Systemic Acrolein Elevations in Mice With Experimental Autoimmune Encephalomyelitis and Patients With Multiple Sclerosis

Demyelination and axonal injury are the key pathological processes in multiple sclerosis (MS), driven by inflammation and oxidative stress. Acrolein, a byproduct and instigator of oxidative stress, has been demonstrated as a neurotoxin in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. However, due to the invasive nature of acrolein detection using immunoblotting techniques, the investigation of acrolein in MS has been limited to animal models. Recently, detection of a specific acrolein-glutathione metabolite, 3-HPMA, has been demonstrated in urine, enabling the noninvasive quantification of acrolein for the first time in humans with neurological disorders. In this study, we have demonstrated similar elevated levels of acrolein in both urine (3-HPMA) and in spinal cord tissue (acrolein-lysine adduct) in mice with EAE, which can be reduced through systemic application of acrolein scavenger hydralazine. Furthermore, using this approach we have demonstrated an increase of 3-HPMA in both the urine and serum of MS patients relative to controls. It is expected that this noninvasive acrolein detection could facilitate the investigation of the role of acrolein in the pathology of MS in human. It may also be used to monitor putative therapies aimed at suppressing acrolein levels, reducing severity of symptoms, and slowing progression as previously demonstrated in animal studies

Genome-wide redistribution of MeCP2 in dorsal root ganglia after peripheral nerve injury.

BACKGROUND: Methyl-CpG-binding protein 2 (MeCP2), a protein with affinity for methylated cytosines, is crucial for neuronal development and function. MeCP2 regulates gene expression through activation, repression and chromatin remodeling. Mutations in MeCP2 cause Rett syndrome, and these patients display impaired nociception. We observed an increase in MeCP2 expression in mouse dorsal root ganglia (DRG) after peripheral nerve injury. The functional implication of increased MeCP2 is largely unknown. To identify regions of the genome bound by MeCP2 in the DRG and the changes induced by nerve injury, a chromatin immunoprecipitation of MeCP2 followed by sequencing (ChIP-seq) was performed 4 weeks after spared nerve injury (SNI). RESULTS: While the number of binding sites across the genome remained similar in the SNI model and sham control, SNI induced the redistribution of MeCP2 to transcriptionally relevant regions. To determine how differential binding of MeCP2 can affect gene expression in the DRG, we investigated mmu-miR-126, a microRNA locus that had enriched MeCP2 binding in the SNI model. Enriched MeCP2 binding to miR-126 locus after nerve injury repressed miR-126 expression, and this was not mediated by alterations in methylation pattern at the miR-126 locus. Downregulation of miR-126 resulted in the upregulation of its two target genes Dnmt1 and Vegfa in Neuro 2A cells and in SNI model compared to control. These target genes were significantly downregulated in Mecp2-null mice compared to wild-type littermates, indicating a regulatory role for MeCP2 in activating Dnmt1 and Vegfa expression. Intrathecal delivery of miR-126 was not sufficient to reverse nerve injury-induced mechanical and thermal hypersensitivity, but decreased Dnmt1 and Vegfa expression in the DRG. CONCLUSIONS: Our study shows a regulatory role for MeCP2 in that changes in global redistribution can result in direct and indirect modulation of gene expression in the DRG. Alterations in genome-wide binding of MeCP2 therefore provide a molecular basis for a better understanding of epigenetic regulation-induced molecular changes underlying nerve injury

Information Retrieval and Classification of Real-Time Multi-Source Hurricane Evacuation Notices

