Host Recovery from Respiratory Viral Infection.

Emerging and re-emerging respiratory viral infections pose a tremendous threat to human society, as exemplified by the ongoing COVID-19 pandemic. Upon viral invasion of the respiratory tract, the host initiates coordinated innate and adaptive immune responses to defend against the virus and to promote repair of the damaged tissue. However, dysregulated host immunity can also cause acute morbidity, hamper lung regeneration, and/or lead to chronic tissue sequelae. Here, we review our current knowledge of the immune mechanisms regulating antiviral protection, host pathogenesis, inflammation resolution, and lung regeneration following respiratory viral infections, mainly using influenza virus and SARS-CoV-2 infections as examples. We hope that this review sheds light on future research directions to elucidate the cellular and molecular cross talk regulating host recovery and to pave the way to the development of pro-repair therapeutics to augment lung regeneration following viral injury.

Multiple Signaling Roles of CD3ε and Its Application in CAR-T Cell Therapy.

A T cell receptor (TCR) mediates antigen-induced signaling through its associated CD3ε, δ, γ, and ζ, but the contributions of different CD3 chains remain elusive. Using quantitative mass spectrometry, we simultaneously quantitated the phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) of all CD3 chains upon TCR stimulation. A subpopulation of CD3ε ITAMs was mono-phosphorylated, owing to Lck kinase selectivity, and specifically recruited the inhibitory Csk kinase to attenuate TCR signaling, suggesting that TCR is a self-restrained signaling machinery containing both activating and inhibitory motifs. Moreover, we found that incorporation of the CD3ε cytoplasmic domain into a second-generation chimeric antigen receptor (CAR) improved antitumor activity of CAR-T cells. Mechanistically, the Csk-recruiting ITAM of CD3ε reduced CAR-T cytokine production whereas the basic residue rich sequence (BRS) of CD3ε promoted CAR-T persistence via p85 recruitment. Collectively, CD3ε is a built-in multifunctional signal tuner, and increasing CD3 diversity represents a strategy to design next-generation CAR.

Uncoupling of macrophage inflammation from self-renewal modulates host recovery from respiratory viral infection.

Tissue macrophages self-renew during homeostasis and produce inflammatory mediators upon microbial infection. We examined the relationship between proliferative and inflammatory properties of tissue macrophages by defining the impact of the Wnt/ß-catenin pathway, a central regulator of self-renewal, in alveolar macrophages (AMs). Activation of ß-catenin by Wnt ligand inhibited AM proliferation and stemness, but promoted inflammatory activity. In a murine influenza viral pneumonia model, ß-catenin-mediated AM inflammatory activity promoted acute host morbidity; in contrast, AM proliferation enabled repopulation of reparative AMs and tissue recovery following viral clearance. Mechanistically, Wnt treatment promoted ß-catenin-HIF-1α interaction and glycolysis-dependent inflammation while suppressing mitochondrial metabolism and thereby, AM proliferation. Differential HIF-1α activities distinguished proliferative and inflammatory AMs in vivo. This ß-catenin-HIF-1α axis was conserved in human AMs and enhanced HIF-1α expression associated with macrophage inflammation in COVID-19 patients. Thus, inflammatory and reparative activities of lung macrophages are regulated by ß-catenin-HIF-1α signaling, with implications for the treatment of severe respiratory diseases.

Tumour vasculature at single-cell resolution.

Tumours can obtain nutrients and oxygen required to progress and metastasize through the blood supply1. Inducing angiogenesis involves the sprouting of established vessel beds and their maturation into an organized network2,3. Here we generate a comprehensive atlas of tumour vasculature at single-cell resolution, encompassing approximately 200,000 cells from 372 donors representing 31 cancer types. Trajectory inference suggested that tumour angiogenesis was initiated from venous endothelial cells and extended towards arterial endothelial cells. As neovascularization elongates (through angiogenic stages SI, SII and SIII), APLN+ tip cells at the SI stage (APLN+ TipSI) advanced to TipSIII cells with increased Notch signalling. Meanwhile, stalk cells, following tip cells, transitioned from high chemokine expression to elevated TEK (also known as Tie2) expression. Moreover, APLN+ TipSI cells not only were associated with disease progression and poor prognosis but also hold promise for predicting response to anti-VEGF therapy. Lymphatic endothelial cells demonstrated two distinct differentiation lineages: one responsible for lymphangiogenesis and the other involved in antigen presentation. In pericytes, endoplasmic reticulum stress was associated with the proangiogenic BASP1+ matrix-producing pericytes. Furthermore, intercellular communication analysis showed that neovascular endothelial cells could shape an immunosuppressive microenvironment conducive to angiogenesis. This study depicts the complexity of tumour vasculature and has potential clinical significance for anti-angiogenic therapy.

