Proinflammatory IgG Fc structures in patients with severe COVID-19.

Severe acute respiratory syndrome coronavirus 2 infections can cause coronavirus disease 2019 (COVID-19), which manifests with a range of severities from mild illness to life-threatening pneumonia and multi-organ failure. Severe COVID-19 is characterized by an inflammatory signature, including high levels of inflammatory cytokines, alveolar inflammatory infiltrates and vascular microthrombi. Here we show that patients with severe COVID-19 produced a unique serologic signature, including an increased likelihood of IgG1 with afucosylated Fc glycans. This Fc modification on severe acute respiratory syndrome coronavirus 2 IgGs enhanced interactions with the activating Fcγ receptor FcγRIIIa; when incorporated into immune complexes, Fc afucosylation enhanced production of inflammatory cytokines by monocytes, including interleukin-6 and tumor necrosis factor. These results show that disease severity in COVID-19 correlates with the presence of proinflammatory IgG Fc structures, including afucosylated IgG1.

Spheromers reveal robust T cell responses to the Pfizer/BioNTech vaccine and attenuated peripheral CD8+ T cell responses post SARS-CoV-2 infection.

T cells are a critical component of the response to SARS-CoV-2, but their kinetics after infection and vaccination are insufficiently understood. Using "spheromer" peptide-MHC multimer reagents, we analyzed healthy subjects receiving two doses of the Pfizer/BioNTech BNT162b2 vaccine. Vaccination resulted in robust spike-specific T cell responses for the dominant CD4+ (HLA-DRB1∗15:01/S191) and CD8+ (HLA-A∗02/S691) T cell epitopes. Antigen-specific CD4+ and CD8+ T cell responses were asynchronous, with the peak CD4+ T cell responses occurring 1 week post the second vaccination (boost), whereas CD8+ T cells peaked 2 weeks later. These peripheral T cell responses were elevated compared with COVID-19 patients. We also found that previous SARS-CoV-2 infection resulted in decreased CD8+ T cell activation and expansion, suggesting that previous infection can influence the T cell response to vaccination.

Illuminating the Fc dependence of SARS-CoV-2 neutralization.

Monoclonal antibodies show efficacy in treating COVID-19, but the functional requirements for protection are unclear. In this issue of Immunity, Ullah et al. (2021) develop a stable SARS-CoV-2 reporter virus and use bioluminescence imaging to longitudinally monitor infection and assess neutralizing monoclonal antibody interventions in mice. They find that antibody-mediated protection depends on the Fc domain and Fc-gamma receptor-expressing immune cells.

Heterogeneity in IgG-CD16 signaling in infectious disease outcomes.

In this review, we discuss how IgG antibodies can modulate inflammatory signaling during viral infections with a focus on CD16a-mediated functions. We describe the structural heterogeneity of IgG antibody ligands, including subclass and glycosylation that impact binding by and downstream activity of CD16a, as well as the heterogeneity of CD16a itself, including allele and expression density. While inflammation is a mechanism required for immune homeostasis and resolution of acute infections, we focus here on two infectious diseases that are driven by pathogenic inflammatory responses during infection. Specifically, we review and discuss the evolving body of literature showing that afucosylated IgG immune complex signaling through CD16a contributes to the overwhelming inflammatory response that is central to the pathogenesis of severe forms of dengue disease and coronavirus disease 2019 (COVID-19).

Accuracy, transferability, and computational efficiency of interatomic potentials for simulations of carbon under extreme conditions.

Large-scale atomistic molecular dynamics (MD) simulations provide an exceptional opportunity to advance the fundamental understanding of carbon under extreme conditions of high pressures and temperatures. However, the fidelity of these simulations depends heavily on the accuracy of classical interatomic potentials governing the dynamics of many-atom systems. This study critically assesses several popular empirical potentials for carbon, as well as machine learning interatomic potentials (MLIPs), in their ability to simulate a range of physical properties at high pressures and temperatures, including the diamond equation of state, its melting line, shock Hugoniot, uniaxial compressions, and the structure of liquid carbon. Empirical potentials fail to accurately predict the behavior of carbon under high pressure-temperature conditions. In contrast, MLIPs demonstrate quantum accuracy, with Spectral Neighbor Analysis Potential (SNAP) and atomic cluster expansion (ACE) being the most accurate in reproducing the density functional theory results. ACE displays remarkable transferability despite not being specifically trained for extreme conditions. Furthermore, ACE and SNAP exhibit superior computational performance on graphics processing unit-based systems in billion atom MD simulations, with SNAP emerging as the fastest. In addition to offering practical guidance in selecting an interatomic potential with a fine balance of accuracy, transferability, and computational efficiency, this work also highlights transformative opportunities for groundbreaking scientific discoveries facilitated by quantum-accurate MD simulations with MLIPs on emerging exascale supercomputers.

