Functional convergence of a germline-encoded neutralizing antibody response in rhesus macaques immunized with HCV envelope glycoproteins.

Human IGHV1-69-encoded broadly neutralizing antibodies (bnAbs) that target the hepatitis C virus (HCV) envelope glycoprotein (Env) E2 are important for protection against HCV infection. An IGHV1-69 ortholog gene, VH1.36, is preferentially used for bnAbs isolated from HCV Env-immunized rhesus macaques (RMs). Here, we studied the genetic, structural, and functional properties of VH1.36-encoded bnAbs generated by vaccination, in comparison to IGHV1-69-encoded bnAbs from HCV patients. Global B cell repertoire analysis confirmed the expansion of VH1.36-derived B cells in immunized animals. Most E2-specific, VH1.36-encoded antibodies cross-neutralized HCV. Crystal structures of two RM bnAbs with E2 revealed that the RM bnAbs engaged conserved E2 epitopes using similar molecular features as human bnAbs but with a different binding mode. Longitudinal analyses of the RM antibody repertoire responses during immunization indicated rapid lineage development of VH1.36-encoded bnAbs with limited somatic hypermutation. Our findings suggest functional convergence of a germline-encoded bnAb response to HCV Env with implications for vaccination in humans.

Key gp120 Glycans Pose Roadblocks to the Rapid Development of VRC01-Class Antibodies in an HIV-1-Infected Chinese Donor.

VRC01-class antibodies neutralize diverse HIV-1 strains by targeting the conserved CD4-binding site. Despite extensive investigations, crucial events in the early stage of VRC01 development remain elusive. We demonstrated how VRC01-class antibodies emerged in a Chinese donor by antigen-specific single B cell sorting, structural and functional studies, and longitudinal antibody and virus repertoire analyses. A monoclonal antibody DRVIA7 with modest neutralizing breadth was isolated that displayed a subset of VRC01 signatures. X-ray and EM structures revealed a VRC01-like angle of approach, but less favorable interactions between the DRVIA7 light-chain CDR1 and the N terminus with N276 and V5 glycans of gp120. Although the DRVIA7 lineage was unable to acquire broad neutralization, longitudinal analysis revealed a repertoire-encoded VRC01 light-chain CDR3 signature and VRC01-like neutralizing heavy-chain precursors that rapidly matured within 2 years. Thus, light chain accommodation of the glycan shield should be taken into account in vaccine design targeting this conserved site of vulnerability.

Planococcus halotolerans sp. nov., isolated from a saline soil sample in China.

A novel Gram-stain-positive, coccoid or short rod-shaped, moderate-orange-pigmented, halotolerant and psychrotolerant bacterium, designated strain SCU63T, was isolated from a saline soil sample in China, and characterized by a polyphasic taxonomic approach. 16S rRNA gene sequence similarity of strain SCU63T to species in the genera Planococcus and Planomicrobium ranged from 96.5 to 98.6 %. Phylogenetic trees as well as diagnostic signature nucleotides in the 16S rRNA gene sequence supported the view that this strain should be assigned to the genus Planococcus. Further, average nucleotide identity and digital DNA-DNA hybridization analyses confirmed the separate species status of strain SCU63T relative to the closely related taxa. The isolate grew at 0-40 °C (optimum, 30-35 °C), at pH 6.5-9.0 (pH 7.0-7.5) and in the presence of 0-15 % (w/v) NaCl (3 %). The principal fatty acids were anteiso-C15 : 0, C16 : 1ω7c alcohol, iso-C16 : 0 and iso-C14 : 0, and the dominant isoprenoid quinones were MK-8 and MK-7. The peptidoglycan type was determined to be A4α (l-Lys-d-Glu), and the polar lipids contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, one unidentified aminophospholipid and one unidentified lipid. The DNA G+C content was 44.6 mol%. Based on the genotypic, phenotypic and chemotaxonomic data, strain SCU63T can be classified as a novel species in the genus Planococcus, for which the name Planococcushalotolerans sp. nov. is proposed. The type strain is SCU63T (=CGMCC 1.13628T=KCTC 43001T).