The Transcription Factor Bhlhe40 Programs Mitochondrial Regulation of Resident CD8+ T Cell Fitness and Functionality.

Tissue-resident memory CD8+ T (Trm) cells share core residency gene programs with tumor-infiltrating lymphocytes (TILs). However, the transcriptional, metabolic, and epigenetic regulation of Trm cell and TIL development and function is largely undefined. Here, we found that the transcription factor Bhlhe40 was specifically required for Trm cell and TIL development and polyfunctionality. Local PD-1 signaling inhibited TIL Bhlhe40 expression, and Bhlhe40 was critical for TIL reinvigoration following anti-PD-L1 blockade. Mechanistically, Bhlhe40 sustained Trm cell and TIL mitochondrial fitness and a functional epigenetic state. Building on these findings, we identified an epigenetic and metabolic regimen that promoted Trm cell and TIL gene signatures associated with tissue residency and polyfunctionality. This regimen empowered the anti-tumor activity of CD8+ T cells and possessed therapeutic potential even at an advanced tumor stage in mouse models. Our results provide mechanistic insights into the local regulation of Trm cell and TIL function.

Mechano-regulation of Peptide-MHC Class I Conformations Determines TCR Antigen Recognition.

TCRs recognize cognate pMHCs to initiate T cell signaling and adaptive immunity. Mechanical force strengthens TCR-pMHC interactions to elicit agonist-specific catch bonds to trigger TCR signaling, but the underlying dynamic structural mechanism is unclear. We combined steered molecular dynamics (SMD) simulation, single-molecule biophysical approaches, and functional assays to collectively demonstrate that mechanical force induces conformational changes in pMHCs to enhance pre-existing contacts and activates new interactions at the TCR-pMHC binding interface to resist bond dissociation under force, resulting in TCR-pMHC catch bonds and T cell activation. Intriguingly, cancer-associated somatic mutations in HLA-A2 that may restrict these conformational changes suppressed TCR-pMHC catch bonds. Structural analysis also indicated that HLA polymorphism might alter the equilibrium of these conformational changes. Our findings not only reveal critical roles of force-induced conformational changes in pMHCs for activating TCR-pMHC catch bonds but also have implications for T cell-based immunotherapy.

Tissue-resident memory T cells and lung immunopathology.

Rapid reaction to microbes invading mucosal tissues is key to protect the host against disease. Respiratory tissue-resident memory T (TRM ) cells provide superior immunity against pathogen infection and/or re-infection, due to their presence at the site of pathogen entry. However, there has been emerging evidence that exuberant TRM -cell responses contribute to the development of various chronic respiratory conditions including pulmonary sequelae post-acute viral infections. In this review, we have described the characteristics of respiratory TRM cells and processes underlying their development and maintenance. We have reviewed TRM -cell protective functions against various respiratory pathogens as well as their pathological activities in chronic lung conditions including post-viral pulmonary sequelae. Furthermore, we have discussed potential mechanisms regulating the pathological activity of TRM cells and proposed therapeutic strategies to alleviate TRM -cell-mediated lung immunopathology. We hope that this review provides insights toward the development of future vaccines or interventions that can harness the superior protective abilities of TRM cells, while minimizing the potential for immunopathology, a particularly important topic in the era of coronavirus disease 2019 (COVID-19) pandemic.

Maternal SARS-CoV-2 infection in pregnancy disrupts gene expression in Hofbauer cells with limited impact on cytotrophoblasts.