Garnet sand reveals rock recycling processes in the youngest exhumed high- and ultrahigh-pressure terrane on Earth.

Rock recycling within the forearcs of subduction zones involves subduction of sediments and hydrated lithosphere into the upper mantle, exhumation of rocks to the surface, and erosion to form new sediment. The compositions of, and inclusions within detrital minerals revealed by electron microprobe analysis and Raman spectroscopy preserve petrogenetic clues that can be related to transit through the rock cycle. We report the discovery of the ultrahigh-pressure (UHP) indicator mineral coesite as inclusions in detrital garnet from a modern placer deposit in the actively exhuming Late Miocene-Recent high- and ultrahigh-pressure ((U)HP) metamorphic terrane of eastern Papua New Guinea. Garnet compositions indicate the coesite-bearing detrital garnets are sourced from felsic protoliths. Carbonate, graphite, and CO2 inclusions also provide observational constraints for geochemical cycling of carbon and volatiles during subduction. Additional discoveries include polyphase inclusions of metastable polymorphs of SiO2 (cristobalite) and K-feldspar (kokchetavite) that we interpret as rapidly cooled former melt inclusions. Application of elastic thermobarometry on coexisting quartz and zircon inclusions in six detrital garnets indicates elastic equilibration during exhumation at granulite and amphibolite facies conditions. The garnet placer deposit preserves a record of the complete rock cycle, operative on <10-My geologic timescales, including subduction of sedimentary protoliths to UHP conditions, rapid exhumation, surface uplift, and erosion. Detrital garnet geochemistry and inclusion suites from both modern sediments and stratigraphic sections can be used to decipher the petrologic evolution of plate boundary zones and reveal recycling processes throughout Earth's history.

Developing an Interactive Environment Through the Teaching of Mathematics with Small Robots.

The article is the product of the study "Development of innovative resources to improve logical-mathematical skills in primary school, through educational robotics", developed during the 2019 school year in three public schools in the province of Chiriquí, Republic of Panama. The teaching-learning process in students is influenced by aspects inside and outside the classroom, since not all schools have the necessary resources to deliver content or teaching material. The general objective of the project is to design, develop and implement educational robotics to improve logical-mathematical skills aimed at preschool and first grade students in public schools, using programmable educational robots. For this, a set of resources and activities were developed to improve the logical-mathematical skills of the initial stages, in public schools, obtaining significant results. Playful activities favor the teaching-learning process. Considering the analysis of the results made on the data obtained through the applied collection instruments, it can be argued that in general terms the values indicate that the students obtained a favorable level of performance in the different challenges proposed. The project has allowed the academic community to have an application of great value that allows teaching about the conservation of natural sites. The project only covers the area of mathematics in preschool and first grade.

The ENTPD1 promoter polymorphism -860 A > G (rs3814159) is associated with increased gene transcription, protein expression, CD39/NTPDase1 enzymatic activity, and thromboembolism risk.

Ectonucleoside triphosphate diphosphohydrolase 1 (NTPDase1) degrades the purines ATP and ADP that are key regulators of inflammation and clotting. We hypothesized that NTPDase1 polymorphisms exist and that they regulate this pathway. We sequenced the ENTPD1 gene (encoding NTPDase1) in 216 subjects then assessed genotypes in 2 cohorts comprising 2213 humans to identify ENTPD1 polymorphisms associated with venous thromboembolism (VTE). The G allele of the intron 1 polymorphism rs3176891 was more common in VTE vs. controls (odds ratio 1.26-1.9); it did not affect RNA splicing, but it was in strong linkage disequilibrium with the G allele of the promoter polymorphism rs3814159, which increased transcriptional activity by 8-fold. Oligonucleotides containing the G allele of this promoter region bound nuclear extracts more avidly. Carriers of rs3176891 G had endothelial cells with increased NTPDase1 activity and protein expression, and had platelets with enhanced aggregation. Thus, the G allele of rs3176891 marks a haplotype associated with increased clotting and platelet aggregation attributable to a promoter variant associated with increased transcription, expression, and activity of NTPDase1. We term this gain-of-function phenotype observed with rs3814159 G "CD39 Denver."-Maloney, J. P., Branchford, B. R., Brodsky, G. L., Cosmic, M. S., Calabrese, D. W., Aquilante, C. L., Maloney, K. W., Gonzalez, J. R., Zhang, W., Moreau, K. L., Wiggins, K. L., Smith, N. L., Broeckel, U., Di Paola, J. The ENTPD1 promoter polymorphism -860 A > G (rs3814159) is associated with increased gene transcription, protein expression, CD39/NTPDase1 enzymatic activity, and thromboembolism risk.

