Abalign: a comprehensive multiple sequence alignment platform for B-cell receptor immune repertoires.

The utilization of high-throughput sequencing (HTS) for B-cell receptor (BCR) immune repertoire analysis has become widespread in the fields of adaptive immunity and antibody drug development. However, the sheer volume of sequences generated by these experiments presents a challenge in data processing. Specifically, multiple sequence alignment (MSA), a critical aspect of BCR analysis, remains inadequate for handling massive BCR sequencing data and lacks the ability to provide immunoglobulin-specific information. To address this gap, we introduce Abalign, a standalone program specifically designed for ultrafast MSA of BCR/antibody sequences. Benchmark tests demonstrate that Abalign achieves comparable or even better accuracy than state-of-the-art MSA tools, and shows remarkable advantages in terms of speed and memory consumption, reducing the time required for high-throughput analysis from weeks to hours. In addition to its alignment capabilities, Abalign offers a broad range of BCR analysis features, including extracting BCRs, constructing lineage trees, assigning VJ genes, analyzing clonotypes, profiling mutations, and comparing BCR immune repertoires. With its user-friendly graphic interface, Abalign can be easily run on personal computers instead of computing clusters. Overall, Abalign is an easy-to-use and effective tool that enables researchers to analyze massive BCR/antibody sequences, leading to new discoveries in the field of immunoinformatics. The software is freely available at http://cao.labshare.cn/abalign/.

Molecular adaptations underlying high-frequency hearing in the brain of CF bats species.

BACKGROUND: The majority of bat species have developed remarkable echolocation ability, especially for the laryngeally echolocating bats along with high-frequency hearing. Adaptive evolution has been widely detected for the cochleae in the laryngeally echolocating bats, however, limited understanding for the brain which is the central to echolocation signal processing in the auditory perception system, the laryngeally echolocating bats brain may also undergo adaptive changes. RESULT: In order to uncover the molecular adaptations related with high-frequency hearing in the brain of laryngeally echolocating bats, the genes expressed in the brain of Rhinolophus ferrumequinum (CF bat) and Myotis pilosus (FM bat) were both detected and also compared. A total of 346,891 genes were detected and the signal transduction mechanisms were annotated by the most abundant genes, followed by the transcription. In hence, there were 3,088 DEGs were found between the two bat brains, with 1,426 highly expressed in the brain of R. ferrumequinum, which were significantly enriched in the neuron and neurodevelopmental processes. Moreover, we found a key candidate hearing gene, ADCY1, playing an important role in the R. ferrumequinum brain and undergoing adaptive evolution in CF bats. CONCLUSIONS: Our study provides a new insight to the molecular bases of high-frequency hearing in two laryngeally echolocating bats brain and revealed different nervous system activities during auditory perception in the brain of CF bats.

Microbiota diversity and anti-Pseudogymnoascus destructans bacteria isolated from Myotis pilosus skin during late hibernation.

Symbiotic microorganisms that reside on the host skin serve as the primary defense against pathogens in vertebrates. Specifically, the skin microbiome of bats may play a crucial role in providing resistance against Pseudogymnoascus destructans (Pd), the pathogen causing white-nose syndrome. However, the epidermis symbiotic microbiome and its specific role in resisting Pd in highly resistant bats in Asia are still not well understood. In this study, we collected and characterized skin microbiota samples of 19 Myotis pilosus in China and explored the differences between Pd-positive and negative individuals. We identified inhibitory effects of these bacteria through cultivation methods. Our results revealed that the Simpson diversity index of the skin microbiota for positive individuals was significantly lower than that of negative individuals, and the relative abundance of Pseudomonas was significantly higher in positive bats. Regardless of whether individuals were positive or negative for Pd, the relative abundance of potentially antifungal genera in skin microbiota was high. Moreover, we successfully isolated 165 microbes from bat skin and 41 isolates from positive individuals able to inhibit Pd growth compared to only 12 isolates from negative individuals. A total of 10 genera of Pd-inhibiting bacteria were screened, among which the genera Algoriella, Glutamicibacter, and Psychrobacter were newly discovered as Pd-inhibiting genera. These Pd-inhibiting bacteria metabolized a variety of volatile compounds, including dimethyl trisulfide, dimethyl disulfide, propylene sulfide, 2-undecanone, and 2-nonanone, which were able to completely inhibit Pd growth at low concentrations.IMPORTANCERecently, white-nose syndrome has caused the deaths of millions of hibernating bats, even threatening some with regional extinction. Bats in China with high resistance to Pseudogymnoascus destructans can provide a powerful reference for studying the management of white-nose syndrome and understanding the bats against the pathogen's intrinsic mechanisms. This study sheds light on the crucial role of host symbiotic skin microorganisms in resistance to pathogenic fungi and highlights the potential for harnessing natural defense mechanisms for the prevention and treatment of white-nose syndrome. In addition, this may also provide promising candidates for the development of bioinsecticides and fungicides that offer new avenues for addressing fungal diseases in wildlife and agricultural environments.