Actinocorallia populi sp. nov., an endophytic actinomycete isolated from a root of Populus adenopoda (Maxim.).

An endophytic actinobacterium, strain A251T, was isolated from the root of Populus adenopoda Maxim and subjected to characterization using polyphasic taxonomy. Analysis of the 16S rRNA gene sequence revealed that the isolate represented a member of the phylogenetic cluster of the genus Actinocorallia and was most closely related to Actinocorallia aurantiaca JCM 8201T (98.0 %) and Actinocorallia libanotica IFO 10495T (98.0 %). DNA-DNA hybridization values between A251T and these strains were 41.2 % and 45.0 %, respectively. The G+C content of the DNA was 71.5 mol%. Major fatty acids were C16 : 0, C16 : 1ω7c and C18 : 1ω9c. The peptidoglycan diamino acid of A251T was meso-diaminopimelic acid and the whole-cell hydrolysates contained glucose and ribose. The major menaquinones were MK-9(H4) and MK-9(H6). The phospholipid profile included diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, an undefined aminophospholipid and two undefined phospholipids. DNA-DNA hybridization data in combination with differences in the biochemical and physiological properties, indicated that A251T should be classified as representing a novel species within the genus Actinocorallia, for which the name Actinocorallia populi sp. nov. is proposed, with A251T (=CGMCC 4.7421T=JCM 32178T) as the type strain.

Culturable epiphytic bacteria isolated from Teleogryllus occipitalus crickets metabolize insecticides.

The development of insecticide resistance is attributed to evolutionary changes in pest insect genomes, such as alteration of drug target sites, upregulation of degrading enzymes, and enhancement of drug excretion. Beyond these well-known mechanisms, symbiotic bacteria may confer insecticide resistance to host crickets. The current study was designed to screen all possible culturable bacterial groups found living in and on the bodies of Teleogryllus occipitalis crickets. We recovered 263 visible bacterial colonies and cultured them individually. After identifying the colonies based on morphology and phylogenetic analysis, we shortlisted 55 bacterial strains belonging to 28 genera. Of these 55 bacterial strains, 18 degraded at least 50% of the original amount of 400 mg/L chlorpyrifos (CP) after 24 hr of coculture. Six of these strains degraded more than 70% of the original amount of 400 mg/L CP. Three strains had antagonistic effects on Bacillus thuringiensis growth. Additionally, the ability of the isolates to degrade glyphosate, phoxim, and esfenvalerate was assessed. We also detected extracellular hydrolase enzyme activities in these isolates. We propose that epiphytic bacterial strains play multiple roles in cricket biology, one of which contributes to chemical and biological pesticide resistance.

Streptomyces dioscori sp. nov., a Novel Endophytic Actinobacterium Isolated from Bulbil of Dioscorea bulbifera L.

A novel endophytic actinobacterium strain, A217T, was isolated from the bulbil of Dioscorea bulbifera L. Its taxonomic position was characterized using a polyphasic study. Morphological and chemotaxonomic characteristics of strain A217T were consistent with those of members of the genus Streptomyces: long straight to flexuous spore chain; cellular components contained LL-diaminopimelic acid, ribose, and small traces of glucose in whole-cell hydrolysates; MK-9(H6) and MK-9(H8) as predominant menaquinones. The patterns of major fatty acids are C16:0, anteiso-C15:0, C15:0, iso-C14:0, C16:1 ω7c, anteiso-C17:0, and iso-C17:1 ω5c. The polar lipids comprised diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol mannoside, and glycolipid, as well as two unidentified phospholipids, one unidentified aminolipid, and one unidentified aminophospholipid. The DNA G + C content of draft genome is 70.7 mol%. Analysis of the 16S rRNA gene sequence and phylogenetic trees revealed that the isolate was most closely related to S. aurantiacus JCM 4453T (99.0%), S. glomeroaurantiacus JCM 4677T (99.0%), and S. tauricus JCM 4837T (98.8%). The DNA-DNA hybridization values between the strain A217T and three reference strains ranged from 34.6% to 51.7%. On the basis of phenotypic and genotypic differentiation from all tested strains, isolate A217T is proposed to represent a novel species of the genus Streptomyces, named Streptomyces dioscori sp. nov. The type strain is A217T (= CGMCC 4.7415T = JCM 32173T).

