Urinary volatile organic compound metabolites and COPD among US adults: mixture, interaction and mediation analysis.

BACKGROUND: Volatile organic compounds (VOCs) encompass hundreds of high production volume chemicals and have been reported to be associated with adverse respiratory outcomes such as chronic obstructive pulmonary disease (COPD). However, research on the combined toxic effects of exposure to various VOCs on COPD is lacking. We aimed to assess the effect of VOC metabolite mixture on COPD risk in a large population sample. METHODS: We assessed the effect of VOC metabolite mixture on COPD risk in 5997 adults from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2020 (pre-pandemic) using multivariate logistic regression, Bayesian weighted quantile sum regression (BWQS), quantile-based g-Computation method (Qgcomp), and Bayesian kernel machine regression (BKMR). We explored whether these associations were mediated by white blood cell (WBC) count and total bilirubin. RESULTS: In the logistic regression model, we observed a significantly increased risk of COPD associated with 9 VOC metabolites. Conversely, N-acetyl-S-(benzyl)-L-cysteine (BMA) and N-acetyl-S-(n-propyl)-L-cysteine (BPMA) showed insignificant negative correlations with COPD risk. The overall mixture exposure demonstrated a significant positive relationship with COPD in both the BWQS model (adjusted odds ratio (OR) = 1.30, 95% confidence interval (CI): 1.06, 1.58) and BKMR model, and with marginal significance in the Qgcomp model (adjusted OR = 1.22, 95% CI: 0.98, 1.52). All three models indicated a significant effect of the VOC metabolite mixture on COPD in non-current smokers. WBC count mediated 7.1% of the VOC mixture associated-COPD in non-current smokers. CONCLUSIONS: Our findings provide novel evidence suggesting that VOCs may have adverse associations with COPD in the general population, with N, N- Dimethylformamide and 1,3-Butadiene contributing most. These findings underscore the significance of understanding the potential health risks associated with VOC mixture and emphasize the need for targeted interventions to mitigate the adverse effects on COPD risk.

Validation and Evaluation of 5 Scoring Systems for Predicting Metastatic Risk in Pheochromocytoma and Paraganglioma.

Currently, 5 scoring systems have been proposed in the literature for predicting metastatic risk in pheochromocytoma and paraganglioma (PPGL): Pheochromocytoma of the Adrenal Gland Scaled Score (PASS), Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP), Composite Pheochromocytoma/paraganglioma Prognostic Score (COPPS), Age, Size, Extra-adrenal location, Secretion type (ASES) score, and Size, Genetic, Age, and PASS (SGAP) model. To validate and evaluate these 5 scoring systems, we conducted a retrospective review of cases diagnosed as PPGL at the Department of Pathology, West China Hospital of Sichuan University, between January 2012 and December 2019. A total of 185 PPGL cases were included, comprising 35 cases with metastasis and 150 cases remained metastasis-free for over 8 years after surgery. The criteria of the 5 scoring systems were used for scoring and risk classification. The predictive performance of the 5 scoring systems was validated, compared, and evaluated using concordance index (C-index) and decision curve analysis (DCA). The C-indices for PASS, GAPP, and SGAP were 0.600, 0.547, and 0.547, respectively, indicating low discriminative ability. In contrast, COPPS and ASES had C-indices of 0.740 and 0.706, respectively, indicating better discriminative performance. DCA also showed that the predictive capability of COPPS was superior to that of ASES, with both outperformed PASS, while PASS had better predictive ability than GAPP and SGAP. Our analysis indicated that pathology-based scoring systems cannot accurately predict metastatic risk of PPGL. Establishing a precise prediction system requires integrating clinical, pathologic, and molecular information, using a scientific methodology for predictive factor selection and weight assessment.

Exploring the Efficacy Enhancement Mechanism of Qixue Shuangbu prescription after TCM processing for treating chronic heart failure by regulating ERK/Bcl-2/Bax/Caspases-3 signaling pathway.

