2D petal-like PdAg nanosheets promote efficient electrocatalytic oxidation of ethanol and methanol.

The development of efficient alcohol electrooxidation catalysts is of vital importance for the commercialization of direct liquid fuel cells. As emerging advanced catalysts, two-dimensional (2D) noble metal nanomaterials have attracted much research attention due to their intrinsic structural advantages. Herein, we report the synthesis of petal-like PdAg nanosheets (NSs) with an ultrathin 2D structure and jagged edges via a facile wet-chemical approach, combining doping engineering and morphology tuning. Notably, the highly active sites and Pd-Ag composition endowed PdAg NSs with improved toxicity tolerance and substantially improved the durability toward the ethanol/methanol oxidation reaction (EOR/MOR). Moreover, the electronic effect and synergistic effect significantly enhanced the EOR and MOR activities in comparison with Pd NSs and commercial Pd/C. This work provides efficient catalysts for fuel electrooxidations and deep insight into the rational design and fabrication of novel 2D nanoarchitecture.

Insights into the formation and growth of high entropy PdPtSnPbNi nanowires to obtain catalysts with high alcohol electrocatalytic oxidation activity.

High-entropy alloys have raised great interest in recent years because of their potential applications for multi-electron reactions owing to their diverse active sites and multielement tunability. However, the difficulty of synthesis is an obstacle to their development due to phase separation often exists. In addition, it's a challenge to precisely control morphology in harsh conditions, thus leading to nanoparticles in many cases. We report a facile method to obtain PdPtPbSnNi HEA NWs by solvothermal synthesis method that no existing phase separation. PdPb nucleation plays a role in the formation of the high-entropy structure that serves as a PdPb nucleus for Sn, Ni, and Pt reduction subsequently, thus forming a single phase and an orderly-arranged nanowire structure. Significantly, the optimized PdPtPbSnNi NWs exhibit excellent catalytic activity and stability for both EOR and MOR which is 4.36 A mgPd+Pt-1 and 4.34 A mgPd+Pt-1, respectively. This study highlights a novel strategy for morphology tuning, providing a prospect for designing superior high-entropy nano-catalysts for multi-step reactions.

Protective effects of ginsenosides on ulcerative colitis: a meta-analysis and systematic review to reveal the mechanisms of action.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. Ginsenoside may be an ideal agent for UC treatment. However, its efficacy and safety are unknown. We aim to conduct a systematic evaluation to assess the effects and potential mechanisms of ginsenosides in animal models of UC. METHODS: Six electronic databases will be searched (PubMed, Embase, Web of Science, China Knowledge Network (CNKI), China Science and Technology Journal Database (CQVIP), and Wanfang Data Knowledge). SYRCLE list will be used to assess the quality of literature, and STATA 15.1 for data analysis. Time-dose effects analysis will be used to reveal the time-dosage response relations between ginsenosides and UC. RESULTS: Ultimately, fifteen studies involving 300 animals were included. Preliminary evidence was shown that ginsenosides could reduce Disease Activity Index (DAI) scores, weight loss, histological colitis score (HCS), spleen weight, Malondialdehyde (MDA), Myeloperoxidase (MPO) activity, interleukin-1ß (IL-1ß), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α) and increase colon length (CL), myeloperoxidase (GSH), interleukin 4 (IL-4), interleukin 10 (IL-10), Zonula Occludens-1 (ZO-1) and occludin. Results of time-dose interval analysis indicated that ginsenosides at a dosage of 5-200 mg/kg with an intervention time of 7-28 days were relatively effective. CONCLUSIONS: Preclinical evidence suggests that ginsenoside is a novel treatment for UC. And the mechanisms of ginsenosides in treating UC may involve anti-inflammatory, antioxidant, barrier protection, intestinal flora regulation, and immune regulation. Although, due to the high heterogeneity, further large-scale and high-quality preclinical studies are needed to examine the protection of ginsenosides against UC.

A comparative immunological assessment of multiple clinical-stage adjuvants for the R21 malaria vaccine in nonhuman primates.

