Maturation and Diversity of the VRC01-Antibody Lineage over 15 Years of Chronic HIV-1 Infection.

HIV-1-neutralizing antibodies develop in most HIV-1-infected individuals, although highly effective antibodies are generally observed only after years of chronic infection. Here, we characterize the rate of maturation and extent of diversity for the lineage that produced the broadly neutralizing antibody VRC01 through longitudinal sampling of peripheral B cell transcripts over 15 years and co-crystal structures of lineage members. Next-generation sequencing identified VRC01-lineage transcripts, which encompassed diverse antibodies organized into distinct phylogenetic clades. Prevalent clades maintained characteristic features of antigen recognition, though each evolved binding loops and disulfides that formed distinct recognition surfaces. Over the course of the study period, VRC01-lineage clades showed continuous evolution, with rates of ∼2 substitutions per 100 nucleotides per year, comparable to that of HIV-1 evolution. This high rate of antibody evolution provides a mechanism by which antibody lineages can achieve extraordinary diversity and, over years of chronic infection, develop effective HIV-1 neutralization.

High-resolution genome-wide mapping of the primary structure of chromatin.

The genomic organization of chromatin is increasingly recognized as a key regulator of cell behavior, but deciphering its regulation mechanisms requires detailed knowledge of chromatin's primary structure-the assembly of nucleosomes throughout the genome. This Primer explains the principles for mapping and analyzing the primary organization of chromatin on a genomic scale. After introducing chromatin organization and its impact on gene regulation and human health, we then describe methods that detect nucleosome positioning and occupancy levels using chromatin immunoprecipitation in combination with deep sequencing (ChIP-Seq), a strategy that is now straightforward and cost efficient. We then explore current strategies for converting the sequence information into knowledge about chromatin, an exciting challenge for biologists and bioinformaticians.

A Deep Learning Model for Accurate Diagnosis of Infection Using Antibody Repertoires.

The adaptive immune receptor repertoire consists of the entire set of an individual's BCRs and TCRs and is believed to contain a record of prior immune responses and the potential for future immunity. Analyses of TCR repertoires via deep learning (DL) methods have successfully diagnosed cancers and infectious diseases, including coronavirus disease 2019. However, few studies have used DL to analyze BCR repertoires. In this study, we collected IgG H chain Ab repertoires from 276 healthy control subjects and 326 patients with various infections. We then extracted a comprehensive feature set consisting of 10 subsets of repertoire-level features and 160 sequence-level features and tested whether these features can distinguish between infected individuals and healthy control subjects. Finally, we developed an ensemble DL model, namely, DL method for infection diagnosis (https://github.com/chenyuan0510/DeepID), and used this model to differentiate between the infected and healthy individuals. Four subsets of repertoire-level features and four sequence-level features were selected because of their excellent predictive performance. The DL method for infection diagnosis outperformed traditional machine learning methods in distinguishing between healthy and infected samples (area under the curve = 0.9883) and achieved a multiclassification accuracy of 0.9104. We also observed differences between the healthy and infected groups in V genes usage, clonal expansion, the complexity of reads within clone, the physical properties in the α region, and the local flexibility of the CDR3 amino acid sequence. Our results suggest that the Ab repertoire is a promising biomarker for the diagnosis of various infections.

A Robust Planar Marker-Based Visual SLAM.

Many visual SLAM systems are generally solved using natural landmarks or optical flow. However, due to textureless areas, illumination change or motion blur, they often acquire poor camera poses or even fail to track. Additionally, they cannot obtain camera poses with a metric scale in the monocular case. In some cases (such as when calibrating the extrinsic parameters of camera-IMU), we prefer to sacrifice the flexibility of such methods to improve accuracy and robustness by using artificial landmarks. This paper proposes enhancements to the traditional SPM-SLAM, which is a system that aims to build a map of markers and simultaneously localize the camera pose. By placing the markers in the surrounding environment, the system can run stably and obtain accurate camera poses. To improve robustness and accuracy in the case of rotational movements, we improve the initialization, keyframes insertion and relocalization. Additionally, we propose a novel method to estimate marker poses from a set of images to solve the problem of planar-marker pose ambiguity. Compared with the state-of-art, the experiments show that our system achieves better accuracy in most public sequences and is more robust than SPM-SLAM under rotational movements. Finally, the open-source code is publicly available and can be found at GitHub.

