mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant.

Recent surveillance has revealed the emergence of the SARS-CoV-2 Omicron variant (BA.1/B.1.1.529) harboring up to 36 mutations in spike protein, the target of neutralizing antibodies. Given its potential to escape vaccine-induced humoral immunity, we measured the neutralization potency of sera from 88 mRNA-1273, 111 BNT162b, and 40 Ad26.COV2.S vaccine recipients against wild-type, Delta, and Omicron SARS-CoV-2 pseudoviruses. We included individuals that received their primary series recently (<3 months), distantly (6-12 months), or an additional "booster" dose, while accounting for prior SARS-CoV-2 infection. Remarkably, neutralization of Omicron was undetectable in most vaccinees. However, individuals boosted with mRNA vaccines exhibited potent neutralization of Omicron, only 4-6-fold lower than wild type, suggesting enhanced cross-reactivity of neutralizing antibody responses. In addition, we find that Omicron pseudovirus infects more efficiently than other variants tested. Overall, this study highlights the importance of additional mRNA doses to broaden neutralizing antibody responses against highly divergent SARS-CoV-2 variants.

Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity.

Vaccination elicits immune responses capable of potently neutralizing SARS-CoV-2. However, ongoing surveillance has revealed the emergence of variants harboring mutations in spike, the main target of neutralizing antibodies. To understand the impact of these variants, we evaluated the neutralization potency of 99 individuals that received one or two doses of either BNT162b2 or mRNA-1273 vaccines against pseudoviruses representing 10 globally circulating strains of SARS-CoV-2. Five of the 10 pseudoviruses, harboring receptor-binding domain mutations, including K417N/T, E484K, and N501Y, were highly resistant to neutralization. Cross-neutralization of B.1.351 variants was comparable to SARS-CoV and bat-derived WIV1-CoV, suggesting that a relatively small number of mutations can mediate potent escape from vaccine responses. While the clinical impact of neutralization resistance remains uncertain, these results highlight the potential for variants to escape from neutralizing humoral immunity and emphasize the need to develop broadly protective interventions against the evolving pandemic.

Temporal memory for threatening events encoded in a haunted house.

Despite the salient experience of encoding threatening events, these memories are prone to distortions and often non-veridical from encoding to recall. Further, threat has been shown to preferentially disrupt the binding of event details and enhance goal-relevant information. While extensive work has characterised distinctive features of emotional memory, research has not fully explored the influence threat has on temporal memory, a process putatively supported by the binding of event details into a temporal context. Two primary competing hypotheses have been proposed; that threat can impair or enhance temporal memory. We analysed two datasets to assess temporal memory for an in-person haunted house experience. In study 1, we examined the temporal structure of memory by characterising memory contiguity in free recall as a function of individual levels of heart rate as a proxy of threat. In study 2, we replicated marginal findings of threat-related increases in memory contiguity found in study 1. We extended these findings by showing threat-related increases in recency discriminations, an explicit test of temporal memory. Together, these findings demonstrate that threat enhances temporal memory regarding free recall structure and during explicit memory judgments.

Hippocampal Threat Reactivity Interacts with Physiological Arousal to Predict PTSD Symptoms.

Hippocampal impairments are reliably associated with post-traumatic stress disorder (PTSD); however, little research has characterized how increased threat-sensitivity may interact with arousal responses to alter hippocampal reactivity, and further how these interactions relate to the sequelae of trauma-related symptoms. In a sample of individuals recently exposed to trauma (N=116, 76 Female), we found that PTSD symptoms at 2-weeks were associated with decreased hippocampal responses to threat as assessed with functional magnetic resonance imaging (fMRI). Further, the relationship between hippocampal threat sensitivity and PTSD symptomology only emerged in individuals who showed transient, high threat-related arousal, as assayed by an independently collected measure of Fear Potentiated Startle. Collectively, our finding suggests that development of PTSD is associated with threat-related decreases in hippocampal function, due to increases in fear-potentiated arousal.Significance StatementAlterations in hippocampal function linked to threat-related arousal are reliably associated with post-traumatic stress disorder (PTSD); however, how these alterations relate to the sequelae of trauma-related symptoms is unknown. Prior models based on non-trauma samples suggest that arousal may impact hippocampal neurophysiology leading to maladaptive behavior. Here we show that decreased hippocampal threat sensitivity interacts with fear-potentiated startle to predict PTSD symptoms. Specifically, individuals with high fear-potentiated startle and low, transient hippocampal threat sensitivity showed the greatest PTSD symptomology. These findings bridge literatures of threat-related arousal and hippocampal function to better understand PTSD risk.