Novel phases and superconductivity of tin sulfide compounds.

Tin sulfides, Sn x S y , are an important class of materials that are actively investigated as novel photovoltaic and water splitting materials. A first-principles evolutionary crystal structure search is performed with the goal of constructing the complete phase diagram of Sn x S y and discovering new phases as well as new compounds of varying stoichiometry at ambient conditions and pressures up to 100 GPa. The ambient phase of SnS2 with P 3 ¯ m 1 symmetry remains stable up to 28 GPa. Another ambient phase, SnS, experiences a series of phase transformations including α-SnS to ß-SnS at 9 GPa, followed by ß-SnS to γ-SnS at 40 GPa. γ-SnS is a new high-pressure metallic phase with P m 3 ¯ m space group symmetry stable up to 100 GPa, which becomes a superconductor with a maximum T c = 9.74 K at 40 GPa. Another new metallic compound, Sn3S4 with I 4 ¯ 3 d space group symmetry, is predicted to be stable at pressures above 15 GPa, which also becomes a superconductor with relatively high T c = 21.9 K at 30 GPa.

Effect of allergic rhinitis on nasal obstruction outcomes after functional open septorhinoplasty.

OBJECTIVE: To evaluate whether a diagnosis of allergic rhinitis affects surgical outcomes of open septorhinoplasty (OSR) and to examine whether OSR provides the same level of improvement in quality of life to patients with and without allergic rhinitis. STUDY DESIGN, SETTING, SUBJECTS AND METHODS: We performed a retrospective evaluation of 646 patients who underwent open septorhinoplasty in a tertiary otolaryngology practice between 2008 and 2015. Preoperative and postoperative quality of life (QoL) measurement using the validated Nasal Obstruction Symptom Evaluation (NOSE) Scale was performed on 307 patients meeting inclusion criteria. These patients were then divided into two groups based on a diagnosis of allergic rhinitis (non-AR vs AR). Comparisons were then made based on quality of life improvements by the NOSE score. RESULTS: There were 213 patients in the non-AR group vs. 94 patients in the AR group. After OSR, patients in both groups experienced significant improvement in nasal airway obstruction. Pre-op NOSE score averages were similar for the non-AR and AR groups (69.9 vs 73.4 p = 0.087). Average improvement in NOSE score for the non-AR and AR groups at 30 days was 48.6 vs 45.9 (p = 0.41); and at 90 day of 48.1 vs 51.5 (p = 0.402). CONCLUSION: Patients with and without allergic rhinitis experience similar OSR outcomes as measured by the NOSE score. Open septorhinoplasty addresses multiple components contributing to nasal airway obstruction, and may offset the effects of allergic rhinitis. When indicated, it should be offered to patients with allergic rhinitis after complete medical management.

The Twisted Nose: What to Do When It's Not Straight.

Septorhinoplasty is among the most common facial plastic and reconstructive surgeries and its complexities are reflected in a relatively high revision rate. The patient with a postoperative twisted nose presents an additional challenge and requires that the surgeon display empathy and possess a deep knowledge of the aesthetic and functional intricacies of the nose. Correction of the twisted nose should be approached in a systematic fashion with unique considerations for each "third" of the nose. While there are many options in the overall surgical armamentarium, each surgeon will find specific techniques that are most efficacious and reproducible for their individual practice. This article discusses select surgical "pearls" and techniques that can aid the surgeon in their own surgical decision-making.

Competitive, substrate-dependent reductive debromination/dehydrobromination of 1,2-dibromides with triethylamine.

The interaction of various 1,2-dibromides with NEt3 under various conditions (THF and DMF, respectively) at different temperatures was investigated. Our results from these reactions show that substrate dependent dehydrobrominations compete with reductive debrominations. A comprehensive discussion of these competitive pathways is offered.