Qixue Shuangbu prescription (QSP) has been used for the treatment of chronic heart failure (CHF) with remarkable curative effect. Processed QSP (PQSP) could significantly improve the treatment of CHF after traditional Chinese medicine (TCM) processing. This study elucidated the underlying efficacy enhancement mechanism of QSP after TCM processing for treating CHF in vitro and in vivo. The injury of rat cardiomyoblast H9c2 cells was induced by anoxia/reoxygenation to mimic CHF state in vitro. Sixty Sprague-Dawley rats were used to established CHF model by intraperitoneally injecting doxorubicin (the accumulative dose 15 mg/kg). Biochemical examinations were performed in serum and cellular supernatant, respectively. Cardiac functions and histopathological changes were evaluated in CHF model rats. The protein and mRNA levels of ERK1/2, Bcl-2, Bax and Caspase-3 were evaluated by Western blot and RT-PCR, respectively. All above results of low dose crude QSP-treated group (L-CQSP), high dose CQSP-treated group (H-CQSP), low dose PQSP-treated group (L-PQSP), high dose PQSP-treated group (H-PQSP) were compared to systematically explore correlations between TCM processing and the efficacy enhancement for treating CHF of PQSP. Compared with the model group, the L-CQSP group showed significant improvement in cardiac function at 8th weeks, while no significant improvement in cardiomyocyte apoptosis and fibrosis. Both H-CQSP, L-PQSP and H-PQSP exerted beneficial therapeutic effects in injured H9c2 cardiomyocytes and CHF model rats. L-PQSP and H-PQSP significantly increased cell viability and the activity of SOD, decreased the activities of LDH, MDA and NO, up-regulated the expression of ERK1/2 and Bcl-2, down-regulated the expression of Bax and Caspase-3 compared to the same dosage of CQSP. The efficacy enhancement mechanism of PQSP after TCM processing for treating CHF was directly related to the regulation of ERK/Bcl-2/Bax/Caspases-3 signaling pathway.

Gut-brain bidirectional determination in regulating the residual feed intake of small-sized meat ducks.

The gut-brain axis is essential in maintaining the homeostasis of neuronal system, endocrine system, and intestinal microbiota in both the afferent and efferent directions. This axis is considered to be a key mechanism that regulates feed efficiency (FE). This study aimed to investigate the regulatory mechanisms of gut-brain axis-related genes on the residual feed intake (RFI) in H-strain small-sized meat ducks. A total of 500 ducks with similar initial BW (635.2 ± 15.1 g) were selected and reared in the same experimental facility until slaughter at 42 d of age. RFI was calculated from the average daily gain (ADG), average daily feed intake (ADFI), and metabolic body weight (MBW0.75). Thirty high-RFI (H-RFI) and 30 low-RFI (L-RFI) birds were selected for further evaluation of growth performance, carcass characteristics, and blood biochemical parameter measurements. Six L-RFI and 6 H-RFI birds were then subjected to hypothalamic transcriptomic and cecal microbial sequencing analyses. Results indicated that L-RFI birds exhibited lower production performance (ADFI, FCR, and RFI) and blood biochemical indices (total cholesterol and ghrelin content) compared with H-RFI birds (P < 0.05). Gene expression differed significantly between the L-RFI and H-RFI birds, with 70 upregulated and 50 downregulated genes. The bacterial communities of L-RFI birds showed higher abundances of Bacteroides, Bifidobacterium, and Lactococcus, and lower abundances of Erysipelatoclostridium, Parasutterella, Fournierella, and Blautia compared with H-RFI birds (P < 0.05). Interactive analysis revealed bacterial communities associated with FE were significantly correlated with hypothalamic genes (P < 0.05), for example, Bacteroides was positively correlated with DGKH and LIPT2, while negatively correlated with CAPN9, GABRD, and PDE1A. Bifidobacterium showed significant correlations with ATP2A3, CALHM6, and TMEM121B. Overall, RFI was a crucial indicator of FE, regulated by interactions between brain gene expression and gut microbiota through cAMP signaling, neuroactive ligand-receptor interaction, and calcium signaling pathways. Notably, increased expression of hypothalamic genes and abundance of carbohydrate-utilization microbiota in L-RFI meat ducks improved FE by enhancing energy metabolism and volatile fatty acids absorption.