Differential Severe Acute Respiratory Syndrome Coronavirus 2 Antibody Profiles After Allergic Reactions to Messenger RNA Coronavirus Disease 2019 Vaccine.

Allergic symptoms after messenger RNA (mRNA) coronavirus disease 2019 (COVID-19) vaccines occur in up to 2% of recipients. Compared to nonallergic controls (n = 18), individuals with immediate allergic reactions to mRNA COVID-19 vaccines (n = 8) mounted lower immunoglobulin G1 (IgG1) to multiple antigenic targets in severe acute respiratory syndrome coronavirus 2 spike following vaccination, with significantly lower IgG1 to full-length spike (P = .04). Individuals with immediate allergic reactions to mRNA COVID-19 vaccines bound Fcγ receptors similarly to nonallergic controls. Although there was a trend toward an overall reduction in opsonophagocytic function in individuals with immediate allergic reactions compared to nonallergic controls, allergic patients produced functional antibodies exhibiting a high ratio of opsonophagocytic function to IgG1 titer.

Comparative Immunogenicity and Effectiveness of mRNA-1273, BNT162b2, and Ad26.COV2.S COVID-19 Vaccines.

BACKGROUND: Understanding immunogenicity and effectiveness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines is critical to guide rational use. METHODS: We compared the immunogenicity of mRNA-1273, BNT-162b2, and Ad26.COV2.S in healthy ambulatory adults. We performed an inverse-variance meta-analysis of population-level effectiveness from public health reports in > 40 million individuals. RESULTS: A single dose of either mRNA vaccine yielded comparable antibody and neutralization titers to convalescent individuals. Ad26.COV2.S yielded lower antibody concentrations and frequently undetectable neutralization titers. Bulk and cytotoxic T-cell responses were higher in mRNA1273 and BNT162b2 than Ad26.COV2.S recipients. Regardless of vaccine, <50% of vaccinees demonstrated CD8+ T-cell responses. Antibody concentrations and neutralization titers increased comparably after the first dose of either vaccine, and further in recipients of a second dose. Prior infection was associated with high antibody concentrations and neutralization even after a single dose and regardless of vaccine. Neutralization of Beta, Gamma, and Delta strains were poorer regardless of vaccine. In meta-analysis, relative to mRNA1273 the effectiveness of BNT162b2 was lower against infection and hospitalization, and Ad26COV2.S was lower against infection, hospitalization, and death. CONCLUSIONS: Variation in the immunogenicity correlates with variable effectiveness of the 3 vaccines deployed in the United States.

Silk Fibroin as a Functional Biomaterial for Tissue Engineering.

Tissue engineering (TE) is the approach to combine cells with scaffold materials and appropriate growth factors to regenerate or replace damaged or degenerated tissue or organs. The scaffold material as a template for tissue formation plays the most important role in TE. Among scaffold materials, silk fibroin (SF), a natural protein with outstanding mechanical properties, biodegradability, biocompatibility, and bioresorbability has attracted significant attention for TE applications. SF is commonly dissolved into an aqueous solution and can be easily reconstructed into different material formats, including films, mats, hydrogels, and sponges via various fabrication techniques. These include spin coating, electrospinning, freeze drying, physical, and chemical crosslinking techniques. Furthermore, to facilitate fabrication of more complex SF-based scaffolds with high precision techniques including micro-patterning and bio-printing have recently been explored. This review introduces the physicochemical and mechanical properties of SF and looks into a range of SF-based scaffolds that have been recently developed. The typical TE applications of SF-based scaffolds including bone, cartilage, ligament, tendon, skin, wound healing, and tympanic membrane, will be highlighted and discussed, followed by future prospects and challenges needing to be addressed.