BACKGROUND: Hofbauer cells (HBCs) and cytotrophoblasts (CTBs) are major cell populations in placenta. The indirect impact of maternal SARS-CoV-2 disease on these cells that are not directly infected has not been extensively studied. Herein, we profiled gene expression in HBCs and CTBs isolated from placentae of recovered pregnant subjects infected with SARS-CoV-2 during all trimesters of pregnancy, placentae from subjects with active infection, SARS-CoV-2 vaccinated subjects, and those who were unexposed to the virus. METHODS: Placentae were collected within 4 h post-delivery and membrane-free tissues were enzymatically digested for the isolation of HBCs and CTBs. RNA extracted from HBCs and CTBs were sequenced using 150bp paired-end reads. Differentially expressed genes (DEGs) were identified by DESeq2 package in R and enriched in GO Biological Processes, KEGG Pathway, Reactome Gene Sets, Hallmark Gene Sets, and Canonical Pathways. Protein-protein interactions among the DEGs were modelled using STRING and BioGrid. RESULTS: Pregnant subjects (n = 30) were recruited and categorized into six groups: infected with SARS-CoV-2 in i) the first (1T, n = 4), ii) second (2T, n = 5), iii) third (3T, n = 5) trimester, iv) tested positive at delivery (Delivery, n = 5), v) never infected (Control, n = 6), and vi) fully mRNA-vaccinated by delivery (Vaccinated, n = 5). Compared to the Control group, gene expression analysis showed that HBCs from infected subjects had significantly altered gene expression profiles, with the 2T group having the highest number of DEGs (1,696), followed by 3T and 1T groups (1,656 and 958 DEGs, respectively). These DEGs were enriched for pathways involved in immune regulation for host defense, including production of cytokines, chemokines, antimicrobial proteins, ribosomal assembly, neutrophil degranulation inflammation, morphogenesis, and cell migration/adhesion. Protein-protein interaction analysis mapped these DEGs with oxidative phosphorylation, translation, extracellular matrix organization, and type I interferon signaling. Only 95, 23, and 8 DEGs were identified in CTBs of 1T, 2T, and 3T groups, respectively. Similarly, 11 and 3 DEGs were identified in CTBs and HBCs of vaccinated subjects, respectively. Reassuringly, mRNA vaccination did not induce an inflammatory response in placental cells. CONCLUSIONS: Our studies demonstrate a significant impact of indirect SARS-CoV-2 infection on gene expression of inner mesenchymal HBCs, with limited effect on lining CTB cells isolated from pregnant subjects infected and recovered from SARS-CoV-2. The pathways associated with these DEGs identify potential targets for therapeutic intervention.

Fast-Charging Phosphorus-Based Anodes: Promises, Challenges, and Pathways for Improvement.

Fast-charging batteries are highly sought after. However, the current battery industry has used carbon as the preferred anode, which can suffer from dendrite formation problems at high current density, causing failure after prolonged cycling and posing safety hazards. The phosphorus (P) anode is being considered as a promising successor to graphite due to its safe lithiation potential, low ion diffusion energy barrier, and high theoretical storage capacity. Since 2019, fast-charging P-based anodes have realized the goals of extreme fast charging (XFC), which enables a 10 min recharging time to deliver a capacity retention larger than 80%. Rechargeable battery technologies that use P-based anodes, along with high-capacity conversion-type cathodes or high-voltage insertion-type cathodes, have thus garnered substantial attention from both the academic and industry communities. In spite of this activity, there remains a rather sparse range of high-performance and fast-charging P-based cell configurations. Herein, we first systematically examine four challenges for fast-charging P-based anodes, including the volumetric variation during the cycling process, the electrode interfacial instability, the dissolution of polyphosphides, and the long-lasting P/electrolyte side reactions. Next, we summarize a range of strategies with the potential to circumvent these challenges and rationally control electrochemical reaction processes at the P anode. We also consider both binders and electrode structures. We also propose other remaining issues and corresponding strategies for the improvement and understanding of the fast-charging P anode. Finally, we review and discuss the existing full cell configurations based on P anodes and forecast the potential feasibility of recycling spent P-based full cells according to the trajectory of recent developments in batteries. We hope this review affords a fresh perspective on P science and engineering toward fast-charging energy storage devices.