Association of Sleep Pattern and Genetic Susceptibility with Obstructive Sleep Apnea: A Prospective Analysis of the UK Biobank.

Purpose: The prevalence of obstructive sleep apnea (OSA) is high worldwide. This study aimed to quantify the relationship between the incidence of OSA and sleep patterns and genetic susceptibility. Methods: A total of 355,133 white British participants enrolled in the UK Biobank between 2006 and 2010 with follow-up data until September 2021 were recruited. We evaluated sleep patterns using a customized sleep scoring method based on the low-risk sleep phenotype, defined as follows: morning chronotype, 7-8 hours of sleep per day, never/rarely experience insomnia, no snoring, no frequent daytime sleepiness, never/rarely nap, and easily getting up early. The polygenic risk score was calculated to assess genetic susceptibility to OSA. Cox proportional hazard models were used to evaluate the associations between OSA and sleep patterns and genetic susceptibility. Results: During a mean follow-up of 12.57 years, 4618 participants were diagnosed with OSA (age: 56.83 ± 7.69 years, women: 31.3%). Compared with those with a poor sleep pattern, participants with a normal (HR: 0.42, 95% CI: 0.38-0.46), ideal (HR: 0.21, 95% CI: 0.19-0.24), or optimal (HR: 0.15, 95% CI: 0.12-0.18) sleep pattern were significantly more likely to have OSA. The genetic susceptibility of 173,239 participants was calculated, and the results showed that poor (HR: 3.67, 95% CI: 2.95-4.57) and normal (HR: 1.89, 95% CI: 1.66-2.16) sleep patterns with high genetic susceptibility can increase the risk for OSA. Conclusion: This large-scale prospective study provides evidence suggesting that sleep patterns across seven low-risk sleep phenotypes may protect against OSA in individuals with varying degrees of genetic susceptibility.

Newly developed oral bioavailable EHMT2 inhibitor as a potential epigenetic therapy for Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is the prototypic genomic disorder resulting from deficiency of paternally expressed genes in the human chromosome 15q11-q13 region. The unique molecular mechanism involving epigenetic modifications renders PWS as the most attractive candidate to explore a proof-of-concept of epigenetic therapy in humans. The premise is that epigenetic modulations could reactivate the repressed PWS candidate genes from the maternal chromosome and offer therapeutic benefit. Our prior study identifies an EHMT2/G9a inhibitor, UNC0642, that reactivates the expression of PWS genes via reduction of H3K9me2. However, low brain permeability and poor oral bioavailability of UNC0642 preclude its advancement into translational studies in humans. In this study, a newly developed inhibitor, MS152, modified from the structure of UNC0642 has better brain penetration, more potency and selectivity against EHMT2/G9a. MS152 reactivated maternally silenced PWS genes in PWS patient fibroblasts and in brain and liver tissues of PWS mouse models. Importantly, the molecular efficacy of oral administration is comparable to intraperitoneal route. MS152 treatment in newborns ameliorated the perinatal lethality and poor growth, maintaining reactivation in a PWS mouse model at postnatal 90 days. Our findings provide strong support for MS152 as a first-in-class inhibitor to advance the epigenetic therapy of PWS in humans.

Photo-thermal Catalytic Hydrogenation of Halogenated Nitrobenzenes over Ni/P25 Catalyst.

