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Upon entering the biological milieu, nanomedicines swiftly interact with the surrounding tissue fluid, subsequently being enveloped by a dynamic interplay of biomacromolecules, such as carbohydrates, nucleic acids, and cellular metabolites, but with predominant serum proteins within the biological corona. A notable consequence of the protein corona phenomenon is the unintentional loss of targeting ligands initially designed to direct nanomedicines toward particular cells or organs within the in vivo environment. mRNA nanomedicine displays high demand for specific cell and tissue-targeted delivery to effectively transport mRNA molecules into target cells, where they can exert their therapeutic effects with utmost efficacy. In this review, focusing on the delivery systems and tissue-specific applications, we aim to update the nanomedicine population with the prevailing and still enigmatic paradigm of nano-bio interactions, a formidable hurdle in the pursuit of targeted mRNA delivery. We also elucidate the current impediments faced in mRNA therapeutics and, by contemplating prospective avenues-either to modulate the corona or to adopt an 'ally from adversary' approach-aim to chart a course for advancing mRNA nanomedicine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Donor-recipient (D-R) mismatches outside of human leukocyte antigens (HLAs) contribute to kidney allograft loss, but the mechanisms remain unclear, specifically for intronic mismatches. We quantified non-HLA mismatches at variant-, gene-, and genome-wide scales from single nucleotide polymorphism (SNP) data of D-Rs from 2 well-phenotyped transplant cohorts: Genomics of Chronic Allograft Rejection (GoCAR; n = 385) and Clinical Trials in Organ Transplantation-01/17 (CTOT-01/17; n = 146). Unbiased gene-level screening in GoCAR uncovered the LIMS1 locus as the top-ranked gene where D-R mismatches associated with death-censored graft loss (DCGL). A previously unreported, intronic, LIMS1 haplotype of 30 SNPs independently associated with DCGL in both cohorts. Haplotype mismatches showed a dosage effect, and minor-allele introduction to major-allele-carrying recipients showed greater hazard of DCGL. The LIMS1 haplotype and the previously reported LIMS1 SNP rs893403 are expression quantitative trait loci (eQTL) in immune cells for GCC2 (not LIMS1), which encodes a protein involved in mannose-6-phosphase receptor (M6PR) recycling. Peripheral blood and T cell transcriptome analyses associated the GCC2 gene and LIMS1 SNPs with the TGF-β1/SMAD pathway, suggesting a regulatory effect. In vitro GCC2 modulation impacted M6PR-dependent regulation of active TGF-β1 and downstream signaling in T cells. Together, our data link LIMS1 locus D-R mismatches to DCGL via GCC2 eQTLs that modulate TGF-β1-dependent effects on T cells.

Objective: To investigate the value of a clinical-MRI radiomics model based on clinical characteristics and T2-weighted imaging (T2WI) for preoperatively evaluating lymph node (LN) metastasis in patients with MRI-predicted low tumor (T) staging rectal cancer (mrT1, mrT2, and mrT3a with extramural spread ≤ 5 mm)., Methods: This retrospective study enrolled 303 patients with low T-staging rectal cancer (training cohort, n = 213, testing cohort n = 90). A total of 960 radiomics features were extracted from T2WI. Minimum redundancy and maximum relevance (mRMR) and support vector machine were performed to select the best performed radiomics features for predicting LN metastasis. Multivariate logistic regression analysis was then used to construct the clinical and clinical-radiomics combined models. The model performance for predicting LN metastasis was assessed by receiver operator characteristic curve (ROC) and clinical utility implementing a nomogram and decision curve analysis (DCA). The predictive performance for LN metastasis was also compared between the combined model and human readers (2 seniors)., Results: Fourteen radiomics features and 2 clinical characteristics were selected for predicting LN metastasis. In the testing cohort, a higher positive predictive value of 75.9% for the combined model was achieved than those of the clinical model (44.8%) and two readers (reader 1: 54.9%, reader 2: 56.3%) in identifying LN metastasis. The interobserver agreement between 2 readers was moderate with a kappa value of 0.416. A clinical-radiomics nomogram and decision curve analysis demonstrated that the combined model was clinically useful., Conclusion: T2WI-based radiomics combined with clinical data could improve the efficacy in noninvasively evaluating LN metastasis for the low T-staging rectal cancer and aid in tailoring treatment strategies., Competing Interests: Authors YG and SD were employed by GE Healthcare. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dong, Ren, Chen, Yong, Zhang, Yin, Zhang, Yuan, Ge, Duan, Liu and Wang.)

Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3. These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease., (© 2023. The Author(s).)

The microbiota present in the respiratory tract (RT) responds to environmental stimuli and engages in a continuous interaction with the host immune system to maintain homeostasis. A total of 40 C57BL/6 mice were divided into four groups and exposed to varying concentrations of PM 2.5 nitrate aerosol and clean air. After 10 weeks of exposure, assessments were conducted on the lung and airway microbiome, lung functions, and pulmonary inflammation. Additionally, we analyzed data from both mouse and human respiratory tract (RT) microbiomes to identify possible biomarkers for PM 2.5 exposure-induced pulmonary damages. On average, 1.5 and 13.5% inter-individual microbiome variations in the lung and airway were explained by exposure, respectively. In the airway, among the 60 bacterial OTUs (operational taxonomic units) > 0.05% proportion, 40 OTUs were significantly affected by PM 2.5 exposure (FDR ≤ 10%). Further, the airway microbiome was associated with peak expiratory flow (PEF) ( p = 0.003), pulmonary neutrophil counts ( p = 0.01), and alveolar 8-OHdG oxidative lesions ( p = 0.0078). The Clostridiales order bacteria showed the strongest signals. For example, the o_Clostridiales;f_;g_ OTU was elevated by PM 2.5 nitrate exposure ( p = 4.98 × 10 -5 ) and negatively correlated with PEF ( r = -0.585 and p = 2.4 × 10 -4 ). It was also associated with the higher pulmonary neutrophil count ( p = 8.47 × 10 -5 ) and oxidative lesion ( p = 7.17 × 10 -3 ). In human data, we confirmed the association of airway Clostridiales order bacteria with PM 2.5 exposure and lung function. For the first time, this study characterizes the impact of PM 2.5 exposure on the microbiome of multiple sites in the respiratory tract (RT) and its relevance to airflow obstructive diseases. By analyzing data from both humans and mice, we have identified bacteria belonging to the Clostridiales order as a promising biomarker for PM 2.5 exposure-induced decline in pulmonary function and inflammation.

Bacterial biofilms are linked to several diseases and cause resistant and chronic infections in immune-compromised patients. Nanomotors comprise a new field of research showing a great promise within biomedicine but pose challenges in terms of biocompatibility. Nanomotors propelled by thermophoresis could overcome this challenge, as they leave no waste product during propulsion. In this study, mesoporous-silica nanoparticles are coated with a thin layer of gold to make nanomotors, which can be driven by near-infrared (NIR) light irradiation. The prepared mesoporous SiO 2 -Au nanomotors exhibit efficient self-propulsion when exposed to NIR irradiation, they penetrate deep through a biofilm matrix, and disperse the biofilm in situ due to the photothermal effect on the Au part of the nanomotors. The velocities of such nanomotors are investigated at different wavelengths and laser powers. Furthermore, the study examines the ability of these nanomotors to eradicate Pseudomonas aeruginosa (P. aeruginosa) biofilm under NIR light irradiation. The conducted study shows that the nanomotor's velocity increases with increasing laser power. The mesoporous SiO 2 /Au nanomotors show excellent capabilities to eradicate P. aeruginosa biofilms even under short (30 s-3 min) irradiation time. This study shows great promise for overcoming the challenges related to bacterial biofilm eradication., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

Apolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss, but whether recipient risk allele expression affects transplant outcomes is unclear. To test whether recipient APOL1 risk alleles independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data on donors and recipients from 2 kidney transplant cohorts: Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation 01/17 (CTOT-01/17). We estimated genetic ancestry (quantified as the proportion of African ancestry, or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we noted that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with an increased risk of death-censored allograft loss (DCAL), independent of ancestry (HR = 2.14; P = 0.006), as well as within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with an increased risk of any T cell-mediated rejection (TCMR) event. These associations were validated in CTOT-01/17. Ex vivo studies of PMBCs revealed, unexpectedly, high expression levels of APOL1 in activated CD4+/CD8+ T cells and NK cells. We detected enriched immune response gene pathways in risk allele carriers compared with noncarriers on the kidney transplant waitlist and among healthy controls. Our findings demonstrate an immunomodulatory role for recipient APOL1 risk alleles associated with TCMR and DCAL. We believe this finding has broader implications for immune-mediated injury to native kidneys.

Competing Interests: The authors declare no conflicts of interest.

