Evidence of the Role of Inflammation and the Hormonal Environment in the Pathogenesis of Adrenal Myelolipomas in Congenital Adrenal Hyperplasia.

Adrenal myelolipomas (AML) are composed of mature adipose and hematopoietic components. They represent approximately 3 percent of adrenal tumors and are commonly found in patients with congenital adrenal hyperplasia (CAH). CAH provides a unique environment to explore AML pathogenesis. We aimed to evaluate the role of the immune system and hormones that accumulate in poorly controlled CAH in the development of AML. When compared to normal adrenal tissue, CAH-affected adrenal tissue and myelolipomas showed an increased expression of inflammatory cells (CD68, IL2Rbeta), stem cells (CD117) B cells (IRF4), and adipogenic markers (aP2/FABP4, AdipoQ, PPARγ, Leptin, CideA), and immunostaining showed nodular lymphocytic accumulation. Immunohistochemistry staining revealed a higher density of inflammatory cells (CD20, CD3, CD68) in CAH compared to non-CAH myelolipomas. In vitro RNA-sequencing studies using NCI-H295R adrenocortical cells with exogenous exposure to ACTH, testosterone, and 17-hydroxyprogesterone hormones, showed the differential expression of genes involved in cell cycle progression, phosphorylation, and tumorigenesis. Migration of B-lymphocytes was initiated after the hormonal treatment of adrenocortical cells using the Boyden chamber chemotaxis assay, indicating a possible hormonal influence on triggering inflammation and the development of myelolipomas. These findings demonstrate the important role of inflammation and the hormonal milieu in the development of AML in CAH.

Polybrominated diphenyl ethers in dust, hair and urine: Exposure, excretion.

Polybrominated diphenyl ethers (PBDEs) have been detected in various environmental media and human tissues. PBDEs concentrations in dust from college buildings and homes and in paired hair and urine samples from students were determined. This is of great significance to explore the accumulation and excretion patterns of PBDEs in the human body. The median PBDEs concentrations in the dust (College: 84.59 ng/g; Home: 170.32 ng/g) and hair (undergraduate: 6.16 ng/g; Home: 3.25 ng/g) samples were generally lower than were found in the majority of previous studies. The PBDEs concentrations in the hair and urine samples were subjected to principal component analysis, and the results combined with the PBDEs detection rates confirmed that hair is a useful non-invasive sampling medium for assessing PBDEs exposure and the risks posed. Body mass indices (BMIs) were used to divide students who had not been exposed to large amounts of PBDEs into groups. Body fat percentage is an important factor affecting the accumulation of PBDE in the human body. Environmental factors were found to affect the PBDEs concentrations in the hair and urine samples less for normal-weight students (BMI≤24) than overweight students (BMI>24). Short-term environmental changes to more readily affect the PBDEs concentrations in the tissues of the normal-weight than overweight students. PBDEs with seven or more bromine substituents were found not to be readily excreted in urine. Performing molecular docking simulations of the binding of isomers BDE-99 and BDE-100 to megalin. The binding energy was higher for BDE-100 and megalin than for BDE-99 and megalin, meaning BDE-99 would be more readily excreted than BDE-100.

The scaffold of neutrophil extracellular traps promotes CCA progression and modulates angiogenesis via ITGAV/NFκB.

Neutrophil extracellular traps (NETs) have garnered attention for their dual role in host defense and tumor promotion. With their involvement documented across a spectrum of tumors, their influence on the progression of cholangiocarcinoma (CCA) is of paramount interest. We employed immunohistochemistry and immunofluorescence to detect NET deposition in CCA tissues. Through in vitro and in vivo investigation, including CCA organoid and transposon-based models in PAD4 KO mice, we explored the effects of NETs on cell proliferation and metastasis. Molecular insights were gained through RNA sequencing, enzyme linked immunosorbent assay, and chromatin immunoprecipitation. Elevated intratumoral NET deposition within CCA tissues was associated with poor survival. The influence of NETs on CCA proliferation, migration and invasion was primarily mediated by NET-DNA. RNA sequencing unveiled the activation of the NFκB signaling pathway due to NET-DNA stimulation. NET-DNA pull-down assay coupled with mass spectrometry revealed the interaction between NET-DNA and αV integrin (ITGAV), culmination in the activation of the NFκB pathway. Furthermore, NET-DNA directly upregulated the expression of VEGF-A in cancer cells. The study unequivocally establishes NETs as facilitators of CCA progression, orchestrating proliferation, metastasis, and angiogenesis through ITGAV/NFκB pathway activation. This novel insight positions NETs as prospective therapeutic targets for managing CCA patients. By implementing a variety of methodologies and drawing intricate connections between NETs, DNA interactions, and signaling pathways, this research expands our comprehension of the complex interplay between the immune system and cancer progression, offering promising avenues for intervention.