Convenient synthesis of phosphonohydrazines from arylamines.

Phosphonohydrazines were prepared in good yield from corresponding arylamines by a one-pot reaction through diazotization with an organic nitrite and treatment with a trialkyl phosphite. The trialkyl phosphite is postulated to function as a nucleophile as well as a reducing agent.

Th17 cells induce Th1-polarizing monocyte-derived dendritic cells.

In chronically inflamed tissues, such as those affected by autoimmune disease, activated Th cells often colocalize with monocytes. We investigate in this study how murine Th cells influence the phenotype and function of monocytes. The data demonstrate that Th1, Th2, and Th17 subsets promote the differentiation of autologous monocytes into MHC class II(+), CD11b(+), CD11c(+) DC that we call DCTh. Although all Th subsets induce the formation of DCTh, activated Th17 cells uniquely promote the formation of IL-12/IL-23-producing DCTh (DCTh17) that can polarize both naive and Th17 cells to a Th1 phenotype. In the inflamed CNS of mice with Th17-mediated experimental autoimmune encephalomyelitis, Th cells colocalize with DC, as well as monocytes, and the Th cells obtained from these lesions drive the formation of DCTh that are phenotypically indistinguishable from DCTh17 and polarize naive T cells toward a Th1 phenotype. These results suggest that DCTh17 are critical in the interplay of Th17- and Th1-mediated responses and may explain the previous finding that IL-17-secreting Th cells become IFN-γ-secreting Th1 cells in experimental autoimmune encephalomyelitis and other autoimmune disorders.

Investigating the behavior of diffusion models for accelerating electronic structure calculations.

We present an investigation of diffusion models for molecular generation, with the aim of better understanding how their predictions compare to the results of physics-based calculations. The investigation into these models is driven by their potential to significantly accelerate electronic structure calculations using machine learning, without requiring expensive first-principles datasets for training interatomic potentials. We find that the inference process of a popular diffusion model for de novo molecular generation is divided into an exploration phase, where the model chooses the atomic species, and a relaxation phase, where it adjusts the atomic coordinates to find a low-energy geometry. As training proceeds, we show that the model initially learns about the first-order structure of the potential energy surface, and then later learns about higher-order structure. We also find that the relaxation phase of the diffusion model can be re-purposed to sample the Boltzmann distribution over conformations and to carry out structure relaxations. For structure relaxations, the model finds geometries with ∼10× lower energy than those produced by a classical force field for small organic molecules. Initializing a density functional theory (DFT) relaxation at the diffusion-produced structures yields a >2× speedup to the DFT relaxation when compared to initializing at structures relaxed with a classical force field.

The genetic landscape of antibiotic sensitivity in Staphylococcus aureus.

Despite the critical importance of essential genes, systems-level investigations of their contribution to antibiotic sensitivity have been limited. Using CRISPR Adaptation-mediated Library Manufacturing (CALM), we generated ultra-dense CRISPR interference (CRISPRi) libraries in methicillin-sensitive and -resistant strains of Staphylococcus aureus, which allowed us to quantify gene fitness on a global scale across ten clinically relevant antibiotics. This led to the identification of a comprehensive set of known and novel biological processes modulating bacterial fitness in the antibiotics. Notably, we found that essential genes from diverse processes dominated antibiotic-gene interactions, including a large number of synergistic interactions between bactericidal antibiotics and processes such as cell wall synthesis/cell division (CC), DNA replication/DNA recombination (DD), protein export, and coenzyme A biosynthesis. Simultaneous genetic perturbations of diverse CC and DD processes aggravated bacterial fitness, revealing a widespread synergy between the two highly coordinated processes. In contrast, perturbation of transcriptional, translational, and select energy processes antagonized the effects of bactericidal antibiotics. Finally, we show that small molecule inhibitors recapitulated synergistic antibiotic-gene interactions, providing a rational foundation for developing novel combinatorial antimicrobial therapies.

Extreme Metastability of Diamond and its Transformation to the BC8 Post-Diamond Phase of Carbon.