Donor-recipient (D-R) differences at human leukocyte antigen (HLA) loci are currently incorporated into organ sharing, allocation and immunosuppression decisions. However, while acute rejection episodes have substantially diminished, progressive histologic damage occurs in allografts and improved long-term survival remains an unrealized goal among kidney recipients. Here we tested the hypothesis that non-HLA dependent, genome-wide D-R genetic differences could contribute to unchecked alloimmunity with histologic and functional consequences, culminating in long-term allograft failure. Genome-wide single nucleotide polymorphism (SNP) array data, excluding the HLA region, was utilized from 385 transplants to study the role of D-R differences upon serial histology and allograft survival. ADMIXTURE analysis was performed to quantitatively estimate ancestry in each D-R pair and PLINK was used to estimate the proportion of genome-shared identity-by-descent (pIBD) between D-R pairs. Subsequently, quantitative measures of recipient ancestry based on non-HLA SNPs was associated with death-censored allograft survival in adjusted Cox models. In D-R pairs of similar ancestry, pIBD was significantly associated with allograft survival independent of HLA mismatches in 224 transplants. Surprisingly, pIBD and recipient ancestry were not associated with clinical or subclinical rejection at any time post-transplant. Significantly, in multivariable analysis, pIBD inversely correlated with vascular intimal fibrosis in 160 biopsies obtained less than one year which in turn was significantly associated with allograft survival. Thus, our novel data show that non-HLA D-R differences associate with early vascular intimal fibrosis and allograft survival., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To identify roles of rare and common variants on BP, we conducted genetic analyses in 26 Colombia and Costa Rica pedigrees ascertained for bipolar disorder 1 (BP1), the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 838 individuals and high-coverage whole-genome sequencing of 449 individuals. We compared polygenic risk scores (PRS), estimated using the latest BP1 genome-wide association study (GWAS) summary statistics, between BP1 individuals and related controls. We also evaluated whether BP1 individuals had a higher burden of rare deleterious single-nucleotide variants (SNVs) and rare copy number variants (CNVs) in a set of genes related to BP1. We found that compared with unaffected relatives, BP1 individuals had higher PRS estimated from BP1 GWAS statistics (P = 0.001 ~ 0.007) and displayed modest increase in burdens of rare deleterious SNVs (P = 0.047) and rare CNVs (P = 0.002 ~ 0.033) in genes related to BP1. We did not observe rare variants segregating in the pedigrees. These results suggest that small-to-moderate effect rare and common variants are more likely to contribute to BP1 risk in these extended pedigrees than a few large-effect rare variants.

In kidney transplantation, short-term allograft survival has improved due to improvements in acute rejection episodes without corresponding improvements in long-term survival. Although current organ allocation algorithms take into account human leukocyte antigen (HLA) matching to reduce antidonor alloimmune responses, it is likely that genomic variation at non-HLA loci (ie, non-HLA donor-recipient [D-R] pair mismatches) play a role in the "non-self" responses and ultimately affect long-term allograft survival. Existing data from both animal models and human studies suggest an association between non-HLA D-R mismatches and kidney allograft outcomes. In this minireview, we examine existing and emerging data and discuss putative mechanisms on the role of non-HLA D-R mismatches on long-term allograft outcomes in kidney transplantation., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