As haloanilines (HANs) are important organic intermediates and fine chemicals, their preparation over non-noble-metal-based catalysts by catalytic hydrogenation has attracted wide attention. However, the reaction suffers from relatively harsh conditions. Herein, we found that a 3.5%Ni/P25 catalyst exhibited superior photo-thermal catalytic activity with a TOFs of 5207 h-1 for hydrogenation of p-chloronitrobenzene (p-CNB) to p-chloroaniline under a 300 W full spectrum, which was much higher than that of photo- and thermal catalysis alone. Moreover, the 3.5%Ni/P25 catalyst could be recycled 4 times and was effective for the hydrogenation of various halonitrobenzenes (HNBs) with superior selectivity. Furthermore, the kinetic research showed that the excellent catalytic performance could be attributed to the better activation and dissociation of H2 by photo-thermal catalysis and the hydrogenation of p-CNB obeyed the condensation routine by ionic hydrogenation over 3.5%Ni/P25.

Scalable Dual In Situ Synthesis of Polyester Nanocomposites for High-Energy Storage.

Incorporating ultralow loading of nanoparticles into polymers has realized increases in dielectric constant and breakdown strength for excellent energy storage. However, there are still a series of tough issues to be dealt with, such as organic solvent uses, which face enormous challenges in scalable preparation. Here, a new strategy of dual in situ synthesis is proposed, namely polymerization of polyethylene terephthalate (PET) synchronizes with growth of calcium borate nanoparticles, making polyester nanocomposites from monomers directly. Importantly, this route is free of organic solvents and surface modification of nanoparticles, which is readily accessible to scalable synthesis of polyester nanocomposites. Meanwhile, uniform dispersion of as ultralow as 0.1 wt% nanoparticles and intense bonding at interfaces have been observed. Furthermore, the PET-based nanocomposite displays obvious increases in both dielectric constant and breakdown strength as compared to the neat PET. Its maximum discharged energy density reaches 15 J cm-3 at 690 MV m-1 and power density attains 218 MW cm-3 under 150 Ω resistance at 300 MV m-1, which is far superior to the current dielectric polymers that can be produced at large scales. This work presents a scalable, safe, low-cost, and environment-friendly route toward polymer nanocomposites with superior capacitive performance.

The FAITHS2 Model Predicts Functional Disability in Patients With Acute Ischemic Stroke.

The present study aimed to develop a model to predict functional disability at 3 months in patients with acute ischemic stroke (AIS) (n = 5,406). The primary outcome was functional disability (modified Rankin Scale [mRS] >2) at 3 months. A prediction model including blood biomarkers was developed based on a multivariable logistic regression model, which was internally validated by the 100-time bootstrap method. A nomogram and a web-based calculator were developed for usage in clinical practice. At 3 months, 11% (638/5,406) of the patients had functional disability. Seven independent predictors of functional disability at 3 months were incorporated into the FAITHS2 model (fasting plasma glucose, age, interleukin-6, stroke history, National Institute of Health Stroke Scale [NIHSS] at admission, sex, and systolic blood pressure). The Area Under Curves (AUCs) were 0.814 (95% confidence interval [CI] 0.796-0.832) and 0.808 (95% CI 0.806-0.810), and the Brier scores were 0.088 ± 0.214 and 0.089 ± 0.003 for the derivation cohort and internal validation, respectively, showing optimal performance of the model. The FAITHS2 model has excellent potential to be a dependable application for individualized clinical decision making.

Human-like adrenal features in Chinese tree shrews revealed by multi-omics analysis of adrenal cell populations and steroid synthesis.

