Miracle-dz/UniFAR-FTUs huggingface dataset:
Synthetic repertoires derived from convalescent COVID-19 patients enable discovery of SARS-CoV-2 neutralizing antibodies and a novel quaternary binding modality

The ongoing evolution of SARS-CoV-2 into more easily transmissible and infectious variants has sparked concern over the continued effectiveness of existing therapeutic antibodies and vaccines. Hence, together with increased genomic surveillance, methods to rapidly develop and assess effective interventions are critically needed. Here we report the discovery of SARS-CoV-2 neutralizing antibodies isolated from COVID-19 patients using a high-throughput platform. Antibodies were identified from unpaired donor B-cell and serum repertoires using yeast surface display, proteomics, and public light chain screening. Cryo-EM and functional characterization of the antibodies identified N3-1, an antibody that binds avidly (Kd,app = 68 pM) to the receptor binding domain (RBD) of the spike protein and robustly neutralizes the virus in vitro. This antibody likely binds all three RBDs of the trimeric spike protein with a single IgG. Importantly, N3-1 equivalently binds spike proteins from emerging SARS-CoV-2 variants of concern, neutralizes UK variant B.1. 1.7, and binds SARS-CoV spike with nanomolar affinity. Taken together, the strategies described herein will prove broadly applicable in interrogating adaptive immunity and developing rapid response biological countermeasures to emerging pathogens.
Identification and validation of a six immune-related gene signature for prediction of biochemical recurrence in localized prostate cancer following radical prostatectomy

Background Prostate cancer (PCa) is the second lethal heterogeneous cancer among males worldwide, and approximately 20% of PCa patients following radical prostatectomy (RP) will undergo biochemical recurrence (BCR). This study is aimed to identify the immune-related gene signature that can predict BCR in localized PCa following RP. Methods Expression profile of genes together with clinical parameters from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus database (GEO) and the immune-related genes from the Molecular Signatures Database v4.0 were applied to construct and validate the gene signature. The Cox regression analyses were conducted to identify the candidate genes and establish the gene signature. To estimate the prognostic power of the risk score, the time-dependent receiver operating characteristic (ROC) analysis and Harrell’s index of concordance (C-index) were utilized. We also established a nomogram to forecast the probability of patients’ survival. Results A total of 268 patients from the TCGA and 77 patients from GSE70770 and six immune-related genes (SCIN, THY1, TBX1, NOTCH4, MAL, BNIP3L) were eventually selected. The Kaplan-Meier analysis demonstrated that patients in the low-risk group had a significantly longer recurrence-free survival (RFS) compared to those in the high-risk group. In the multivariate Cox model, the signature was identified as an independent prognostic factor, which was significantly associated with RFS (TCGA: HR =5.232, 95% CI: 1.762–15.538, P=0.003; GSE70770: HR =2.158, 95% CI: 1.051–4.432, P=0.036). Moreover, the C-index got improved after incorporating the risk score into original clinicopathological parameters. In addition, the novel nomogram was constructed to better predict the 1-, 3- and 5-year RFS. Conclusions This signature could serve as an independent prognostic factor for BCR. Incorporation of our signature into traditional risk classification might further stratify patients with different prognosis, which could assist practitioners in developing clinical decision-making.
Enhanced oral bioavailability and gastroprotective effect of ibuprofen through mixed polymer-lipid nanoparticles.

Objectives: The aim of this study was to design and formulate mixed polymer-lipid nanoparticles (PLNs) for the delivery of ibuprofen. Methods: The mixed PLNs were prepared by a single modified emulsification solvent evaporation method. Key findings: Core-shell-shaped mixed PLNs were successfully prepared, with sizes in the nano range (193.3 ± 0.70 to 795.8 ± 0.70 nm) and ζ potential (-26.8 ± 0.45 to -42.8 ± 0.30 mV). Entrapment efficiency ranged from 80.3 to 93.6%. Conclusions: Pharmacokinetic parameters showed great improvement in Cmax and Tmax of ibuprofen from the formulation PLNs8 compared with the respective Brufen® and pure drugs, indicating improvement in bioavailability of the drug.
A long non-coding RNAs expression signature to improve prognostic prediction of Wilms tumor in children

