Molecular signatures of antibody responses derived from a systems biology study of five human vaccines.

Many vaccines induce protective immunity via antibodies. Systems biology approaches have been used to determine signatures that can be used to predict vaccine-induced immunity in humans, but whether there is a 'universal signature' that can be used to predict antibody responses to any vaccine is unknown. Here we did systems analyses of immune responses to the polysaccharide and conjugate vaccines against meningococcus in healthy adults, in the broader context of published studies of vaccines against yellow fever virus and influenza virus. To achieve this, we did a large-scale network integration of publicly available human blood transcriptomes and systems-scale databases in specific biological contexts and deduced a set of transcription modules in blood. Those modules revealed distinct transcriptional signatures of antibody responses to different classes of vaccines, which provided key insights into primary viral, protein recall and anti-polysaccharide responses. Our results elucidate the early transcriptional programs that orchestrate vaccine immunity in humans and demonstrate the power of integrative network modeling.

Structure Elucidation Using Gas Chromatography-Infrared Spectroscopy/Mass Spectrometry Supported by Quantum Chemical IR Spectrum Simulations.

An improved strategy for compound identification incorporating gas chromatography hyphenated with Fourier transform infrared spectroscopy and mass spectroscopy (GC-FTIR/MS) is reported. (Over)reliance on MS may lead either to ambiguous identity or to incorrect identification of a compound. However, the MS result is useful to provide a cohort of possible compounds. The IR result for each tentative compound match was then simulated using molecular modeling, to provide functional group and isomer differentiation information, and then compared with the experimental FTIR result, offering identification based on both MS and IR. Several basis sets were evaluated for IR simulations; Def2-TZVPP was a suitable basis set and correlated well with experimental data. The approach was applied to industrial applications, confirming the isomers of 2,3-bis(thiosulfanyl)-but-2-enedinitrile, bromination products of 1-bromo-2,3-dimethylbenzene, and autoxidative degradation of phenyl-di-tert-butylphosphine.

Determining the Regiochemistry and Relative Stereochemistry of Small and Druglike Molecules Using an Alignment Algorithm for Infrared Spectra.

The relative stereochemistry and isomeric substitution pattern of organic molecules is typically determined using nuclear magnetic resonance spectroscopy (NMR). However, NMR spectra are sometimes nonconclusive, e.g., if spectra are extremely crowded, coupling patterns are not resolved, or if symmetry reasons preclude interpretation. Infrared spectroscopy (IR) can provide additional information in such cases, because IR represents a molecule comprehensively by depiction of the complete set of its normal vibrations. The challenge is thereby that diastereomers and substitution isomers often give rise to highly similar IR spectra, and visual distinction is insufficient and may be biased. Here we show the adaptation of an alignment algorithm, originally developed for vibrational circular dichroism (VCD) spectroscopy, to automatically match IR spectra and provide a quantitative measure of the goodness of fit, which can be used to distinguish isomers. The performance of the approach is demonstrated for different use cases: diastereomers of flexible druglike molecules, E/Z-isomers, and substitution isomers of pyrazine and naphthalene. It can be applied to IR spectra measured both in the gas phase (gas chromatography IR) and in solution.

Hurricane Evacuation Laws in Eight Southern U.S. Coastal States - December 2018.

National Preparedness month is observed every September as a public service reminder of the importance of personal and community preparedness for all events; it coincides with the peak of the hurricane season in the United States. Severe storms and hurricanes can have long-lasting effects at all community levels. Persons who are prepared and well-informed are often better able to protect themselves and others (1). Major hurricanes can devastate low-lying coastal areas and cause injury and loss of life from storm surge, flooding, and high winds (2). State and local government entities play a significant role in preparing communities for hurricanes and by evacuating coastal communities before landfall to reduce loss of life from flooding, wind, and power outages (3). Laws can further improve planning and outreach for catastrophic events by ensuring explicit statutory authority over evacuations of communities at risk (4). State evacuation laws vary widely and might not adequately address information and communication flows to reach populations living in disaster-prone areas who are at risk. To understand the range of evacuation laws in coastal communities that historically have been affected by hurricanes, a systematic policy scan of the existing laws supporting hurricane evacuation in eight southern coastal states (Alabama, Florida, Georgia, Louisiana, Mississippi, North Carolina, South Carolina, and Texas) was conducted. After conducting a thematic analysis, this report found that all eight states have laws to execute evacuation orders, traffic control (egress/ingress), and evacuation to shelters. However, only four of the states have laws related to community outreach, delivery of public education programs, and public notice requirements. The findings in this report suggest a need for authorities in hurricane-prone states to review how to execute evacuation policies, particularly with respect to community outreach and communication to populations at risk. Implementation of state evacuation laws and policies that support hurricane evacuation management can help affected persons avoid harm and enhance community resiliency (5). Newly emerging and re-emerging infectious diseases, such as SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), have and will continue to additionally challenge hurricane evacuations.

