BNT162b2 vaccine induces divergent B cell responses to SARS-CoV-2 S1 and S2.

The first ever US Food and Drug Administration-approved messenger RNA vaccines are highly protective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1-3. However, the contribution of each dose to the generation of antibodies against SARS-CoV-2 spike (S) protein and the degree of protection against novel variants warrant further study. Here, we investigated the B cell response to the BNT162b2 vaccine by integrating B cell repertoire analysis with single-cell transcriptomics pre- and post-vaccination. The first vaccine dose elicits a recall response of IgA+ plasmablasts targeting the S subunit S2. Three weeks after the first dose, we observed an influx of minimally mutated IgG+ memory B cells that targeted the receptor binding domain on the S subunit S1 and likely developed from the naive B cell pool. This response was strongly boosted by the second dose and delivers potently neutralizing antibodies against SARS-CoV-2 and several of its variants.

Chemical reservoir computation in a self-organizing reaction network.

Chemical reaction networks, such as those found in metabolism and signalling pathways, enable cells to process information from their environment1,2. Current approaches to molecular information processing and computation typically pursue digital computation models and require extensive molecular-level engineering3. Despite considerable advances, these approaches have not reached the level of information processing capabilities seen in living systems. Here we report on the discovery and implementation of a chemical reservoir computer based on the formose reaction4. We demonstrate how this complex, self-organizing chemical reaction network can perform several nonlinear classification tasks in parallel, predict the dynamics of other complex systems and achieve time-series forecasting. This in chemico information processing system provides proof of principle for the emergent computational capabilities of complex chemical reaction networks, paving the way for a new class of biomimetic information processing systems.

Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM.

Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system. B lymphocytes in the cerebrospinal fluid (CSF) of patients with MS contribute to inflammation and secrete oligoclonal immunoglobulins1,2. Epstein-Barr virus (EBV) infection has been epidemiologically linked to MS, but its pathological role remains unclear3. Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM) and provide structural and in vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements and the crystal structure of the EBNA1-peptide epitope in complex with the autoreactive Fab fragment enabled tracking of the development of the naive EBNA1-restricted antibody to a mature EBNA1-GlialCAM cross-reactive antibody. Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates disease in a mouse model of MS, and anti-EBNA1 and anti-GlialCAM antibodies are prevalent in patients with MS. Our results provide a mechanistic link for the association between MS and EBV and could guide the development of new MS therapies.

The monocyte cell surface is a unique site of autoantigen generation in rheumatoid arthritis.

Although anti-citrullinated protein autoantibodies (ACPAs) are a hallmark serological feature of rheumatoid arthritis (RA), the mechanisms and cellular sources behind the generation of the RA citrullinome remain incompletely defined. Peptidylarginine deiminase IV (PAD4), one of the key enzymatic drivers of citrullination in the RA joint, is expressed by granulocytes and monocytes; however, the subcellular localization and contribution of monocyte-derived PAD4 to the generation of citrullinated autoantigens remain underexplored. In this study, we demonstrate that PAD4 displays a widespread cellular distribution in monocytes, including expression on the cell surface. Surface PAD4 was enzymatically active and capable of citrullinating extracellular fibrinogen and endogenous surface proteins in a calcium dose-dependent manner. Fibrinogen citrullinated by monocyte-surface PAD4 could be specifically recognized over native fibrinogen by a panel of eight human monoclonal ACPAs. Several unique PAD4 substrates were identified on the monocyte surface via mass spectrometry, with citrullination of the CD11b and CD18 components of the Mac-1 integrin complex being the most abundant. Citrullinated Mac-1 was found to be a target of ACPAs in 25% of RA patients, and Mac-1 ACPAs were significantly associated with HLA-DRB1 shared epitope alleles, higher C-reactive protein and IL-6 levels, and more erosive joint damage. Our findings implicate the monocyte cell surface as a unique and consequential site of extracellular and cell surface autoantigen generation in RA.

Fishing for biomarkers with antigen mimics.