The Chinese tree shrew ( Tupaia belangeri chinensis) has emerged as a promising model for investigating adrenal steroid synthesis, but it is unclear whether the same cells produce steroid hormones and whether their production is regulated in the same way as in humans. Here, we comprehensively mapped the cell types and pathways of steroid metabolism in the adrenal gland of Chinese tree shrews using single-cell RNA sequencing, spatial transcriptome analysis, mass spectrometry, and immunohistochemistry. We compared the transcriptomes of various adrenal cell types across tree shrews, humans, macaques, and mice. Results showed that tree shrew adrenal glands expressed many of the same key enzymes for steroid synthesis as humans, including CYP11B2, CYP11B1, CYB5A, and CHGA. Biochemical analysis confirmed the production of aldosterone, cortisol, and dehydroepiandrosterone but not dehydroepiandrosterone sulfate in the tree shrew adrenal glands. Furthermore, genes in adrenal cell types in tree shrews were correlated with genetic risk factors for polycystic ovary syndrome, primary aldosteronism, hypertension, and related disorders in humans based on genome-wide association studies. Overall, this study suggests that the adrenal glands of Chinese tree shrews may consist of closely related cell populations with functional similarity to those of the human adrenal gland. Our comprehensive results (publicly available at http://gxmujyzmolab.cn:16245/scAGMap/) should facilitate the advancement of this animal model for the investigation of adrenal gland disorders.

Metagenomic insights into the relationship between intestinal flora and residual feed intake of meat ducks.

In this study, we sought to determine the effects of intestinal flora on the feed efficiency of meat ducks by evaluating the correlation between intestinal flora and residual feed intake. The F2 generation of Cherry Valley ducks × Runzhou Crested White ducks was used as the study subjects, and feed consumption being recorded from d 21 to 42. RFI was calculated based on growth performance, and 20 low RFI and 20 high RFI ducks were randomly selected to characterize the effect of RFI on growth performance. To analyze the intestinal flora affecting RFI, 16s rDNA sequencing was performed on the contents of 5 intestinal segments from the HR and LR groups, and macrogenomic sequencing was performed on the cecal contents. Feed intake, average daily feed intake, feed conversion ratio, and residual feed intake were lower in low RFI. Analysis of the intestinal flora revealed the cecum to be more highly enriched in the carbohydrate metabolism pathway and less enriched with potentially pathogenic taxa than the other assessed intestinal regions. Further analysis of the cecal microbiota identified nine significantly differentially enriched intestinal flora. In this study, we accordingly identified a basis for the mechanisms underlying the effects of the intestinal flora on meat duck feed efficiency.

Distinct structure, assembly, and gene expression of microplankton in two Arctic estuaries with varied terrestrial inputs.

The Laptev Sea is a major Marginal Sea in the Western Arctic Ocean. The Arctic amplification brought by global warming influences the hydrological properties of rivers passing through the permafrost zone, which would alter the biological community structure at continental margin. In this study, the structure, assembly, and gene expression of planktonic microbial communities in two estuaries (Protoka Ularovskaya River Estuary, PURE; Lena River Estuary, LRE) of Laptev Sea were examined to investigate the environmental effects of polar rivers. PURE and LRE exhibited distinct environmental characteristics: low temperature and high salinity for PURE, and high temperature and low salinity for LRE, influenced by runoff size. Salinity more closely influenced microbial communities in LRE, with freshwater species playing a significant role in community composition. The findings revealed differences between two estuaries in community composition and diversity. Prokaryotes and microeukaryotes had shown different assembly patterns in response to habitat changes caused by terrestrial freshwater input. Furthermore, compared with the PURE, the co-occurrence and inter-domain network of the LRE, which was more affected by terrestrial input, was more complex and stable. Functional gene prediction revealed a higher gene expression of methane metabolism in LRE than in PURE, particularly those related to methane oxidation, and this conclusion could help better explore the impact of global warming on the methane cycle in the Arctic Marginal Seas. This study explored the increased freshwater runoffs under the background of global warming dramatically affect Arctic microplankton communities from community structure, assembly and gene expression aspects.

An Ultra-broadband Metallic Plasmonic Antenna for Ultrasensitive Molecular Fingerprint Identification.