Carboxymethyl starch as a solid dispersion carrier to enhance the dissolution and bioavailability of piperine and 18ß-glycyrrhetinic acid.

OBJECTIVE: To investigate the applicability of carboxymethyl starch (CMS) as a carrier to prepare solid dispersions (SDs) of piperine (PIP) and 18ß-glycyrrhetinic acid (ß-GA) (PIP-CMS and ß-GA-CMS SDs) and to explore the influence of drug properties on carrier selection. SIGNIFICANCE: The low oral bioavailability of natural therapeutic molecules, including PIP and ß-GA, severely restricts their pharmaceutical applications. Moreover, CMS, a natural polymer, is rarely reported as a carrier for SDs. METHODS: PIP-CMS and ß-GA-CMS SDs were prepared using the solvent evaporation method. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier transform infrared (FT-IR) spectroscopy, and scanning electron microscopy (SEM) were used for formulation characterization. Additionally, drug release characteristics were investigated. RESULTS: In vitro dissolution studies showed that the dissolutions of PIP-CMS and ß-GA-CMS SDs were 1.90-2.04 and 1.97-2.22 times higher than pure PIP and ß-GA, respectively, at a drug:polymer ratio of 1:6. DSC, XRPD, FT-IR, and SEM analyses confirmed the formation of SDs in their amorphous states. Significant improvements in Cmax and AUC0-24 h of PIP-CMS and ß-GA-CMS SDs (17.51 ± 8.15 µg/mL and 210.28 ± 117.13 µg·h/mL, respectively) and (32.17 ± 9.45 µg/mL and 165.36 ± 38.75 µg·h/mL, respectively) were observed in the pharmacokinetic study. Compared with weakly acidic ß-GA, loading weakly basic PIP seemed to have a profound effect on stability through intermolecular forces. CONCLUSIONS: Our findings showed CMS could be a promising carrier for SDs, and loading weakly basic drug may be more suitable, especially in binary SDs system.

Sodium hyaluronates applied in the face affects the diversity of skin microbiota in healthy people.

OBJECTIVE: A healthy and stable microbiome has many beneficial effects on the host, while an unbalanced or disordered microbiome can lead to various skin diseases. Hyaluronic acid is widely used in the cosmetics and pharmaceutical industries; however, specific reports on its effect on the skin microflora of healthy people have not been published. This study aimed to determine the effect of sodium hyaluronate on the facial microflora of healthy individuals. METHODS: Face of 20 healthy female volunteers between 18 and 24 years was smeared with sodium hyaluronate solution once per day. Cotton swabs were used to retrieve samples on days 0, 14, and 28, and high-throughput sequencing of 16 S rRNA was used to determine the changes in bacterial community composition. RESULTS: Facial application of HA can reduce the abundance of pathogenic bacteria, such as Cutibacterium and S. aureus, and increase the colonization of beneficial bacteria. CONCLUSION: This is the first intuitive report to demonstrate the effect of hyaluronic acid on facial microflora in healthy people. Accordingly, sodium hyaluronate was found to have a positive effect on facial skin health.

Tools for fundamental analysis functions of TCR repertoires: a systematic comparison.

The full set of T cell receptors (TCRs) in an individual is known as his or her TCR repertoire. Defining TCR repertoires under physiological conditions and in response to a disease or vaccine may lead to a better understanding of adaptive immunity and thus has great biological and clinical value. In the past decade, several high-throughput sequencing-based tools have been developed to assign TCRs to germline genes and to extract complementarity-determining region 3 (CDR3) sequences using different algorithms. Although these tools claim to be able to perform the full range of fundamental TCR repertoire analyses, there is no clear consensus of which tool is best suited to particular projects. Here, we present a systematic analysis of 12 available TCR repertoire analysis tools using simulated data, with an emphasis on fundamental analysis functions. Our results shed light on the detailed functions of TCR repertoire analysis tools and may therefore help researchers in the field to choose the right tools for their particular experimental design.