Authorization of the Matrix-M (MM)-adjuvanted R21 vaccine by three countries and its subsequent endorsement by the World Health Organization for malaria prevention in children are a milestone in the fight against malaria. Yet, our understanding of the innate and adaptive immune responses elicited by this vaccine remains limited. Here, we compared three clinically relevant adjuvants [3M-052 + aluminum hydroxide (Alum) (3M), a TLR7/8 agonist formulated in Alum; GLA-LSQ, a TLR4 agonist formulated in liposomes with QS-21; and MM, the now-approved adjuvant for R21] for their capacity to induce durable immune responses to R21 in macaques. R21 adjuvanted with 3M on a 0, 8, and 23-week schedule elicited anti-circumsporozoite antibody responses comparable in magnitude to the R21/MM vaccine administered using a 0-4-8-week regimen and persisted up to 72 weeks with a half-life of 337 days. A booster dose at 72 weeks induced a recall response similar to the R21/MM vaccination. In contrast, R21/GLA-LSQ immunization induced a lower, short-lived response at the dose used. Consistent with the durable serum antibody responses, MM and 3M induced long-lived plasma cells in the bone marrow and other tissues, including the spleen. Furthermore, whereas 3M stimulated potent and persistent antiviral transcriptional and cytokine signatures after primary and booster immunizations, MM induced enhanced expression of interferon- and TH2-related signatures more highly after the booster vaccination. Collectively, these findings provide a resource on the immune responses of three clinically relevant adjuvants with R21 and highlight the promise of 3M as another adjuvant for malarial vaccines.

NOx precipitation and valorization driven by photocatalysis and adsorption over red soil.

Nitrogen oxides (NOx) emissions can cause air pollution that is harmful to human health, even producing serious ecological problems. Whether it is diluted in the air or not, the management and valorization of NOx from industrial emissions have been constrained by technology and finance. This study shows that red soil can be used as a photocatalyst to convert NOx into soil nitrate nitrogen (NO3--N) in the soil. The addition of zinc oxide (ZnO) and titanium dioxide (TiO2) onto the soil surface improves the photocatalytic precipitation efficiency of 1 ppm NO, approaching a removal efficiency of 77 % under ultraviolet (UV) light. The efficiency of red soil in precipitating NOx through adsorption exceeded that of photocatalysis at 100 ppm NOx (e.g. 16.02 % versus 7.70 % in 0.1-mm soil). Pot experiment reveals that the precipitated NO3--N promoted biomass of water spinach (Ipomoea aquatica Forsk). Additionally, adding ZnO or TiO2 also affects mineral nutrition. This demonstration of converting air pollutants into available nitrogen (N) for plant growth not only provides a new perspective on treatment and valorization for NOx but also sheds light on the transport of N in the air-soil-plant path.

AS03 adjuvant enhances the magnitude, persistence, and clonal breadth of memory B cell responses to a plant-based COVID-19 vaccine in humans.

Vaccine adjuvants increase the breadth of serum antibody responses, but whether this is due to the generation of antigen-specific B cell clones with distinct specificities or the maturation of memory B cell clones that produce broadly cross-reactive antibodies is unknown. Here, we longitudinally analyzed immune responses in healthy adults after two-dose vaccination with either a virus-like particle COVID-19 vaccine (CoVLP), CoVLP adjuvanted with AS03 (CoVLP+AS03), or a messenger RNA vaccination (mRNA-1273). CoVLP+AS03 enhanced the magnitude and durability of circulating antibodies and antigen-specific CD4+ T cell and memory B cell responses. Antigen-specific CD4+ T cells in the CoVLP+AS03 group at day 42 correlated with antigen-specific memory B cells at 6 months. CoVLP+AS03 induced memory B cell responses, which accumulated somatic hypermutations over 6 months, resulting in enhanced neutralization breadth of monoclonal antibodies. Furthermore, the fraction of broadly neutralizing antibodies encoded by memory B cells increased between day 42 and 6 months. These results indicate that AS03 enhances the antigenic breadth of B cell memory at the clonal level and induces progressive maturation of the B cell response.