Near-field enhanced mid-infrared light-matter interactions via metallic plasmonic antennae (PA) have attracted much attention but are inevitably limited by the detuning between their narrow band and the broad applied spectral range. Here, we develop a new low-temperature incubation synthetic method to acquire uniform Ag microparticles (MPs) with numerous hotspots. Their plasmonic band is remarkably extended by the plasmonic coupling of numerous hotspots and covers the entire mid-infrared range (400-4000 cm-1). Hence, the almost complete molecular fingerprint of 4-mercaptobenzonitrile was successfully probed for the first time via resonant surface-enhanced infrared absorption (rSEIRA), and the rSEIRA spectra of different essential amino acids were further detected and exhibit a high spectral identification degree assisted by machine learning. This work changes the inertia perception of "narrow band and large size but small hotspot area" of mid-infrared metallic PA and paves the way for the ultrasensitive mid-infrared optical sensing.

Remodeling ceramide homeostasis promotes functional maturation of human pluripotent stem cell-derived ß cells.

Human pluripotent stem cell-derived ß cells (hPSC-ß cells) show the potential to restore euglycemia. However, the immature functionality of hPSC-ß cells has limited their efficacy in application. Here, by deciphering the continuous maturation process of hPSC-ß cells post transplantation via single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq), we show that functional maturation of hPSC-ß cells is an orderly multistep process during which cells sequentially undergo metabolic adaption, removal of negative regulators of cell function, and establishment of a more specialized transcriptome and epigenome. Importantly, remodeling lipid metabolism, especially downregulating the metabolic activity of ceramides, the central hub of sphingolipid metabolism, is critical for ß cell maturation. Limiting intracellular accumulation of ceramides in hPSC-ß cells remarkably enhanced their function, as indicated by improvements in insulin processing and glucose-stimulated insulin secretion. In summary, our findings provide insights into the maturation of human pancreatic ß cells and highlight the importance of ceramide homeostasis in function acquisition.

PKIB, a Novel Target for Cancer Therapy.

The serine-threonine kinase protein kinase A (PKA) is a cyclic AMP (cAMP)-dependent intracellular protein with multiple roles in cellular biology including metabolic and transcription regulation functions. The cAMP-dependent protein kinase inhibitor ß (PKIB) is one of three known endogenous protein kinase inhibitors of PKA. The role of PKIB is not yet fully understood. Hormonal signaling is correlated with increased PKIB expression through genetic regulation, and increasing PKIB expression is associated with decreased cancer patient prognosis. Additionally, PKIB impacts cancer cell behavior through two mechanisms; the first is the nuclear modulation of transcriptional activation and the second is the regulation of oncogenic AKT signaling. The limited research into PKIB indicates the oncogenic potential of PKIB in various cancers. However, some studies suggest a role of PKIB in non-cancerous disease states. This review aims to summarize the current literature and background of PKIB regarding cancer and related issues. In particular, we will focus on cancer development and therapeutic possibilities, which are of paramount interest in PKIB oncology research.

A pseudo-targeted metabolomics for discovery of potential biomarkers of cardiac hypertrophy in rats.

Cardiac hypertrophy (CH) is one of the stages in the occurrence and development of severe cardiovascular diseases, and exploring its biomarkers is beneficial for delaying the progression of severe cardiovascular diseases. In this research, we established a comprehensive and highly efficient pseudotargeted metabolomics method, which demonstrated a superior capacity to identify differential metabolites when compared to traditionaluntargeted metabolomics. The intra/inter-day precision and reproducibility results proved the method is reliable and precise. The established method was then applied to seek the potential differentiated metabolic biomarkers of cardiac hypertrophy (CH) rats, and oxylipins, phosphorylcholine (PC), lysophosphatidylcholine (LysoPC), lysophosphatidylethanolamine (LysoPE), Krebs cycle intermediates, carnitines, amino acids, and bile acids were disclosed to be the possible differentiate components. Their metabolic pathway analysis revealed that the potential metabolic alterations in CH rats were mainly associated with phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, arachidonic acid metabolism, citrate cycle, glyoxylate and dicarboxylate metabolism, and tyrosine metabolism. In sum, this research provided a comprehensiveand reliable LC-MS/MS MRM platform for pseudo-targeted metabolomics investigation of disease condition, and some interesting potential biomarkers were disclosed for CH, which merit further exploration in the future.