A tale of two fusion proteins: understanding the metastability of human respiratory syncytial virus and metapneumovirus and implications for rational design of uncleaved prefusion-closed trimers.

Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) cause human respiratory diseases and are major targets for vaccine development. In this study, we designed uncleaved prefusion-closed (UFC) trimers for the fusion (F) proteins of both viruses by examining mutations critical to F metastability. For RSV, we assessed four previous prefusion F designs, including the first and second generations of DS-Cav1, SC-TM, and 847A. We then identified key mutations that can maintain prefusion F in a native-like, closed trimeric form (up to 76%) without introducing any interprotomer disulfide bond. For hMPV, we developed a stable UFC trimer with a truncated F2-F1 linkage and an interprotomer disulfide bond. Tens of UFC constructs were characterized by negative-stain electron microscopy (nsEM), x-ray crystallography (11 RSV-F and one hMPV-F structures), and antigenic profiling. Using an optimized RSV-F UFC trimer as bait, we identified three potent RSV neutralizing antibodies (NAbs) from a phage-displayed human antibody library, with a public NAb lineage targeting sites Ø and V and two cross-pneumovirus NAbs recognizing site III. In mouse immunization, rationally designed RSV-F and hMPV-F UFC trimers induced robust antibody responses with high neutralizing titers. Our study provides a foundation for future prefusion F-based RSV and hMPV vaccine development.

Serum N-terminal pro-B-type natriuretic peptide and cystatin C for acute kidney injury detection in critically ill adults in China: a prospective, observational study.

OBJECTIVE: Serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cystatin C (sCysC) are available clinically and beneficial in diagnosing acute kidney injury (AKI). Our purpose is to identify the performance of their combined diagnosis for AKI in critically ill patients. DESIGN: A prospectively recruited, observational study was performed. SETTING: Adults admitted to the intensive care unit of a tertiary hospital in China. PARTICIPANTS: A total of 1222 critically ill patients were enrolled in the study. MAIN OUTCOME MEASURES: To identify the performance of the combined diagnosis of serum NT-proBNP and sCysC for AKI in critically ill patients. The area under the receiver operating characteristic curve (AUC-ROC), category-free net reclassification index (NRI) and incremental discrimination improvement (IDI) were utilised for comparing the discriminative powers of a combined and single biomarker adjusted model of clinical variables enriched with NT-proBNP and sCysC for AKI. RESULTS: AKI was detected in 256 out of 1222 included patients (20.9%). AUC-ROC for NT-proBNP and sCysC to detect AKI had a significantly higher accuracy than any individual biomarker (p<0.05). After multivariate adjustment, a level of serum NT-proBNP ≥204 pg/mL was associated with 3.5-fold higher odds for AKI compared with those below the cut-off value. Similar results were obtained for sCysC levels (p<0.001). To detect AKI, adding NT-proBNP and sCysC to a clinical model further increased the AUC-ROC to 0.859 beyond that of the clinical model with or without sCysC (p<0.05). Moreover, the addition of these two to the clinical model significantly improved risk reclassification of AKI beyond that of the clinical model alone or with single biomarker (p<0.05), as measured by NRI and IDI. CONCLUSIONS: In critically ill individuals, serum NT-proBNP, sCysC and clinical risk factors combination improve the discriminative power for diagnosing AKI.

Prediction of acute kidney injury after total aortic arch replacement with serum cystatin C and urine N-acetyl-ß-d-glucosaminidase: A prospective observational study.