The Tao Hong Si Wu Decoction ameliorates diabetes-associated cognitive dysfunction by inhibiting the formation of amyloid plaques.

OBJECTIVES: The herbs in Tao Hong Si Wu Decoction (THSWD) are beneficial in the treatment of cognitive impairment. However, the underlying mechanisms of THSWD in treating diabetes-associated cognitive dysfunction (DACD) are not entirely explored. This study is aimed to investigate the therapeutic effects of THSWD in DACD model rats and the underlying mechanism. METHODS: Ultra-high-phase liquid chromatography was employed to identify the main compounds contained in the THSWD extract. DACD rat model was induced by feeding with a high-sugar and high-fat diet and injecting streptozotocin (35 mg/kg). DACD rats were gavaged with THSWD for 1 week. The learning and memory abilities of the rats were measured by using the Morris water maze. Western blotting was used to detect the changes in DACD rat targets. Statistical methods were used to evaluate the correlation between proteins. RESULTS: The results show that THSWD effectively reduced the escape latency, hippocampal neuron damage, glycosylated hemoglobin, type A1C, and blood lipid levels in DACD rats. Furthermore, DACD rats showed significantly increased amyloid precursor protein, ß-secretase, Aß1-40 , Aß1-42 , Tau phosphorylation, and advanced glycation end products (AGEs) expression. However, THSWD treatment can reverse this phenomenon. CONCLUSIONS: THSWD can improve the learning and memory abilities of DACD rats by inhibiting the expression of AEGs-AGE receptors pathway, which provides an experimental basis for the clinical application of THSWD. In addition, the experiment combines pharmacological and statistical methods, which offers a new perspective for the study of Chinese herbal medicine.

Associations between maternal urinary isoflavone concentrations and anogenital distance of offspring throughout infancy: a prospective cohort study.