Current efforts to identify antibodies that are biomarkers of disease rely on knowing the antigens they target. In many diseases, however, the relevant antigens are unknown. Reddy et al. (2010) now present an approach for discovering antibody biomarkers that avoids the need for antigen identification.

Antibody cross-reactivity between casein and myelin-associated glycoprotein results in central nervous system demyelination.

Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease of the central nervous system (CNS) with a high socioeconomic relevance. The pathophysiology of MS, which is both complex and incompletely understood, is believed to be influenced by various environmental determinants, including diet. Since the 1990s, a correlation between the consumption of bovine milk products and MS prevalence has been debated. Here, we show that C57BL/6 mice immunized with bovine casein developed severe spinal cord pathology, in particular, demyelination, which was associated with the deposition of immunoglobulin G. Furthermore, we observed binding of serum from casein-immunized mice to mouse oligodendrocytes in CNS tissue sections and in culture where casein-specific antibodies induced complement-dependent pathology. We subsequently identified myelin-associated glycoprotein (MAG) as a cross-reactive antigenic target. The results obtained from the mouse model were complemented by clinical data showing that serum samples from patients with MS contained significantly higher B cell and antibody reactivity to bovine casein than those from patients with other neurologic diseases. This reactivity correlated with the B cell response to a mixture of CNS antigens and could again be attributed to MAG reactivity. While we acknowledge disease heterogeneity among individuals with MS, we believe that consumption of cow's milk in a subset of patients with MS who have experienced a previous loss of tolerance to bovine casein may aggravate the disease. Our data suggest that patients with antibodies to bovine casein might benefit from restricting dairy products from their diet.

Mobilization of innate and adaptive antitumor immune responses by the RNP-targeting antibody ATRC-101.

Immunotherapy approaches focusing on T cells have provided breakthroughs in treating solid tumors. However, there remains an opportunity to drive anticancer immune responses via other cell types, particularly myeloid cells. ATRC-101 was identified via a target-agnostic process evaluating antibodies produced by the plasmablast population of B cells in a patient with non-small cell lung cancer experiencing an antitumor immune response during treatment with checkpoint inhibitor therapy. Here, we describe the target, antitumor activity in preclinical models, and data supporting a mechanism of action of ATRC-101. Immunohistochemistry studies demonstrated tumor-selective binding of ATRC-101 to multiple nonautologous tumor tissues. In biochemical analyses, ATRC-101 appears to target an extracellular, tumor-specific ribonucleoprotein (RNP) complex. In syngeneic murine models, ATRC-101 demonstrated robust antitumor activity and evidence of immune memory following rechallenge of cured mice with fresh tumor cells. ATRC-101 increased the relative abundance of conventional dendritic cell (cDC) type 1 cells in the blood within 24 h of dosing, increased CD8+ T cells and natural killer cells in blood and tumor over time, decreased cDC type 2 cells in the blood, and decreased monocytic myeloid-derived suppressor cells in the tumor. Cellular stress, including that induced by chemotherapy, increased the amount of ATRC-101 target in tumor cells, and ATRC-101 combined with doxorubicin enhanced efficacy compared with either agent alone. Taken together, these data demonstrate that ATRC-101 drives tumor destruction in preclinical models by targeting a tumor-specific RNP complex leading to activation of innate and adaptive immune responses.

The Emergence and Sustainability of Urban Entomology.

Urban entomology is the study of arthropod and other pests of the urban environment. It has gained worldwide recognition as a distinct discipline. Its origin is associated with Walter Ebeling's publication Urban Entomology in 1975. Urbanization, invasive pests, increased demand for pest management services, and changes in legislation collided in the 1970s to create a need for research and extension activities worldwide. This resulted in urban entomology as a discipline and, within two decades, its national and international recognition. In this review, we present the factors that led to the development of urban entomology and how they have shaped its current meaning. As urbanization intensifies and the global economy increases, the demands for urban pest management will continue to grow. We discuss how these future challenges may shape and alter the discipline.

Expanding the landscape of oncogenic drivers and treatment options in acral and mucosal melanomas by targeted genomic profiling.