For an approaching disaster, the tracking of time-sensitive critical information such as hurricane evacuation notices is challenging in the United States. These notices are issued and distributed rapidly by numerous local authorities that may spread across multiple states. They often undergo frequent updates and are distributed through diverse online portals lacking standard formats. In this study, we developed an approach to timely detect and track the locally issued hurricane evacuation notices. The text data were collected mainly with a spatially targeted web scraping method. They were manually labeled and then classified using natural language processing techniques with deep learning models. The classification of mandatory evacuation notices achieved a high accuracy (recall = 96%). We used Hurricane Ian (2022) to illustrate how real-time evacuation notices extracted from local government sources could be redistributed with a Web GIS system. Our method applied to future hurricanes provides live data for situation awareness to higher-level government agencies and news media. The archived data helps scholars to study government responses toward weather warnings and individual behaviors influenced by evacuation history. The framework may be applied to other types of disasters for rapid and targeted retrieval, classification, redistribution, and archiving of real-time government orders and notifications

The next widespread bamboo flowering poses a massive risk to the giant panda

The IUCN Red List has downgraded several species from “endangered” to “vulnerable” that still have largely unknown extinction risks. We consider one of those downgraded species, the giant panda, a bamboo specialist. Massive bamboo flowering could be a natural disaster for giant pandas. Using scenario analysis, we explored possible impacts of the next bamboo flowering in the Qinling and Minshan Mountains that are home to most giant pandas. Our results showed that the Qinling Mountains could experience large-scale bamboo flowering leading to a high risk of widespread food shortages for the giant pandas by 2020. The Minshan Mountains could similarly experience a large-scale bamboo flowering with a high risk for giant pandas between 2020 and 2030 without suitable alternative habitat in the surrounding areas. These scenarios highlight thus-far unforeseen dangers of conserving giant pandas in a fragmented habitat. We recommend advance measures to protect giant panda from severe population crashes when flowering happens. This study also suggests the need to anticipate and manage long-term risks to other downgraded species

Modeling of the Natural Product Deboning Process Using Biological and Human Models

©1999 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other users, including reprinting/ republishing this material for advertising or promotional purposes, creating new collective works for resale or redistribution to servers or lists, or reuse of any copyrighted components of this work in other works.Presented at the 1999 IEEE/ASME International Conference on Advanced Intelligent Mechatronics (AIM 1999), 19-23 September 1999, Atlanta, GA.DOI: 10.1109/AIM.1999.803141One critical area in automation for commercial deboning systems for meat processing, is the inability of existing equipment to adapt to varying sizes and shapes of products. This usually results in less than desirable outcomes when measured in terms of yield of the operations. In poultry processing for example, the initial cut of wing-shoulder joints is the most critical step in the deboning process. Two approaches for determining a trajectory for the cut is presented. The first is a technique using x-ray and visual images to obtain a 2-D model that locates the shoulder joint with respect to the surface features of the product. The second approach is obtained by determining a 3-D cutting trajectory and the associated forces/torques using a motion analysis system and a force/torque sensor incorporated with a knife. We then discuss the potential application of these results in the design of an automated cutting system that uses the obtained trajectory as a nominal cutting path. The system would make'adjustments during the cut using force feedback so as to emulate the manual cutting process

Dickkopf-related protein 1 (Dkk1) regulates the accumulation and function of myeloid derived suppressor cells in cancer

Tumor–stroma interactions contribute to tumorigenesis. Tumor cells can educate the stroma at primary and distant sites to facilitate the recruitment of heterogeneous populations of immature myeloid cells, known as myeloid-derived suppressor cells (MDSCs). MDSCs suppress T cell responses and promote tumor proliferation. One outstanding question is how the local and distant stroma modulate MDSCs during tumor progression. Down-regulation of β-catenin is critical for MDSC accumulation and immune suppressive functions in mice and humans. Here, we demonstrate that stroma-derived Dickkopf-1 (Dkk1) targets β-catenin in MDSCs, thus exerting immune suppressive effects during tumor progression. Mice bearing extraskeletal tumors show significantly elevated levels of Dkk1 in bone microenvironment relative to tumor site. Strikingly, Dkk1 neutralization decreases tumor growth and MDSC numbers by rescuing β-catenin in these cells and restores T cell recruitment at the tumor site. Recombinant Dkk1 suppresses β-catenin target genes in MDSCs from mice and humans and anti-Dkk1 loses its antitumor effects in mice lacking β-catenin in myeloid cells or after depletion of MDSCs, demonstrating that Dkk1 directly targets MDSCs. Furthermore, we find a correlation between CD15(+) myeloid cells and Dkk1 in pancreatic cancer patients. We establish a novel immunomodulatory role for Dkk1 in regulating tumor-induced immune suppression via targeting β-catenin in MDSCs

