptic function, respectively. Methods: We examined whether this adversity and EE exposure can cause alterations in Ngpf2 and Psd-95 expression. In this study, CD-1 mice received intraperitoneal injection of lipopolysaccharide (50 µg/kg) or normal saline from gestational days 15-17. After weaning, half of the male offspring under each treatment were exposed to EE. The Morris water maze was used to assess spatial learning and memory at 3 and 15 months of age, whereas quantitative real-time polymerase chain reaction and Western blotting were used to measure hippocampal mRNA and protein levels of NGPF2 and PSD-95, respectively. Meanwhile, serum levels of IL-6, IL-1ß, and TNF-α were determined by enzyme-linked immunosorbent assay. Results: The results showed that aged mice exhibited poor spatial learning and memory ability, elevated NGPF2 mRNA and protein levels, and decreased PSD-95 mRNA and protein levels relative to their young counterparts during natural aging. Embryonic inflammatory exposure accelerated age-related changes in spatial cognition, and in Ngpf2 and Psd-95 expression. Additionally, the levels of Ngpf2 and Psd-95 products were significantly positively and negatively correlated with cognitive dysfunction, respectively, particularly in prenatal inflammation-exposed aged mice. Changes in serum levels of IL-6, IL-1ß, and TNF-α reflective of systemic inflammation and their correlation with cognitive decline during accelerated aging were similar to those of hippocampal NGPF2. EE exposure could partially restore the accelerated decline in age-related cognitive function and in Psd-95 expression, especially in aged mice. Discussion: Overall, the aggravated cognitive disabilities in aged mice may be related to the alterations in Ngpf2 and Psd-95 expression and in systemic state of inflammation due to prenatal inflammatory exposure, and long-term EE exposure may ameliorate this cognitive impairment by upregulating Psd-95 expression.

Prenatal exposure to inflammation increases anxiety-like behaviors in F1 and F2 generations: possible links to decreased FABP7 in hippocampus.

Anxiety disorder has a high prevalence, and the risk of anxiety increases with age. Prenatal inflammation during key developmental timepoints can result in long-term changes in anxiety phenotype, even over a lifetime and across generations. However, whether maternal inflammation exposure during late gestation has intergenerational transmission effects on age-related anxiety-like behaviors and the possible underlying mechanisms are largely unknown. Fatty acid binding protein 7 (FABP7) is critical in hippocampal neurogenesis and is closely related to neuropsychiatric diseases, including anxiety disorder. The current study investigated the effects of maternal (F0 generation) lipopolysaccharide administration (50 µg/kg, i.p.) during late gestation on anxiety-like behaviors and FABP7 expression in F1 and F2 offspring, as well as the potential sex-specificity of intergenerational effects. Anxiety-like behaviors were evaluated using open field (OF), elevated plus maze, and black-white alley (BWA) tests at 3 and 13 months of age. The protein and messenger RNA levels of FABP7 in the hippocampus were measured using Western blot and real-time quantitative polymerase chain reaction (PCR), respectively. Overall, gestational LPS exposure in the F0 generation increased anxiety levels and decreased FABP7 expression levels in the F1 generation, which carried over to the F2 generation, and the intergenerational effects were mainly transferred via the maternal lineage. Moreover, hippocampal FABP7 expression was significantly correlated with performance in the battery of anxiety tests. The present study suggested that prenatal inflammation could increase age-related anxiety-like behaviors both in F1 and F2 offspring, and these effects possibly link to the FABP7 expression.

LINC00152 induced by TGF-ß promotes metastasis via HuR in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the main causes of cancer-related mortality, with a strong tendency to metastasize early. Transforming growth factor-ß (TGF-ß) signaling is a powerful regulator to promote metastasis of LUAD. Here, we screened long non-coding RNAs (lncRNAs) responsive to TGF-ß and highly expressed in LUAD cells, and finally obtained our master molecular LINC00152. We proved that the TGF-ß promoted transcription of LINC00152 through the classical TGF-ß/SMAD3 signaling pathway and maintained its stability through the RNA-binding protein HuR. Moreover, LINC00152 increased ZEB1, SNAI1 and SNAI2 expression via increasing the interactions of HuR and these transcription factors, ultimately promoting epithelial-mesenchymal transition of LUAD cell and enhancing LUAD metastasis in vivo. These data provided evidence that LINC00152 induced by TGF-ß promotes metastasis depending HuR in lung adenocarcinoma. Designing targeting LINC00152 and HuR inhibitors may therefore be an effective therapeutic strategy for LUAD treatment.