Despite advancements in treating cutaneous melanoma, patients with acral and mucosal (A/M) melanomas still have limited therapeutic options and poor prognoses. We analyzed 156 melanomas (101 cutaneous, 28 acral, and 27 mucosal) using the Foundation One cancer-gene specific clinical testing platform and identified new, potentially targetable genomic alterations (GAs) in specific anatomic sites of A/M melanomas. Using novel pre-clinical models of A/M melanoma, we demonstrate that several GAs and corresponding oncogenic pathways associated with cutaneous melanomas are similarly targetable in A/M melanomas. Other alterations, including MYC and CRKL amplifications, were unique to A/M melanomas and susceptible to indirect targeting using the BRD4 inhibitor JQ1 or Src/ABL inhibitor dasatinib, respectively. We further identified new, actionable A/M-specific alterations, including an inactivating NF2 fusion in a mucosal melanoma responsive to dasatinib in vivo. Our study highlights new molecular differences between cutaneous and A/M melanomas, and across different anatomic sites within A/M, which may change clinical testing and treatment paradigms for these rare melanomas.

High prevalence of hepatitis C virus infection among incarcerated persons: Results from the Louisiana Hepatitis C Elimination Plan's opt-out testing program in prisons.

In the United States, modelling studies suggest a high prevalence of hepatitis C virus (HCV) infection in incarcerated populations. However, limited HCV testing has been conducted in prisons. Through the Louisiana Hepatitis C Elimination Plan, persons incarcerated in the eight state prisons were offered HCV testing from 20 September 2019 to 14 July 2022, and facility entry/exit HCV testing was introduced. Multivariable logistic regression was used to evaluate associations with HCV antibody (anti-HCV) positivity and viremia. Of 17,231 persons in the eight state prisons screened for anti-HCV, 95.1% were male, 66.7% were 30-57 years old, 3% were living with HIV, 68.2% were Black and 2904 (16.9%) were anti-HCV positive. HCV RNA was detected in 69.3% of anti-HCV positive individuals tested. In the multivariable model, anti-HCV positivity was associated with older age including those 30-57 (odds ratio [OR] 3.53, 95% confidence interval [CI] 2.96-4.20) and those ≥58 (OR 10.43, 95% CI 8.66-12.55) as compared to those ≤29 years of age, living with HIV (OR 1.68, 95% CI 1.36-2.07), hepatitis B (OR 1.83, 95% CI 1.25-2.69) and syphilis (OR 1.51, 95% CI 1.23-1.86). HCV viremia was associated with male sex (OR 1.89, 95% CI 1.36-2.63) and Black race (OR 1.42, 95% CI 1.20-1.68). HCV prevalence was high in the state prisons in Louisiana compared to community estimates. To the extent that Louisiana is representative, to eliminate HCV in the United States, it will be important for incarcerated persons to have access to HCV testing and treatment.

Genetic association between atopic disease and osteoarthritis.

OBJECTIVES: To evaluate the association between genetically determined risk for atopic disease and osteoarthritis (OA). METHODS: We performed linkage disequilibrium (LD) score regression using 1000 Genomes Project European samples as a reference for patterns of genome-wide LD. Summary statistics for atopic disease traits were obtained from the UK Biobank. We generated a pairwise genetic correlation between OA and traits for atopic disease to estimate the genetic correlation between traits (rg) and heritability for each trait. The association between atopy-related traits and OA was examined using Mendelian randomization (MR) on summary statistics; we reported inverse-variance weighted (IVW), MR-Egger, maximum likelihood estimation, weighted median, and weighted mode. RESULTS: There was a significant positive correlation between the genome-wide genetic architecture of asthma and all OA traits. Using the IVW (random effects), there was a significant association between asthma and knee OA ((odds ratio) OR = 1.04, 95% (confidence interval) CI 1.01-1.08, p = 0.0169). Using IVW (fixed effects), significant associations were identified between knee OA and allergic disease (OR = 1.07, 95% CI 1.01-1.14, p = 0.0342), allergic rhinitis (OR = 1.07, 95% CI 1.00-1.13, p = 0.0368), and asthma (OR = 1.04, 95% CI 1.01-1.07, p = 0.0139), as well as for OA at any site and asthma (OR = 1.02, 95% CI 1.00-1.04, p = 0.0166). CONCLUSIONS: We found a significant correlation between the overall genetic architecture of asthma and OA, as well as an increased risk of developing OA in patients with genetic variants associated with asthma and allergic rhinitis; predominately, this risk was for the development of knee OA. These results support a causal relationship between asthma and/or allergic rhinitis and knee OA.