Bhlhe40 Promotes CD4+ T Helper 1 Cell and Suppresses T Follicular Helper Cell Differentiation during Viral Infection.

In response to acute infection, naive CD4+ T cells primarily differentiate into T helper 1 (Th1) or T follicular helper (Tfh) cells that play critical roles in orchestrating cellular or humoral arms of immunity, respectively. However, despite the well established role of T-bet and BCL-6 in driving Th1 and Tfh cell lineage commitment, respectively, whether additional transcriptional circuits also underlie the fate bifurcation of Th1 and Tfh cell subsets is not fully understood. In this article, we study how the transcriptional regulator Bhlhe40 dictates the Th1/Tfh differentiation axis in mice. CD4+ T cell-specific deletion of Bhlhe40 abrogates Th1 but augments Tfh differentiation. We also assessed an increase in germinal center B cells and Ab production, suggesting that deletion of Bhlhe40 in CD4+ T cells not only alters Tfh differentiation but also their capacity to provide help to B cells. To identify molecular mechanisms by which Bhlhe40 regulates Th1 versus Tfh lineage choice, we first performed epigenetic profiling in the virus specific Th1 and Tfh cells following LCMV infection, which revealed distinct promoter and enhancer activities between the two helper cell lineages. Furthermore, we identified that Bhlhe40 directly binds to cis-regulatory elements of Th1-related genes such as Tbx21 and Cxcr6 to activate their expression while simultaneously binding to regions of Tfh-related genes such as Bcl6 and Cxcr5 to repress their expression. Collectively, our data suggest that Bhlhe40 functions as a transcription activator to promote Th1 cell differentiation and a transcription repressor to suppress Tfh cell differentiation.

Deep neural network learning biological condition information refines gene-expression-based cell subtypes.

With the recent advent of single-cell level biological understanding, a growing interest is in identifying cell states or subtypes that are homogeneous in terms of gene expression and are also enriched in certain biological conditions, including disease samples versus normal samples (condition-specific cell subtype). Despite the importance of identifying condition-specific cell subtypes, existing methods have the following limitations: since they train models separately between gene expression and the biological condition information, (1) they do not consider potential interactions between them, and (2) the weights from both types of information are not properly controlled. Also, (3) they do not consider non-linear relationships in the gene expression and the biological condition. To address the limitations and accurately identify such condition-specific cell subtypes, we develop scDeepJointClust, the first method that jointly trains both types of information via a deep neural network. scDeepJointClust incorporates results from the power of state-of-the-art gene-expression-based clustering methods as an input, incorporating their sophistication and accuracy. We evaluated scDeepJointClust on both simulation data in diverse scenarios and biological data of different diseases (melanoma and non-small-cell lung cancer) and showed that scDeepJointClust outperforms existing methods in terms of sensitivity and specificity. scDeepJointClust exhibits significant promise in advancing our understanding of cellular states and their implications in complex biological systems.

Lyophilized lymph nodes for improved delivery of chimeric antigen receptor T cells.

Lymph nodes are crucial organs of the adaptive immune system, orchestrating T cell priming, activation and tolerance. T cell activity and function are highly regulated by lymph nodes, which have a unique structure harbouring distinct cells that work together to detect and respond to pathogen-derived antigens. Here we show that implanted patient-derived freeze-dried lymph nodes loaded with chimeric antigen receptor T cells improve delivery to solid tumours and inhibit tumour recurrence after surgery. Chimeric antigen receptor T cells can be effectively loaded into lyophilized lymph nodes, whose unaltered meshwork and cytokine and chemokine contents promote chimeric antigen receptor T cell viability and activation. In mouse models of cell-line-derived human cervical cancer and patient-derived pancreatic cancer, delivery of chimeric antigen receptor T cells targeting mesothelin via the freeze-dried lymph nodes is more effective in preventing tumour recurrence when compared to hydrogels containing T-cell-supporting cytokines. This tissue-mediated cell delivery strategy holds promise for controlled release of various cells and therapeutics with long-term activity and augmented function.

