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The Chimpanzee SIV Envelope Trimer: Structure and Deployment as an HIV Vaccine Template
No full textEpitope-targeted HIV vaccine design seeks to focus antibody responses to broadly neutralizing antibody (bnAb) sites by sequential immunization. A chimpanzee simian immunodeficiency virus (SIV) envelope (Env) shares a single bnAb site, the variable loop 2 (V2)-apex, with HIV, suggesting its possible utility in an HIV immunization strategy. Here, we generate a chimpanzee SIV Env trimer, MT145K, which displays selective binding to HIV V2-apex bnAbs and precursor versions, but no binding to other HIV specificities. We determine the structure of the MT145K trimer by cryo-EM and show that its architecture is remarkably similar to HIV Env. Immunization of an HIV V2-apex bnAb precursor Ab-expressing knockin mouse with the chimpanzee MT145K trimer induces HIV V2-specific neutralizing responses. Subsequent boosting with an HIV trimer cocktail induces responses that exhibit some virus cross-neutralization. Overall, the chimpanzee MT145K trimer behaves as expected from design both in vitro and in vivo and is an attractive potential component of a sequential immunization regimen to induce V2-apex bnAbs
Female-male differences in prescription pain reliever dependence levels: Evidence on newly incident adolescent and young adult users in the United States, 2002-2014
No full textBackground: A comprehensive epidemiology of dependence on prescription opioid pain relievers requires evidence about age-specific female-male differences, possibly manifest during adolescent and early adult years. In this study, we identified newly incident extra-medical users of prescription pain relievers (EMPPR), all observed with onsets before the 22nd birthday. We then quantified female-male differences in clinical features or manifestations of opioid dependence (OD), devised a measurement-equivalent OD dimension, and estimated age-specific female-male differences in OD levels. Method: The population under study included 12-to-21-year-old non-institutionalized civilian community residents of United States sampled for recent nation-scale surveys. Confidential computer-assisted self-interviews identified newly incident EMPPR users (n = 10,188). Analysis-weighted estimation procedures yielded cumulative incidence proportions for each OD feature, evaluated measurement non-equivalence across subgroups, and estimated female-male differences age-by-age. Results: (1) Tolerance and salience (‘spending a lot of time’) are most common OD features. (2) Measurement non-equivalence (bias) was found across sex- and onset-age groups. (3) With biasing features removed, we can see elevated OD levels for female new initiates, age-by-age. Subsidiary analyses suggested possibly accelerated progression toward higher OD levels when extra-medical PPR use starts before age 18. Conclusions: Dimensional approaches to OD and other drug use disorders have gained popularity but can be fragile when differential measurement biases are left uncontrolled. This study’s bias-corrected dimensional view of female-male differences shows elevated OD levels among newly incident female EMPPR users relative to new male initiates. Future studies can check for accelerated progression to higher OD levels when EM use starts before age 18 years
gem-Diethyl Pyrroline Nitroxide Spin Labels: Synthesis, EPR Characterization, Rotamer Libraries and Biocompatibility
No full textThe availability of bioresistant spin labels is crucial for the optimization of site‐directed spin labeling protocols for EPR structural studies of biomolecules in a cellular context. As labeling can affect proteins’ fold and/or function, having the possibility to choose between different spin labels will increase the probability to produce spin‐labeled functional proteins. Here, we report the synthesis and characterization of iodoacetamide‐ and maleimide‐functionalized spin labels based on the gem‐diethyl pyrroline structure. The two nitroxide labels are compared to conventional gem‐dimethyl analogs by site‐directed spin labeling (SDSL) electron paramagnetic resonance (EPR) spectroscopy, using two water soluble proteins: T4 lysozyme and Bid. To foster their use for structural studies, we also present rotamer libraries for these labels, compatible with the MMM software. Finally, we investigate the “true” biocompatibility of the gem‐diethyl probes comparing the resistance towards chemical reduction of the NO group in ascorbate solutions and E. coli cytosol at different spin concentrations
Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study