Investigating the impact of suboptimal prescription of preoperative antiplatelets and statins on race and ethnicity-related disparities in major limb amputation.

BACKGROUND: Non-Hispanic Black and Hispanic patients with symptomatic PAD may receive different treatments than White patients with symptomatic PAD. The delivery of guideline-directed medical treatment may be a modifiable upstream driver of race and ethnicity-related disparities in outcomes such as limb amputation. The purpose of our study was to investigate the prescription of preoperative antiplatelets and statins in producing disparities in the risk of amputation following revascularization for symptomatic peripheral artery disease (PAD). METHODS: We used data from the Vascular Quality Initiative, a vascular procedure-based registry in the United States (2011-2018). We estimated the probability of preoperative antiplatelet and statin prescriptions and 1-year incidence of amputation. We then estimated the amputation risk difference between race/ethnicity groups that could be eliminated under a hypothetical intervention. RESULTS: Across 100,579 revascularizations, the 1-year amputation risk was 2.5% (2.4%, 2.6%) in White patients, 5.3% (4.9%, 5.6%) in Black patients, and 5.3% (4.7%, 5.9%) in Hispanic patients. Black (57.5%) and Hispanic patients (58.7%) were only slightly less likely than White patients (60.9%) to receive antiplatelet and statin therapy. However, the effect of antiplatelets and statins was greater in Black and Hispanic patients such that, had all patients received these medications, the estimated risk difference comparing Black to White patients would have reduced by 8.9% (-2.9%, 21.9%) and the risk difference comparing Hispanic to White patients would have been reduced by 17.6% (-0.7%, 38.6%). CONCLUSION: Even though guideline-directed care appeared evenly distributed by race/ethnicity, increasing access to such care may decrease health care disparities in major limb amputation.

Dynamic Environmental Conditions Affect the Composition of a Model Prebiotic Reaction Network.

Prebiotic environments are dynamic, containing a range of periodic and aperiodic variations in reaction conditions. However, the impact of the temporal dynamics of environmental conditions upon prebiotic chemical reaction networks has not been investigated. Here, we demonstrate how the magnitude and rate of temporal fluctuations of the catalysts Ca2+ and hydroxide control the product distributions of the formose reaction. Surprisingly, the product compositions of the formose reaction under dynamic conditions deviate significantly from those under steady state conditions. We attribute these compositional changes to the non-uniform propagation of fluctuations through the network, thereby shaping reaction outcomes. An examination of temporal concentration patterns showed that collections of compounds responded collectively to perturbations, indicating that key gating reactions branching from the Breslow cycle may be important responsive features of the formose reaction. Our findings show how the compositions of prebiotic reaction networks were shaped by sequential environmental events, illustrating the necessity for considering the temporal traits of prebiotic environments that supported the origin of life.

Increased macrophage phagocytic activity with TLR9 agonist conjugation of an anti- Borrelia burgdorferi monoclonal antibody.

Borrelia burgdorferi (Bb) infection causes Lyme disease, for which there is need for more effective therapies. Here, we sequenced the antibody repertoire of plasmablasts in Bb-infected humans. We expressed recombinant monoclonal antibodies (mAbs) representing the identified plasmablast clonal families, and identified their binding specificities. Our recombinant anti-Bb mAbs exhibit a range of activity in mediating macrophage phagocytosis of Bb. To determine if we could increase the macrophage phagocytosis-promoting activity of our anti-Bb mAbs, we generated a TLR9-agonist CpG-oligo-conjugated anti-BmpA mAb. We demonstrated that our CpG-conjugated anti-BmpA mAb exhibited increased peak Bb phagocytosis at 12-24 h, and sustained macrophage phagocytosis over 60+ hrs. Further, our CpG-conjugated anti-BmpA mAb induced macrophages to exhibit a sustained activation morphology. Our findings demonstrate the potential for TLR9-agonist CpG-oligo conjugates to enhance mAb-mediated clearance of Bb, and this approach might also enhance the activity of other anti-microbial mAbs.