BACKGROUND: Acute kidney injury (AKI) after total aortic arch replacement (TAAR) is frequent and associated with adverse outcomes, whereas its early detection remains a challenge. Serum cystatin C (sCysC) and urinary N-acetyl-ß-d-glucosaminidase (uNAG) are clinically available renal biomarkers, but their combination for AKI detection requires more evidence. This study aimed to assess the discriminative abilities of these biomarkers in AKI after TAAR. MATERIALS AND METHODS: Patients undergoing TAAR were included in this prospective observational study. The AKI prediction model was developed and internal verificated, and the significance of each variable was analyzed by random forest (RF). Finally, the best predictive critical values of sCysC and uNAG were explored by the AUC-ROC curve. RESULTS: The AUC-ROC of the prediction model was substantially enhanced by adding sCysC and uNAG (0.909 vs 0.844, p < 0.001), and the clinical utility and risk reclassification were significantly improved. Additionally, the RF showed that sCysC and uNAG ranked first and second. The AUC-ROC for each were 0.864 and 0.802 respectively, and the cut-off values were 1.395 mg/L and 31.90 U/g Cre respectively. CONCLUSION: The prediction model incorporating functional marker sCysC and tubular injury marker uNAG can improve the discriminative abilities of AKI after TAAR.

Defining a postoperative mean arterial pressure threshold in association with acute kidney injury after cardiac surgery: a prospective observational study.

Acute kidney injury (AKI) is a common but fatal complication after cardiac surgery. In the absence of effective treatments, the identification and modification of risk factors has been a major component of disease management. However, the optimal blood pressure target for preventing cardiac surgery-associated acute kidney injury (CSA-AKI) remains unclear. We sought to determine the effect of postoperative mean arterial pressure (MAP) in CSA-AKI. It is hypothesized that longer periods of hypotension after cardiac surgery are associated with an increased risk of AKI. This prospective cohort study was conducted on adult patients who underwent cardiac surgery requiring cardiopulmonary bypass at a tertiary center between October 2018 and May 2020. The primary outcome is the occurrence of CSA-AKI. MAP and its duration in the ranges of less than 65, 65 to 74, and 75 to 84 mmHg within 24 h after surgery were recorded. The association between postoperative MAP and CSA-AKI was examined by using logistic regression. Among the 353 patients enrolled, 217 (61.5%) had a confirmed diagnosis of CSA-AKI. Each 1 h epoch of postoperative MAP less than 65 mmHg was associated with an adjusted odds ratio of 1.208 (95% CI, 1.007 to 1.449; P = 0.042), and each 1 h epoch of postoperative MAP between 65 and 74 mmHg was associated with an adjusted odds ratio of 1.144 (95% CI, 1.026 to 1.275; P = 0.016) for CSA-AKI. A potentially modifiable risk factor, postoperative MAP less than 75 mmHg for 1 h or more is associated with an increased risk of CSA-AKI.

Evaluation of the contribution of gut microbiome dysbiosis to cardiac surgery-associated acute kidney injury by comparative metagenome analysis.

Introduction: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common hospital-acquired AKI that carries a grave disease burden. Recently, gut-kidney crosstalk has greatly changed our understanding of the pathogenesis of kidney diseases. However, the relationship between gut microbial dysbiosis and CSA-AKI remains unclear. The purpose of this study was to investigate the possible contributions of gut microbiota alterations in CSA-AKI patients. Methods: Patients undergoing cardiac surgery were enrolled and divided into acute kidney injury (AKI) and Non_AKI groups. Faecal samples were collected before the operation. Shotgun metagenomic sequencing was performed to identify the taxonomic composition of the intestinal microbiome. All groups were statistically compared with alpha- and beta-diversity analysis, and linear discriminant analysis effect size (LEfSe) analysis was performed. Results: A total of 70 individuals comprising 35 AKI and 35 Non_AKI were enrolled in the study. There was no significant difference between the AKI and Non_AKI groups with respect to the alpha-and beta-diversity of the Shannon index, Simpson or Chao1 index values except with respect to functional pathways (p < 0.05). However, the relative abundance of top 10 gut microbiota in CSA-AKI was different from the Non_AKI group. Interestingly, both LEfSe and multivariate analysis confirmed that the species Escherichia coli, Rothia mucilaginosa, and Clostridium innocuum were associated with CSA-AKI. Moreover, correlation heat map indicated that altered pathways and disrupted function could be attributed to disturbances of gut microbiota involving Escherichia coli. Conclusion: Dysbiosis of the intestinal microbiota in preoperative stool affects susceptibility to CSA-AKI, indicating the crucial role of key microbial players in the development of CSA-AKI. This work provides valuable knowledge for further study of the contribution of gut microbiota in CSA-AKI.