No full textBackground There is a clinical concern that prescribing methylphenidate, the most common pharmacological treatment for attention-deficit hyperactivity disorder (ADHD), might increase the risk of psychotic events, particularly in young people with a history of psychosis. We aimed to determine whether the risk of psychotic events increases immediately after initiation of methylphenidate treatment or, in the longer term, 1 year after treatment initiation in adolescents and young adults with and without a previously diagnosed psychotic disorder. Methods In this cohort study, we used population-based observational data from the Swedish Prescribed Drug Register, the National Patient Register, and the Total Population Register, three population-based registers containing data on all individuals in Sweden, to attain data on sex, birth, death, migration, medication use, and psychotic events for all eligible participants. We screened individuals on these registers to identify those receiving methylphenidate treatment, and who were aged 12–30 years at the start of treatment, for their inclusion in the study. We used a within-individual design to compare the incidence of psychotic events in these individuals during the 12-week periods immediately before and after methylphenidate initiation. Longer term risk was assessed by comparing the incidence of psychotic events 12 weeks before methylphenidate initiation and during a 12-week period one calendar year before the initiation of methylphenidate with the incidence of these events during the 12-week period one calendar year after methylphenidate initiation. We estimated the incidence rate ratios (IRR) and 95% CIs of psychotic events after the initation of methylphenidate treatment, relative to the events before treatment, which were defined as any hospital visit (inpatient admission or outpatient attendance, based on data from the National Patient Register) because of psychosis, using the International Classification of Diseases version 10 definition. Analyses were stratified by whether the individual had a history of psychosis. Findings We searched the Swedish Prescribed Drug Register to find eligible individuals who had received methylphenidate between Jan 1, 2007 and June 30, 2012. 61 814 individuals were screened, of whom 23 898 (38·7%) individuals were assessed and 37 916 (61·3%) were excluded from the study because they were outside of the age criteria at the start of treatment, they had immigrated, emigrated, or died during the study period, or because they were administered other ADHD medications. The median age at methylphenidate initiation was 17 years, and a history of psychosis was reported in 479 (2·0%) participants. The IRR of psychotic events in the 12-week period after initiation of methylphenidate treatment relative to that in the 12-week period before treatment start was 1·04 (95% CI 0·80–1·34) in adolescents and young adults without a history of psychosis and 0·95 (0·69–1·30) among those with a history of psychosis. Interpretation Contrary to clinical concerns, we found no evidence that initiation of methylphenidate treatment increases the risk of psychotic events in adolescents and young adults, including in those individuals with a history of psychosis. Our study should reassure clinicians considering initiating methylphenidate treatment for ADHD in adolescents and young adults, and it challenges the widely held view in clinical practice that methylphenidate should be avoided, or its use restricted, in individuals with a history of psychosis. Funding Swedish Research Council, National Institute of Mental Health, UK National Institute of Health Research Nottingham Biomedical Research Centre
Experiential Education and Access-to-Justice in U.S. Law Schools: Designing and Evaluating an Access-to-Justice Service Learning Program within the First-Year Curriculum
No full textIn this Article, we describe the creation and evaluation of a curricular intervention designed to help first-year law students develop lawyering skills while fostering their ethical and social-emotional development. We call this curricular intervention an Access-to-Justice Service Learning Program. We believe that, at the time of this writing, this was the first such program administered within the first-year curriculum of a U.S. law school. We designed and launched this Access-to-Justice Service Learning Program in Fall 2016 within the first- year curriculum of the Indiana University Maurer School of Law. In so doing, we taught 187 first-year law students how to put into practice human-centered design thinking, perspective-taking, and professional skills to promote access to justice. While human-centered design thinking is increasingly being woven into law school curricula in upper-level project management courses to address access-to-justice problems—including at Stanford Law School, Harvard Law School, and Georgetown University Law Center—this Access-to-Justice Service Learning Program was introduced within the first-year curriculum to teach students the professional skills, human-centered design thinking, and problem-solving techniques necessary