STUDY QUESTION: Are maternal urinary isoflavone (ISO) concentrations during pregnancy associated with anogenital distance (AGD) in infants at birth, and at 6 and 12 months of age? SUMMARY ANSWER: Higher maternal urinary ISO concentrations during pregnancy were associated with longer AGD in infants of both sexes, and equol (EQU) and daidzein (DAD) were identified as the important ISO mixture components in the observed associations. WHAT IS KNOWN ALREADY: Evidence of the association of prenatal exposure to ISO with offspring's AGD is mainly derived from animal studies, which used different study designs and had inconsistent results. Only one human study has been reported and it found null associations between maternal ISO exposure during pregnancy and AGD among boys at birth, with a small sample size and a wide range of exposure windows. No human study on girls was found. STUDY DESIGN, SIZE, DURATION: Prospective cohort study (Shanghai-Minhang Birth Cohort Study), with pregnant women recruited at 12-16 weeks of gestation in Shanghai, China between April and December 2012. One thousand two hundred and twenty-five live singletons were left in the cohort at delivery of which 480 mother-infant pairs had data on both maternal urinary ISO concentrations and at least one AGD measurement and were included in the present study. Anopenile distance (AGDAP) and anoscrotal distance (AGDAS) of boys and anoclitoral distance (AGDAC) and anofourchette distance (AGDAF) of girls were measured at birth and at 6 and 12 months of age. PARTICIPANTS/MATERIALS, SETTING, METHODS: Multiple linear regression models were used to examine the associations between maternal ISO concentrations and AGD. Bayesian kernel machine regression (BKMR) was implemented to examine both the overall effects of ISO mixture and the single effect of each ISO and identify important components of ISO mixture. MAIN RESULTS AND THE ROLE OF CHANCE: A general profile of higher concentrations of maternal ISO associated with longer AGD in infants of both sexes was observed, when maternal education, parity, BMI before pregnancy (BMI, categorical variable), passive smoking during early pregnancy, age at delivery, gestational weeks and infant body size were adjusted for. Among boys, EQU was associated with increased AGDAS at birth and at 6 and 12 months, and DAD was associated with increased AGDAP at birth. Among girls, the associations of EQU and DAD with increased AGDAC and AGDAF at birth were found. When gestational weight gain and feeding patterns of infants in the first 6 months were additionally adjusted for, and maternal BMI was adjusted for as a continuous variable, more pronounced associations were observed, especially for associations of genistein (GEN), DAD and glycitein (GLY) with increased AGDAP and AGDAS at 6 months in boys. However, these associations were not always observed in the highest tertile group, and no consistent dose-response relationships were found. Similar results were observed in BKMR models, showing positive correlations of concentration of ISO mixture with increased AGDAS at both 6 and 12 months among boys, and increased AGDAC and AGDAF at birth among girls. Statistically significant increments of 4.96 mm (95% credible interval (CrI): 1.40, 8.52) and 1.07 mm (95% CrI: 0.02, 2.13) in AGDAS at 6 months among boys and AGDAC at birth among girls, respectively, were observed at the 75th percentile of ISO mixture, compared with 25th percentile. EQU and DAD were identified as the important components among ISO-AGD associations. LIMITATIONS, REASONS FOR CAUTION: First, due to the short half-lives of ISO, the accuracy of a single spot urine sample reflecting ISO exposure during pregnancy may be limited, and thus may cause non-differential misclassification. Second, despite the adjustments for several important covariates in the study, unmeasured and residual confounding factors may remain a concern. Third, false discovery due to multiple testing may remain. Finally, the reduced sample sizes attributed to the loss of follow-up and missing data of confounders may limit our ability to detect an association, if any existed. WIDER IMPLICATIONS OF THE FINDINGS: Prenatal ISO exposure may affect the reproductive development of offspring. As ISO can be widely detected in pregnant women, especially in Eastern countries, more studies are warranted to provide evidence of the effects of prenatal ISO exposure on long-term reproductive outcomes. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the National Key Research and Development Program of China (2021YFC2701003), the National Natural Science Foundation of China (22076123), the Science and Technology Commission of Shanghai Municipality (21ZR1454700 and 20ZR1448000), the Shanghai Municipal Health Commission (20194Y0160) and Innovation-oriented Science and Technology Grant from NHC Key Laboratory of Reproduction Regulation (CX2022-04). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

DrugRep: an automatic virtual screening server for drug repurposing.

Computationally identifying new targets for existing drugs has drawn much attention in drug repurposing due to its advantages over de novo drugs, including low risk, low costs, and rapid pace. To facilitate the drug repurposing computation, we constructed an automated and parameter-free virtual screening server, namely DrugRep, which performed molecular 3D structure construction, binding pocket prediction, docking, similarity comparison and binding affinity screening in a fully automatic manner. DrugRep repurposed drugs not only by receptor-based screening but also by ligand-based screening. The former automatically detected possible binding pockets of the receptor with our cavity detection approach, and then performed batch docking over drugs with a widespread docking program, AutoDock Vina. The latter explored drugs using seven well-established similarity measuring tools, including our recently developed ligand-similarity-based methods LigMate and FitDock. DrugRep utilized easy-to-use graphic interfaces for the user operation, and offered interactive predictions with state-of-the-art accuracy. We expect that this freely available online drug repurposing tool could be beneficial to the drug discovery community. The web site is http://cao.labshare.cn/drugrep/ .

Research on Comprehensive Evaluation and Early Warning of Transmission Lines' Operation Status Based on Dynamic Cloud Computing.

The current methods for evaluating the operating condition of electricity transmission lines (ETLs) and providing early warning have several problems, such as the low correlation of data, ignoring the influence of seasonal factors, and strong subjectivity. This paper analyses the sensitive factors that influence dynamic key evaluation indices such as grounding resistance, sag, and wire corrosion, establishes the evaluation criteria of the ETL operation state, and proposes five ETL status levels and seven principles for selecting evaluation indices. Nine grade I evaluation indices and twenty-nine grade II evaluation indices, including passageway and meteorological environments, are determined. The cloud model theory is embedded and used to propose a warning technology for the operation state of ETLs based on inspection defect parameters and the cloud model. Combined with the inspection defect parameters of a line in the Baicheng district of Jilin Province and the critical evaluation index data such as grounding resistance, sag, and wire corrosion, which are used to calculate the timeliness of the data, the solid line is evaluated. The research shows that the dynamic evaluation model is correct and that the ETL status evaluation and early warning method have reasonable practicability.