In bone tissue engineering, electrospun fibrous scaffolds can provide excellent mechanical support, extracellular matrix mimicking components, such as 3D spacial fibrous environment for cell growth and controlled release of signaling molecules for osteogenesis. Here, a facile strategy comprising the incorporation of an osteogenic inductive peptide H1, derived from the cysteine knot (CT) domain of connective tissue growth factor (CTGF), in the core of Silk Fibroin (SF) was developed for osteogenic induction, synergistically with co-delivering hydroxyapatite (HA) from the shell of poly(l-lactic acid-co-ε-caprolactone) (PLCL). The core-shell nanofibrous structure was confirmed by transmission electron microscopy (TEM). Furthermore, the sustained released H1 has effectively promoted proliferation and osteoblastic differentiation of human induced pluripotent stem cells-derived mesenchymal stem cells (hiPS-MSCs). Moreover, after 8 weeks implantation in mice, this SF-H1/PLCL-HA composite induced bone tissue formation significantly faster than SF/PLCL as indicated by μCT. The present study is the first to demonstrate that release of short hydrophilic peptides derived from CTGF combined with HA potentiated the regenerative capacity for healing critical sized calvarial defect in vivo., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Air pollution is a leading cause of global disease burden. Lack of suitable methods for long term measuring exposure level at individual level is crippling environmental epidemiology research of air pollution., Methods: We report an integrative system, Bio 3 Air, for long term measurement of individual level air pollution exposure, currently focusing on ambient particulate matter (PM). The novel system in real-time quantifies individual's outdoor/indoor status, geological location, lung ventilation rate and PM concentration of individual's surrounding environment, and these metrics are subsequently incorporated in calculating PM exposure., Results: The system is fully developed and tested in China, USA and Canada, and has been successfully applied in epidemiology study. Bio 3 Air offers high reliability, sensitivity, reproducibility (>99%) and accuracy. It has high time- and spatial- resolution (≤ 2 min and ≤ 20 m, respectively). Bio 3 Air achieved 91.89% consistency with "gold-standard" method (membrane collection and off-line analysis)., Conclusions: Bio 3 Air represents a substantial methodological advance in environmental health research of air pollution. It captures information relevant in measuring individual's PM exposure (e.g. real-time outdoor/indoor status, location and lung ventilation rate). Such information is typically missed by conventional approaches. Additional features of Bio 3 Air include easy-to-use, cost-effectiveness and automated data collection, making it a powerful tool facilitating studies of air pollution exposure and health consequences., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Protein misfolding and abnormal self-assembly lead to the aggregates of oligomers, fibrils, or senior amyloid β (Aβ) plaques, which are associated with the pathogenesis of many neurodegenerative diseases. Progressive cerebral accumulation of Aβ protein was widely proposed to explain the cause of Alzheimer's disease, for which one promising direction of the preclinical study is to convert the preformed β-sheet structure of Aβ aggregates into innocent structures. However, the conversion is even harder than the modulation of the amyloidosis process. Herein, a graphene oxide/carbon nitride composite was developed as a good photocatalyst for irreversibly disassembling the Aβ aggregates of Aβ(33-42) under UV. Quartz crystal microbalance, circular dichroism spectrum, atomic force microscopy, fluorescent spectra, and mechanical property analysis were performed to analyze this photodegradation process from different aspects for fully understanding the mechanism, which may provide an important enlightenment for the relevant research in this field and neurodegenerative disease study.

Somatic copy number alterations (SCNAs) are profound in cancer genomes at different stages: oncogenesis, progression, and metastasis. Accurate detection and characterization of SCNA landscape at genome-wide scale are of great importance. Next-generation sequencing and SNP array are current technology of choice for SCNA analysis. They are able to quantify SCNA with high resolution and meanwhile raise great challenges in data analysis. To this end, we have developed an R package saasCNV for SCNA analysis using (1) whole-genome sequencing (WGS), (2) whole-exome sequencing (WES) or (3) whole-genome SNP array data. In this chapter, we provide the features of the package and step-by-step instructions in detail.

Purpose: To evaluate the expression level of integrin αvβ3 on activated hepatic stellate cells (HSCs) at different stages of liver fibrosis induced by carbon tetrachloride (CCl4) in rat model and the feasibility to stage liver fibrosis by using molecular magnetic resonance imaging (MRI) with arginine-glycine-aspartic acid (RGD) peptide modified ultrasmall superparamagnetic iron oxide nanoparticle (USPIO) specifically targeting integrin αvβ3., Materials and Methods: All experiments received approval from our Institutional Animal Care and Use Committee. Thirty-six rats were randomly divided into three groups of 12 subjects each, and intraperitoneally injected with CCl4 for either 3, 6, or 9 weeks. Controls (n=10) received pure olive oil. The change in T2* relaxation rate (ΔR2*) pre- and postintravenous administration of RGD-USPIO or naked USPIO was measured by 3.0T clinical MRI and compared by one-way analysis of variance or the Student's t-test. The relationship between expression level of integrin αvβ3 and liver fibrotic degree was evaluated by Spearman's ranked correlation., Results: Activated HSCs were confirmed to be the main cell types expressing integrin αvβ3 during liver fibrogenesis. The protein level of integrin αv and β3 subunit expressed on activated HSCs was upregulated and correlated well with the progression of liver fibrosis (r=0.954, P<0.001; r=0.931, P<0.001, respectively). After injection of RGD-USPIO, there is significant difference in ΔR2* among rats treated with 0, 3, 6, and 9 weeks of CCl4 (P<0.001). The accumulation of iron particles in fibrotic liver specimen is significantly greater for RGD-USPIO than naked USPIO after being injected with equal dose of iron., Conclusion: Molecular MRI of integrin αvβ3 expressed on activated HSCs by using RGD-USPIO may distinguish different liver fibrotic stages in CCl4 rat model and shows promising to noninvasively monitor the progression of the liver fibrosis and therapeutic response to antifibrotic treatment.