Maternal inflammation induces spatial learning and memory impairment in the F1 and F2 generations of mice via sex-specific epigenetic mechanisms.

Mounting evidence indicates that histone modifications are involved in aging-associated cognitive decline (AACD) and can be transmitted to offspring over multiple generations under conditions of stress. Here, we investigated the effects of maternal sub-chronic inflammation caused by lipopolysaccharide (LPS) on AACD and histone modifications in the F1 and F2 generations of experimental mice as well as the potential sex specificity of intergenerational effects. In brief, F0-generation CD-1 dams were exposed to LPS (50 µg/kg) or saline (CON) during late pregnancy. Subsequently, F1 males and females (at 2 months-of-age) from the LPS treatment group were mated with non-littermates from the LPS group or wild-type mice to produce F2 generations of parental- (F2-LPS2), paternal- (F2M-LPS1) and maternal-origin (F2F-LPS1) mice. Then, CON-F1 males and females were mated with wild-type mice to generate F2 generations of paternal- (F2M-CON1) and maternal-origin (F2F-CON1). Next, we evaluated the cognitive ability and levels of hippocampal H4K12ac and H3K9me3 in the F1 and F2 offspring at 3- and 13 months-of-age. Overall, F1 male and female LPS groups presented with elevated corticosterone (P < 0.001, P = 0.036, P = 0.025, 0.012, respectively) and cytokine responses, poorer cognitive performance (all P < 0.05) and H3K9 hypermethylation and H4K12 hypoacetylation in the dorsal hippocampus (all P < 0.05); these issues were carried over to the F2 generation via the parents, predominantly in the paternal lineage. Moreover, the levels of H3K9me3 and H4K12ac were significant correlated with cognitive performance (all P < 0.05), regardless of whether inflammatory insults had been incurred directly or indirectly. These findings indicated that gestational inflammatory insults in the F0 generation accelerated AACD in the F2 generation, along with H3K9 hypermethylation and H4K12 hypoacetylation in the hippocampus, and that these issues were derived from the F1 parents, especially from the F1 fathers.

Long-Term Environmental Enrichment Relieves Dysfunctional Cognition and Synaptic Protein Levels Induced by Prenatal Inflammation in Older CD-1 Mice.

A mounting body of evidence suggests that prenatal inflammation may enhance the rate of age-associated cognitive decline and may involve aberrant amounts of synaptic proteins in the hippocampus, including synaptotagmin-1 (Syt1) and activity-regulated cytoskeleton-associated protein (Arc). However, little is known about the specific impact of adolescent environmental enrichment (EE) on age-associated cognitive decline and the changes in synaptic proteins caused by prenatal inflammation. In this study, CD-1 mice in late pregnancy were given intraperitoneal doses of lipopolysaccharide (LPS, 50 µg/kg) or normal saline. Offspring arising from LPS dams were divided into a LPS group and a LPS plus EE (LPS-E) group. The LPS-E mice were exposed to EE from 2 months of age until the end of the experiment (3 or 15 months old). The Morris water maze (MWM) was used to assess the spatial learning and memory capacities of experimental mice, while western blotting and RNA-scope were used to determine the expression levels of Arc and Syt1 in the hippocampus at the protein and mRNA levels, respectively. Analysis revealed that at 15 months of age, the control mice experienced a reduction in cognitive ability and elevated expression levels of Arc and Syt1 genes when compared to control mice at 3 months of age. The LPS-E group exhibited better cognition and lower protein and mRNA levels of Arc and Syt1 than mice in the LPS group of the same age. However, the enriched environment mitigated but did not counteract, the effects of prenatal inflammation on cognitive and synaptic proteins when tested at either 3 or 15 months of age. Our findings revealed that long-term environmental enrichment improved the expression levels of synaptic proteins in CD-1 mice and that this effect was linked to the dysfunctional cognition caused by prenatal inflammation; this process may also be involved in the reduction of hippocampal Arc and Syt1 gene expression.