Controlled Construction of Heteroleptic [Pd2 (LA )2 (LB )(LC )]4+ Cages: A Facile Approach for Site-Selective endo-Functionalization of Supramolecular Cavities.

Construction of supramolecular structures with internal functionalities is a promising approach to build enzyme-like cavities. The endo-functionalized [Pd12 L24 ] and [Pd2 L4 ] coordination cages represent the most successful systems in this regard. However, these systems mainly contain one type of endo-moiety. We herein provide a solution for the controlled endo-functionalization of [Pd2 L4 ] cages. Site-selective introduction of the endo-functional group was achieved through the formation of heteroleptic [Pd2 (LA )2 (LB )(LC )] cages. Using two orthogonal steric control elements is the key for the selective formation of the hetero-assemblies. We demonstrated the construction of two hetero-cages with a single internal functional group as well as a hetero-cage with two distinct endohedral functionalities. The endo-functionalized hetero-cages bound sulfonate guests with fast-exchange dynamics. This strategy provides a new solution for the controlled endo-functionalization of supramolecular cavities.

The dynamic alteration of transcriptional regulation by crucial TFs during tumorigenesis of gastric cancer.

BACKGROUND: The mechanisms of Gastric cancer (GC) initiation and progression are complicated, at least partly owing to the dynamic changes of gene regulation during carcinogenesis. Thus, investigations on the changes in regulatory networks can improve the understanding of cancer development and provide novel insights into the molecular mechanisms of cancer. METHODS: Differential co-expression analysis (DCEA), differential gene regulation network (GRN) modeling and differential regulation analysis (DRA) were integrated to detect differential transcriptional regulation events between gastric normal mucosa and cancer samples based on GSE54129 dataset. Cytological experiments and IHC staining assays were used to validate the dynamic changes of CREB1 regulated targets in different stages. RESULTS: A total of 1955 differentially regulated genes (DRGs) were identified and prioritized in a quantitative way. Among the top 1% DRGs, 14 out of 19 genes have been reported to be GC relevant. The four transcription factors (TFs) among the top 1% DRGs, including CREB1, BPTF, GATA6 and CEBPA, were regarded as crucial TFs relevant to GC progression. The differentially regulated links (DRLs) around the four crucial TFs were then prioritized to generate testable hypotheses on the differential regulation mechanisms of gastric carcinogenesis. To validate the dynamic alterations of gene regulation patterns of crucial TFs during GC progression, we took CREB1 as an example to screen its differentially regulated targets by using cytological and IHC staining assays. Eventually, TCEAL2 and MBNL1 were proved to be differentially regulated by CREB1 during tumorigenesis of gastric cancer. CONCLUSIONS: By combining differential networking information and molecular cell experiments verification, testable hypotheses on the regulation mechanisms of GC around the core TFs and their top ranked DRLs were generated. Since TCEAL2 and MBNL1 have been reported to be potential therapeutic targets in SCLC and breast cancer respectively, their translation values in GC are worthy of further investigation.

Bacterial community dynamics on bats and the implications for pathogen resistance.

The bats skin microbiota plays an important role in reducing pathogen infection, including the deadly fungal pathogen Pseudogymnoascus destructans, the causative agent of white-nose syndrome. However, the dynamic of skin bacterial communities response to environmental perturbations remains poorly described. We characterized skin bacterial community over time and space in Rhinolophus ferrumequinum, a species with high resistance to the infection with P. destructans. We collected environmental covariate data to determine what factors influenced changes in community structure. We observed significant temporal and spatial shifts in the skin bacterial community, which was mainly associated with variation in operational taxonomic units. The skin bacterial community differed by the environmental microbial reservoirs and was most influenced by host body condition, bat roosting temperature and geographic distance between sites, but was not influenced by pathogen infection. Furthermore, the skin microbiota was enriched in particular taxa with antifungal abilities, such as Enterococcus, Burkholderia, Flavobacterium, Pseudomonas, Corynebacterium and Rhodococcus. And specific strains of Pseudomonas, Corynebacterium and Rhodococcus even inhibited P. destructans growth. Our findings provide new insights in characterizing the variation in bacterial communities can inform us about the processes of driving community assembly and predict the host's ability to resist or survive pathogen infection.