The role of enteric dysbacteriosis and modulation of gut microbiota in the treatment of inflammatory bowel disease.

The incidence of inflammatory bowel disease (IBD) is globally increasing. This disorder seriously affects the quality of life in patients. Interestingly, studies have detected that the intestinal flora imbalance is a critical factor in the progression of IBD. One potential treatment strategy for IBD involves regulating the composition and function of the intestinal flora. To date, a multitude of experiments have confirmed the relationship between intestinal flora, immune regulation, and anti-inflammation. The intestinal flora can reduce intestinal inflammation by regulating immunity and increasing the secretion of metabolic short-chain fatty acids. In this review, we discuss the composition and function of the intestinal flora, the relationship between the intestinal flora and the host, the role of intestinal flora disorders in IBD, and the progress in IBD treatment. Combining the regulation of the intestinal flora with probiotics treatment is considered a promising strategy for substantially improving the treatment of IBD.

Multidonor analysis reveals structural elements, genetic determinants, and maturation pathway for HIV-1 neutralization by VRC01-class antibodies.

Antibodies of the VRC01 class neutralize HIV-1, arise in diverse HIV-1-infected donors, and are potential templates for an effective HIV-1 vaccine. However, the stochastic processes that generate repertoires in each individual of >10(12) antibodies make elicitation of specific antibodies uncertain. Here we determine the ontogeny of the VRC01 class by crystallography and next-generation sequencing. Despite antibody-sequence differences exceeding 50%, antibody-gp120 cocrystal structures reveal VRC01-class recognition to be remarkably similar. B cell transcripts indicate that VRC01-class antibodies require few specific genetic elements, suggesting that naive-B cells with VRC01-class features are generated regularly by recombination. Virtually all of these fail to mature, however, with only a few-likely one-ancestor B cell expanding to form a VRC01-class lineage in each donor. Developmental similarities in multiple donors thus reveal the generation of VRC01-class antibodies to be reproducible in principle, thereby providing a framework for attempts to elicit similar antibodies in the general population.

A role of the CTCF binding site at enhancer Eα in the dynamic chromatin organization of the Tcra-Tcrd locus.

The regulation of T cell receptor Tcra gene rearrangement has been extensively studied. The enhancer Eα plays an essential role in Tcra rearrangement by establishing a recombination centre in the Jα array and a chromatin hub for interactions between Vα and Jα genes. But the mechanism of the Eα and its downstream CTCF binding site (here named EACBE) in dynamic chromatin regulation is unknown. The Hi-C data showed that the EACBE is located at the sub-TAD boundary which separates the Tcra-Tcrd locus and the downstream region including the Dad1 gene. The EACBE is required for long-distance regulation of the Eα on the proximal Vα genes, and its deletion impaired the Tcra rearrangement. We also noticed that the EACBE and Eα regulate the genes in the downstream sub-TAD via asymmetric chromatin extrusion. This study provides a new insight into the role of CTCF binding sites at TAD boundaries in gene regulation.

Oxybutynin nanosuspension gel for enhanced transdermal treatment for overactive bladder syndrome.

Oxybutynin (OXY) is the most common drug to treat overactive bladder (OAB) syndrome. Transdermal administration is a more ideal route replacing oral administration to resolve problems of low bioavailability and severe side effects. However, commercial transdermal products of OXY frequently cause skin irritation and low permeation efficiency arising discontinued medication. Here, oxybutynin nanosuspension (OXY-NS) and its gel preparation (OXY-NG) were constructed to resolve these issues. In vitro permeation test and in vivo pharmacokinetics study confirmed that OXY-NG significantly enhanced the transdermal permeation of OXY, about 4-fold and 3-fold higher than oxybutynin coarse suspension (OXY-CG), respectively, and in vitro retention test certified that OXY-NG increased OXY concentration especially in viable epidermis (VE) and Dermis (about 3 times that of OXY-CG), consequently improving the bioavailability. Skin irritation assay demonstrated that OXY-NG would not trigger skin adverse effects. In addition, selectively blocking hair follicles test evidenced that hair follicles pathway played an important role in OXY-NS transdermal delivery. In general, by virtue of excellent drug loading, low toxicity and ease of scale-up, OXY-NG is a promising strategy to ameliorate skin permeation of insoluble OXY for better transdermal treatment for OAB, hence increasing its bioavailability, reducing adverse effects, and achieving good patient compliance.

