Rough surfaces are ubiquitous in nature. Near-surface processes both encounter and create surface roughness. Recent advances in surveying have improved the resolution, extent and availability of ...topographic datasets. This broad review synthesises efforts to represent surface roughness in such datasets, drawing examples from a number of branches of Earth Science, with the aim of facilitating a more systematic exchange of roughness formulations. A number of issues surround the definition of roughness. The term ‘roughness’ has been applied variously to represent a property of a surface, a property of a flow and as a model tuning parameter; yet these distinctions are articulated rarely. There has been a proliferation of methods of quantifying surface roughness. Given the wide range of applications of roughness in the Earth Sciences, attempts to create a standardised parameter set will likely be problematic. Yet a standard protocol for reporting roughness calculation would be appropriate, especially considering the importance of the choice of partition scale in the distinction between roughness and topography. Applications of surface roughness treat it as a variable (in the mapping of landforms, for example), a surrogate for less measurable variables (as in the estimation of resistance to flows) or as an indicator of near-surface processes. Recent developments examining interactions between roughness elements (e.g. sheltering) highlight the need to consider the pattern of surface roughness (e.g. anisotropy, connectivity of peaks) if appropriate parameterisations are to be developed. Addressing these issues will maximise the exciting potential offered by advances in topographic surveys.
Although recent methods for the engineering of antibody-drug conjugates (ADCs) have gone some way to addressing the challenging issues of ADC construction, significant hurdles still remain. There is ...clear demand for the construction of novel ADC platforms that offer greater stability, homogeneity and flexibility. Here we describe a significant step towards a platform for next-generation antibody-based therapeutics by providing constructs that combine site-specific modification, exceptional versatility and high stability, with retention of antibody binding and structure post-modification. The relevance of the work in a biological context is also demonstrated in a cytotoxicity assay and a cell internalization study with HER2-positive and -negative breast cancer cell lines.
Social learning theory, as originally proposed by Albert Bandura, followed 2000 years of intellectual inquiry into the determinants of human behavior. Reciprocal determinism is a central component of ...this theory and proposes that human behavior is determined by functional relationships between (1) personal factors, (2) the external environment, and (3) the behavior itself. Using this model, drug addiction can be viewed as resulting from the functional relationships between an individual’s personal characteristics, social environment, and drug-centric behaviors. In other words, addiction can be viewed as a chronically evolving biopsychosocial disorder, encompassing dimensions that are both internal and external to the individual. Effective treatment interventions should thus target all nodes of the model and the functional relationships between them, and they must constantly evolve with the progression of the disorder. An argument is thus constructed that emphasizes the need for an organized structure of metacontingencies, operating within an individual’s social environment, that targets the functional relationships between the factors that drive drug use. Optimally, these metacontingencies would operate within socially connected individuals who have the power to control the functional relationships that influence drug use, the vested interest to monitor individual and collective outcomes, the skills to determine what moment-to-moment decisions are needed to influence behavioral change, and the relative permanence necessary to carry through with the implementation of new strategies to produce outcomes that are cumulatively significant.
The National Institute on Drug Abuse (NIDA) recently released a Request for Information (RFI) soliciting comments on nonhuman animal models of substance use disorders (SUD).
A literature review was ...performed to address the four topics outlined in the RFI and one topic inspired by the RFI: (1) animal models that best recapitulate SUD, (2) animal models that best balance the trade-offs between resources and ecological validity, (3) animal models whose translational value are frequently misrepresented or overrepresented by the scientific community, (4) aspects of SUD that are not currently being modeled in animals, and (5) animal models that are optimal for examining the basic mechanisms by which drugs produce their abuse-related effects.
Models that employ response-contingent drug administration, use complex schedules of reinforcement, measure behaviors that mimic the distinguishing features of SUD, and use animals that are phylogenetically similar to humans have the greatest translational value. Models that produce stable and reproducible baselines of behavior, lessen the number of uncontrolled variables, and minimize the influence of extraneous factors are best at examining basic mechanisms contributing to drug reward and reinforcement.