DysRegSig: an R package for identifying gene dysregulations and building mechanistic signatures in cancer.

SUMMARY: Dysfunctional regulations of gene expression programs relevant to fundamental cell processes can drive carcinogenesis. Therefore, systematically identifying dysregulation events is an effective path for understanding carcinogenesis and provides insightful clues to build predictive signatures with mechanistic interpretability for cancer precision medicine. Here, we implemented a machine learning-based gene dysregulation analysis framework in an R package, DysRegSig, which is capable of exploring gene dysregulations from high-dimensional data and building mechanistic signature based on gene dysregulations. DysRegSig can serve as an easy-to-use tool to facilitate gene dysregulation analysis and follow-up analysis. AVAILABILITY AND IMPLEMENTATION: The source code and user's guide of DysRegSig are freely available at Github: https://github.com/SCBIT-YYLab/DysRegSig. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Full-Length Transcriptome of Myotis pilosus as a Reference Resource and Mining of Auditory and Immune Related Genes.

Rickett's big-footed bat, Myotis pilosus, which belongs to the family Vespertilionida, is the only known piscivorous bat in East Asia. Accurate whole genome and transcriptome annotations are essential for the study of bat biological evolution. The lack of a whole genome for M. pilosus has limited our understanding of the molecular mechanisms underlying the species' evolution, echolocation, and immune response. In the present work, we sequenced the entire transcriptome using error-corrected PacBio single-molecule real-time (SMRT) data. Then, a total of 40 GB of subreads were generated, including 29,991 full-length non-chimeric (FLNC) sequences. After correction by Illumina short reads and de-redundancy, we obtained 26,717 error-corrected isoforms with an average length of 3018.91 bp and an N50 length of 3447 bp. A total of 1528 alternative splicing (AS) events were detected by transcriptome structural analysis. Furthermore, 1032 putative transcription factors (TFs) were identified, with additional identification of several long non-coding RNAs (lncRNAs) with high confidence. Moreover, several key genes, including PRL-2, DPP4, Glul, and ND1 were also identified as being associated with metabolism, immunity, nervous system processes, and auditory perception. A multitude of pattern recognition receptors was identified, including NLR, RLR, SRCR, the antiviral molecule IRF3, and the IFN receptor subunit IFNAR1. High-quality reference genomes at the transcriptome level may be used to quantify gene or transcript expression, evaluate alternative splicing levels, identify novel transcripts, and enhance genome annotation in bats.

AutoCNV: a semiautomatic CNV interpretation system based on the 2019 ACMG/ClinGen Technical Standards for CNVs.

BACKGROUND: The American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen) presented technical standards for interpretation and reporting of constitutional copy-number variants in 2019 (the standards). Although ClinGen developed a web-based CNV classification calculator based on scoring metrics, it can only track and tally points that have been assigned based on observed evidence. Here, we developed AutoCNV (a semiautomatic automated CNV interpretation system) based on the standards, which can automatically generate predictions on 18 and 16 criteria for copy number loss and gain, respectively. RESULTS: We assessed the performance of AutoCNV using 72 CNVs evaluated by external independent reviewers and 20 illustrative case examples. Using AutoCNV, it showed that 100 % (72/72) and 95 % (19/20) of CNVs were consistent with the reviewers' and ClinGen-verified classifications, respectively. AutoCNV only required an average of less than 5 milliseconds to obtain the result for one CNV with automated scoring. We also applied AutoCNV for the interpretation of CNVs from the ClinVar database and the dbVar database. We also developed a web-based version of AutoCNV (wAutoCNV). CONCLUSIONS: AutoCNV may serve to assist users in conducting in-depth CNV interpretation, to accelerate and facilitate the interpretation process of CNVs and to improve the consistency and reliability of CNV interpretation.

Single-Cell Infrared Microspectroscopy Quantifies Dynamic Heterogeneity of Mesenchymal Stem Cells during Adipogenic Differentiation.