to enhance access to justice for low-income members of society. U.S. law schools are increasingly being called to train their students to become ethical members of society who address access-to-justice challenges that the public experiences when encountering and navigating the civil justice system. Millions of Americans lack meaningful access to justice and suffer from unmet legal needs.3 For most low-income and many middle-income people living in the United States, the inability to receive legal advice or secure legal representation renders our civil justice system inaccessible. Absent legal advice, many Americans often fail to understand that legal relief is available for the problems they encounter “at the intersection of civil law and everyday adversity” such as problems that affect human needs, including shelter, livelihood, and the care of dependents. Moreover, even when people do realize their problems are potentially addressable through law, most poor and many middle-income people are left to navigate complex procedures and bewildering bureaucracies in search of legal relief without counsel, which only serves to compound their problems. Given the reality that many Americans are unable to defend their legal rights, wide swaths of U.S. society become vulnerable to those who, casting aside ethics and morality, have an economic incentive to engage in abuse. In turn, interlocking webs of social, environmental, financial, and health problems stemming from unmet legal needs metastasize into social, psychological, environmental, financial, and health problems that imperil human well-being. This Access-to-Justice Service Learning Program was designed to help law students understand the values that guide our profession—including a commitment to the rule of law, access to justice, and public service—and to help law students empathize with those affected by the civil justice system. First-year law students learned the perspectives of affected members of the community and were matched with legal-aid partners, such as Indiana Legal Services, the United States District Court for the Southern District of Indiana, the Neighborhood Christian Legal Clinic, and the Indianapolis Legal Aid Society. These first-year law students worked with community partners to help deliver legal services more effectively to low-income members of the community by engaging in a human-centered access-to-justice design process. Our evaluation of the program reveals the curriculum may be promising as an intervention in the first-year curriculum within U.S. law schools. The first- year law students who took part grew not only as individuals, but by working together in teams, they also developed as future members of the legal profession. The Article will proceed as follows: In Part I, we will situate the curricular intervention by introducing the three apprenticeships implicit in legal education and theorized by the Carnegie Foundation’s 2007 report, as well as the rise of experiential pedagogies in law schools more generally. In Part II, we will describe human- centered civil justice design and human-centered design thinking in technologies that address access-to-justice barriers. In Part III, we will describe the creation of the program, including the ways in which we backward designed the program from the law school’s J.D. learning outcomes, and forward designed the program to address the cognitive, emotional, and experiential bottlenecks law students experience in the first-year curriculum. In Part IV, we will discuss the results of an empirical analysis of the program that harnesses a variety of quantitative and qualitative data and uses results from the Law School Survey of Student Engagement (LSSSE)
Emergence of power laws in noncritical neuronal systems
No full textExperimental and computational studies provide compelling evidence that neuronal systems are characterized by power-law distributions of neuronal avalanche sizes. This fact is interpreted as an indication that these systems are operating near criticality, and, in turn, typical properties of critical dynamical processes, such as optimal information transmission and stability, are attributed to neuronal systems. The purpose of this Rapid Communication is to show that the presence of power-law distributions for the size of neuronal avalanches is not a sufficient condition for the system to operate near criticality. Specifically, we consider a simplistic model of neuronal dynamics on networks and show that the degree distribution of the underlying neuronal network may trigger power-law distributions for neuronal avalanches even when the system is not in its critical regime. To certify and explain our findings we develop an analytical approach based on percolation theory and branching processes techniques
Identification of N-terminal protein processing sites by chemical labeling mass spectrometry.