High-Strength, Freeze-Resistant, Recyclable, and Biodegradable Polyvinyl Alcohol/Glycol/Wheat Protein Complex Organohydrogel for Wearable Sensing Devices.

The application of flexible wearable sensing devices based on conductive hydrogels in human motion signal monitoring has been widely studied. However, conventional conductive hydrogels contain a large amount of water, resulting in poor mechanical properties and limiting their application in harsh environments. Here, a simple one-pot method for preparing conductive hydrogels is proposed, that is, polyvinyl alcohol (PVA), wheat protein (WP), and lithium chloride (LiCl) are dissolved in an ethylene glycol (EG)/water binary solvent. The obtained PVA/EG/WP (PEW) conductive organohydrogel has good mechanical properties, and its tensile strength and elongation at break reach 1.19 MPa and 531%, respectively, which can withstand a load of more than 6000 times its own weight without breaking. The binary solvent system composed of EG/water endows the hydrogel with good frost resistance and water retention. PEW organohydrogel as a wearable strain sensor also has good strain sensitivity (GF = 2.36), which can be used to detect the movement and physiological activity signals in different parts of the human body. In addition, PEW organohydrogels exhibit good degradability, reducing the environmental footprint of the flexible sensors after disposal. This research provides a new and viable way to prepare a new generation of environmentally friendly sensors.

Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion.

Introduction: Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides. Methods: Following the identification of a loss-of-function variant (p.Arg703Gln) in the peptidylglycine a-amidating monooxygenase (PAM) gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated PA kindreds for PAM variants. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. Results: In germline DNA, we detected seven heterozygous, likely pathogenic missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with growth hormone excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, splicing by minigene assays, and amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction. Conclusion: The identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.

PCBs, PCNs, and PCDD/Fs in Soil around an Industrial Park in Northwest China: Levels, Source Apportionment, and Human Health Risk.

The concentrations of polychlorinated biphenyls (PCBs), polychlorinated naphthalenes (PCNs), and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) were determined in soil samples collected around an industrial park in Northwest China, to investigate the potential impacts of park emissions on the surrounding environment. The total concentration ranges of PCBs, PCNs, and PCDD/Fs in the soil samples were in 13.2-1240, 141-832, and 3.60-156 pg/g, respectively. The spatial distribution and congener patterns of PCBs, PCNs, and PCCD/Fs indicated that there might be multiple contamination sources in the study area, so source apportionments of PCBs, PCNs, and PCCD/Fs were performed by a positive matrix factorization model based on the concentrations of all target congeners together. The results revealed that these highly chlorinated congeners (CB-209, CN-75, and OCDF) might be derived from phthalocyanine pigments, the legacy of Halowax 1051 and 2,4-D products, which together contributed nearly half of the total concentration of target compounds (44.5%). In addition to highly chlorinated congeners, the local industrial thermal processes were mainly responsible for the contamination of PCBs, PCNs, and PCDD/Fs in the surrounding soil. The total carcinogenic risk of PCBs, PCNs, and PCDD/Fs in a few soil samples (0.22 × 10-6, 0.32 × 10-6, and 0.40 × 10-6) approached the threshold of potential carcinogenic risk (1.0 × 10-6). Since these pollutants can continuously accumulate in the soil, the contamination of PCBs, PCNs, and PCDD/Fs in surrounding soil deserves continuous attention.

Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion.

Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. Following the identification of a loss-of-function variant (p.Arg703Gln) in the PAM gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated pituitary adenomas kindreds for PAM variants. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. No germline CNVs or somatic single nucleotide variants (SNVs) were identified. We detected seven likely pathogenic heterozygous missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with GH excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or with different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, for splicing by minigene assays, and for amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs to diagnoses linked to pituitary gland hyperfunction. Identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.

Nanomicelles for GLUT1-targeting hepatocellular carcinoma therapy based on NADPH depletion.