Polyphyllin B inhibited STAT3/NCOA4 pathway and restored gut microbiota to ameliorate lung tissue injury in cigarette smoke-induced mice.

OBJECTIVE: Smoking was a major risk factor for chronic obstructive pulmonary disease (COPD). This study plan to explore the mechanism of Polyphyllin B in lung injury induced by cigarette smoke (CSE) in COPD. METHODS: Network pharmacology and molecular docking were applied to analyze the potential binding targets for Polyphyllin B and COPD. Commercial unfiltered CSE and LPS were used to construct BEAS-2B cell injury in vitro and COPD mouse models in vivo, respectively, which were treated with Polyphyllin B or fecal microbiota transplantation (FMT). CCK8, LDH and calcein-AM were used to detect the cell proliferation, LDH level and labile iron pool. Lung histopathology, Fe3+ deposition and mitochondrial morphology were observed by hematoxylin-eosin, Prussian blue staining and transmission electron microscope, respectively. ELISA was used to measure inflammation and oxidative stress levels in cells and lung tissues. Immunohistochemistry and immunofluorescence were applied to analyze the 4-HNE, LC3 and Ferritin expression. RT-qPCR was used to detect the expression of FcRn, pIgR, STAT3 and NCOA4. Western blot was used to detect the expression of Ferritin, p-STAT3/STAT3, NCOA4, GPX4, TLR2, TLR4 and P65 proteins. 16S rRNA gene sequencing was applied to detect the gut microbiota. RESULTS: Polyphyllin B had a good binding affinity with STAT3 protein, which as a target gene in COPD. Polyphyllin B inhibited CS-induced oxidative stress, inflammation, mitochondrial damage, and ferritinophagy in COPD mice. 16S rRNA sequencing and FMT confirmed that Akkermansia and Escherichia_Shigella might be the potential microbiota for Polyphyllin B and FMT to improve CSE and LPS-induced COPD, which were exhausted by the antibiotics in C + L and C + L + P mice. CSE and LPS induced the decrease of cell viability and the ferritin and LC3 expression, and the increase of NCOA4 and p-STAT3 expression in BEAS-2B cells, which were inhibited by Polyphyllin B. Polyphyllin B promoted ferritin and LC3II/I expression, and inhibited p-STAT3 and NCOA4 expression in CSE + LPS-induced BEAS-2B cells. CONCLUSION: Polyphyllin B improved gut microbiota disorder and inhibited STAT3/NCOA4 pathway to ameliorate lung tissue injury in CSE and LPS-induced mice.

TaLBD41 interacts with TaNAC2 to regulate nitrogen uptake and metabolism in response to nitrate availability.

Nitrate is the main source of nitrogen (N) available to plants and also is a signal that triggers complex regulation of transcriptional networks to modulate a wide variety of physiological and developmental responses in plants. How plants adapt to soil nitrate fluctuations is a complex process involving a fine-tuned response to nitrate provision and N starvation, the molecular mechanisms of which remain largely uncharted. Here, we report that the wheat transcription factor TaLBD41 interacts with the nitrate-inducible transcription factor TaNAC2 and is repressed by nitrate provision. Electrophoretic mobility shift assay and dual-luciferase system show that the TaLBD41-NAC2 interaction confers homeostatic coordination of nitrate uptake, reduction, and assimilation by competitively binding to TaNRT2.1, TaNR1.2, and TaNADH-GOGAT. Knockdown of TaLBD41 expression enhances N uptake and assimilation, increases spike number, grain yield, and nitrogen harvest index under different N supply conditions. We also identified an elite haplotype of TaLBD41-2B associated with increased spike number and grain yield. Our study uncovers a novel mechanism underlying the interaction between two transcription factors in mediating wheat adaptation to nitrate availability by antagonistically regulating nitrate uptake and assimilation, providing a potential target for designing varieties with efficient N use in wheat (Triticum aestivum).

Scope and inclination of voluntary service for urban community-living older adults provided by volunteers with nursing background: A qualitative study.