Amygdala and ventral tegmental area differentially interact with hippocampus and cortical medial temporal lobe during rest in humans.

Neuromodulatory regions that detect salience, such as amygdala and ventral tegmental area (VTA), have distinct effects on memory. Yet, questions remain about how these modulatory regions target subregions across the hippocampus and medial temporal lobe (MTL) cortex. Here, we sought to characterize how VTA and amygdala subregions (i.e., basolateral amygdala and central-medial amygdala) interact with hippocampus head, body, and tail, as well as cortical MTL areas of perirhinal cortex and parahippocampal cortex in a task-free state. To quantify these interactions, we used high-resolution resting state fMRI and characterized pair-wise, partial correlations across regions-of-interest. We found that basolateral amygdala showed greater functional coupling with hippocampus head, hippocampus tail, and perirhinal cortex when compared to either VTA or central-medial amygdala. Furthermore, the VTA showed greater functional coupling with hippocampus tail when compared to central-medial amygdala. There were no significant differences in functional coupling with hippocampus body and parahippocampal cortex. These results support a framework by which neuromodulatory regions do not indiscriminately influence all MTL subregions equally, but rather bias information processing to discrete MTL targets. These findings provide a more specified model of the intrinsic properties of systems underlying MTL neuromodulation. This emphasizes the need to consider heterogeneity both across and within neuromodulatory systems to better understand affective memory.

Symbiont-mediated protection varies with wasp genotype in the Drosophila melanogaster-Spiroplasma interaction.

The ability of an insect to survive attack by natural enemies can be modulated by the presence of defensive symbionts. Study of aphid-symbiont-enemy interactions has indicated that protection may depend on the interplay of symbiont, host and attacking parasite genotypes. However, the importance of these interactions is poorly understood outside of this model system. Here, we study interactions within a Drosophila model system, in which Spiroplasma protect their host against parasitoid wasps and nematodes. We examine whether the strength of protection conferred by Spiroplasma to its host, Drosophila melanogaster varies with strain of attacking Leptopilina heterotoma wasp. We perform this analysis in the presence and absence of ethanol, an environmental factor that also impacts the outcome of parasitism. We observed that Spiroplasma killed all strains of wasp. However, the protection produced by Spiroplasma following wasp attack depended on wasp strain. A composite measure of protection, including both the chance of the fly surviving attack and the relative fecundity/fertility of the survivors, varied from a <4% positive effect of the symbiont following attack of the fly host by the Lh14 strain of wasp to 21% for the Lh-Fr strain in the absence of ethanol. We also observed that environmental ethanol altered the pattern of protection against wasp strains. These data indicate that the dynamics of the Spiroplasma-Drosophila-wasp tripartite interaction depend upon the genetic diversity within the attacking wasp population, and that prediction of symbiont dynamics in natural systems will thus require analysis across natural enemy genotypes and levels of environmental ethanol.

The effect of talc particles on phagocytes in co-culture with ovarian cancer cells.

Talc and titanium dioxide are naturally occurring water-insoluble mined products usually available in the form of particulate matter. This study was prompted by epidemiological observations suggesting that perineal use of talc powder is associated with increased risk of ovarian cancer, particularly in a milieu with higher estrogen. We aimed to test the effects of talc vs. control particles on the ability of prototypical macrophage cell lines to curb the growth of ovarian cancer cells in culture in the presence of estrogen. We found that murine ovarian surface epithelial cells (MOSEC), a prototype of certain forms of ovarian cancer, were present in larger numbers after co-culture with macrophages treated to a combination of talc and estradiol than to either agent alone or vehicle. Control particles (titanium dioxide, concentrated urban air particulates or diesel exhaust particles) did not have this effect. Co-exposure of macrophages to talc and estradiol has led to increased production of reactive oxygen species and changes in expression of macrophage genes pertinent in cancer development and immunosurveillance. These findings suggest that in vitro exposure to talc, particularly in a high-estrogen environment, may compromise immunosurveillance functions of macrophages and prompt further studies to elucidate this mechanism.