Hepatocellular carcinoma (HCC) is a malignant tumor leading cancer-associated high mortality worldwide. Unfortunately, the most commonly used drug therapeutics not only lack of target ability and efficiency, but also exhibit severe systemic toxicity to normal tissues. Thus, effective and targeted nanodrug of HCC therapy is emerging as a more important issue. Here, we design and develop the novel nanomicelles, namely Mannose-polyethylene glycol 600-Nitroimidazole (Man-NIT). This micelle compound with high purity comprise two parts, which can self-assemble into nanoscale micelle. The outer shell is selected mannose as hydrophilic moiety, while the inner core is nitroimidazole as hydrophobic moiety. In the cell experiment, Man-NIT was more cellular uptake by HCCLM3 cells due to the mannose modification. Mannose as a kind of glucose transporter 1 (GLUT1) substrate, can specifically recognize and bind to over-expressed GLUT1 on carcinoma cytomembrane. The nitroimidazole moiety of Man-NIT was reduced by the over-expressed nitroreductase with reduced nicotinamide adenine dinucleotide phosphate (NADPH) as the cofactor, resulting in transient deletion of NADPH and glutathione (GSH). The increase of reactive oxygen species (ROS) in HCCLM3 cells disturbed the balance of redox, and finally caused the death of tumor cells. Additional in vivo experiment was conducted using twenty-four male BALB/c nude mice to build the tumor model. The results showed that nanomicelles were accumulated in the liver of mice. The tumor size and pathological features were obviously improved after nanomicelles treatment. It indicates that namomicelles have a tumor inhibition effect, especially Man-NIT, which may be a potential nanodrug of chemotherapeutics for HCC therapy.

Impact of exercise training on gut microbiome imbalance in obese individuals: a study based on Mendelian randomization analysis.

Objective: The aim of this study was to investigate the relationship between exercise and gut Microbiome and to assess its possible causality. Methods: Using Mendelian randomization (MR) research methods, we collected genetic data from different populations, including genetic variants associated with relative abundance or presence of microbial taxa as instrumental variables. At the same time, we extracted results related to obesity and gut Microbiome from existing relevant studies and used inverse variance weighting (IVW), weighted median, and MR-Egger regression to assess the causal relationship between obesity and gut Microbiome. We plotted forest plots and scatter plots of the association between obesity and gut Microbiome. Results: Gut Microbiome was positively associated with obesity, and four bacterial genera (Akkermansia, RuminococcaceaeUCG011, Holdemania, and Intestinimonas) were associated with obesity according to inverse variance-weighted estimation in at least one MR method. Inverse variance weighted estimation showed that obesity was associated with obesity in Akkermansia (OR = 0.810, 95% CI 0.608-1.079, p = 0.04), RuminococcaceaeUCG011 (OR = 1.238, 95% CI 0. 511-2.999, p = 0.04), Holdemania Intestinimonas (OR = 1.214, 95% CI 1.002-1.470, p = 0.03), and Intestinimonas (OR = 0.747, 95% CI 0.514-1.086, p = 0.01) had a relevant effect. Obesity decreased the abundance of Akkermansia, Intestinimonas microbiome and increased the abundance of RuminococcaceaeUCG011, Holdemania microbiome. Conclusion: The results of this study, conducted using a two-sample Mendelian randomization method, suggest a causal relationship between obesity and intestinal microbiome. Obesity decreased the abundance of Akkermansia, Intestinimonas microbiome and increased the abundance of RuminococcaceaeUCG011, Holdemania microbiome. More randomized controlled trials are necessary to elucidate the protective effects of exercise on gut Microbiome and its unique protective mechanisms.

Concentration, Distribution and Biomagnification of Novel Brominated Flame Retardant in Grassland Food Chain and Sheep from Inner Mongolia, China.

Novel brominated flame retardants (NBFRs) have been of great concern in the past few years due to their ubiquity in the environment and potential bioconcentration characteristics. This study takes Xilingol grassland in Inner Mongolia as the research area to analyze the pollution characteristics of NBFRs (pTBX, HBB, PBT, PBBz, and PBEB) in the grassland food chain. pTBX was more likely to be biomagnified in the food chain of amphibians, reptiles, and birds, whereas PBT and HBB were more likely to be biomagnified in the food chain of mammals. This may be because these animals have different diets and metabolic patterns. According to the concentration distribution of NBFRs in sheep organs and tissues, PBT, HBB, and PBBz easy bioaccumulated in sheep. The biomagnification effect of sheep adipose tissue and internal organs on NBFRs was inconsistent, so the biomagnification of chemicals in organisms cannot be determined only by the biomagnification of adipose tissue.