BACKGROUND: With the growing challenge of an aging population, addressing the needs of elderly individuals who face living difficulties and lack family support becomes increasingly difficult. Volunteer services are crucial in this context, yet their effectiveness is hindered by unclear service scopes and uncertain volunteer inclinations. AIM: To explore the role and specific preference of volunteers with nursing backgrounds in support of older adults living in the urban community. DESIGN, SETTING AND PARTICIPANTS: A descriptive qualitative study was conducted between September and October 2022. Twenty-three participants (hospital nurses [10], community nurses [4], nursing teachers [4] and nursing students [5]) were selected. Data analysis followed conventional content analysis. RESULTS: Nine major themes were identified based on interview data. Four themes described the service scope of nursing volunteers: (1) environment domain, (2) physiological domain, (3) psychosocial domain and (4) health-related behaviours domain. Another five themes highlighted the service inclination of these volunteers: (1) service frequency, (2) service duration per person/time, (3) service coverage, (4) service place and (5) service object. CONCLUSION: This study clarifies the service focus and scope of necessary support for volunteers, exploring the potential service capabilities of scarce volunteers to the greatest extent. Meanwhile, the results of this study also provide a foundation for stakeholders to fully exploit the synergy. The important findings of this study will help the government and relevant authorities better understand the service attributes of nursing volunteers, allowing them to develop detailed training plans and provide nursing volunteers with targeted support and assistance to meet the health expectations of urban community-living older adults in need. PATIENT OR PUBLIC CONTRIBUTION: Developing research questions, participation and conduct and provision and interpretation of evidence.

Healthy diet intervention reverses the progression of NASH through gut microbiota modulation.

IMPORTANCE: The link between gut microbiota and diet is crucial in the development of non-alcoholic steatohepatitis (NASH). This study underscores the essential role of a healthy diet in preventing and treating NASH by reversing obesity, lipidemia, and gut microbiota dysbiosis. Moreover, the supplementation of functional food or drug to the diet can provide additional advantages by inhibiting hepatic inflammation through the modulation of the hepatic inflammasome signaling pathway and partially mediating the gut microbiota and lipopolysaccharide signaling pathway. This study highlights the importance of adopting healthy dietary habits in treating NASH and proposes that supplementing with ginger essential oil or obeticholic acid may offer additional benefits. Nonetheless, further clinical studies are necessary to validate these findings.

Multi-omics analysis of mucosal and systemic immunity to SARS-CoV-2 after birth.

The dynamics of immunity to infection in infants remain obscure. Here, we used a multi-omics approach to perform a longitudinal analysis of immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in infants and young children by analyzing blood samples and weekly nasal swabs collected before, during, and after infection with Omicron and non-Omicron variants. Infection stimulated robust antibody titers that, unlike in adults, showed no sign of decay for up to 300 days. Infants mounted a robust mucosal immune response characterized by inflammatory cytokines, interferon (IFN) α, and T helper (Th) 17 and neutrophil markers (interleukin [IL]-17, IL-8, and CXCL1). The immune response in blood was characterized by upregulation of activation markers on innate cells, no inflammatory cytokines, but several chemokines and IFNα. The latter correlated with viral load and expression of interferon-stimulated genes (ISGs) in myeloid cells measured by single-cell multi-omics. Together, these data provide a snapshot of immunity to infection during the initial weeks and months of life.

Volume plasma grating by noncollinear interaction of femtosecond filament arrays.

Stable propagation of multifilament arrays in transparent bulk media with adjustable separation distances between adjacent child filaments has always been desired for advanced manufacturing. Here, we report on the generation of an ionization-induced volume plasma grating (VPG) by the interaction of two batches of noncollinearly propagating arrays of multiple filaments (AMF). The VPG can externally arrange the propagation of the pulses along regular plasma waveguides via spatial reconstruction of electrical fields, which is compared with the self-formation of randomly distributed multiple filamentation originated from noises. The separation distances of filaments in VPG are controllable by readily changing the crossing angle of the excitation beams. In addition, an innovative method to efficiently fabricate multidimensional grating structures in transparent bulk media through laser modification using VPG was demonstrated.