Discrete class I molecules on brain endothelium differentially regulate neuropathology in experimental cerebral malaria.

Cerebral malaria is the deadliest complication that can arise from Plasmodium infection. CD8 T-cell engagement of brain vasculature is a putative mechanism of neuropathology in cerebral malaria. To define contributions of brain endothelial cell major histocompatibility complex (MHC) class I antigen-presentation to CD8 T cells in establishing cerebral malaria pathology, we developed novel H-2Kb LoxP and H-2Db LoxP mice crossed with Cdh5-Cre mice to achieve targeted deletion of discrete class I molecules, specifically from brain endothelium. This strategy allowed us to avoid off-target effects on iron homeostasis and class I-like molecules, which are known to perturb Plasmodium infection. This is the first endothelial-specific ablation of individual class-I molecules enabling us to interrogate these molecular interactions. In these studies, we interrogated human and mouse transcriptomics data to compare antigen presentation capacity during cerebral malaria. Using the Plasmodium berghei ANKA model of experimental cerebral malaria (ECM), we observed that H-2Kb and H-2Db class I molecules regulate distinct patterns of disease onset, CD8 T-cell infiltration, targeted cell death and regional blood-brain barrier disruption. Strikingly, ablation of either molecule from brain endothelial cells resulted in reduced CD8 T-cell activation, attenuated T-cell interaction with brain vasculature, lessened targeted cell death, preserved blood-brain barrier integrity and prevention of ECM and the death of the animal. We were able to show that these events were brain-specific through the use of parabiosis and created the novel technique of dual small animal MRI to simultaneously scan conjoined parabionts during infection. These data demonstrate that interactions of CD8 T cells with discrete MHC class I molecules on brain endothelium differentially regulate development of ECM neuropathology. Therefore, targeting MHC class I interactions therapeutically may hold potential for treatment of cases of severe malaria.

Structural insights into Ras regulation by SIN1.

Over the years it has been established that SIN1, a key component of mTORC2, could interact with Ras family small GTPases through its Ras-binding domain (RBD). The physical association of Ras and SIN1/mTORC2 could potentially affect both mTORC2 and Ras-ERK pathways. To decipher the precise molecular mechanism of this interaction, we determined the high-resolution structures of HRas/KRas-SIN1 RBD complexes, showing the detailed interaction interface. Mutation of critical interface residues abolished Ras-SIN1 interaction and in SIN1 knockout cells we demonstrated that Ras-SIN1 association promotes SGK1 activity but inhibits insulin-induced ERK activation. With structural comparison and competition fluorescence resonance energy transfer (FRET) assays we showed that HRas-SIN1 RBD association is much weaker than HRas-Raf1 RBD but is slightly stronger than HRas-PI3K RBD interaction, providing a possible explanation for the different outcome of insulin or EGF stimulation. We also found that SIN1 isoform lacking the PH domain binds stronger to Ras than other longer isoforms and the PH domain appears to have an inhibitory effect on Ras-SIN1 binding. In addition, we uncovered a Ras dimerization interface that could be critical for Ras oligomerization. Our results advance our understanding of Ras-SIN1 association and crosstalk between growth factor-stimulated pathways.

Tas2R activation relaxes airway smooth muscle by release of Gαt targeting on AChR signaling.

Both chronic obstructive pulmonary disease (COPD) and asthma are severe respiratory diseases. Bitter receptor-mediated bronchodilation is a potential therapy for asthma, but the mechanism underlying the agonistic relaxation of airway smooth muscle (ASM) is not well defined. By exploring the ASM relaxation mechanism of bitter substances, we observed that pretreatment with the bitter substances nearly abolished the methacholine (MCh)-induced increase in the ASM cell (ASMC) calcium concentration, thereby suppressing the calcium-induced contraction release. The ASM relaxation was significantly inhibited by simultaneous deletion of three Gαt proteins, suggesting an interaction between Tas2R and AChR signaling cascades in the relaxation process. Biochemically, the Gαt released by Tas2R activation complexes with AChR and blocks the Gαq cycling of AChR signal transduction. More importantly, a bitter substance, kudinoside A, not only attenuates airway constriction but also significantly inhibits pulmonary inflammation and tissue remodeling in COPD rats, indicating its modulation of additional Gαq-associated pathological processes. Thus, our results suggest that Tas2R activation may be an ideal strategy for halting multiple pathological processes of COPD.