School District Crisis Preparedness, Response, and Recovery Plans - United States, 2012.

The unique characteristics of children dictate the need for school-based all-hazards response plans during natural disasters, emerging infectious diseases, and terrorism (1-3). Schools are a critical community institution serving a vulnerable population that must be accounted for in public health preparedness plans; prepared schools are adopting policies and plans for crisis preparedness, response, and recovery (2-4). The importance of having such plans in place is underscored by the development of a new Healthy People 2020 objective (PREP-5) to "increase the percentage of school districts that require schools to include specific topics in their crisis preparedness, response, and recovery plans" (5). Because decisions about such plans are usually made at the school district level, it is important to examine district-level policies and practices. Although previous reports have provided national estimates of the percentage of districts with policies and practices in place (6), these estimates have not been analyzed by U.S. Census region* and urbanicity.(†) Using data from the 2012 School Health Policies and Practices Study (SHPPS), this report examines policies and practices related to school district preparedness, response, and recovery. In general, districts in the Midwest were less likely to require schools to include specific topics in their crisis preparedness plans than districts in the Northeast and South. Urban districts tended to be more likely than nonurban districts to require specific topics in school preparedness plans. Southern districts tended to be more likely than districts in other regions to engage with partners when developing plans. No differences in district collaboration (with the exception of local fire department engagement) were observed by level of urbanicity. School-based preparedness planning needs to be coordinated with interdisciplinary community partners to achieve Healthy People 2020 PREP-5 objectives for this vulnerable population.

Kinetic response of a photoperturbed allosteric protein.

By covalently linking an azobenzene photoswitch across the binding groove of a PDZ domain, a conformational transition, similar to the one occurring upon ligand binding to the unmodified domain, can be initiated on a picosecond timescale by a laser pulse. The protein structures have been characterized in the two photoswitch states through NMR spectroscopy and the transition between them through ultrafast IR spectroscopy and molecular dynamics simulations. The binding groove opens on a 100-ns timescale in a highly nonexponential manner, and the molecular dynamics simulations suggest that the process is governed by the rearrangement of the water network on the protein surface. We propose this rearrangement of the water network to be another possible mechanism of allostery.

The content of goals in individual educational programs for students with complex communication needs.

The aim of the study was to explore the contents of communication-related goals in individualized education programs (IEPs) for students with complex communication needs. Goals in 43 IEPs were linked to the International Classification of Functioning, Disability and Health, Children and Youth version (ICF-CY). The results show that the communication-related IEP goals contain information on multiple domains of functioning in the ICF-CY. However, judging by the amount of codes linked to ICF-CY chapters, the IEPs contain a relatively small proportion of goals that focus on interaction with others, or participation in classroom and leisure activities. Special education teachers and speech-language pathologists working with students with complex communication needs may need support to formulate communication-related IEP goals with a focus on interaction and participation in school activities.

Naturally acquired antibodies against Haemophilus influenzae type a in Aboriginal adults, Canada.