mPEG-Cholic acid/TPGS mixed micelles for combined delivery of paclitaxel and bufalin to treat hepatocellular carcinoma.

In this study, amphiphilic block copolymer mPEG-cholic acid was synthesized in conjunction with TPGS as stabilizer to prepare multifunctional micelles. The formed polymeric micelles (PCTm) were used for the delivery of paclitaxel (PTX) and bufalin (BF). PEG group could enhance solubility and extend circulation time, while cholic acid groups achieved the liver targeted function. Combinations of these approaches could realize a synergistic therapeutic effect in the treatment of advanced hepatocellular carcinoma. CLSM in vitro results demonstrated that drug capsulation into PCTm could enhance cellular uptake. FCM results confirmed the uptake amount of C6/PCTm was 7.5-fold higher than that of free C6 after incubation for 2 h. Competitive inhibition test proved the Na+-taurocholate co-transporting polypeptide (NTCP) involved in the uptake mechanism of PCTm. Meanwhile, in vivo imaging assays demonstrated that the fluorescence intensity of Cy5.5/PCTm was higher than that of free Cy5.5 on liver and tumor with extended circulation time to 48 h. In addition, in vivo studies confirmed that the combined therapy exhibited the strongest tumor inhibition rate of 82.29% with lower systemic toxicity. Hence, these results indicated that PCTm could provide a promising strategy for targeting hepatocellular carcinoma and achieve the goal of synergism and attenuation.

High-fidelity acoustic signal enhancement for phase-OTDR using supervised learning.

Phase-measuring phase-sensitive optical time-domain reflectometry (OTDR) has been widely used for the distributed acoustic sensing. However, the demodulated phase signals are generally noisy due to the laser frequency drift, laser phase noise, and interference fading. These issues are usually addressed individually. In this paper, we propose to address them simultaneously using supervised learning. We first use numerical simulations to generate the corresponding noisy differential phase signals for the given acoustic signals. Then we use the generated acoustic signals and noises together with some real noise data to train an end-to-end convolutional neutral network (CNN) for the acoustic signal enhancement. Three experiments are conduct to evaluate the performance of the proposed signal enhancement method. After enhancement, the average signal-to-noise ratio (SNR) of the recovered PZT vibration signals is improved from 13.4 dB to 42.8 dB, while the average scale-invariant signal-to-distortion ratio (SI-SDR) of the recovered speech signals is improved by 7.7 dB. The results show that, the proposed method can well suppress the noise and signal distortion caused by the laser frequency drift, laser phase noise, and interference fading, while recover the acoustic signals with high fidelity.

TWIST1 transcriptionally regulates glycolytic genes to promote the Warburg metabolism in pancreatic cancer.

Reprogrammed glucose metabolism is essential for tumor initiation and development, especially for pancreatic ductal adenocarcinoma (PDAC). Most cancer cells rely on aerobic glycolysis, a phenomenon termed "the Warburg effect", to support uncontrolled proliferation and evade apoptosis. However, the direct regulators of the Warburg effect remain areas of active investigation. In this study, we found that the highly conserved transcription factor, TWIST1, is a crucial regulator of aerobic glycolysis in PDAC. Genetic silencing of TWIST1 significantly inhibited the glycolytic phenotypes of PDAC cells as revealed by reduced glucose uptake, lactate production, and extracellular acidification rate, which can be restored by re-expression of siRNA-resistant TWIST1. Moreover, tamoxifen-inducible expression of TWIST1 promoted the Warburg metabolism of PDAC cells. Mechanistically, by luciferase reporter assay and chromatin immunoprecipitation experiment, we showed that TWIST1 can directly increase the expression of several glycolytic genes, including SLC2A1, HK2, ENO1, and PKM2. Of note, the transcriptional regulation by TWIST1 was not dependent on HIF1α or c-Myc. In The Cancer Genome Atlas and Gene Expression Omnibus accession GSE15471, we confirmed that TWIST1 was closely associated with the glycolysis pathway. Collectively, our findings indicate that TWIST1 is likely to act as important regulator of the Warburg effect in PDAC.