Single-Component Multilayered Self-Assembling Protein Nanoparticles Displaying Extracellular Domains of Matrix Protein 2 as a Pan-influenza A Vaccine.

The development of a cross-protective pan-influenza A vaccine remains a significant challenge. In this study, we designed and evaluated single-component self-assembling protein nanoparticles (SApNPs) presenting the conserved extracellular domain of matrix protein 2 (M2e) as vaccine candidates against influenza A viruses. The SApNP-based vaccine strategy was first validated for human M2e (hM2e) and then applied to tandem repeats of M2e from human, avian, and swine hosts (M2ex3). Vaccination with M2ex3 displayed on SApNPs demonstrated higher survival rates and less weight loss compared to the soluble M2ex3 antigen against the lethal challenges of H1N1 and H3N2 in mice. M2ex3 I3-01v9a SApNPs formulated with a squalene-based adjuvant were retained in the lymph node follicles over 8 weeks and induced long-lived germinal center reactions. Notably, a single low dose of M2ex3 I3-01v9a SApNP formulated with a potent adjuvant, either a Toll-like receptor 9 (TLR9) agonist or a stimulator of interferon genes (STING) agonist, conferred 90% protection against a lethal H1N1 challenge in mice. With the ability to induce robust and durable M2e-specific functional antibody and T cell responses, the M2ex3-presenting I3-01v9a SApNP provides a promising pan-influenza A vaccine candidate.

Single-component multilayered self-assembling protein nanoparticles presenting glycan-trimmed uncleaved prefusion optimized envelope trimmers as HIV-1 vaccine candidates.

Uncleaved prefusion-optimized (UFO) design can stabilize diverse HIV-1 envelope glycoproteins (Envs). Single-component, self-assembling protein nanoparticles (1c-SApNP) can display 8 or 20 native-like Env trimers as vaccine candidates. We characterize the biophysical, structural, and antigenic properties of 1c-SApNPs that present the BG505 UFO trimer with wildtype and modified glycans. For 1c-SApNPs, glycan trimming improves recognition of the CD4 binding site without affecting broadly neutralizing antibodies (bNAbs) to major glycan epitopes. In mice, rabbits, and nonhuman primates, glycan trimming increases the frequency of vaccine responders (FVR) and steers antibody responses away from immunodominant glycan holes and glycan patches. The mechanism of vaccine-induced immunity is examined in mice. Compared with the UFO trimer, the multilayered E2p and I3-01v9 1c-SApNPs show 420 times longer retention in lymph node follicles, 20-32 times greater presentation on follicular dendritic cell dendrites, and up-to-4 times stronger germinal center reactions. These findings can inform future HIV-1 vaccine development.

Sepsis-Induced Gut Dysbiosis Mediates the Susceptibility to Sepsis-Associated Encephalopathy in Mice.