Nonhuman animal models of SUD have undergone significant refinements to increase their utility for basic science and translational value for SUD. The existing literature describes numerous examples of how these models may best be utilized to answer mechanistic questions of drug reward and identify potential therapeutic interventions for SUD. Progress in the field could be accelerated by further collaborations between researchers using animals versus humans.
Significant technological and methodological advances in solid-state NMR techniques in recent years have increased the accessibility of nuclei with small magnetic moments (hereafter termed low-γ) ...underpinning an increased range of applications of such nuclei. These methodological advances are briefly summarised, including improvements in hardware and pulse sequences, as well as important developments in associated computational methods (
first principles calculations, spectral simulation). Here spin-½ nuclei are the focus, with this Perspective complementing a very recent review that looked at half-integer spin low-γ quadrupolar nuclei. Reference is made to some of the original reports of such spin-½ nuclei, but recent progress in the relevant methodology and applications to inorganic materials (most within the last 10 years) of these nuclei are the focus. An overview of the current state-of-the-art of studying these nuclei is thereby provided for both NMR spectroscopists and materials researchers.
In a study conducted across an urban school district, we tested a classroom-based intervention in which students were taught online evaluation strategies drawn from research with professional fact ...checkers. Students practiced the heuristic of lateral reading: leaving an unfamiliar website to search the open Web before investing attention in the site at hand. Professional development was provided to high school teachers who then implemented six 50-minute lessons in a district-mandated government course. Using a matched control design, students in treatment classrooms (n = 271) were compared to peers (n = 228) in regular classrooms. A multilevel linear mixed model showed that students in experimental classrooms grew significantly in their ability to judge the credibility of digital content. These findings inform efforts to prepare young people to make wise decisions about the information that darts across their screens.
Educational Impact and Implications StatementThis study tested the effectiveness of an intervention that taught high school students to make sound decisions on the Internet. Less than 6 hr of classroom instruction significantly improved students' judgment about the credibility of online sources.
The maleimide motif is widely used for the selective chemical modification of cysteine residues in proteins. Despite widespread utilization, there are some potential limitations, including the ...irreversible nature of the reaction and, hence, the modification and the number of attachment positions. We conceived of a new class of maleimide which would address some of these limitations and provide new opportunities for protein modification. We report herein the use of mono- and dibromomaleimides for reversible cysteine modification and illustrate this on the SH2 domain of the Grb2 adaptor protein (L111C). After initial modification of a protein with a bromo- or dibromomaleimide, it is possible to add an equivalent of a second thiol to give further bioconjugation, demonstrating that bromomaleimides offer opportunities for up to three points of attachment. The resultant protein−maleimide products can be cleaved to regenerate the unmodified protein by addition of a phosphine or a large excess of a thiol. Furthermore, dibromomaleimide can insert into a disulfide bond, forming a maleimide bridge, and this is illustrated on the peptide hormone somatostatin. Fluorescein-labeled dibromomaleimide is synthesized and inserted into the disulfide to construct a fluorescent somatostatin analogue. These results highlight the significant potential for this new class of reagents in protein modification.
Physical activity, and specifically exercise, has been suggested as a potential treatment for drug addiction. In this review, we discuss clinical and preclinical evidence for the efficacy of exercise ...at different phases of the addiction process. Potential neurobiological mechanisms are also discussed focusing on interactions with dopaminergic and glutamatergic signaling and chromatin remodeling in the reward pathway. While exercise generally produces an efficacious response, certain exercise conditions may be either ineffective or lead to detrimental effects depending on the level/type/timing of exercise exposure, the stage of addiction, the drug involved, and the subject population. During drug use initiation and withdrawal, its efficacy may be related to its ability to facilitate dopaminergic transmission, and once addiction develops, its efficacy may be related to its ability to normalize glutamatergic and dopaminergic signaling and reverse drug-induced changes in chromatin via epigenetic interactions with brain-derived neurotrophic factor (BDNF) in the reward pathway. We conclude with future directions, including the development of exercise-based interventions alone or as an adjunct to other strategies for treating drug addiction.
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