A Pilot Study on the Concentration, Distribution and Bioaccumulation of Polybrominated Diphenyl Ethers (PBDEs) in Tissues and Organs of Grassland Sheep.

Polybrominated diphenyl ether (PBDE) concentrations in various tissues and organs of grassland sheep from Inner Mongolia, China, were determined. The abilities of PBDEs binding to ovine serum albumin (OSA) and Cytochrome P450 enzyme (CYP3A24) were assessed by fluorescence spectroscopy and molecular docking simulations. The PBDE concentrations in the sheep tissue and organ samples were 33.4-167 pg/g dw. The distribution of PBDEs in sheep organs and tissues is affected not only by the function of organs and tissues, but also by the characteristics of PBDEs. Adipose tissue tends to bioaccumulate more-brominated BDEs (BDE-154, -153, and -183), but muscle tissues and visceral organs mainly bioaccumulate less-brominated BDEs. The distribution of PBDEs in visceral organs is mainly affected by the transport of ovine serum albumin (OSA) and the metabolism of CYP3A24 enzyme. The distribution of PBDEs in adipose tissue and brain is mainly affected by their logKOW.

Exploring the role of mast cells in the progression of liver disease.

In addition to being associated with allergic diseases, parasites, bacteria, and venoms, a growing body of research indicates that mast cells and their mediators can regulate liver disease progression. When mast cells are activated, they degranulate and release many mediators, such as histamine, tryptase, chymase, transforming growth factor-ß1 (TGF-ß1), tumor necrosis factor-α(TNF-α), interleukins cytokines, and other substances that mediate the progression of liver disease. This article reviews the role of mast cells and their secretory mediators in developing hepatitis, cirrhosis and hepatocellular carcinoma (HCC) and their essential role in immunotherapy. Targeting MC infiltration may be a novel therapeutic option for improving liver disease progression.

Modeling SARS-CoV-2 and influenza infections and antiviral treatments in human lung epithelial tissue equivalents.

There is a critical need for physiologically relevant, robust, and ready-to-use in vitro cellular assay platforms to rapidly model the infectivity of emerging viruses and develop new antiviral treatments. Here we describe the cellular complexity of human alveolar and tracheobronchial air liquid interface (ALI) tissue models during SARS-CoV-2 and influenza A virus (IAV) infections. Our results showed that both SARS-CoV-2 and IAV effectively infect these ALI tissues, with SARS-CoV-2 exhibiting a slower replication peaking at later time-points compared to IAV. We detected tissue-specific chemokine and cytokine storms in response to viral infection, including well-defined biomarkers in severe SARS-CoV-2 and IAV infections such as CXCL10, IL-6, and IL-10. Our single-cell RNA sequencing analysis showed similar findings to that found in vivo for SARS-CoV-2 infection, including dampened IFN response, increased chemokine induction, and inhibition of MHC Class I presentation not observed for IAV infected tissues. Finally, we demonstrate the pharmacological validity of these ALI tissue models as antiviral drug screening assay platforms, with the potential to be easily adapted to include other cell types and increase the throughput to test relevant pathogens.

Levels, profiles and potential human health risks of brominated and parent polycyclic aromatic hydrocarbons in soils around three different types of industrial areas in China.

Brominated polycyclic aromatic hydrocarbons (Br-PAHs) are an emerging class of persistent organic pollutants with toxicity similar to dioxins. Industrial thermal processes have been identified as major sources of Br-PAHs in the current environment. However, studies on soil contaminations with Br-PAHs around industrial areas were scarce. In this study, 18 Br-PAHs and 16 PAHs were analyzed in soils around an electronic waste dismantling area (EDA), an industrial area that mainly performed steel smelting (SSP), and an industrial area mainly performed secondary copper smelting (SCS). The mean concentrations of Br-PAHs and PAHs were 1362 pg/g and 1034 ng/g, 582 pg/g and 13,938 ng/g, and 307 pg/g and 2211 ng/g in the soil around EDA, SSP, and SCS, respectively. The order of Br-PAH concentrations among three industrial areas was inconsistent with that of PAHs, suggesting that there may be some differences in contamination characteristics of Br-PAHs in three types of industrial areas. The significant correlation between Br-PAHs and parent PAHs indicated that direct bromination may be the main formation pathway of Br-PAHs in soils in EDA. The result of principal component analysis further revealed that the congener pattern of Br-PAHs in soils around EDA is different from that of SSP and SCS. It was found that the ratio of 1-BrPyr and 3-BrFlu can be applied to identify environmental contamination with Br-PAHs from e-waste dismantling. The health risk assessment results showed that there were some soil samples with carcinogenic risks above the risk threshold in each industrial area, and deserve our concern.