In the post-Haemophilus influenzae type b (Hib) vaccine era that began in the 1980's, H. influenzae type a (Hia) emerged as a prominent cause of invasive disease in North American Aboriginal populations. To test whether a lack of naturally acquired antibodies may underlie increased rates of invasive Hia disease, we compared serum bactericidal activity against Hia and Hib and IgG and IgM against capsular polysaccharide between Canadian Aboriginal and non-Aboriginal healthy and immunocompromised adults. Both healthy and immunocompromised Aboriginal adults exhibited significantly higher bactericidal antibody titers against Hia than did non-Aboriginal adults (p = 0.042 and 0.045 respectively), with no difference in functional antibody activity against Hib. IgM concentrations against Hia were higher than IgG in most study groups; the inverse was true for antibody concentrations against Hib. Our results indicate that Aboriginal adults possess substantial serum bactericidal activity against Hia that is mostly due to IgM antibodies. The presence of sustained IgM against Hia suggests recent Hia exposure.

Transcriptional adaptation of pneumococci and human pharyngeal cells in the presence of a virus infection.

BACKGROUND: Viral upper respiratory tract infections are associated with increased colonization by Streptococcus pneumoniae but the mechanisms underlying this relationship are unclear. The objective of this study is to describe a comprehensive picture of the cellular interaction between the adhering bacteria and host cells in the presence or absence of a viral co-infection. RESULTS: Gene expression profiles of Detroit-562 pharyngeal cells, which were either mock-infected or infected with human respiratory syncytial virus (RSV) or human parainfluenza virus 3 (HPIV3), were analyzed using human microarrays. Transcription response of S. pneumoniae strain TIGR4 (serotype 4) in the presence of either mock- or viral-infected cells was analyzed by pneumococcal microarray. Significantly regulated genes were identified by both significance analysis of microarray (SAM) and a ≥ 2-fold change ratio cut-off. The adherence of S. pneumoniae to human pharyngeal cells was significantly augmented in the presence of RSV or HPIV3 infection. Global gene expression profiling of the host cells during infection with RSV or HPIV3 revealed increased transcription of carcinoembryonic antigen-related cell adhesion molecules (CEACAM1), CD47, fibronectin, interferon-stimulated genes and many other host cell adhesion molecules. Pneumococci increased transcription of several genes involved in adhesive functions (psaA, pilus islet), choline uptake and incorporation (lic operon), as well as transport and binding. CONCLUSIONS: We have identified a core transcriptome that represents the basic machinery required for adherence of pneumococci to D562 cells infected or not infected with a virus. These bacterial genes and cell adhesion molecules can potentially be used to control pneumococcal adherence occurring secondary to a viral infection.

Phenotypic, genomic, and transcriptional characterization of Streptococcus pneumoniae interacting with human pharyngeal cells.

BACKGROUND: Streptococcus pneumoniae is a leading cause of childhood morbidity and mortality worldwide, despite the availability of effective pneumococcal vaccines. Understanding the molecular interactions between the bacterium and the host will contribute to the control and prevention of pneumococcal disease. RESULTS: We used a combination of adherence assays, mutagenesis and functional genomics to identify novel factors involved in adherence. By contrasting these processes in two pneumococcal strains, TIGR4 and G54, we showed that adherence and invasion capacities vary markedly by strain. Electron microscopy showed more adherent bacteria in association with membranous pseudopodia in the TIGR4 strain. Operons for cell wall phosphorylcholine incorporation (lic), manganese transport (psa) and phosphate utilization (phn) were up-regulated in both strains on exposure to epithelial cells. Pneumolysin, pili, stress protection genes (adhC-czcD) and genes of the type II fatty acid synthesis pathway were highly expressed in the naturally more invasive strain, TIGR4. Deletion mutagenesis of five gene regions identified as regulated in this study revealed attenuation in adherence. Most strikingly, ∆SP_1922 which was predicted to contain a B-cell epitope and revealed significant attenuation in adherence, appeared to be expressed as a part of an operon that includes the gene encoding the cytoplasmic pore-forming toxin and vaccine candidate, pneumolysin. CONCLUSION: This work identifies a list of novel potential pneumococcal adherence determinants.

Strategic use of conformational bias and structure based design to identify potent JAK3 inhibitors with improved selectivity against the JAK family and the kinome.

Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and improved selectivity within the JAK family.

Peptide binding to the PDZ3 domain by conformational selection.