Risk factors for metabolic bone disease among preterm infants less than 32 weeks gestation with Bronchopulmonary dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) infants present an increased incidence of metabolic bone disease (MBD), but it is unknown which factors contribute to this. The aim of this study was to determine the risk factors for developing MBD in BPD infants. METHODS: A retrospective review of the medical records of BPD infants admitted to the Neonatal intensive care unit at Zhangzhou Hospital between Jun 2016 and May 2020 was performed. BPD infants with MBD were identified, two contemporaneous without MBD matched by gestational age and gender were randomly selected as controls for each case of MBD. The association between putative risk factors and MBD was estimated with ORs and 95% CIs. A P-value threshold ≤0.2 was used in univariate analysis for inclusion into a multivariate (adjusted) model with a P-value of < 0.05 as statistically significant. RESULTS: A total of 156 BPD infants were enrolled with 52 cases of MBD and 104 controls. Fetal growth restriction (OR 6.00, 95% CI, 1.81-19.84), extremely low birth weight (OR 3.10, 95% CI, 1.07-8.94), feeding volume < 80 mL/kg/d at the end of the 4th week after birth (OR 14.98, 95% CI, 4.04-55.58), cholestasis (OR 4.44, 95% CI, 1.59-12.40), late onset sepsis (OR 3.95, 95% CI, 1.12-13.98) and prolonged (> 2 weeks) diuretics application (OR 5.45, 95% CI, 1.25-23.84) were found to be statistically significant risk factors for MBD in BPD infants. CONCLUSION: In BPD infants of homogeneous gestational age, fetal growth restriction, extremely low birth weight, feeding volume < 80 mL/kg/d at the end of the 4th week after birth, cholestasis and late onset sepsis are significant risk factors for MBD. These findings provide potential predictive factors for MBD in BPD infants and warrant prospective validation.

Avermectin induced DNA damage to the apoptosis and autophagy in human lung epithelial A549 cells.

Avermectin (AVM), as a biological insecticide, is widely used in agriculture and forestry production globally. However, inhalation of AVM may pose a risk, and the lung is the direct target, but the cytotoxicity of AVM on human lung cells is still unclear. Here, we attempted to elucidate the cytotoxic effect and molecular mechanism of AVM on human lung A549 cells. The results indicated that AVM inhibits cell proliferation, and enhances programmed cell death (apoptosis and autophagy). In addition, we found the AVM-treated cells showed an obvious drop in mitochondrial membrane potential and LC3-I/II, increased ROS production, DNA double-strand breaks, caspase-3/9 activated, PARP cleaved, cytochrome c and Bax/Bcl-2 content rise. The results showed that AVM induced mitochondria-related apoptosis and autophagy in lung A549 cells. These results indicate that AVM can pose a potential threat to human health by inducing DNA damage and programmed cell death.

Research on Design, Calibration and Real-Time Image Expansion Technology of Unmanned System Variable-Scale Panoramic Vision System.

This paper summarized the research status, imaging model, systems calibration, distortion correction, and panoramic expansion of panoramic vision systems, pointed out the existing problems and put forward the prospect of future research. According to the research status of panoramic vision systems, a panoramic vision system with single viewpoint of refraction and reflection is designed. The systems had the characteristics of fast acquisition, low manufacturing cost, fixed single-view imaging, integrated imaging, and automatic switching depth of field. Based on these systems, an improved nonlinear optimization polynomial fitting method is proposed to calibrate the monocular HOVS, and the binocular HOVS is calibrated with the Aruco label. This method not only improves the robustness of the calibration results, but also simplifies the calibration process. Finally, a real-time method of panoramic map of multi-function vehicle based on vcam is proposed.