Adeno-associated virus vector intraperitoneal injection induces colonic mucosa and submucosa transduction and alters the diversity and composition of the faecal microbiota in rats.

Background: Viral vector technology, especially recombinant adeno-associated virus vector (rAAV) technology, has shown great promise in preclinical research for clinical applications. Several studies have confirmed that rAAV can successfully transduce the enteric nervous system (ENS), and rAAV gene therapy has been approved by the Food and Drug Administration (FDA) for the treatment of the early childhood blindness disease Leber congenital amaurosis and spinal muscular atrophy (SMA). However, until now, it has not been possible to determine the effect of AAV9 on intestinal microbiota. Methods: We examined the efficiency of AAV9-mediated ascending colon, transverse colon and descending colon transduction through intraperitoneal (IP) injection, performed 16S rRNA gene amplicon sequencing and analysed specific faecal microbial signatures following AAV9 IP injection via bioinformatics methods in Sprague-Dawley (SD) rats. Results: Our results showed (1) efficient transduction of the mucosa and submucosa of the ascending, transverse, and descending colon following AAV9 IP injection; (2) a decreased alpha diversity and an altered overall microbial composition following AAV9 IP injection; (3) significant enrichments in a total of 5 phyla, 10 classes, 13 orders, 15 families, 29 genera, and 230 OTUs following AAV9 IP injection; and (4) AAV9 can significantly upregulate the relative abundance of anaerobic microbiota which is one of the seven high-level phenotypes that BugBase could predict. Conclusion: In summary, these data show that IP injection of AAV9 can successfully induce the transduction of the colonic mucosa and submucosa and alter the diversity and composition of the faecal microbiota in rats.

Comparison of percutaneous transforaminal endoscopic decompression and short-segment fusion in the treatment of elderly degenerative lumbar scoliosis with spinal stenosis.

BACKGROUND: Degenerative lumbar scoliosis (DLS) combined with spinal stenosis is increasingly being diagnosed in the elderly. However, the appropriate surgical approach remains somewhat controversial. The aim of this study was to compare the results of percutaneous transforaminal endoscopic decompression (PTED) and short-segment fusion for the treatment of mild degenerative lumbar scoliosis combined with spinal stenosis in older adults over 60 years of age. METHODS: Of the 54 consecutive patients included, 30 were treated with PTED and 24 were treated with short-segment open fusion. All patients were followed up for at least 12 months (12-24 months). Patient demographics, and perioperative and clinical outcomes were recorded. Visual analog scale (VAS) scores, Oswestry disability index (ODI) scores, and modified Macnab criteria were used to assess clinical outcomes. At the same time, changes in disc height, segmental lordosis, coronal Cobb angle, and lumbar lordosis were compared. RESULTS: The mean age was 68.7 ± 6.5 years in the PTED group and 66.6 ± 5.1 years in the short-segment fusion group. At 1 year postoperatively, both groups showed significant improvement in VAS and ODI scores compared with preoperative scores (p < 0.05), with no statistically significant difference between groups. However, VAS-Back and ODI were lower in the PTED group at 1 week postoperatively (p < 0.05). According to the modified Macnab criteria, the excellent rates were 90.0 and 91.6% in the PTED and short-segment fusion groups, respectively. However, the PTED group had a significantly shorter operative time, blood loss, postoperative hospital stay, postoperative bed rest, and complication rate. There was no significant difference in radiological parameters between the two groups preoperatively. At the last follow-up, there were significant differences in disc height, segmental lordosis at the L4-5 and L5-S1 levels, and Cobb angle between the two groups. CONCLUSION: Both PTED and short-segment fusion for mild degenerative lumbar scoliosis combined with spinal stenosis have shown good clinical results. PTED under local anesthesia may be an effective supplement to conventional fusion surgery in elderly patients with DLS combined with spinal stenosis.