Advanced diffusion tensor imaging in white matter injury after subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is recognized as an especially severe stroke variant, notorious for its high mortality and long-term disability rates, in addition to a range of both immediate and enduring neurological impacts. Over half of the SAH survivors experience varying degrees of neurological disorders, with many enduring chronic neuropsychiatric conditions. Due to the limitations of traditional imaging techniques in depicting subtle changes within brain tissues post-hemorrhage, the accurate detection and diagnosis of white matter (WM) injuries are complicated. Against this backdrop, Diffusion Tensor Imaging (DTI) has emerged as a promising biomarker for structural imaging, renowned for its enhanced sensitivity in identifying axonal damage. This capability positions DTI as an invaluable tool for forming precise and expedient prognoses for SAH survivors. This study synthesizes an assessment of DTI for the diagnosis and prognosis of neurological dysfunctions in patients with SAH, emphasizing the notable changes observed in DTI metrics and their association with potential pathophysiological processes. Despite challenges associated with scanning technology differences and data processing, DTI demonstrates significant clinical potential for early diagnosis of cognitive impairments following SAH and monitoring therapeutic effects. Future research requires the development of highly standardized imaging paradigms to enhance diagnostic accuracy and devise targeted therapeutic strategies for SAH patients. In sum, DTI technology not only augments our understanding of the impact of SAH but also may offer new avenues for improving patient prognoses.

Role of T cells in liver metastasis.

The liver is a major metastatic site (organ) for gastrointestinal cancers (such as colorectal, gastric, and pancreatic cancers) as well as non-gastrointestinal cancers (such as lung, breast, and melanoma cancers). Due to the innate anatomical position of the liver, the apoptosis of T cells in the liver, the unique metabolic regulation of hepatocytes and other potential mechanisms, the liver tends to form an immunosuppressive microenvironment and subsequently form a pre-metastatic niche (PMN), which can promote metastasis and colonization by various tumor cells(TCs). As a result, the critical role of immunoresponse in liver based metastasis has become increasingly appreciated. T cells, a centrally important member of adaptive immune response, play a significant role in liver based metastases and clarifying the different roles of the various T cells subsets is important to guide future clinical treatment. In this review, we first introduce the predisposing factors and related mechanisms of liver metastasis (LM) before introducing the PMN and its transition to LM. Finally, we detail the role of different subsets of T cells in LM and advances in the management of LM in order to identify potential therapeutic targets for patients with LM.

Novel protein-truncating variants of a chromatin-modifying gene MSL2 in syndromic neurodevelopmental disorders.

Numerous large scale genomic studies have uncovered rare but recurrent pathogenetic variants in a significant number of genes encoding epigenetic machinery in cases with neurodevelopmental disorders (NDD) especially autism spectrum disorder (ASD). These findings provide strong support for the functional importance of epigenetic regulators in neurodevelopment. After the clinical genomics evaluation of the patients using exome sequencing, we have identified, three novel protein-truncating variants (PTVs) in the MSL2 gene (OMIM: 614802) which encodes a chromatin modifying enzyme. MSL2 modifies chromatin through both mono-ubiquitination of histone 2B on lysine 34 (K34) and acetylation of histone H4 on lysine 16 (K16). We reported first time the detailed clinical features associated with 3 MSL2 PTVs. There are 15 PTVs (13 de novo) reported from the large genomics studies (12 cases) or ClinVar (3 cases) of NDD, ASD, and developmental disorders (DD) but the specific clinical features for these cases are not described. Taken together, our descriptions of dysmorphic face and other features support the causal role of MSL2 in a likely syndromic neurodevelopmental disorder and add MSL2 to a growing list of epigenetic genes implicated in ASD.