Diamond possesses exceptional physical properties due to its remarkably strong carbon-carbon bonding, leading to significant resilience to structural transformations at very high pressures and temperatures. Despite several experimental attempts, synthesis and recovery of the theoretically predicted post-diamond BC8 phase remains elusive. Through quantum-accurate multimillion atom molecular dynamics (MD) simulations, we have uncovered the extreme metastability of diamond at very high pressures, significantly exceeding its range of thermodynamic stability. We predict the post-diamond BC8 phase to be experimentally accessible only within a narrow high pressure-temperature region of the carbon phase diagram. The diamond to BC8 transformation proceeds through premelting followed by BC8 nucleation and growth in the metastable carbon liquid. We propose a double-shock compression pathway for BC8 synthesis, which is currently being explored in experiments at the National Ignition Facility.

Cardiovascular Risk Factors and Echocardiographic Findings in a Predominantly Black Population with Rheumatoid Arthritis and Heart Failure.

Among White rheumatoid arthritis (RA) cohorts, heart failure with preserved ejection fraction (HFpEF) is the most prevalent type of heart failure (HF). We aimed to assess the type of HF affecting Black RA patients. 64 patients with RA-HF were compared to age-, sex-, and race-matched RA patients without HF. Left ventricular ejection fraction (LVEF), wall motion abnormalities, left ventricle (LV) mass, and wall thickness were reviewed. 87.3% were Black, 84.4% were women, with a mean age of 69.6 ± 1.38 (± SEM) and BMI (kg/m 2) 29.6 ± 1.07. RA-HF patients had higher rates of hypertension (HTN), chronic kidney disease, and atrial fibrillation. 66.7% had ≥3 cardiovascular risk factors compared to RA patients without HF. 2D-echocardiograms of RA-HF revealed that 62.3% had LVEF ≥50%, 37% had diastolic dysfunction, and 43.1% had wall motion abnormalities. LV mass and relative wall thickness measurements indicated LV eccentric remodeling. The odds ratio for HF was 4.7 (1.5-14.53 CI), p<0.01, among RA-HTN group and 3.5 (1.091-11.7 CI) p<0.01 among smokers. In our predominantly Black RA-HF patients, HFpEF was the most common type of HF. HTN was associated with the highest OR for HF. Eccentric hypertrophic remodeling, a known poor prognostic indicator for cardiovascular events, was found. Further studies are required to confirm our findings.

A Rare Case of a Panic Attack Inducing a Junctional Escape Rhythm on ECG.

We present a unique and rare case of a young female patient who presented with complaints typical of her prior panic attacks and was found to have a junctional escape rhythm on ECG. Upon resolution of her symptoms, a repeat ECG demonstrated a return to normal sinus rhythm. Given that alternative etiologies had been ruled out, it was postulated that her panic attack induced a transient junctional escape rhythm.

Rett-like Phenotypes in HNRNPH2-Related Neurodevelopmental Disorder.

Rett Syndrome (RTT) is a neurodevelopmental disorder with a prevalence of 1:10,000 to 15,000 females worldwide. Classic Rett Syndrome presents in early childhood with a period of developmental regression, loss of purposeful hand skills along with hand stereotypies, gait abnormalities, and loss of acquired speech. Atypical RTT is diagnosed when a child shows some but not all the phenotypes of classic RTT, along with additional supporting criteria. Over 95% of classic RTT cases are attributed to pathogenic variants in Methyl-CpG Binding Protein 2 (MECP2), though additional genes have been implicated in other RTT cases, particularly those with the atypical RTT clinical picture. Other genetic etiologies have emerged with similar clinical characteristics to RTT Syndrome. Our team has characterized HNRNPH2-related neurodevelopmental disorder (HNRNPH2-RNDD) in 33 individuals associated with de novo pathogenic missense variants in the X-linked HNRNPH2 gene, characterized by developmental delay, intellectual disability, seizures, autistic-like features, and motor abnormalities. We sought to further characterize RTT clinical features in this group of individuals by using caregiver report. Twenty-six caregivers completed electronic surveys, with only 3 individuals having previously received an atypical RTT diagnosis, and no individuals with a typical RTT diagnosis. Caregivers reported a high number of behaviors and/or phenotypes consistent with RTT, including the major criteria of the syndrome, such as regression of developmental skills and abnormal gait. Based on the survey results, 12 individuals could meet the diagnostic clinical criteria for atypical RTT Syndrome. In summary, individuals with HNRNPH2-RNDD exhibit clinical characteristics that overlap with those of RTT, and therefore, HNRNPH2-RNDD, should be considered on the differential diagnosis list with this clinical picture.