Astroglial Mechanisms Underlying Chronic Insomnia Disorder: A Clinical Study.

PURPOSE: The objective of this study was to investigate whether the serum biomarkers S100 calcium binding protein B (S100B), glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) change in patients with chronic insomnia disorder (CID), and if this is the case, whether the altered levels of these serum biomarkers are associated with poor sleep quality and cognitive decline in CID. PATIENTS AND METHODS: Fifty-seven CID outpatients constituted the CID group; thirty healthy controls (HC) were also enrolled. Questionnaires, polysomnography, Chinese-Beijing Version of Montreal Cognitive Assessment (MoCA-C) and Nine Box Maze Test (NBMT) were used to assess their sleep and neuropsychological function. Serum S100B, GFAP, BDNF, and GDNF were evaluated using enzyme-linked immunosorbent assay. RESULTS: The CID group had higher levels of S100B and GFAP and lower levels of BDNF and GDNF than the HC group. Spearman correlation analysis revealed that poor sleep quality, assessed by subjective and objective measures, was positively correlated with S100B level and negatively correlated with BDNF level. GFAP level correlated positively with poor subjective sleep quality. Moreover, S100B and GFAP levels correlated negatively with general cognitive function assessed using MoCA-C. GFAP level correlated positively with poor spatial working memory (SWM) in the NBMT; BDNF level was linked to poor SWM and object recognition memory (ORcM) in the NBMT. However, principal component analysis revealed that serum S100B level was positively linked to the errors in object working memories, BDNF and GDNF concentrations were negatively linked with errors in ORcM, and GFAP concentration was positively correlated with the errors in the SWM and spatial reference memories. CONCLUSION: Serum S100B, GFAP, BDNF, and GDNF levels were altered in patients with CID, indicating astrocyte damage, and were associated with insomnia severity or/and cognitive dysfunction.

Effects of Embryonic Inflammation and Adolescent Psychosocial Environment on Cognition and Hippocampal Staufen in Middle-Aged Mice.

Accumulating evidence has indicated that embryonic inflammation could accelerate age-associated cognitive impairment, which can be attributed to dysregulation of synaptic plasticity-associated proteins, such as RNA-binding proteins (RBPs). Staufen is a double-stranded RBP that plays a critical role in the modulation of synaptic plasticity and memory. However, relatively few studies have investigated how embryonic inflammation affects cognition and neurobiology during aging, or how the adolescent psychosocial environment affects inflammation-induced remote cognitive impairment. Consequently, the aim of this study was to investigate whether these adverse factors can induce changes in Staufen expression, and whether these changes are correlated with cognitive impairment. In our study, CD-1 mice were administered lipopolysaccharides (LPS, 50 µg/kg) or an equal amount of saline (control) intraperitoneally during days 15-17 of gestation. At 2 months of age, male offspring were randomly exposed to stress (S), an enriched environment (E), or not treated (CON) and then assigned to five groups: LPS, LPS+S, LPS+E, CON, and CON+S. Mice were evaluated at 3-month-old (young) and 15-month-old (middle-aged). Cognitive function was assessed using the Morris water maze test, while Staufen expression was examined at both the protein and mRNA level using immunohistochemistry/western blotting and RNAscope technology, respectively. The results showed that the middle-aged mice had worse cognitive performance and higher Staufen expression than young mice. Embryonic inflammation induced cognitive impairment and increased Staufen expression in the middle-aged mice, whereas adolescent stress/an enriched environment would accelerated/mitigated these effects. Meanwhile, Staufen expression was closely correlated with cognitive performance. Our findings suggested embryonic inflammation can accelerate age-associated learning and memory impairments, and these effects may be related to the Staufen expression.

Effects of Prenatal Exposure to Inflammation Coupled With Stress Exposure During Adolescence on Cognition and Synaptic Protein Levels in Aged CD-1 Mice.