Sepsis-associated encephalopathy (SAE) is common in septic patients and is associated with adverse outcomes. The gut microbiota has been recognized as a key mediator of neurological disease development. However, the exact role of the gut microbiota in regulating SAE remains elusive. Here, we investigated the role of the gut microbiota in SAE and its underlying mechanisms. Cecal ligation and puncture (CLP) was conducted to induce sepsis in mice. Neurological scores were recorded to distinguish SAE-resistant (SER) (score of >6 at 36 h postoperatively) from SAE-susceptible (SES) (score of ≤6 at 36 h postoperatively) mice. 16S rRNA gene sequencing and metabolomics analyses were used to characterize the gut microbiota in the two groups. Fecal microbiota transplantation was performed to validate the role of the gut microbiota in SAE progression. The gut microbiota was more severely disrupted in SES mice than in SER mice after sepsis modeling. Interestingly, mice receiving postoperative feces from SES mice exhibited more severe cortical inflammation than mice receiving feces from SER mice. Indole-3-propionic acid (IPA), a neuroprotective molecule, was more enriched in feces from SER mice than in feces from SES mice. IPA alleviated CLP-induced anxiety and spatial memory impairment in septic mice. Moreover, IPA markedly inhibited NLRP3 inflammasome activation and interleukin-1ß (IL-1ß) secretion in lipopolysaccharide-stimulated microglia. These responses were attenuated after antagonizing the aryl hydrocarbon receptor. Our study indicates that the variability in sepsis-induced gut dysbiosis mediates the differential susceptibility to SAE in CLP-induced experimental sepsis mice, and microbially derived IPA is possibly involved in SAE development as a neuroprotective compound. IMPORTANCE The bidirectional interactions between the gut microbiota and sepsis-associated encephalopathy (SAE) are not well characterized. We found that the gut microbiota was more severely disturbed in SAE-susceptible (SES) mice than in SAE-resistant (SER) mice after sepsis modeling. Mice gavaged with postoperative feces from SES mice exhibited more severe neuroinflammation than mice gavaged with feces from SER mice. The gut microbiota from SER mice enriched a neuroprotective metabolite, IPA, which appeared to protect mice from SAE. The potential underlying mechanism of the protective effect of IPA may be mediated via the inhibition of NLRP3 inflammasome activation and IL-1ß secretion in microglia. These anti-inflammatory effects of IPA may be regulated by aryl hydrocarbon receptors. These results enhance our understanding of the role of the intestinal microbiota in sepsis. In particular, gut microbiota-derived IPA may serve as a potential therapeutic agent to prevent neuroinflammation in SAE.

Indole-3-Propionic Acid as a Potential Therapeutic Agent for Sepsis-Induced Gut Microbiota Disturbance.

The effects of using gut microbiota metabolites instead of live microorganisms to modulate sepsis-induced gut dysbiosis remain largely unknown. We assessed the effects of microbiota metabolite indole-3-propionic acid (IPA) on gut microbiota in mice during sepsis. Sepsis models were constructed by cecal ligation and puncture (CLP) methods. Fecal microbiota composition analysis was performed to characterize the gut microbiota composition. Fecal microbiota transplantation was performed to validate the roles of gut microbiota on sepsis progression. IPA-treated mice exhibited lower serum inflammatory mediator levels and a higher survival rate than those of saline-treated mice after modeling of sepsis, which were negated in the presence of antibiotics. Compared with saline-treated mice after modeling, IPA-treated mice showed a markedly different intestinal microbiota composition, with an enrichment of Bifidobacteriaceae family and a depletion of Enterobacteriaceae family. Mice gavaged with postoperative feces from IPA-treated animals displayed better survival than mice gavaged with feces from saline-treated animals. Overall, these data suggest that IPA offers a microbe-modulated survival advantage in septic mice, indicating that some microbiota metabolites could replace live microorganisms as potential options for regulation of sepsis-induced gut dysbiosis. IMPORTANCE The role of gut microbiota in the pathophysiology of sepsis is gaining increasing attention and developing effective and safe sepsis therapies targeting intestinal microorganisms is promising. Given the safety of probiotic supplementation or fecal microbiota transplantation in critically ill patients, identifying an abiotic agent to regulate the intestinal microbiota of septic patients is of clinical significance. This study revealed that IPA, a microbiota-generated tryptophan metabolite, ameliorated sepsis-induced mortality and decreased the serum levels of proinflammatory cytokines by modulating intestinal microbiota. Although IPA did not increase the abundance and diversity of the microbiota of septic mice, it significantly decreased the number of Enterobacteriaceae family. These findings indicate that a specific microbiota metabolite (e.g., IPA) can mediate the intestinal microbiota apart from FMT or probiotics.