Factors Influencing Dechlorane plus Distributions in Various Sheep Tissues.

Dechlorane plus (DP) is a potential persistent organic pollutant and its distribution in various tissues and organs of terrestrial organisms is currently unknown. DP concentrations in sheep tissues were determined in this study. The DP concentrations in the tissues decreased in the following order: abdominal fat > liver > stomach > heart > outer tenderloin > lung > hind leg meat > kidney > small intestine > tail fat > spleen > brain. Apart from brain and fat, anti-DP is enriched more readily than syn-DP in sheep tissues, but syn-DP is more readily enriched in brain and abdominal fat. The factors influencing DP distributions in sheep tissues were assessed by determining the DP to sheep serum albumin binding forces, binding types, and binding sites by fluorescence spectroscopy. The results indicated that anti-DP more readily binds to sheep serum albumin than does syn-DP. Therefore, sheep serum albumin will more readily transport anti-DP than syn-DP to sheep tissues, and anti-DP will be enriched more than syn-DP in the tissues. The molecular diameter of DP is the main factor affecting DP concentrations in sheep brain and fat because of the blood−brain barrier and because the main source of DP to abdominal fat is dermal contact.

The Therapeutic Potential and Clinical Significance of Exosomes as Carriers of Drug Delivery System.

Drug delivery system (DDS) realizes the drug delivery process through the drug carrier. As an important part of DDS, the selection of the drug carrier material is extremely critical, which requires the carrier material to possess excellent biocompatibility and targeting and not affect the pharmacological action of the drug. As one of the endogenous extracellular vesicles, exosomes are 30-100 nm in diameter, which are considered a new generation of a natural nanoscale delivery system. Exosomes secreted by different types of cells carry signaling molecules (such as proteins and nucleic acid) playing an important role in cell behaviors. Owing to their ability to specialize in intercellular communication, exosomes provide a distinctive method to deliver therapeutic drugs to target cells. In this concept, exosomes as the natural liposomes carry endogenous biomolecules, have excellent biocompatibility, and could be loaded with cargo both in vivo and in vitro. In addition, modifications by genetic and/or chemical engineering to part of the exosome surface or complement the desired natural effect may enhance the targeting with drug loading capability. Notably, exosomes weakly react with serum proteins prolonging cargo half-life. Overall, exosomes as natural carriers integrate the superiority of synthetic nanocarriers and cellular communication while precluding their limitations, which provides novel and reliable methods for drug delivery and treatment. Our review focuses on the therapeutic potentials and clinical values of exosomes as a carrier of drug delivery system in multiple diseases, including cancer, nervous, immune, and skeletal system diseases.

Morphologic and Molecular Characterization of Adrenals and Adrenal Rest Affected by Congenital Adrenal Hyperplasia.