Exceptional Rate Performances of Li-Rich Mn-Based Cathodes Enabled by Boron-Based Additives-Driven Self-Optimized Interface.

Li-rich Mn-based cathode material (LRM), as a promising cathode for high energy density lithium batteries, suffers from severe side reactions in conventional lithium hexafluorophosphate (LiPF6)-based carbonate electrolytes, leading to unstable interfaces and poor rate performances. Herein, a boron-based additives-driven self-optimized interface strategy is presented to dissolve low ionic conductivity LiF nanoparticles at the outer cathode electrolyte interface, leading to the optimized interfacial components, as well as the enhanced Li ion migration rate in electrolytes. Being attributed to these superiorities, the LRM||Li battery delivers a high-capacity retention of 92.19% at 1C after 200 cycles and a low voltage decay of 1.08 mV/cycle. This work provides a new perspective on the rational selection of functional additives with an interfacial self-optimized characteristic to achieve a long lifespan LRM with exceptional rate performances.

Trade-Off between Rough and Smooth Electrode Surfaces toward Stable Zn Stripping/Plating in Aqueous Electrolytes.

The effects of surface roughness on the performance of the Zn metal anode in aqueous electrolytes are investigated by experiments and computational simulations. Smooth surfaces can homogenize the nucleation and growth of Zn, which helps to form a flat Zn anode under high current density. In spite of these advantages, the whole surface of the smooth electrode serves as the reactive contact area for parasitic reactions, generating severe hydrogen evolution, corrosion, and byproduct formation, which seriously hinder the long-term cycle stability of the Zn anode. To trade off this double-sided effect, we identify a medium degree of surface roughness that could stabilize the Zn anode for 1000 h cycling at 1.0 mAh cm-2. The electrode also enabled stable cycling for 800 h at a high current density of 5.0 mAh cm-2. This naked Zn metal anode with optimized surface roughness holds great promise for direct use in aqueous zinc ion batteries.

Vertical Transmission of SARS-CoV-2-Specific Antibodies and Cytokine Profiles in Pregnancy.

Despite intensive characterization of immune responses after COVID-19 infection and vaccination, research examining protective correlates of vertical transmission in pregnancy are limited. Herein, we profiled humoral and cellular characteristics in pregnant women infected or vaccinated at different trimesters and in their corresponding newborns. We noted a significant correlation between spike S1-specific IgG antibody and its RBD-ACE2 blocking activity (receptor-binding domain-human angiotensin-converting enzyme 2) in maternal and cord plasma (P < .001, R > 0.90). Blocking activity of spike S1-specific IgG was significantly higher in pregnant women infected during the third trimester than the first and second trimesters. Elevated levels of 28 cytokines/chemokines, mainly proinflammatory, were noted in maternal plasma with infection at delivery, while cord plasma with maternal infection 2 weeks before delivery exhibited the emergence of anti-inflammatory cytokines. Our data support vertical transmission of protective SARS-CoV-2-specific antibodies. This vertical antibody transmission and the presence of anti-inflammatory cytokines in cord blood may offset adverse outcomes of inflammation in exposed newborns.

Acetylation of GhCaM7 enhances cotton resistance to Verticillium dahliae.