Clinical and economic burden of colorectal and bariatric anastomotic leaks.

BACKGROUND: Anastomotic leaks cause a significant clinical and economic burden on patients undergoing bariatric and colorectal surgeries. Current literature shows a wide variation in incidence of anastomotic leaks and a significant gap in associated economic metrics. This analysis utilized claims data to quantify the full episode-of-care cost burden of leaks following colorectal and bariatric surgeries. METHODS: Medicare Fee-for-Service and commercial claims data from a large U.S.-based health plan were queried for cost and utilization of members that underwent bariatric and colorectal surgical procedures between January 1, 2013 and August 31, 2015. Outcomes were collected for members with anastomotic leaks versus those without leaks during the initial hospital stay (index) and within 30 days of the procedure. These outcomes included leak frequency, payer reimbursement, and length of stay (LOS). RESULTS: The colorectal Medicare analysis identified 239,350 patients undergoing colorectal surgery. For patients with a leak compared to those without, index admission costs were $30,670 greater ($48,982 vs. $18,312; p < 0.0001) and the index LOS was 12 days longer (19 vs. 7 days; p < 0.0001). This finding was similar for the bariatric patients (n = 62,292) where cost was $30,885 higher ($43,918 vs. $13,033; p < 0.0001) and LOS was 15 days longer (17 vs. 2 days; p < 0.0001). Furthermore, readmissions and associated costs were also substantially higher for those with an index leak. The commercial analysis of both the bariatric and colorectal populations trended similarly to the Medicare population in regards to all outcomes measured. CONCLUSION: Patients experiencing anastomotic leaks during and after bariatric and colorectal surgery have significantly higher costs and longer LOS both at the initial stay and within 30 days of the procedure. It is important that providers and hospitals understand the economic consequences of these procedures and implement technologies and techniques to prevent/reduce anastomotic leaks.

Reactive Inkjet Printing of Functional Silk Stirrers for Enhanced Mixing and Sensing.

Stirring small volumes of solution can reduce immunoassay readout time, homogenize cell cultures, and increase enzyme reactivity in bioreactors. However, at present many small scale stirring methods require external actuation, which can be cumbersome. To address this, here, reactive inkjet printing is shown to be able to produce autonomously rotating biocompatible silk-based microstirrers that can enhance fluid mixing. Rotary motion is generated either by release of a surface active agent (small molecular polyethylene glycol) resulting in Marangoni effect, or by catalytically powered bubble propulsion. The Marangoni driven devices do not require any chemicals to be added to the fluid as the "fuel," while the catalytically powered devices are powered by decomposing substrate molecules in solution. A comparison of Marangoni effect and enzyme powered stirrers is made. Marangoni effect driven stirrers rotate up to 600 rpm, 75-100-fold faster than enzyme driven microstirrers, however enzyme powered stirrers show increased longevity. Further to stirring applications, the sensitivity of the motion generation mechanisms to fluid properties allows the rotating devices to also be exploited for sensing applications, for example, acting as motion sensors for water pollution.

Catalytic Janus Colloids: Controlling Trajectories of Chemical Microswimmers.