Broadly neutralizing antibodies against sarbecoviruses generated by immunization of macaques with an AS03-adjuvanted COVID-19 vaccine.

The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that evade immunity elicited by vaccination has placed an imperative on the development of countermeasures that provide broad protection against SARS-CoV-2 and related sarbecoviruses. Here, we identified extremely potent monoclonal antibodies (mAbs) that neutralized multiple sarbecoviruses from macaques vaccinated with AS03-adjuvanted monovalent subunit vaccines. Longitudinal analysis revealed progressive accumulation of somatic mutation in the immunoglobulin genes of antigen-specific memory B cells (MBCs) for at least 1 year after primary vaccination. Antibodies generated from these antigen-specific MBCs at 5 to 12 months after vaccination displayed greater potency and breadth relative to those identified at 1.4 months. Fifteen of the 338 (about 4.4%) antibodies isolated at 1.4 to 6 months after the primary vaccination showed potency against SARS-CoV-2 BA.1, despite the absence of serum BA.1 neutralization. 25F9 and 20A7 neutralized authentic clade 1 sarbecoviruses (SARS-CoV, WIV-1, SHC014, SARS-CoV-2 D614G, BA.1, and Pangolin-GD) and vesicular stomatitis virus-pseudotyped clade 3 sarbecoviruses (BtKY72 and PRD-0038). 20A7 and 27A12 showed potent neutralization against all SARS-CoV-2 variants and multiple Omicron sublineages, including BA.1, BA.2, BA.3, BA.4/5, BQ.1, BQ.1.1, and XBB. Crystallography studies revealed the molecular basis of broad and potent neutralization through targeting conserved sites within the RBD. Prophylactic protection of 25F9, 20A7, and 27A12 was confirmed in mice, and administration of 25F9 particularly provided complete protection against SARS-CoV-2, BA.1, SARS-CoV, and SHC014 challenge. These data underscore the extremely potent and broad activity of these mAbs against sarbecoviruses.

A ferritin-based COVID-19 nanoparticle vaccine that elicits robust, durable, broad-spectrum neutralizing antisera in non-human primates.

While the rapid development of COVID-19 vaccines has been a scientific triumph, the need remains for a globally available vaccine that provides longer-lasting immunity against present and future SARS-CoV-2 variants of concern (VOCs). Here, we describe DCFHP, a ferritin-based, protein-nanoparticle vaccine candidate that, when formulated with aluminum hydroxide as the sole adjuvant (DCFHP-alum), elicits potent and durable neutralizing antisera in non-human primates against known VOCs, including Omicron BQ.1, as well as against SARS-CoV-1. Following a booster ~one year after the initial immunization, DCFHP-alum elicits a robust anamnestic response. To enable global accessibility, we generated a cell line that can enable production of thousands of vaccine doses per liter of cell culture and show that DCFHP-alum maintains potency for at least 14 days at temperatures exceeding standard room temperature. DCFHP-alum has potential as a once-yearly (or less frequent) booster vaccine, and as a primary vaccine for pediatric use including in infants.

Durability of immune responses to mRNA booster vaccination against COVID-19.

BackgroundMaintaining durable immunity following vaccination represents a major challenge, but whether mRNA booster vaccination improves durability is unknown.MethodsWe measured antibody responses in 55 healthy adults, who received a booster dose of the Pfizer-BioNTech or Moderna vaccine against SARS-CoV-2 and calculated the half-life of the antibody titers. We also measured memory B and T cell responses in a subset of 28 participants. In 13 volunteers who received a second booster vaccine, we measured serum antibody titers and memory B and T cell responses.ResultsThe booster (third immunization) dose at 6 to 10 months increased the half-life of the serum-neutralizing antibody (nAb) titers to 76 days from 56 to 66 days after the primary 2-dose vaccination. A second booster dose (fourth immunization) a year after the primary vaccination further increased the half-life to 88 days. However, despite this modestly improved durability in nAb responses against the ancestral (WA.1) strain, there was a loss of neutralization capacity against the Omicron subvariants BA.2.75.2, BQ.1.1, and XBB.1.5 (48-, 71-, and 66-fold drop in titers, respectively, relative to the WA.1 strain). Although only 45% to 65% of participants demonstrated a detectable nAb titer against the newer variants after the booster (third dose), the response declined to below the detection limit in almost all individuals by 6 months. In contrast, booster vaccination induced antigen-specific memory B and T cells that persisted for at least 6 months.ConclusionThe durability of serum antibody responses improves only marginally following booster immunizations with the Pfizer-BioNTech or Moderna mRNA vaccines.