Dichloroacetate prevents cisplatin-induced nephrotoxicity without compromising cisplatin anticancer properties

Cisplatin is an effective anticancer drug; however, cisplatin use often leads to nephrotoxicity, which limits its clinical effectiveness. In this study, we determined the effect of dichloroacetate, a novel anticancer agent, in a mouse model of cisplatin-induced AKI. Pretreatment with dichloroacetate significantly attenuated the cisplatin-induced increase in BUN and serum creatinine levels, renal tubular apoptosis, and oxidative stress. Additionally, pretreatment with dichloroacetate accelerated tubular regeneration after cisplatin-induced renal damage. Whole transcriptome sequencing revealed that dichloroacetate prevented mitochondrial dysfunction and preserved the energy-generating capacity of the kidneys by preventing the cisplatin-induced downregulation of fatty acid and glucose oxidation, and of genes involved in the Krebs cycle and oxidative phosphorylation. Notably, dichloroacetate did not interfere with the anticancer activity of cisplatin in vivo. These data provide strong evidence that dichloroacetate preserves renal function when used in conjunction with cisplatin

Venlafaxine treatment reduces the deficit of executive control of attention in patients with major depressive disorder

Attention plays an essential role in supporting other cognitive functions and behavior, and disturbance of attention is one of the most common symptoms in major depressive disorder (MDD). Although treatment with venlafaxine for MDD symptoms has been shown to reduce deficits in cognition and emotion regulation, it remains unclear whether venlafaxine improves specific attentional functions. We used the Attention Network Test to measure the attentional functions of alerting, orienting, and executive control before and after treatment with venlafaxine in patients with MDD compared to untreated healthy controls. Before treatment, the MDD group showed a selective impairment in alerting and executive control of attention, while there were no significant group differences in the orienting function. The interaction between group and session was significant for executive control, and after treatment with venlafaxine, the performance of the MDD group on executive control of attention was not significantly different from that of controls. Reported symptoms of MDD were also significantly reduced after treatment with venlafaxine. These results demonstrate that treatment with venlafaxine selectively normalizes the executive control function of attention in addition to improving clinical symptoms in MDD

«Ахеменидская Авеста» через призму античных источников

The epidemiologic evidence for the carcinogenicity of lead is inconsistent and requires improved exposure assessment to estimate risk. We evaluated historical occupational lead exposure for a population-based cohort of women (n=74,942) by calibrating a job-exposure matrix (JEM) with lead fume (n=20,084) and lead dust (n=5383) measurements collected over four decades in Shanghai, China. Using mixed-effect models, we calibrated intensity JEM ratings to the measurements using fixed-effects terms for year and JEM rating. We developed job/industry-specific estimates from the random-effects terms for job and industry. The model estimates were applied to subjects' jobs when the JEM probability rating was high for either job or industry; remaining jobs were considered unexposed. The models predicted that exposure increased monotonically with JEM intensity rating and decreased 20-50-fold over time. The cumulative calibrated JEM estimates and job/industry-specific estimates were highly correlated (Pearson correlation=0.79-0.84). Overall, 5% of the person-years and 8% of the women were exposed to lead fume; 2% of the person-years and 4% of the women were exposed to lead dust. The most common lead-exposed jobs were manufacturing electronic equipment. These historical lead estimates should enhance our ability to detect associations between lead exposure and cancer risk in the future epidemiologic analyses