Background Wilms tumor (WT) is the most frequent malignancy of the kidney in children, and a subset of patients remains with a poor prognosis. This study aimed to identify key long non-coding RNAs (lncRNAs) related to prognosis and establish a genomic-clinicopathologic nomogram to predict survival in children with WT. Methods Clinical data of 124 WT patients and the relevant RNA sequencing data including lncRNAs expression signature of primary WT samples were obtained from the Therapeutically Applicable Research to Generate Effective Treatment (TARGET) Data Matrix. Then, lncRNAs associated with overall survival (OS) were identified through univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses. The risk scores of 124 participants were calculated, and survival analyses were performed between low- and high-risk groups. A genomic-clinicopathologic nomogram was then developed and evaluated by time-dependent receiver operating characteristic (ROC) curves, including the area under the curve (AUC), calibration curve, and decision curve analysis. Subsequently, bioinformatics analyses were performed to explore the potential molecular mechanisms that affect the prognosis of WT. The package “DESeq2” was used to identify differentially expressed protein-coding genes (DEPCGs) between groups. Gene Set Enrichment Analysis (GSEA) was applied to explore the differences in pathways enrichment. The analytical tools CIBERSORTx and ESTIMATE were used to investigate the discrepancies of the immune microenvironment. Results A total of 10 lncRNAs were selected as independent predictors associated with OS (P<0.05). Participants in the high-risk group had a significantly worse OS and event-free survival (EFS) than those in the low-risk group (P<2E-16 and P=2.03E-04, respectively). The risk score and 3 clinicopathological features (gender, cooperative group protocol, and stage) were identified to construct the nomogram (combined model) (P=5.11E-17). The combined model (1-year AUC: 0.9272, 3-year AUC: 0.9428, 5-year AUC: 0.9259) and risk score model (1-year AUC: 0.9285, 3-year AUC: 0.9399, 5-year AUC: 0.9266) displayed higher predictive accuracy than that of the other models. Subsequently, 105 DEPCGs were identified. The GSEA revealed 4 significant pathways. Analysis with CIBERSORTx demonstrated that monocytes, macrophages M1, activated dendritic cells, and resting mast cells had significant infiltration differences between groups. Conclusions This study constructed a genomic-clinicopathologic nomogram, which might present a novel and efficient method for treating patients with WT.
Simple, rapidly electroassembled thiolated PEG‐based sensor interfaces enable rapid interrogation of antibody titer and glycosylation

Process conditions established during the development and manufacture of recombinant protein therapeutics dramatically impacts their quality and clinical efficacy. Technologies that enable rapid assessment of product quality are critically important. Here, we describe the development of sensor interfaces that directly connect to electronics and enable near real‐time assessment of antibody titer and N‐linked galactosylation. We make use of a spatially resolved electroassembled thiolated polyethylene glycol hydrogel that enables electroactivated disulfide linkages. For titer assessment, we constructed a cysteinylated protein G that can be linked to the thiolated hydrogel allowing for robust capture and assessment of antibody concentration. For detecting galactosylation, the hydrogel is linked with thiolated sugars and their corresponding lectins, which enables antibody capture based on glycan pattern. Importantly, we demonstrate linear assessment of total antibody concentration over an industrially relevant range and the selective capture and quantification of antibodies with terminal β‐galactose glycans. We also show that the interfaces can be reused after surface regeneration using a low pH buffer. Our functionalized interfaces offer advantages in their simplicity, rapid assembly, connectivity to electronics, and reusability. As they assemble directly onto electrodes that also serve as I/O registers, we envision incorporation into diagnostic platforms including those in manufacturing settings.
Reduced mucosal immunity to poliovirus after cessation of trivalent oral polio vaccine