The PDZ domains, a large family of peptide recognition proteins, bind to the C-terminal segment of membrane ion channels and receptors thereby mediating their localization. The peptide binding process is not known in detail and seems to differ among different PDZ domains. For the third PDZ domain of the synaptic protein PSD-95 (PDZ3), a lock-and-key mechanism was postulated on the basis of the almost perfect overlap of the crystal structures in the presence and absence of its peptide ligand. Here, peptide binding to PDZ3 is investigated by explicit solvent molecular dynamics (MD) simulations (for a total of 1.3 µs) and the cut-based free energy profile method for determining free energy barriers and basins. The free energy landscape of apo PDZ3 indicates that there are multiple basins within the native state. These basins differ by the relative orientation of the α2 helix and ß2 strand, the two secondary structure elements that make up the peptide binding site. Only the structure with the smallest aperture of the binding site is populated in the MD simulations of the complex whose analysis reveals that the peptide ligand binds to PDZ3 by selecting one of three conformations. Thus, the dynamical information obtained by the atomistic simulations increment the static, that is, partial, picture of the PDZ3 binding mechanism based on the X-ray crystallography data. Importantly, the simulation results show for the first time that conformational selection is a possible mechanism of peptide binding by PDZ domains in general.

Developing the ICF-CY for AAC profile and code set for children who rely on AAC.

We describe the ICF-CY for AAC Profile, a tool to integrate information about the multiple factors affecting communication skill development and use in school-aged children with complex communication needs. The Profile uses the World Health Organization's International Classification of Functioning, Disability and Health - Children & Youth Version ( WHO, 2007 ) as its framework. We propose that the ICF-CY for AAC Profile constitutes a code set for AAC users and discuss the iterative process of code-set development. The Profile is one component of a proposed process to guide the development of educational goals for children in Grades kindergarten-12 who currently or potentially rely on AAC.

A Policy Analysis of Preparedness for Hurricane Evacuations in the United States, 1990 to 2019: Implementation in Coastal States.

Hurricane or typhoon evacuations in the United States are typically managed by state, territorial, or tribal emergency management officials with federal, state, and local agency operational support. The evacuation process may involve issuing mandatory or "voluntary" evacuation orders to alert the community and mitigate loss of life and injury. We conducted an analysis of state and local hurricane evacuation policies identified through a literature review (January 1990 to June 2019) and key informant interviews with state public health and emergency management officials in Florida, Georgia, Louisiana, Mississippi, North Carolina, South Carolina, and Texas in October and November 2019. Findings from the literature review show that most gaps in hurricane evacuation preparedness-based on 44 policy-related publications identified in the review-could be categorized into 4 themes: shelters, evacuation decisionmaking, at-risk populations, and transportation. Findings from key informant interviews for 7 states revealed that coastal states have been able to address most of these gaps since Hurricane Katrina in 2005. However, an important remaining gap in preparedness is providing timely warnings to at-risk populations during hurricane evacuations.

Discovery of Novel Allosteric EGFR L858R Inhibitors for the Treatment of Non-Small-Cell Lung Cancer as a Single Agent or in Combination with Osimertinib.

Addressing resistance to third-generation EGFR TKIs such as osimertinib via the EGFRC797S mutation remains a highly unmet need in EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we present the discovery of the allosteric EGFR inhibitor 57, a novel fourth-generation inhibitor to overcome EGFRC797S-mediated resistance in patients harboring the activating EGFRL858R mutation. 57 exhibits an improved potency compared to previous allosteric EGFR inhibitors. To our knowledge, 57 is the first allosteric EGFR inhibitor that demonstrates robust tumor regression in a mutant EGFRL858R/C797S tumor model. Additionally, 57 is active in an H1975 EGFRL858R/T790M NSCLC xenograft model and shows superior efficacy in combination with osimertinib compared to the single agents. Our data highlight the potential of 57 as a single agent against EGFRL858R/C797S and EGFRL858R/T790M/C797S and as combination therapy for EGFRL858R- and EGFRL858R/T790M-driven NSCLC.

Revaccination with a 23-valent pneumococcal polysaccharide vaccine induces elevated and persistent functional antibody responses in adults aged 65 > or = years.