No full textRationale Proteins undergo post‐translational modifications and proteolytic processing that can affect their biological function. Processing often involves the loss of single residues. Cleavage of signal peptides from the N‐terminus is commonly associated with translocation. Recent reports have suggested that other processing sites also exist. Methods The secreted proteins from S. aureus N315 were precipitated with trichloroacetic acid (TCA) and amidinated with S‐methyl thioacetimidate (SMTA). Amidinated proteins were digested with trypsin and analyzed with a high‐resolution orbitrap mass spectrometer. Results Sixteen examples of Staphylococcus aureus secretory proteins that lose an N‐terminal signal peptide during their export were identified using this amidination approach. The N‐termini of proteins with and without methionine were identified. Unanticipated protein cleavages due to sortase and an unknown protease were also uncovered. Conclusions A simple N‐terminal amidination based mass spectrometry approach is described that facilitates identification of the N‐terminus of a mature protein and the discovery of unexpected processing sites
City-wide electronic health records reveal gender and age biases in administration of known drug-drug interactions
No full textThe occurrence of drug–drug-interactions (DDI) from multiple drug dispensations is a serious problem, both for individuals and health-care systems, since patients with complications due to DDI are likely to reenter the system at a costlier level. We present a large-scale longitudinal study (18 months) of the DDI phenomenon at the primary- and secondary-care level using electronic health records (EHR) from the city of Blumenau in Southern Brazil (pop. ≈340,000). We found that 181 distinct drug pairs known to interact were dispensed concomitantly to 12% of the patients in the city’s public health-care system. Further, 4% of the patients were dispensed drug pairs that are likely to result in major adverse drug reactions (ADR)—with costs estimated to be much larger than previously reported in smaller studies. The large-scale analysis reveals that women have a 60% increased risk of DDI as compared to men; the increase becomes 90% when considering only DDI known to lead to major ADR. Furthermore, DDI risk increases substantially with age; patients aged 70–79 years have a 34% risk of DDI when they are dispensed two or more drugs concomitantly. Interestingly, a statistical null model demonstrates that age- and female-specific risks from increased polypharmacy fail by far to explain the observed DDI risks in those populations, suggesting unknown social or biological causes. We also provide a network visualization of drugs and demographic factors that characterize the DDI phenomenon and demonstrate that accurate DDI prediction can be included in health care and public-health management, to reduce DDI-related ADR and costs
Human Group Presence, Group Characteristics, and Group Norms Affect Human-Robot Interaction in Naturalistic Settings
No full textAs robots become more prevalent in public spaces, such as museums, malls, and schools, they are coming into increasing contact with groups of people, rather than just individuals. Groups, compared to individuals, can differ in robot acceptance based on the mere presence of a group, group characteristics such as entitativity (i.e., cohesiveness), and group social norms; however, group dynamics are seldom studied in relation to robots in naturalistic settings. To examine how these factors affect human-robot interaction, we observed 2,714 people in a Japanese mall receiving directions from the humanoid robot Robovie. Video and survey responses evaluating the interaction indicate that groups, especially entitative groups, interacted more often, for longer, and more positively with the robot than individuals. Participants also followed the social norms of the groups they were part of; participants who would not be expected to interact with the robot based on their individual characteristics were more likely to interact with it if other members of their group did. These results illustrate the importance of taking into account the presence of a group, group characteristics, and group norms when designing robots for successful interactions in naturalistic settings
Environmental influences on the stable carbon isotopic composition of Devonian and Early Carboniferous land plants
No full textSystematic analysis of the stable carbon isotopic composition of fossil land plants (C) has the potential to offer new insights regarding paleoclimate variation and plant-environment interactions in early terrestrial ecosystems. C was measured for 190 fossil plant specimens belonging to 10 genera of Early to Late Devonian age (Archaeopteris, Drepanophycus, Haskinsia, Leclercqia, Pertica, Psilophyton, Rhacophyton, Sawdonia, Tetraxylopteris, and Wattieza) and 2 genera of Early Carboniferous age (Genselia and Rhodeopteridium) collected from sites located mainly in the Appalachian Basin (22–30°S paleolatitude). For the full carbon-isotopic dataset (n = 309), C ranges from −20.3‰ to −30.5‰ with a mean of −25.5‰, similar to values for modern C land plants. In addition to a secular trend, C exhibits both intra- and intergeneric variation. Intrageneric variation is expressed as a small (mean 0.45‰) C-enrichment of leaves and spines relative to stems that may reflect differential compound-specific compositions. Intergeneric variation is expressed as a much larger (to ~5‰) spread in the mean C values of coeval plant genera that was probably controlled by taxon-specific habitat preferences and local environmental humidity. Among Early Devonian taxa, Sawdonia yielded the most C-depleted values (−27.1 ± 1.7‰), reflecting lower water-use efficiency that was probably related to growth in wetter habitats, and Leclercqia, Haskinsia, and Psilophyton yielded the most C-enriched values (−23.0 ± 1.6‰, −22.3 ± 1.3‰, and −24.8 ± 1.6‰, respectively), reflecting higher water-use efficiency probably related to growth in drier habitats