ABSTRACT The switch from using only trivalent oral polio vaccine (tOPV) to sequential schedules combining inactivated poliovirus vaccine (IPV) and bivalent oral polio vaccine (bOPV) for polio vaccination will cause changes to mucosal immunity against polio in infants, which plays an important role in preventing the poliovirus spread. Here, we analyzed mucosal immunity against poliovirus in the intestine during different sequential vaccination schedules. We conducted clinical trials in Guangxi Province, China on 1,200 2-month-old infants who were randomly assigned to one of three vaccination schedule groups: IPV-bOPV-bOPV, IPV-IPV-tOPV, and IPV-IPV-bOPV, with vaccine doses administered at 8, 12, and 16 weeks of age. Stool samples were collected from 10% of participants in each group before administration of the second vaccine doses and at 1, 2, and 4 weeks after the administrations of the second and third vaccine doses. Immunoglobulin A (IgA) in the stool samples was measured to analyze the mucosal immune response in the intestine. Because of the absence of poliovirus type 2 in bOPV, the vaccination schedule of IPV-IPV-bOPV did not sufficiently raise intestinal mucosal immunity against poliovirus type 2, although some cross-immunity was seen. The level of intestinal mucosal immunity was related to shedding status; shedders could produce intestinal mucosa IgA more quickly. The intestinal mucosal immunity level was not related to serum neutralizing antibody level. In the combined sequential vaccination schedule of IPV and bOPV, the risk of circulating vaccine-derived poliovirus type 2 (cVDPV2) may be increased owing to insufficient intestinal mucosal immunity against poliovirus type 2.
Artificial Intelligence in hair research: A proof‐of‐concept study on evaluating hair assembly features

The first objective of this study was to apply computer vision and machine learning techniques to quantify the effects of haircare treatments on hair assembly and to identify correctly whether unknown tresses were treated or not. The second objective was to explore and compare the performance of human assessment with that obtained from artificial intelligence (AI) algorithms.
Acute ketosis inhibits appetite and decreases plasma concentrations of acyl ghrelin in healthy young men

To investigate the acute effect of ketone ester (KE) ingestion on appetite and plasma concentrations of acyl ghrelin (AG), unacylated ghrelin (UAG) and glucagon‐like peptide‐1 (GLP‐1) secretion, and to compare responses with those elicited by isocaloric glucose (GLU) administration.
Physiological effects of intraperitoneal versus subcutaneous insulin infusion in patients with diabetes mellitus type 1: A systematic review and meta-analysis

The intraperitoneal route of administration accounts for less than 1% of insulin treatment regimes in patients with diabetes mellitus type 1 (DM1). Despite being used for decades, a systematic review of various physiological effects of this route of insulin administration is lacking. Thus, the aim of this systematic review was to identify the physiological effects of continuous intraperitoneal insulin infusion (CIPII) compared to those of continuous subcutaneous insulin infusion (CSII) in patients with DM1. Four databases (EMBASE, PubMed, Scopus and CENTRAL) were searched beginning from the inception date of each database to 10th of July 2020, using search terms related to intraperitoneal and subcutaneous insulin administration. Only studies comparing CIPII treatment (≥ 1 month) with CSII treatment were included. Primary outcomes were long-term glycaemic control (after ≥ 3 months of CIPII inferred from glycated haemoglobin (HbA1c) levels) and short-term (≥ 1 day for each intervention) measurements of insulin dynamics in the systematic circulation. Secondary outcomes included all reported parameters other than the primary outcomes. The search identified a total of 2242 records; 39 reports from 32 studies met the eligibility criteria. This meta-analysis focused on the most relevant clinical end points; the mean difference (MD) in HbA1c levels during CIPII was significantly lower than during CSII (MD = -6.7 mmol/mol, [95% CI: -10.3 –-3.1]; in percentage: MD = -0.61%, [95% CI: -0.94 –- 0.28], p = 0.0002), whereas fasting blood glucose levels were similar (MD = 0.20 mmol/L, [95% CI: -0.34–0.74], p = 0.47; in mg/dL: MD = 3.6 mg/dL, [95% CI: -6.1–13.3], p = 0.47). The frequencies of severe hypo- and hyper-glycaemia were reduced. The fasting insulin levels were significantly lower during CIPII than during CSII (MD = 16.70 pmol/L, [95% CI: -23.62 –-9.77], p < 0.0001). Compared to CSII treatment, CIPII treatment improved overall glucose control and reduced fasting insulin levels in patients with DM1.
Generation of a new mouse line with conditionally activated signaling through the BMP receptor, ACVR1: A tool to characterize pleiotropic roles of BMP functions