Variations of urinary N-acetyl-ß-D-glucosaminidase levels and its performance in detecting acute kidney injury under different thyroid hormones levels: a prospectively recruited, observational study.

OBJECTIVE: Changes in thyroid function will be accompanied by changes in urinary N-acetyl-ß-D-glucosaminidase (uNAG) levels. Therefore, whether thyroid hormones interfere the ability of uNAG in detecting acute kidney injury (AKI) has raised concern in patients with critical illness. DESIGN: A prospectively recruited, observational study was performed. SETTING: Adults admitted to the intensive care unit of a grade A tertiary hospital in China. PARTICIPANTS: A total of 1919 critically ill patients were enrolled in the study. MAIN OUTCOME MEASURES: To investigate the variations of the ability of uNAG to detect AKI in patients with critical illness under different thyroid hormones levels (differences in area under the curve (AUC) for uNAG diagnosis and prediction of AKI with different thyroid hormones levels). RESULTS: The bivariate correlation analysis revealed that FT3 and TT3 levels were independently associated with uNAG levels (p<0.001). FT3 and uNAG also showed correlation in multivariable linear regression analysis (p<0.001). After stratification according to the levels of FT3 or TT3, significant variation was observed in the uNAG levels with different quartiles (p<0.05). However, in patients with varying FT3 and TT3 levels, no significant difference was found in the AUCs of uNAG to detect AKI (p>0.05). CONCLUSIONS: Even if uNAG levels varied with FT3 and TT3 levels, these hormones did not interfere with uNAG's ability to detect AKI in patients with critical illness.

Mechanism of a COVID-19 nanoparticle vaccine candidate that elicits a broadly neutralizing antibody response to SARS-CoV-2 variants.

Vaccines that induce potent neutralizing antibody (NAb) responses against emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are essential for combating the coronavirus disease 2019 (COVID-19) pandemic. We demonstrated that mouse plasma induced by self-assembling protein nanoparticles (SApNPs) that present 20 rationally designed S2GΔHR2 spikes of the ancestral Wuhan-Hu-1 strain can neutralize the B.1.1.7, B.1.351, P.1, and B.1.617 variants with comparable potency. The adjuvant effect on vaccine-induced immunity was investigated by testing 16 formulations for the multilayered I3-01v9 SApNP. Using single-cell sorting, monoclonal antibodies (mAbs) with diverse neutralization breadth and potency were isolated from mice immunized with the receptor binding domain (RBD), S2GΔHR2 spike, and SApNP vaccines. The mechanism of vaccine-induced immunity was examined in the mouse model. Compared with the soluble spike, the I3-01v9 SApNP showed sixfold longer retention, fourfold greater presentation on follicular dendritic cell dendrites, and fivefold stronger germinal center reactions in lymph node follicles.

Mechanism of a COVID-19 nanoparticle vaccine candidate that elicits a broadly neutralizing antibody response to SARS-CoV-2 variants.

Vaccines that induce potent neutralizing antibody (NAb) responses against emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are essential for combating the coronavirus disease 2019 (COVID-19) pandemic. We demonstrated that mouse plasma induced by self-assembling protein nanoparticles (SApNPs) that present 20 rationally designed S2GΔHR2 spikes of the ancestral Wuhan-Hu-1 strain can neutralize the B.1.1.7, B.1.351, P.1, and B.1.617 variants with the same potency. The adjuvant effect on vaccine-induced immunity was investigated by testing 16 formulations for the multilayered I3-01v9 SApNP. Using single-cell sorting, monoclonal antibodies (mAbs) with diverse neutralization breadth and potency were isolated from mice immunized with the receptor binding domain (RBD), S2GΔHR2 spike, and SApNP vaccines. The mechanism of vaccine-induced immunity was examined in mice. Compared with the soluble spike, the I3-01v9 SApNP showed 6-fold longer retention, 4-fold greater presentation on follicular dendritic cell dendrites, and 5-fold stronger germinal center reactions in lymph node follicles.