Systems biological assessment of the temporal dynamics of immunity to a viral infection in the first weeks and months of life.

The dynamics of innate and adaptive immunity to infection in infants remain obscure. Here, we used a multi-omics approach to perform a longitudinal analysis of immunity to SARS-CoV-2 infection in infants and young children in the first weeks and months of life by analyzing blood samples collected before, during, and after infection with Omicron and Non-Omicron variants. Infection stimulated robust antibody titers that, unlike in adults, were stably maintained for >300 days. Antigen-specific memory B cell (MCB) responses were durable for 150 days but waned thereafter. Somatic hypermutation of V-genes in MCB accumulated progressively over 9 months. The innate response was characterized by upregulation of activation markers on blood innate cells, and a plasma cytokine profile distinct from that seen in adults, with no inflammatory cytokines, but an early and transient accumulation of chemokines (CXCL10, IL8, IL-18R1, CSF-1, CX3CL1), and type I IFN. The latter was strongly correlated with viral load, and expression of interferon-stimulated genes (ISGs) in myeloid cells measured by single-cell transcriptomics. Consistent with this, single-cell ATAC-seq revealed enhanced accessibility of chromatic loci targeted by interferon regulatory factors (IRFs) and reduced accessibility of AP-1 targeted loci, as well as traces of epigenetic imprinting in monocytes, during convalescence. Together, these data provide the first snapshot of immunity to infection during the initial weeks and months of life.

Transcriptome and Proteome Analysis Revealed the Influence of High-Molecular-Weight Glutenin Subunits (HMW-GSs) Deficiency on Expression of Storage Substances and the Potential Regulatory Mechanism of HMW-GSs.

The processing quality of wheat is affected by seed storage substances, such as protein and starch. High-molecular-weight glutenin subunits (HMW-GSs) are the major components of wheat seed storage proteins (SSPs); they are also key determinators of wheat end-use quality. However, the effects of HMW-GSs absence on the expression of other storage substances and the regulation mechanism of HMW-GSs are still limited. Previously, a wheat transgenic line LH-11 with complete deletions of HMW-GSs was obtained through introducing an exogenous gene Glu-1Ebx to the wild-type cultivar Bobwhite by transgenic approach. In this study, comparative seed transcriptomics and proteomics of transgenic and non-transgenic lines at different seed developmental stages were carried out to explore the changes in genes and proteins and the underlying regulatory mechanism. Results revealed that a number of genes, including genes related to SSPs, carbohydrates metabolism, amino acids metabolism, transcription, translation, and protein process were differentially enriched. Seed storage proteins displayed differential expression patterns between the transgenic and non-transgenic line, a major rise in the expression levels of gliadins were observed at 21 and 28 days post anthesis (DPA) in the transgenic line. Changes in expressions of low-molecular-weight glutenins (LMW-GSs), avenin-like proteins (ALPs), lipid transfer proteins (LTPs), and protease inhibitors (PIs) were also observed. In addition, genes related to carbohydrate metabolism were differentially expressed, which probably leads to a difference in starch component and deposition. A list of gene categories participating in the accumulation of SSPs was proposed according to the transcriptome and proteome data. Six genes from the MYB and eight genes from the NAC transcription families are likely important regulators of HMW-GSs accumulation. This study will provide data support for understanding the regulatory network of wheat storage substances. The screened candidate genes can lay a foundation for further research on the regulation mechanism of HMW-GSs.