GsmPlot: a web server to visualize epigenome data in NCBI.

BACKGROUND: Epigenetic regulation is essential in regulating gene expression across a variety of biological processes. Many high-throughput sequencing technologies have been widely used to generate epigenetic data, such as histone modification, transcription factor binding sites, DNA modifications, chromatin accessibility, and etc. A large scale of epigenetic data is stored in NCBI Gene Expression Omnibus (GEO). However, it is a great challenge to reanalyze these large scale and complex data, especially for researchers who do not specialize in bioinformatics skills or do not have access to expensive computational infrastructure. RESULTS: GsmPlot can simply accept GSM IDs to automatically download NCBI data or can accept user's private bigwig files as input to plot the concerned data on promoters, exons or any other user-defined genome locations and generate UCSC visualization tracks. By linking public data repository and private data, GsmPlot can spark data-driven ideas and hence promote the epigenetic research. CONCLUSIONS: GsmPlot web server allows convenient visualization and efficient exploration of any NCBI epigenetic data in any genomic region without need of any bioinformatics skills or special computing resources. GsmPlot is freely available at https://gsmplot.deqiangsun.org/.

Modelling the effects of Wuhan's lockdown during COVID-19, China.

OBJECTIVE: To design a simple model to assess the effectiveness of measures to prevent the spread of coronavirus disease 2019 (COVID-19) to different regions of mainland China. METHODS: We extracted data on population movements from an internet company data set and the numbers of confirmed cases of COVID-19 from government sources. On 23 January 2020 all travel in and out of the city of Wuhan was prohibited to control the spread of the disease. We modelled two key factors affecting the cumulative number of COVID-19 cases in regions outside Wuhan by 1 March 2020: (i) the total the number of people leaving Wuhan during 20-26 January 2020; and (ii) the number of seed cases from Wuhan before 19 January 2020, represented by the cumulative number of confirmed cases on 29 January 2020. We constructed a regression model to predict the cumulative number of cases in non-Wuhan regions in three assumed epidemic control scenarios. FINDINGS: Delaying the start date of control measures by only 3 days would have increased the estimated 30 699 confirmed cases of COVID-19 by 1 March 2020 in regions outside Wuhan by 34.6% (to 41 330 people). Advancing controls by 3 days would reduce infections by 30.8% (to 21 235 people) with basic control measures or 48.6% (to 15 796 people) with strict control measures. Based on standard residual values from the model, we were able to rank regions which were most effective in controlling the epidemic. CONCLUSION: The control measures in Wuhan combined with nationwide traffic restrictions and self-isolation reduced the ongoing spread of COVID-19 across China.

Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies.

Antibodies capable of neutralizing HIV-1 often target variable regions 1 and 2 (V1V2) of the HIV-1 envelope, but the mechanism of their elicitation has been unclear. Here we define the developmental pathway by which such antibodies are generated and acquire the requisite molecular characteristics for neutralization. Twelve somatically related neutralizing antibodies (CAP256-VRC26.01-12) were isolated from donor CAP256 (from the Centre for the AIDS Programme of Research in South Africa (CAPRISA)); each antibody contained the protruding tyrosine-sulphated, anionic antigen-binding loop (complementarity-determining region (CDR) H3) characteristic of this category of antibodies. Their unmutated ancestor emerged between weeks 30-38 post-infection with a 35-residue CDR H3, and neutralized the virus that superinfected this individual 15 weeks after initial infection. Improved neutralization breadth and potency occurred by week 59 with modest affinity maturation, and was preceded by extensive diversification of the virus population. HIV-1 V1V2-directed neutralizing antibodies can thus develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation. These data provide important insights relevant to HIV-1 vaccine development.