Catalytic Janus colloids produce rapid motion in fluids by decomposing dissolved fuel. There is great potential to exploit these "autonomous chemical swimmers" in applications currently performed by diffusion limited passive colloids. Key application areas for colloids include transporting active ingredients for drug delivery, gathering analytes for medical diagnostics, and self-assembling into regular structures used for photonic materials and lithographic templating. For drug delivery and medical diagnostics, controlling colloidal motion is key in order to target therapies, and transport analytes through lab-on-a-chip devices. Here, the autonomous motion of catalytic Janus colloids can remove the current requirements to induce and control colloid motion using external fields, thereby reducing the technological complexity required for medical therapies and diagnostics. For materials applications exploiting colloidal self-assembly, the additional interactions introduced by catalytic activity and rapid motion are predicted to allow access to new reconfigurable and responsive structures. In order to realize these goals, it is vital to develop methods to control both individual colloidal paths and collective behavior in motile catalytic colloidal systems. However, catalytic Janus colloids' trajectories are randomized by Brownian effects, and so require new strategies in order to be harnessed for transport. This is achievable using a variety of different approaches. For example, self-assembly and control of catalyst geometry can introduce controlled amounts of rotary motion, or "spin" into chemical swimmer trajectories. Furthermore, rotary motion combined with gravity, produces well-defined orientated helical trajectories. In addition, when catalytic colloids interact with topographical features, such as edges and trenches, they are steered. This gives rise to a new approach for autonomous colloidal microfluidic transport that could be deployed in future lab-on-a-chip devices. Chemical gradients can also influence the motion of catalytic Janus colloids, for example, to cause collective accumulations at specific locations. However, at present, the predicted theoretical degree of control over this phenomenon has not been fully verified in experimental systems. Collective behavior control for chemical swimmers is also possible by exploiting the potential for the complex interactions in these systems to allow access to self-assembled, dynamic and reconfigurable ordered structures. Again, current experiments have not yet accessed the breadth of possible behavior. Consequently, continued efforts are required to understand and control these interaction mechanisms in real world systems. Ultimately, this will help realize the use of catalytic Janus colloids for tasks that require well-controlled motion and structural organization, enabling functions such as analyte capture and concentration, or targeted drug delivery.

Identification of Foreign Particles in Human Tissues Using Raman Microscopy.

The goal of this study was to precisely and unambiguously identify foreign particles in human tissues using a combination of polarized light microscopy and Raman microscopy, which provides chemical composition and microstructural characterization of complex materials with submicrometer spatial resolution. This identification for patient care and research has been traditionally studied using polarized light microscopy, electron microscopy with X-ray analysis, and electron diffraction, all with some limitations. We designed a model system of stained and unstained cells that contained birefringent talc particles and systematically investigated the influence of slide and coverslip materials, laser wavelengths, and mounting media on the Raman spectra obtained. Hematoxylin and eosin stained slides did not produce useful results because of fluorescence interference from the stains. Unstained cell samples prepared with standard slides and coverslips produce high quality Raman spectra when excited at 532 nm; the spectra are uniquely assigned to talc. We also obtain high quality Raman spectra specific for talc in unstained tissue samples (pleural tissue following talc pleurodesis and ovarian tissue following long-term perineal talc exposure). Raman microscopy is sufficiently sensitive and compositionally selective to identify particles as small as one micrometer in diameter. Raman spectra have been catalogued for thousands of substances, which suggests that this approach is likely to be successful in identifying other particles of interest in tissues, potentially making Raman microscopy a powerful new tool in pathology.

Pheno4J: a gene to phenotype graph database.

SUMMARY: Efficient storage and querying of large amounts of genetic and phenotypic data is crucial to contemporary clinical genetic research. This introduces computational challenges for classical relational databases, due to the sparsity and sheer volume of the data. Our Java based solution loads annotated genetic variants and well phenotyped patients into a graph database to allow fast efficient storage and querying of large volumes of structured genetic and phenotypic data. This abstracts technical problems away and lets researchers focus on the science rather than the implementation. We have also developed an accompanying webserver with end-points to facilitate querying of the database. AVAILABILITY AND IMPLEMENTATION: The Java and Python code are available at https://github.com/phenopolis/pheno4j. CONTACT: n.pontikos@ucl.ac.uk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Phenopolis: an open platform for harmonization and analysis of genetic and phenotypic data.

SUMMARY: Phenopolis is an open-source web server providing an intuitive interface to genetic and phenotypic databases. It integrates analysis tools such as variant filtering and gene prioritization based on phenotype. The Phenopolis platform will accelerate clinical diagnosis, gene discovery and encourage wider adoption of the Human Phenotype Ontology in the study of rare genetic diseases. AVAILABILITY AND IMPLEMENTATION: A demo of the website is available at https://phenopolis.github.io . If you wish to install a local copy, source code and installation instruction are available at https://github.com/phenopolis . The software is implemented using Python, MongoDB, HTML/Javascript and various bash shell scripts. CONTACT: n.pontikos@ucl.ac.uk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Symmetrical Catalytically Active Colloids Collectively Induce Convective Flow.