BMP signaling plays pleiotropic roles in various tissues during embryogenesis and after birth. We have previously generated a constitutively activated Acvr1(ca‐Acvr1) transgenic mouse line (line L35) through pronuclei injection to investigate impacts of enhanced BMP signaling in a tissue specific manner. However, line L35 shows a restricted expression pattern of the transgene. Here, we generated another ca‐Acvr1 transgenic line, line A11, using embryonic stem (ES) transgenesis. The generated line A11 shows distinctive phenotypes from line L35, along with very limited expression levels of the transgene. When the transgene is activated in the neural crest cells in a Cre‐dependent manner, line A11 exhibits cleft palate and shorter jaws, while line L35 develops ectopic cartilages and highly hypomorphic facial structures. When activated in limb buds, line A11 develops organized but smaller limb skeletal structures, while line L35 forms disorganized limbs with little mineralization. Additionally, no heterotopic ossification (HO) is identified in line A11 when bred with NFATc1‐Cre mice even after induction of tissue injury, which is an established protocol for HO for line L35. Therefore, the newly generated conditional ca‐Acvr1 mouse line A11 provides an additional resource to dissect highly context dependent functions of BMP signaling in development and disease.
Obstetric and perinatal health outcomes after pertussis vaccination during pregnancy in Ontario, Canada: a retrospective cohort study

Background: In February 2018, Canada’s National Advisory Committee on Immunization recommended maternal vaccination with tetanus–diphtheria–acellular pertussis (Tdap) vaccine during pregnancy to prevent severe pertussis infection in young infants. This study assessed the relation between maternal Tdap vaccination and obstetric and perinatal outcomes in Ontario. Methods: We performed a population-based cohort study of all births from April 2012 to March 2017 using multiple linked health administrative databases. We used Cox regression with a time-dependent exposure variable to estimate adjusted hazard ratios (HRs) for preterm birth (< 37 wk), very preterm birth (< 32 wk) and stillbirth. We assessed remaining outcomes (gestational hypertension, chorioamnionitis, postpartum hemorrhage, severe postpartum hemorrhage, being small for gestational age, neonatal intensive care unit stay > 24 h, composite neonatal morbidity) using log-binomial regression to generate adjusted risk ratios (RRs). We adjusted estimates for potential confounding using propensity score weighting. Results: Of 615 213 infants (live births and stillbirths), 11 519 were exposed to Tdap vaccination in utero. There was no increased risk for preterm birth (adjusted HR 0.98, 95% confidence interval [CI] 0.91–1.06), very preterm birth (adjusted HR 1.10, 95% CI 0.86–1.41), stillbirth (adjusted HR 1.15, 95% CI 0.82–1.60) or being small for gestational age (adjusted RR 0.96, 95% CI 0.90–1.02). The risks of a neonatal intensive care unit stay exceeding 24 hours (adjusted RR 0.82, 95% CI 0.76–0.88) and neonatal morbidity (adjusted RR 0.81, 95% CI 0.75–0.87) were decreased. There was no association with chorioamnionitis (adjusted RR 1.17, 95% CI 0.99–1.39), postpartum hemorrhage (adjusted RR 1.01, 95% CI 0.91–1.13) or severe postpartum hemorrhage (adjusted RR 0.79, 95% CI 0.55–1.13), but we observed a reduced risk of gestational hypertension (adjusted RR 0.87, 95% CI 0.78–0.96). Interpretation: Our results complement evidence that maternal Tdap vaccination is not associated with adverse outcomes in mothers or infants. Ongoing evaluation in Canada is needed as maternal Tdap vaccination coverage increases in coming years.
The Evolving Epidemiology of Nasopharyngeal Carcinoma

Background: The epidemiology of nasopharyngeal carcinoma (NPC) has long been a source of fascination due to the malignancy's striking geographic distribution, the involvement of the oncogenic Epstein–Barr virus (EBV), the unique association with intake of Chinese-style salt-preserved fish, and etiologic heterogeneity by histologic subtype. Methods: This review summarizes the current epidemiologic literature on NPC, highlighting recent results from our population-based case–control study in southern China. Results: Findings from our case–control study provide new insight into the epidemiology of NPC, including a diminished role of Chinese-style salt-preserved fish, a profound impact of EBV genetic sequence variation, modest positive associations with passive smoking and household air pollution, and possible effects of oral health and the oral microbiome. Recent findings from other studies include a protective association with infectious mononucleosis, suggesting a causal role of early EBV infection; familial risk conferred by shared genetic variation in the host antibody-mediated immune response to EBV infection; and an unclear association with occupational exposure to formaldehyde. Conclusions: To shed further light on the interplay of environmental, genetic, and viral causes of NPC, large pooled studies must accumulate sufficient cases with detailed exposure data. Impact: New epidemiologic findings have reshaped the causal model for NPC.
High-Strength Electroplated Au–Cu Alloys as Micro-Components in MEMS Devices