Introduction: Adrenocortical hyperplasia and adrenal rest tumor (ART) formation are common in congenital adrenal hyperplasia (CAH). Although driven by excessive corticotropin, much is unknown regarding the morphology and transformation of these tissues. Our study objective was to characterize CAH-affected adrenals and ART and compare with control adrenal and gonadal tissues. Patients/Methods: CAH adrenals, ART and control tissues were analyzed by histology, immunohistochemistry, and transcriptome sequencing. We investigated protein expression of the ACTH receptor (MC2R), steroidogenic (CYP11B2, CYP11B1, CYB5A) and immune (CD20, CD3, CD68) biomarkers, and delta-like 1 homolog (DLK1), a membrane bound protein broadly expressed in fetal and many endocrine cells. RNA was isolated and gene expression was analyzed by RNA sequencing (RNA-seq) followed by principle component, and unsupervised clustering analyses. Results: Based on immunohistochemistry, CAH adrenals and ART demonstrated increased zona reticularis (ZR)-like CYB5A expression, compared to CYP11B1, and CYP11B2, markers of zona fasciculata and zona glomerulosa respectively. CYP11B2 was mostly absent in CAH adrenals and absent in ART. DLK1 was present in CAH adrenal, ART, and also control adrenal and testis, but was absent in control ovary. Increased expression of adrenocortical marker MC2R, was observed in CAH adrenals compared to control adrenal. Unlike control tissues, significant nodular lymphocytic infiltration was observed in CAH adrenals and ART, with CD20 (B-cell), CD3 (T-cell) and CD68 (macrophage/monocyte) markers of inflammation. RNA-seq data revealed co-expression of adrenal MC2R, and testis-specific INSL3, HSD17B3 in testicular ART indicating the presence of both gonadal and adrenal features, and high expression of DLK1 in ART, CAH adrenals and control adrenal. Principal component analysis indicated that the ART transcriptome was more similar to CAH adrenals and least similar to control testis tissue. Conclusions: CAH-affected adrenal glands and ART have similar expression profiles and morphology, demonstrating increased CYB5A with ZR characteristics and lymphocytic infiltration, suggesting a common origin that is similarly affected by the abnormal hormonal milieu. Immune system modulators may play a role in tumor formation of CAH.

Ablation of microRNA-155 and neuroinflammation in a mouse model of CLN1-disease.

Infantile neuronal ceroid lipofuscinosis (INCL), also known as CLN1-disease, is a devastating neurodegenerative lysosomal storage disorder (LSD), caused by inactivating mutations in the CLN1 gene. The Cln1-/- mice, which mimic INCL, manifest progressive neuroinflammation contributing to neurodegeneration. However, the underlying mechanism of neuroinflammation in INCL and in Cln1-/- mice has remained elusive. Previously, it has been reported that microRNA-155 (miR-155) regulates inflammation and miR profiling in Cln1-/- mouse brain showed that the level of miR-155 was upregulated. Thus, we sought to determine whether ablation of miR-155 in Cln1-/- mice may suppress neuroinflammation in these mice. Towards this goal, we generated Cln1-/-/miR-155-/- double-knockout mice and evaluated the inflammatory signatures in the brain. We found that the brains of double-KO mice manifest progressive neuroinflammatory changes virtually identical to those found in Cln1-/- mice. We conclude that ablation of miR-155 in Cln1-/- mice does not alter the neuroinflammatory trajectory in INCL mouse model.

Single-molecule polyadenylated tail sequencing (SM-PAT-Seq) to measure polyA tail lengths transcriptome-wide.

Polyadenylation of the 3' end of mRNAs is an important mechanism for regulating their stability and translation. We developed a nucleotide-resolution, transcriptome-wide, single-molecule SM-PAT-Seq method to accurately measure the polyA tail lengths of individual transcripts using long-read sequencing. The method generates cDNA using a double stranded splint adaptor targeting the far 3' end of the polyA tail for first strand synthesis along with random hexamers for second strand synthesis. This straight-forward method yields accurate polyA tail sequence lengths, can identify non-A residues in those tails, and quantitate transcript abundance.

Dechlorane Plus Biomagnification and Transmission through Prairie Food Webs in Inner Mongolia, China.

Dechlorane Plus (DP) is found widely in the environment. It is important to study DP enrichment and biomagnification in terrestrial ecosystems to improve our understanding of the possible effects of DP on the environment and human health. A total of 90 samples, including plant and animal tissues, were collected from Xilingol Prairie in Inner Mongolia, China. The DP concentrations in different species were assessed, and transmission of DP through food webs containing ectotherms and endotherms was assessed. The compound was detected in the biotic samples (plant; range 0.133-0.422 ng/g dry wt), in animal muscle (range: not dected-5.70 ng/g lipid wt), and in animal hair (range: not dected-2.03 ng/g dry wt), indicating that DP is present in remote environments such as Xilingol Prairie. These findings suggest that DP can undergo long-distance transport in the environment. Biomagnification factors (ectotherms: range 0.146-88.0, endotherms: range 0.866-17.2) and anti-DP/total DP concentration ratios (fanti values of 0.412-0.787) for the prairie animals were calculated. Ectotherms were found to selectively enrich syn-DP, and stereoselective enrichment increased moving up the food web. Lower-trophic-level endotherms strongly stereoselectively enriched syn-DP, and higher-trophic-level endotherms stereoselectively enriched anti-DP. Environ Toxicol Chem 2021;40:413-421. © 2020 SETAC.