Although much attention has focused on self-motile asymmetrical catalytically active "Janus" colloids as a route to enable new fluidic transport applications, the motion of symmetrical catalytically active colloids is less investigated. This is despite isotropically active colloids being more accessible and commonly used as supports for heterogeneous catalysis. Here, we addressed this by systematically investigating the motion of platinum-coated colloids capable of isotropically decomposing hydrogen peroxide. We observed the onset of collective convective flow as the colloidal volume fraction increased above a threshold. The ballistic velocities induced by the collective flow were quantified by particle tracking and were found to increase with the volume fraction. We also determined the associated increase in the Péclet number as evidence of the potential to use convection as a simple method to enhance mass transport rates. By determining the persistence lengths, we were able to correlate the magnitude of convective flow with the overall catalytic activity per unit volume. This suggests that the mechanism for the collective flow is driven by chemical activity-induced local density differences. Finally, we discussed these results in the context of potential new fluidic applications and highlighted the role that activity-induced convection may play in experiments designed to investigate self-motile catalytic systems.

The Pregnant Patient: Managing Common Acute Medical Problems.

Women often see their primary care physicians for common acute conditions during pregnancy. These conditions may be caused by pregnancy (obstetric problems) or worsened by pregnancy (obstetrically aggravated problems), or they may require special consideration during pregnancy because of maternal or fetal risks (nonobstetric problems). Primary care physicians should know the differential diagnosis for common conditions during pregnancy and recognize the important findings of obstetric and urgent nonobstetric problems. The family physician can evaluate and treat most nonobstetric problems, although obstetric problems require referral to a primary maternity care clinician. A tiered approach, including routinely looking for all-cause red flag symptoms and signs, while remaining aware of estimated gestational age, allows for high-quality care and shared decision making between the family physician and the pregnant patient. When treating common causes of nausea and epigastric pain/gastroesophageal reflux, lifestyle modifications are considered the safest and first-choice therapy, followed by well-established low-risk therapies, such as vitamin B6 (pyridoxine) and doxylamine for nausea, and antacids not containing salicylates (found in bismuth combination products) for gastroesophageal reflux. Other common conditions during pregnancy are best treated with low-risk therapies, such as using antihistamines or topical steroids for rashes, first-generation cephalosporins or amoxicillin for cystitis, and physical therapy and acetaminophen for low back pain and headaches.

Functional Validation of ABCA3 as a Miltefosine Transporter in Human Macrophages: IMPACT ON INTRACELLULAR SURVIVAL OF LEISHMANIA (VIANNIA) PANAMENSIS.

Within its mammalian host, Leishmania resides and replicates as an intracellular parasite. The direct activity of antileishmanials must therefore depend on intracellular drug transport, metabolism, and accumulation within the host cell. In this study, we explored the role of human macrophage transporters in the intracellular accumulation and antileishmanial activity of miltefosine (MLF), the only oral drug available for the treatment of visceral and cutaneous leishmaniasis (CL). Membrane transporter gene expression in primary human macrophages infected in vitro with Leishmania Viannia panamensis and exposed to MLF showed modulation of ABC and solute liquid carrier transporters gene transcripts. Among these, ABCA3, a lipid transporter, was significantly induced after exposure to MLF, and this induction was confirmed in primary macrophages from CL patients. Functional validation of MLF as a substrate for ABCA3 was performed by shRNA gene knockdown (KD) in THP-1 monocytes. Intracellular accumulation of radiolabeled MLF was significantly higher in ABCA3(KD) macrophages. ABCA3(KD) resulted in increased cytotoxicity induced by MLF exposure. ABCA3 gene expression inversely correlated with intracellular MLF content in primary macrophages from CL patients. ABCA3(KD) reduced parasite survival during macrophage infection with an L. V. panamensis strain exhibiting low in vitro susceptibility to MLF. Confocal microscopy showed ABCA3 to be located in the cell membrane of resting macrophages and in intracellular compartments in L. V. panamensis-infected cells. These results provide evidence of ABCA3 as an MLF efflux transporter in human macrophages and support its role in the direct antileishmanial effect of this alkylphosphocholine drug.