The central relevance of cellular heterogeneity to biological phenomena raises the rational needs for analytical techniques with single-cell resolution. Here, we developed a single-cell FTIR microspectroscopy-based method for the quantitative evaluation of cellular heterogeneity by calculating the cell-to-cell similarity distance of the infrared spectral data. Based on this method, we revealed the infrared phenotypes might reflect the dynamic heterogeneity changes in the cell population during the adipogenic differentiation of the human mesenchymal stem cells. These findings provide an alternative label-free optical approach for quantifying the cellular heterogeneity, and the combination with other single-cell analysis tools will be very helpful for understanding the genotype-to-phenotype relationship in cellular populations.

A Cuboid Spider Silk: Structure-Function Relationship and Polypeptide Signature.

A unique cuboid spider silk from the outer egg sac of Nephila pilipes, with an unusual square cross-section, is disclosed. The structure-function relationships within this silk are first studied through structural characterization, mechanical measurement, protein conformation, and polypeptide signature of silk proteins. This silk maintains the higher stiffness property of egg sac silks, and also shows a species difference. Environmental response of the mechanical properties within this silk are observed. Synchrotron FTIR microspectroscopy is used to monitor the silk protein conformation in a single natural silk. The ß-sheet structure aligns parallel to the fiber axis with a content of 22% ± 2.6%. The de novo resulting polypeptide from the solid silk fibers are novel, and an abundant polar amino acid insertion is observed. Short polyalanine (An , n ≤ 3), alternating serine and alanine (S/A)X, and alternating glycine and alanine (G/A)X, GGX, and SSX dominates in the resulting de novo polypeptide. This accords with the composition pattern of other egg sac silk proteins, besides the rarely observed GGX. This study broadens the library of egg sac spider silks and provides a new perspective to uncover structure-function relationships in spider silk.

CB-Dock: a web server for cavity detection-guided protein-ligand blind docking.

As the number of elucidated protein structures is rapidly increasing, the growing data call for methods to efficiently exploit the structural information for biological and pharmaceutical purposes. Given the three-dimensional (3D) structure of a protein and a ligand, predicting their binding sites and affinity are a key task for computer-aided drug discovery. To address this task, a variety of docking tools have been developed. Most of them focus on docking in the preset binding sites given by users. To automatically predict binding modes without information about binding sites, we developed a user-friendly blind docking web server, named CB-Dock, which predicts binding sites of a given protein and calculates the centers and sizes with a novel curvature-based cavity detection approach, and performs docking with a popular docking program, Autodock Vina. This method was carefully optimized and achieved ~70% success rate for the top-ranking poses whose root mean square deviation (RMSD) were within 2 Å from the X-ray pose, which outperformed the state-of-the-art blind docking tools in our benchmark tests. CB-Dock offers an interactive 3D visualization of results, and is freely available at http://cao.labshare.cn/cb-dock/.

Route to Rheumatoid Arthritis by Macrophage-Derived Microvesicle-Coated Nanoparticles.

The targeted delivery of therapeutics to sites of rheumatoid arthritis (RA) has been a long-standing challenge. Inspired by the intrinsic inflammation-targeting capacity of macrophages, a macrophage-derived microvesicle (MMV)-coated nanoparticle (MNP) was developed for targeting RA. The MMV was efficiently produced through a novel method. Cytochalasin B (CB) was applied to relax the interaction between the cytoskeleton and membrane of macrophages, thus stimulating MMV secretion. The proteomic profile of the MMV was analyzed by iTRAQ (isobaric tags for relative and absolute quantitation). The MMV membrane proteins were similar to those of macrophages, indicating that the MMV could exhibit bioactivity similar to that of RA-targeting macrophages. A poly(lactic- co-glycolic acid) (PLGA) nanoparticle was subsequently coated with MMV, and the inflammation-mediated targeting capacity of the MNP was evaluated both in vitro and in vivo. The in vitro binding of MNP to inflamed HUVECs was significantly stronger than that of the red blood cell membrane-coated nanoparticle (RNP). Compared with bare NP and RNP, MNP showed a significantly enhanced targeting effect in vivo in a collagen-induced arthritis (CIA) mouse model. The targeting mechanism was subsequently revealed according to the proteomic analysis, indicating that Mac-1 and CD44 contributed to the outstanding targeting effect of the MNP. A model drug, tacrolimus, was encapsulated in MNP (T-RNP) and significantly suppressed the progression of RA in mice. The present study demonstrates MMV as a promising and rich material, with which to mimic macrophages, and demonstrates that MNP is an efficient biomimetic vehicle for RA targeting and treatment.

DRAP: a toolbox for drug response analysis and visualization tailored for preclinical drug testing on patient-derived xenograft models.