Age-associated impairment of spatial learning and memory (AISLM) presents substantial challenges to our health and society. Increasing evidence has indicated that embryonic exposure to inflammation accelerates the AISLM, and this can be attributable, at least partly, to changed synaptic plasticity associated with the activities of various proteins. However, it is still uncertain whether social psychological factors affect this AISLM and/or the expression of synaptic protein-associated genes. Synaptotagmin-1 (Syt1) and activity-regulated cytoskeleton-associated protein (Arc) are two synaptic proteins closely related to cognitive functions. In this study, pregnant CD-1 mice received daily intraperitoneal injections of lipopolysaccharide (LPS) (50 µg/kg) or normal saline at days 15-17 of gestation, and half of the offspring of each group were then subjected to stress for 28 days in adolescence. The Morris water maze (MWM) test was used to separately evaluate spatial learning and memory at 3 and 15 months of age, while western blotting and RNAscope assays were used to measure the protein and mRNA levels of Arc and Syt1 in the hippocampus. The results showed that, at 15 months of age, control mice had worse cognitive ability and higher protein and mRNA levels of Arc and Syt1 than their younger counterparts. Embryonic exposure to inflammation or exposure to stress in adolescence aggravated the AISLM, as well as the age-related increase in Arc and Syt1 expression. Moreover, the hippocampal protein and mRNA levels of Arc and Syt1 were significantly correlated with the performance in the learning and memory periods of the MWM test, especially in the mice that had suffered adverse insults in early life. Our findings indicated that prenatal exposure to inflammation or stress exposure in adolescence exacerbated the AISLM and age-related upregulation of Arc and Syt1 expression, and these effects were linked to cognitive impairments in CD-1 mice exposed to adverse factors in early life.

Lipopolysaccharide exposure during late embryogenesis triggers and drives Alzheimer-like behavioral and neuropathological changes in CD-1 mice.

INTRODUCTION: Infections could contribute to Alzheimer's disease (AD) neuropathology in human. However, experimental evidence for a causal relationship between infections during the prenatal phase and the onset of AD is lacking. METHODS: CD-1 mothers were intraperitoneally received lipopolysaccharide (LPS) with two doses (25 and 50 µg/kg) or normal saline every day during gestational days 15-17. A battery of behavioral tasks was used to assess the species-typical behavior, sensorimotor capacity, anxiety, locomotor activity, recognition memory, and spatial learning and memory in 1-, 6-, 12-, 18-, and 22-month-old offspring mice. An immunohistochemical technology was performed to detect neuropathological indicators consisting of amyloid-ß (Aß), phosphorylated tau (p-tau), and glial fibrillary acidic protein (GFAP) in the hippocampus. RESULTS: Compared to the same-aged controls, LPS-treated offspring had similar behavioral abilities and the levels of Aß42, p-tau, and GFAP at 1 and 6 months old. From 12 months onward, LPS-treated offspring gradually showed decreased species-typical behavior, sensorimotor ability, locomotor activity, recognition memory, and spatial learning and memory, and increased anxieties and the levels of Aß42, p-tau, and GFAP relative to the same-aged controls. Moreover, this damage effect (especially cognitive decline) persistently progressed onwards. The changes in these neuropathological indicators significantly correlated with impaired spatial learning and memory. CONCLUSIONS: Prenatal exposure to low doses of LPS caused AD-related features including behavioral and neuropathological changes from midlife to senectitude.

A Long-Term Enriched Environment Ameliorates the Accelerated Age-Related Memory Impairment Induced by Gestational Administration of Lipopolysaccharide: Role of Plastic Mitochondrial Quality Control.