Increased risk of osteoarthritis in patients with atopic disease.

OBJECTIVES: To determine the incidence of osteoarthrits (OA) in patients with atopic disease compared with matched non-exposed patients. METHODS: We conducted a retrospective cohort study with propensity score matching using claims data from Optum's de-identified Clinformatics Data Mart (CDM) (January 2003 to June 2019) and electronic health record data from the Stanford Research Repository (STARR) (January 2010 to December 2020). We included adult patients without pre-existing OA or inflammatory arthritis who were exposed to atopic disease or who were non-exposed. The primary outcome was the development of incident OA. RESULTS: In Optum CDM, we identified 117 346 exposed patients with asthma or atopic dermatitis (mean age 52 years; 60% female) and 1 247 196 non-exposed patients (mean age 50 years; 48% female). After propensity score matching (n=1 09 899 per group), OA incidence was higher in patients with asthma or atopic dermatitis (26.9 per 1000 person-years) compared with non-exposed patients (19.1 per 1000 person-years), with an adjusted odds ratio (aOR) of 1.58 (95% CI 1.55 to 1.62) for developing OA. This effect was even more pronounced in patients with both asthma and atopic dermatitis compared with non-exposed patients (aOR=2.15; 95% CI 1.93 to 2.39) and in patients with asthma compared with patients with chronic obstructive pulmonary disease (aOR=1.83; 95% CI 1.73 to 1.95). We replicated our results in an independent dataset (STARR), which provided the added richness of body mass index data. The aOR of developing OA in patients with asthma or atopic dermatitis versus non-exposed patients in STARR was 1.42 (95% CI 1.36 to 1.48). CONCLUSIONS: This study demonstrates an increased incidence of OA in patients with atopic disease. Future interventional studies may consider targeting allergic pathways for the prevention or treatment of OA.

Myeloablative autologous haematopoietic stem cell transplantation resets the B cell repertoire to a more naïve state in patients with systemic sclerosis.

OBJECTIVES: Myeloablative autologous haematopoietic stem cell transplant (HSCT) was recently demonstrated to provide significant benefit over cyclophosphamide (CYC) in the treatment of diffuse cutaneous systemic sclerosis (dcSSc) in the Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial. As dysregulation of the B cell compartment has previously been described in dcSSc, we sought to gain insight into the effects of myeloablative autologous HSCT as compared with CYC. METHODS: We sequenced the peripheral blood immunoglobulin heavy chain (IGH) repertoires in patients with dcSSc enrolled in the SCOT trial. RESULTS: Myeloablative autologous HSCT was associated with a sustained increase in IgM isotype antibodies bearing a low mutation rate. Clonal expression was reduced in IGH repertoires following myeloablative autologous HSCT. Additionally, we identified a underusage of immunoglobulin heavy chain V gene 5-51 in patients with dcSSc, and usage normalised following myeloablative autologous HSCT but not CYC treatment. CONCLUSIONS: Together, these findings suggest that myeloablative autologous HSCT resets the IGH repertoire to a more naïve state characterised by IgM-expressing B cells, providing a possible mechanism for the elimination of pathogenic B cells that may contribute to the benefit of HSCT over CYC in the treatment of dcSSc.

Benefits of Frequent HIV Testing in the THRIVE Demonstration Project: United States, 2015-2020.