Au–Cu alloy electroplating is a promising method for fabrication of micro-components used in MEMS devices. Micro-mechanical properties of Au–Cu alloy films fabricated by galvanostatic electroplating are reported in this study. Influences of the current density on surface morphology, crystalline structure, Cu content, and micro-mechanical properties were investigated. An optimum current density at 6 mA/cm2 was attained for the effects of surface smoothening and grain refinement as the current density was applied in the range of 2–9 mA/cm2. Micro-pillars having dimensions of 10 × 10 × 20 μm3 were fabricated from the electroplated Au–Cu alloy films by focus ion beam and used in the uniaxial micro-compression tests. The highest yield stress of 1.15 GPa was achieved from the film electroplated at 6 mA/cm2, which the grain size was about 5.3 nm with Cu content of 12.3 wt%. The high yield stress was a synergistic effect of the grain boundary strengthening mechanism with the solid solution strengthening mechanism.
In vivo CT imaging of gold nanoparticle-labeled exosomes in a myocardial infarction mouse model

Background Acute myocardial infarction (MI) is the primary factor leading to cardiovascular diseases, which are the main causes of morbidity and mortality in developed countries. Mesenchymal stem cell (MSC)-derived exosomes have been reported to improve heart function after MI; however, the molecular mechanisms responsible for this are unknown. In vivo imaging can reveal the trafficking process and in vivo biodistribution of exosomes, which may provide an insight into the communication mechanisms and pharmacokinetics of exosomes. Methods Glucose modified gold nanoparticles were used to label MSC-derived exosomes, aimed at minimizing membrane damage and maintaining the integrity of the exosomes. After labeling, the exosomes were visualized by in vivo computed tomography (CT) imaging to determine the biodistribution at 4 and 24 h after injection into a MI mouse model. Results MSC-derived exosomes were successfully labeled by glucose modified gold nanoparticles and CT imaging of these labeled exosomes indicated that MSC-Exo remained in the MI area for up to 24 h after intramyocardial injection. Additionally, few MSC-Exo were observed in some other organs, particularly the liver, spleen, and kidney. Conclusions A gentle method was used for loading GNPs into exosomes, and their successful labeling without causing aggregation was verified. In vivo CT imaging revealed the retention of MSC-Exo in the MI area, indicating their usefulness for improving heart function after infarction.
Cistrome analysis of YY1 uncovers a regulatory axis of YY1:BRD2/4-PFKP during tumorigenesis of advanced prostate cancer

Abstract Castration-resistant prostate cancer (CRPC) is a terminal disease and the molecular underpinnings of CRPC development need to be better understood in order to improve its treatment. Here, we report that a transcription factor Yin Yang 1 (YY1) is significantly overexpressed during prostate cancer progression. Functional and cistrome studies of YY1 uncover its roles in promoting prostate oncogenesis in vitro and in vivo, as well as sustaining tumor metabolism including the Warburg effect and mitochondria respiration. Additionally, our integrated genomics and interactome profiling in prostate tumor show that YY1 and bromodomain-containing proteins (BRD2/4) co-occupy a majority of gene-regulatory elements, coactivating downstream targets. Via gene loss-of-function and rescue studies and mutagenesis of YY1-bound cis-elements, we unveil an oncogenic pathway in which YY1 directly binds and activates PFKP, a gene encoding the rate-limiting enzyme for glycolysis, significantly contributing to the YY1-enforced Warburg effect and malignant growth. Altogether, this study supports a master regulator role for YY1 in prostate tumorigenesis and reveals a YY1:BRD2/4-PFKP axis operating in advanced prostate cancer with implications for therapy.