Extremely potent pan-sarbecovirus neutralizing antibodies generated by immunization of macaques with an AS03-adjuvanted monovalent subunit vaccine against SARS-CoV-2.

The rapid emergence of SARS-CoV-2 variants that evade immunity to vaccination has placed a global health imperative on the development of therapeutic countermeasures that provide broad protection against SARS-CoV-2 and related sarbecoviruses. Here, we identified extremely potent pan-sarbecovirus antibodies from non-human primates vaccinated with an AS03 adjuvanted subunit vaccine against SARS-CoV-2 that recognize conserved epitopes in the receptor binding domain (RBD) with femtomolar affinities. Longitudinal analysis revealed progressive accumulation of somatic mutation in the immunoglobulin genes of antigen-specific memory B cells for at least one year following primary vaccination. 514 monoclonal antibodies (mAbs) were generated from antigen-specific memory B cells. Antibodies isolated at 5 to 12 months following vaccination displayed greater potency and breadth, relative to those identified at 1.4 months. Notably, 15 out of 338 (∼4.4%) antibodies isolated at 1.4∼6 months after the primary vaccination showed extraordinary neutralization potency against SARS-CoV-2 omicron BA.1, despite the absence of BA.1 neutralization in serum. Two of them, 25F9 and 20A7, neutralized authentic clade Ia sarbecoviruses (SARS-CoV, WIV-1, SHC014) and clade Ib sarbecoviruses (SARS-CoV-2 D614G, SARS-CoV-2 BA.1, Pangolin-GD) with half-maximal inhibition concentrations of (0.85 ng/ml, 3 ng/ml, 6 ng/ml, 6 ng/ml, 42 ng/ml, 6 ng/ml) and (13 ng/ml, 2 ng/ml, 18 ng/ml, 9 ng/ml, 6 ng/ml, 345 ng/ml), respectively. Furthermore, 20A7 and 27A12 showed potent neutralization against all SARS-CoV-2 variants of concern and multiple Omicron sublineages, including BA.1, BA.2, BA.3, BA.4/5, BQ.1, BQ.1.1 and XBB variants. X-ray crystallography studies revealed the molecular basis of broad and potent neutralization through targeting conserved RBD sites. In vivo prophylactic protection of 25F9, 20A7 and 27A12 was confirmed in aged Balb/c mice. Notably, administration of 25F9 provided complete protection against SARS-CoV-2, SARS-CoV-2 BA.1, SARS-CoV, and SHC014 challenge, underscoring that these mAbs are promising pan-sarbecovirus therapeutic antibodies. One Sentence Summary: Extremely potent pan-sarbecovirus neutralizing antibodies.

Clonal composition and persistence of antigen-specific circulating T follicular helper cells.

T follicular helper (TFH ) cells play an essential role in promoting B cell responses and antibody affinity maturation in germinal centers (GC). A subset of memory CD4+ T cells expressing the chemokine receptor CXCR5 has been described in human blood as phenotypically and clonally related to GC TFH cells. However, the antigen specificity and relationship of these circulating TFH (cTFH ) cells with other memory CD4+ T cells remain poorly defined. Combining antigenic stimulation and T cell receptor (TCR) Vß sequencing, we found T cells specific to tetanus toxoid (TT), influenza vaccine (Flu), or Candida albicans (C.alb) in both cTFH and non-cTFH subsets, although with different frequencies and effector functions. Interestingly, cTFH and non-cTFH cells specific for C.alb or TT had a largely overlapping TCR Vß repertoire while the repertoire of Flu-specific cTFH and non-cTFH cells was distinct. Furthermore, Flu-specific but not C.alb-specific PD-1+ cTFH cells had a "GC TFH -like" phenotype, with overexpression of IL21, CXCL13, and BCL6. Longitudinal analysis of serial blood donations showed that Flu-specific cTFH and non-cTFH cells persisted as stable repertoires for years. Collectively, our study provides insights on the relationship of cTFH with non-cTFH cells and on the heterogeneity and persistence of antigen-specific human cTFH cells.