Protein lysine acetylation is an important post-translational modification mechanism involved in cellular regulation in eukaryotes. Calmodulin (CaM) is a ubiquitous Ca2+ sensor in eukaryotes and is crucial for plant immunity, but it is so far unclear whether acetylation is involved in CaM-mediated plant immunity. Here, we found that GhCaM7 is acetylated upon Verticillium dahliae (V. dahliae) infection and a positive regulator of V. dahliae resistance. Overexpressing GhCaM7 in cotton and Arabidopsis enhances V. dahliae resistance and knocking-down GhCaM7 makes cotton more susceptible to V. dahliae. Transgenic Arabidopsis plants overexpressing GhCaM7 with mutation at the acetylation site are more susceptible to V. dahliae than transgenics overexpressing the wild-type GhCaM7, implying the importance of the acetylated GhCaM7 in response to V. dahliae infection. Yeast two-hybrid, bimolecular fluorescent complementation, luciferase complementation imaging, and coimmunoprecipitation assays demonstrated interaction between GhCaM7 and an osmotin protein GhOSM34 that was shown to have a positive role in V. dahliae resistance. GhCaM7 and GhOSM34 are co-localized in the cell membrane. Upon V. dahliae infection, the Ca2+ content reduces almost instantly in plants with downregulated GhCaM7 or GhOSM34. Down regulating GhOSM34 enhances accumulation of Na+ and increases cell osmotic pressure. Comparative transcriptomic analyses between cotton plants with an increased or reduced expression level of GhCaM7 and wild-type plants indicate the involvement of jasmonic acid signaling pathways and reactive oxygen species in GhCaM7-enabled disease resistance. Together, these results demonstrate the involvement of CaM protein in the interaction between cotton and V. dahliae, and more importantly, the involvement of the acetylated CaM in the interaction.

Performance of Thrombectomy-Capable, Comprehensive, and Primary Stroke Centers in Reperfusion Therapies for Acute Ischemic Stroke: Report From the Get With The Guidelines-Stroke Registry.

BACKGROUND: The thrombectomy-capable stroke center (TSC) is a recently introduced intermediate tier of accreditation for hospitals at which patients with acute ischemic stroke receive care. The comparative quality and clinical outcomes of reperfusion therapies at TSCs, primary stroke centers (PSCs), and comprehensive stroke centers (CSCs) have not been well delineated. METHODS: We conducted a retrospective, observational, cohort study from 2018 to 2020 that included patients with acute ischemic stroke who received endovascular thrombectomy (EVT) and intravenous thrombolysis reperfusion therapies at CSCs, TSCs, or PSCs. Participants were recruited from Get With The Guidelines-Stroke registry. Study end points included timeliness of intravenous thrombolysis and EVT, successful reperfusion, discharge destination, discharge mortality, and functional independence at discharge. RESULTS: Among 84 903 patients, 48 682 received EVT, of whom 73% were treated at CSCs, 22% at PSCs, and 4% at TSCs. The median annual EVT volume was 76 for CSCs, 55 for TSCs, and 32 for PSCs. Patient differences by center status included higher National Institutes of Health Stroke Scale score, longer onset-to-arrival time, and higher transfer-in rates for CSCs, TSCs, and PSCs, respectively. In adjusted analyses, the likelihood of achieving the goal door-to-needle time was higher in CSCs compared with PSCs (odds ratio [OR], 1.39 [95% CI, 1.17-1.66]) and in TSCs compared with PSCs (OR, 1.45 [95% CI, 1.08-1.96]). Likewise, the odds of achieving the goal door-to-puncture time were higher in CSCs compared with PSCs (OR, 1.58 [95% CI, 1.13-2.21]). CSCs and TSCs also demonstrated better clinical efficacy outcomes compared with PSCs. The odds of discharge to home or rehabilitation were higher in CSCs compared with PSCs (OR, 1.18 [95% CI, 1.06-1.31]), whereas the odds of in-hospital mortality or discharge to hospice were lower in both CSCs compared with PSCs (OR, 0.87 [95% CI, 0.81-0.94]) and TSCs compared with PSCs (OR, 0.86 [95% CI, 0.75-0.98]). There were no significant differences in any of the quality-of-care metrics and clinical outcomes between TSCs and CSCs. CONCLUSIONS: In this study representing national US practice, CSCs and TSCs exceeded PSCs in key quality-of-care reperfusion metrics and outcomes, whereas TSCs and CSCs demonstrated a similar performance. With more than one-fifth of all EVT procedures during the study period conducted at PSCs, it may be desirable to explore national initiatives aimed at facilitating the elevation of eligible PSCs to a higher certification status.