BACKGROUND: One of the key reasons for the high failure rate of new agents and low therapeutic benefit of approved treatments is the lack of preclinical models that mirror the biology of human tumors. At present, the optimal cancer model for drug response study to date is patient-derived xenograft (PDX) models. PDX recaptures both inter- and intra-tumor heterogeneity inherent in human cancer, which represent a valuable platform for preclinical drug testing and personalized medicine applications. Building efficient drug response analysis tools is critical but far from adequate for the PDX platform. RESULTS: In this work, we first classified the emerging PDX preclinical trial designs into four patterns based on the number of tumors, arms, and animal repeats in every arm. Then we developed an R package, DRAP, which implements Drug Response Analyses on PDX platform separately for the four patterns, involving data visualization, data analysis and conclusion presentation. The data analysis module offers statistical analysis methods to assess difference of tumor volume between arms, tumor growth inhibition (TGI) rate calculation to quantify drug response, and drug response level analysis to label the drug response at animal level. In the end, we applied DRAP in two case studies through which the functions and usage of DRAP were illustrated. CONCLUSION: DRAP is the first integrated toolbox for drug response analysis and visualization tailored for PDX platform. It would greatly promote the application of PDXs in drug development and personalized cancer treatments.

Tmem178 negatively regulates store-operated calcium entry in myeloid cells via association with STIM1.

Store-operated calcium entry (SOCE) modulates cytosolic calcium in multiple cells. Endoplasmic reticulum (ER)-localized STIM1 and plasma membrane (PM)-localized ORAI1 are two main components of SOCE. STIM1:ORAI1 association requires STIM1 oligomerization, its re-distribution to ER-PM junctions, and puncta formation. However, little is known about the negative regulation of these steps to prevent calcium overload. Here, we identified Tmem178 as a negative modulator of STIM1 puncta formation in myeloid cells. Using site-directed mutagenesis, co-immunoprecipitation assays and FRET imaging, we determined that Tmem178:STIM1 association occurs via their transmembrane motifs. Mutants that increase Tmem178:STIM1 association reduce STIM1 puncta formation, SOCE activation, impair inflammatory cytokine production in macrophages and osteoclastogenesis. Mutants that reduce Tmem178:STIM1 association reverse these effects. Furthermore, exposure to plasma from arthritic patients decreases Tmem178 expression, enhances SOCE activation and cytoplasmic calcium. In conclusion, Tmem178 modulates the rate-limiting step of STIM1 puncta formation and therefore controls SOCE in inflammatory conditions.

Gene expression vs. sequence divergence: comparative transcriptome sequencing among natural Rhinolophus ferrumequinum populations with different acoustic phenotypes.

BACKGROUND: Although the sensory drive hypothesis can explain the geographic variation in echolocation frequencies of some bat species, the molecular mechanisms underlying this phenomenon are still unclear. The three lineages of greater horseshoe bat (Rhinolophus ferrumequinum) in China (northeast, central-east, and southwest) have significant geographic variation in resting frequencies (RF) of echolocation calls. Because their cochleae have an acoustic fovea that is highly sensitive to a narrow range of frequencies, we reported the transcriptomes of cochleae collected from three genetic lineages of R. ferrumequinum, which is an ideal organism for studying geographic variation in echolocation signals, and tried to understand the mechanisms behind this bat phenomenon by analyzing gene expression and sequence variation. RESULTS: A total of 8190 differentially expressed genes (DEGs) were identified. We identified five modules from all DEGs that were significantly related to RF or forearm length (FL). DEGs in the RF-related modules were significantly enriched in the gene categories involved in neural activity, learning, and response to sound. DEGs in the FL-related modules were significantly enriched in the pathways related to muscle and actin functions. Using 21,945 single nucleotide polymorphisms, we identified 18 candidate unigenes associated with hearing, five of which were differentially expressed among the three populations. Additionally, the gene ERBB4, which regulates diverse cellular processes in the inner ear such as cell proliferation and differentiation, was in the largest module. We also found 49 unigenes that were under positive selection from 4105 one-to-one orthologous gene pairs between the three R. ferrumequinum lineages and three other Chiroptera species. CONCLUSIONS: The variability of gene expression and sequence divergence at the molecular level might provide evidence that can help elucidate the genetic basis of geographic variation in echolocation signals of greater horseshoe bats.