Development and Validation of a Nomogram Incorporating Colloid Osmotic Pressure for Predicting Mortality in Critically Ill Neurological Patients.

Backgrounds: The plasma colloid osmotic pressure (COP) values for predicting mortality are not well-estimated. A user-friendly nomogram could predict mortality by incorporating clinical factors and scoring systems to facilitate physicians modify decision-making when caring for patients with serious neurological conditions. Methods: Patients were prospectively recruited from March 2017 to September 2018 from a tertiary hospital to establish the development cohort for the internal test of the nomogram, while patients recruited from October 2018 to June 2019 from another tertiary hospital prospectively constituted the validation cohort for the external validation of the nomogram. A multivariate logistic regression analysis was performed in the development cohort using a backward stepwise method to determine the best-fit model for the nomogram. The nomogram was subsequently validated in an independent external validation cohort for discrimination and calibration. A decision-curve analysis was also performed to evaluate the net benefit of the insertion decision using the nomogram. Results: A total of 280 patients were enrolled in the development cohort, of whom 42 (15.0%) died, whereas 237 patients were enrolled in the validation cohort, of which 43 (18.1%) died. COP, neurological pathogenesis and Acute Physiology and Chronic Health Evaluation II (APACHE II) score were predictors in the prediction nomogram. The derived cohort demonstrated good discriminative ability, and the area under the receiver operating characteristic curve (AUC) was 0.895 [95% confidence interval (CI), 0.840-0.951], showing good correction ability. The application of this nomogram to the validation cohort also provided good discrimination, with an AUC of 0.934 (95% CI, 0.892-0.976) and good calibration. The decision-curve analysis of this nomogram showed a better net benefit. Conclusions : A prediction nomogram incorporating COP, neurological pathogenesis and APACHE II score could be convenient in predicting mortality for critically ill neurological patients.

Assessment of 17 clinically available renal biomarkers to predict acute kidney injury in critically ill patients.

BACKGROUND: Systematic estimation of renal biomarkers in the intensive care unit (ICU) patients is lacking. Seventeen biomarkers were assessed to predict acute kidney injury (AKI) after admission to ICU. MATERIALS AND METHODS: A prospective, observational study was conducted in the general ICU of Guangdong Provincial People's Hospital. Seventeen serum or urine biomarkers were studied for their abilities alone or in combination for predicting AKI and severe AKI. RESULTS: Of 1498 patients, 376 (25.1%) developed AKI. Serum cystatin C (CysC) showed the best performance for predicting both AKI (area under the receiver operator characteristic curve [AUC] = 0.785, mean square error [MSE] = 0.118) and severe AKI (AUC = 0.883, MSE = 0.06). Regarding biomarkers combinations, CysC plus N-acetyl-ß-d-glucosaminidase-to-creatinine ratio (NAG/Cr) was the best for predicting AKI (AUC = 0.856, MSE = 0.21). At the same time, CysC plus lactic acid (LAC) performed the best for predicting severe AKI (AUC = 0.907, MSE = 0.058). Regarding combinations of biomarkers and clinical markers, CysC plus Acute Physiology and Chronic Health Evaluation (APACHE) II score showed the best performance for predicting AKI (AUC = 0.868, MSE = 0.407). In contrast, CysC plus Multiple Organ Dysfunction Score (MODS) had the highest predictive ability for severe AKI (AUC = 0.912, MSE = 0.488). CONCLUSION: Apart from CysC, the combination of most clinically available biomarkers or clinical markers does not significantly improve the forecasting ability, and the cost-benefit ratio is not economical.