Studies have shown that gestational inflammation accelerates age-related memory impairment in mother mice. An enriched environment (EE) can improve age-related memory impairment, whereas mitochondrial dysfunction has been implicated in the pathogenesis of brain aging. However, it is unclear whether an EE can counteract the accelerated age-related memory impairment induced by gestational inflammation and whether this process is associated with the disruption of mitochondrial quality control (MQC) processes. In this study, CD-1 mice received daily intraperitoneal injections of lipopolysaccharide (LPS, 50 µg/kg) or normal saline (CON group) during gestational days 15-17 and were separated from their offspring at the end of normal lactation. The mothers that received LPS were divided into LPS group and LPS plus EE (LPS-E) treatment groups based on whether the mice were exposed to an EE until the end of the experiment. At 6 and 18 months of age, the Morris water maze test was used to evaluate spatial learning and memory abilities. Quantitative reverse transcription polymerase chain reaction and Western blot were used to measure the messenber RNA (mRNA) and protein levels of MQC-related genes in the hippocampus, respectively. The results showed that all the aged (18 months old) mice underwent a striking decline in spatial learning and memory performances and decreased mRNA/protein levels related to mitochondrial dynamics (Mfn1/Mfn2, OPA1, and Drp1), biogenesis (PGC-1α), and mitophagy (PINK1/parkin) in the hippocampi compared with the young (6 months old) mice. LPS treatment exacerbated the decline in age-related spatial learning and memory and enhanced the reduction in the mRNA and protein levels of MQC-related genes but increased the levels of PGC-1α in young mice. Exposure to an EE could alleviate the accelerated decline in age-related spatial learning and memory abilities and the accelerated changes in MQC-related mRNA or protein levels resulting from LPS treatment, especially in aged mice. In conclusion, long-term exposure to an EE can counteract the accelerated age-related spatial cognition impairment modulated by MQC in CD-1 mother mice that experience inflammation during pregnancy.

Long noncoding RNA CAR10 promotes lung adenocarcinoma metastasis via miR-203/30/SNAI axis.

Long noncoding RNAs (lncRNAs) play an important role in lung adenocarcinoma (LUAD) metastasis. Here, we found that lncRNA chromatin-associated RNA 10 (CAR10) was upregulated in the tumor tissue of patients with LUAD and enhanced tumor metastasis in vitro and in vivo. Mechanistically, CAR10 induced epithelial-to-mesenchymal transition (EMT) by directly binding with miR-30 and miR-203 and then regulating the expression of SNAI1 and SNAI2. CAR10 overexpression was positively correlated with a poor prognosis in LUAD patients, whereas overexpression of both CAR10 and SNAI was correlated with even worse clinical outcomes. In conclusion, the CAR10/miR-30/203/SNAI axis is a novel and potential therapeutic target for LUAD.

MiR-34b-3 and miR-449a inhibit malignant progression of nasopharyngeal carcinoma by targeting lactate dehydrogenase A.

MicroRNA expression profiling assays have shown that miR-34b/c and miR-449a are down-regulated in nasopharyngeal carcinoma (NPC); however, the targets and functions of miR-34b/c and miR-449a in the pathologenesis of NPC remain elusive. In this study, we verified miR-34b/c and miR-449a were significantly reduced with the advance of NPC. Overexpression of miR-34b-3 and miR-449a suppressed the growth of NPC cells in culture and mouse tumor xenografts. Using tandem mass tags for quantitative labeling and LC-MS/MS analysis to investigate protein changes after restoring expression of miR-34b-3, 251 proteins were found to be down-regulated after miR-34b-3 transfection. Through 3 replicate experiments, we found that miR-34b-3 regulated the expression of 15 potential targeted genes mainly clustered in the key enzymes of glycolysis metabolism, including lactate dehydrogenase A (LDHA). Further investigation revealed that miR-34b-3 and miR-449a negatively regulated LDHA by binding to the 3' untranslated regions of LDHA. Furthermore, LDHA overexpression rescued the miR-34b-3 and miR-449a induced tumor inhibition effect in CNE2 cells. In addition, miR-34b-3 and miR-449a suppressed LDH activity and reduced LD content, which were directly induced by downregulation of the LDHA. Our findings suggest that miR-34b-3 and miR-449a suppress the development of NPC through regulation of glycolysis via targeting LDHA and may be potential therapeutic targets for the treatment of NPC.