Objectives. To describe HIV testing among clients in the Targeted Highly Effective Interventions to Reverse the HIV Epidemic (THRIVE) demonstration project and evaluate testing frequency. Methods. We identified factors associated with an average testing frequency of 180 days or less compared with more than 180 days using adjusted Poisson regression models. We performed the Kaplan-Meier survival analysis to compare time to diagnosis by testing frequency. Results. Among 5710 clients with 2 or more tests and no preexposure prophylaxis (PrEP) prescription, 42.4% were tested frequently. Black/African American clients were 21% less likely and Hispanic/Latino clients were 18% less likely to be tested frequently than were White clients. Among 71 Black/African American and Hispanic/Latino cisgender men who have sex with men and transgender women with HIV diagnoses, those with frequent testing had a median time to diagnosis of 137 days, with a diagnostic testing yield of 1.5% compared with those tested less frequently, with 559 days and 0.8% yield. Conclusions. HIV testing at least every 6 months resulted in earlier HIV diagnosis and was efficient. Persons in communities with high rates of HIV who are not on PrEP can benefit from frequent testing, and collaborative community approaches may help reduce disparities. (Am J Public Health. 2023;113(9):1019-1027. https://doi.org/10.2105/AJPH.2023.307341).

Total Synthesis of Neuroprotective Agents, (+)-Lycibarbarine A and (-)-Lycibarbarine B.

We describe the convergent total syntheses of lycibarbarines A and B which are potent neuroprotective agents recently isolated from the fruits of Lycium barbarum. The synthesis highlights the construction of a unique spiro oxazine heterocyclic motif imbedded in these natural products. The synthesis is accomplished from the commercially available 8-hydroxyquinaline and 2-deoxy-d-ribose as key starting materials. The synthesis features a Reimer-Tiemann reaction, selective amine alkylation with a keto tosylate derivative, and spiroketalization to form an oxazine core.

Examining Pre-Release Interventions on HIV Outcomes 12 Months After Release from Louisiana State Corrections.

Louisiana has the highest proportion of people living with HIV (PLWH) in state prison custody. Linkage to care programs minimize odds of HIV care drop-off after release. Louisiana has two pre-release linkage to HIV care programs, one implemented through Louisiana Medicaid and another through the Office of Public Health. We conducted a retrospective cohort study of PLWH released from Louisiana corrections from January 1, 2017 to December 31, 2019. We compared HIV care continuum outcomes within 12 months after release between intervention groups (received any vs. no intervention) using two proportion z-tests and multivariable logistic regression. Of 681 people, 389 (57.1%) were not released from a state prison facility and thus not eligible to receive interventions, 252 (37%) received any intervention, and 228 (33.5%) achieved viral suppression. Linkage to care within 30 days was significantly higher in people who received any intervention (v. no intervention, p = .0142). Receiving any intervention was associated with higher odds of attaining all continuum steps, though only significantly for linkage to care (AOR = 1.592, p = .0083). We also found differences in outcomes by sex, race, age, urbanicity of the return parish (county), and Medicaid enrollment between intervention groups. Receiving any intervention increased the odds of achieving HIV care outcomes, and was significantly impactful at improving care linkage. Interventions must be improved to enhance long-term post-release HIV care continuity and eliminate disparities in care outcomes.

Interpersonal Firearm Injury and Death in Portland, Oregon: 2018 Through 2021.

The annual number of firearm injuries in Portland, Oregon has been higher in the years since 2020 than in any prior year in the city's history. This descriptive study analyzed data from Gun Violence Archives (GVA) from January 1, 2018, to December 31, 2021. All incidents in GVA of interpersonal firearm injury that occurred in Portland during this period were analyzed for location, number of people injured or killed, and demographic information for those injured or killed. Comparisons in firearm injury rates were made with Seattle and San Francisco. Interpersonal firearm injuries began to rise after the first COVID-19 case in Oregon; July 2020 had the most injuries in the four-year period. Black men suffered the highest rate of interpersonal fatalities, with more than 11-fold higher rate per 100,000 than White men in every year studied. Portland had a higher rate of total interpersonal firearm injuries and a higher rate of firearm fatalities from 2018 through 2021 compared to Seattle and San Francisco. Neighborhoods near Downtown and those on the Eastside of the city had the highest rates of interpersonal injuries and deaths from firearms, whereas those in the Southwest had the lowest. Defining the burden of disease from interpersonal firearm injuries is a fundamental step in designing future public health research and implementing interventions to curb the trauma brought by interpersonal firearm injury.