BACKGROUND: Older adults are at high risk of developing invasive pneumococcal disease, but the optimal timing and number of vaccine doses needed to prevent disease among this group are unknown. We compared revaccination with 23-valent pneumococcal polysaccharide vaccine (PN23) with primary vaccination for eliciting initial and persistent functional antibody responses. METHODS: Subjects aged > or = 65 years were enrolled. Functional (opsonic) and total immunoglobulin (Ig) G antibody levels were measured following either PN23 primary vaccination (n = 60) or revaccination 3-5 years after receiving a first PN23 vaccination (n = 60). Antibody against vaccine serotypes 4, 14, and 23F was measured at prevaccination (day 0), 30 days after vaccination, and 5 years after vaccination. RESULTS: By day 30, both primary vaccination and revaccination induced significant increases in opsonic and IgG antibody levels. Day 30 levels following revaccination were slightly lower but not significantly different than those after primary vaccination. Year 5 levels were similar in both groups and remained significantly higher than prevaccination levels for primary vaccination subjects. There was good agreement between postvaccination opsonic and IgG antibody levels. CONCLUSIONS: Revaccination of older adults with PN23 was comparable to primary vaccination for inducing elevated and persistent functional and IgG antibody responses.

An Innovative United States-Mexico Community Outreach Initiative for Hispanic and Latino People in the United States: A Collaborative Public Health Network.

Collaborative partnerships are a useful approach to improve health conditions of disadvantaged populations. The Ventanillas de Salud (VDS) ("Health Windows") and Mobile Health Units (MHUs) are a collaborative initiative of the Mexican government and US public health organizations that use mechanisms such as health fairs and mobile clinics to provide health information, screenings, preventive measures (eg, vaccines), and health services to Mexican people, other Hispanic people, and underserved populations (eg, American Indian/Alaska Native people, geographically isolated people, uninsured people) across the United States. From 2013 through 2019, the VDS served 10.5 million people (an average of 1.5 million people per year) at Mexican consulates in the United States, and MHUs served 115 461 people from 2016 through 2019. We describe 3 community outreach projects and their impact on improving the health of Hispanic people in the United States. The first project is an ongoing collaboration between VDS and the Centers for Disease Control and Prevention (CDC) to address occupational health inequities among Hispanic people. The second project was a collaboration between VDS and CDC to provide Hispanic people with information about Zika virus infection and health education. The third project is a collaboration between MHUs and the University of Arizona to provide basic health services to Hispanic communities in Pima and Maricopa counties, Arizona. The VDS/MHU model uses a collaborative approach that should be further assessed to better understand its impact on both the US-born and non-US-born Hispanic population and the public at large in locations where it is implemented.

Design, synthesis, and biological evaluation of new monoamine reuptake inhibitors with potential therapeutic utility in depression and pain.

Two new series of monoamine triple reuptake inhibitors (TRIs) have been discovered through scaffold homologation of our recently reported series of 3,3-disubstituted pyrrolidine TRIs. The regioisomeric 2- and 3-ketopyrrolidines demonstrated high levels of potency against all three monoamine transporters as well as good human in vitro stability, low drug-drug interaction potential and a decreased propensity for hERG channel binding. Representative compounds from these series displayed good in vivo pharmacokinetics and high monoamine receptor occupancies which are indicators of good brain penetration.

Electrochemical Behavior of Graphene in a Deep Eutectic Solvent.

Graphene electrodes and deep eutectic solvents (DESs) are two emerging material systems that have individually shown highly promising properties in electrochemical applications. To date, however, it has not been tested whether the combination of graphene and DESs can yield synergistic effects in electrochemistry. We therefore study the electrochemical behavior of a defined graphene monolayer of centimeter-scale, which was produced by chemical vapor deposition and transferred onto insulating SiO2/Si supports, in the common DES choline chloride/ethylene glycol (12CE) under typical electrochemical conditions. We measure the graphene potential window in 12CE and estimate the apparent electron transfer kinetics of an outer-sphere redox couple. We further explore the applicability of the 12CE electrolyte to fabricate nanostructured metal (Zn) and metalloid (Ge) hybrids with graphene by electrodeposition. By comparing our graphene electrodes with common bulk glassy carbon electrodes, a key finding we make is that the two-dimensional nature of the graphene electrodes has a clear impact on DES-based electrochemistry. Thereby, we provide a first framework toward rational optimization of graphene-DES systems for electrochemical applications.