Although most patients with chronic pain are women, the preclinical literature regarding pain processing and the pathophysiology of chronic pain has historically been derived overwhelmingly from the ...study of male rodents. This Review describes how the recent adoption by a number of funding agencies of policies mandating the incorporation of sex as a biological variable into preclinical research has correlated with an increase in the number of studies investigating sex differences in pain and analgesia. Trends in the field are analysed, with a focus on newly published findings of qualitative sex differences: that is, those findings that are suggestive of differential processing mechanisms in each sex. It is becoming increasingly clear that robust differences exist in the genetic, molecular, cellular and systems-level mechanisms of acute and chronic pain processing in male and female rodents and humans.
A clear majority of patients with chronic pain are women; however, it has been surprisingly difficult to determine whether this sex bias corresponds to actual sex differences in pain sensitivity. A ...survey of the currently available epidemiological and laboratory data indicates that the evidence for clinical and experimental sex differences in pain is overwhelming. Various explanations for this phenomenon have been given, ranging from experiential and sociocultural differences in pain experience between men and women to hormonally and genetically driven sex differences in brain neurochemistry.
Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system that are capable of killing virally infected and/or cancerous cells. Nearly 20 years ago, NK cell-mediated ...immunotherapy emerged as a safe and effective treatment approach for patients with advanced-stage leukaemia. Subsequently, the field of NK cell-based cancer therapy has grown exponentially and currently constitutes a major area of immunotherapy innovation. In general, the development of NK cell-directed therapies has two main focal points: optimizing the source of therapeutic NK cells for adoptive transfer and enhancing NK cell cytotoxicity and persistence in vivo. A wide variety of sources of therapeutic NK cells are currently being tested clinically, including haploidentical NK cells, umbilical cord blood NK cells, stem cell-derived NK cells, NK cell lines, adaptive NK cells, cytokine-induced memory-like NK cells and chimeric antigen receptor NK cells. A plethora of methods to augment the cytotoxicity and longevity of NK cells are also under clinical investigation, including cytokine-based agents, NK cell-engager molecules and immune-checkpoint inhibitors. In this Review, we highlight the variety of ways in which diverse NK cell products and their auxiliary therapeutics are being leveraged to target human cancers. We also identify future avenues for NK cell therapy research.
We recently demonstrated the utility of quantifying spontaneous pain in mice via the blinded coding of facial expressions. As the majority of preclinical pain research is in fact performed in the ...laboratory rat, we attempted to modify the scale for use in this species. We present herein the Rat Grimace Scale, and show its reliability, accuracy, and ability to quantify the time course of spontaneous pain in the intraplantar complete Freund's adjuvant, intraarticular kaolin-carrageenan, and laparotomy (post-operative pain) assays. The scale's ability to demonstrate the dose-dependent analgesic efficacy of morphine is also shown. In addition, we have developed software, Rodent Face Finder®, which successfully automates the most labor-intensive step in the process. Given the known mechanistic dissociations between spontaneous and evoked pain, and the primacy of the former as a clinical problem, we believe that widespread adoption of spontaneous pain measures such as the Rat Grimace Scale might lead to more successful translation of basic science findings into clinical application.
The core claim of educational neuroscience is that neuroscience can improve teaching in the classroom. Many strong claims are made about the successes and the promise of this new discipline. By ...contrast, I show that there are no current examples of neuroscience motivating new and effective teaching methods, and argue that neuroscience is unlikely to improve teaching in the future. The reasons are twofold. First, in practice, it is easier to characterize the cognitive capacities of children on the basis of behavioral measures than on the basis of brain measures. As a consequence, neuroscience rarely offers insights into instruction above and beyond psychology. Second, in principle, the theoretical motivations underpinning educational neuroscience are misguided, and this makes it difficult to design or assess new teaching methods on the basis of neuroscience. Regarding the design of instruction, it is widely assumed that remedial instruction should target the underlying deficits associated with learning disorders, and neuroscience is used to characterize the deficit. However, the most effective forms of instruction may often rely on developing compensatory (nonimpaired) skills. Neuroscience cannot determine whether instruction should target impaired or nonimpaired skills. More importantly, regarding the assessment of instruction, the only relevant issue is whether the child learns, as reflected in behavior. Evidence that the brain changed in response to instruction is irrelevant. At the same time, an important goal for neuroscience is to characterize how the brain changes in response to learning, and this includes learning in the classroom. Neuroscientists cannot help educators, but educators can help neuroscientists.
Antibiotics are by far the most common medications prescribed for children. Recent epidemiological data suggests an association between early antibiotic use and disease phenotypes in adulthood. ...Antibiotic use during infancy induces imbalances in gut microbiota, called dysbiosis. The gut microbiome’s responses to antibiotics and its potential link to disease development are especially complex to study in the changing infant gut. Here, we synthesize current knowledge linking antibiotics, dysbiosis, and disease and propose a framework for studying antibiotic-related dysbiosis in children. We recommend future studies into the microbiome-mediated effects of antibiotics focused on four types of dysbiosis: loss of keystone taxa, loss of diversity, shifts in metabolic capacity, and blooms of pathogens. Establishment of a large and diverse baseline cohort to define healthy infant microbiome development is essential to advancing diagnosis, interpretation, and eventual treatment of pediatric dysbiosis. This approach will also help provide evidence-based recommendations for antibiotic usage in infancy.
Antibiotic use during infancy induces imbalances in gut microbiota called dysbiosis, which represents a potential risk for disease in later life. Vangay et al. synthesize current knowledge linking antibiotic use in infancy, pediatric dysbiosis, and disease and propose a framework for studying antibiotic-related dysbiosis in children.
As both CPUs and GPUs become employed in a wide range of applications, it has been acknowledged that both of these Processing Units (PUs) have their unique features and strengths and hence, CPU-GPU ...collaboration is inevitable to achieve high-performance computing. This has motivated a significant amount of research on heterogeneous computing techniques, along with the design of CPU-GPU fused chips and petascale heterogeneous supercomputers. In this article, we survey Heterogeneous Computing Techniques (HCTs) such as workload partitioning that enable utilizing both CPUs and GPUs to improve performance and/or energy efficiency. We review heterogeneous computing approaches at runtime, algorithm, programming, compiler, and application levels. Further, we review both discrete and fused CPU-GPU systems and discuss benchmark suites designed for evaluating Heterogeneous Computing Systems (HCSs). We believe that this article will provide insights into the workings and scope of applications of HCTs to researchers and motivate them to further harness the computational powers of CPUs and GPUs to achieve the goal of exascale performance.
Immunotherapy has moved to the center stage of cancer treatment with the recent success of trials in solid tumors with PD-1/PD-L1 axis blockade. Programmed death-1 or PD-1 is a checkpoint molecule on ...T cells that plays a vital role in limiting adaptive immune responses and preventing autoimmune and auto-inflammatory reactivity in the normal host. In cancer patients, PD-1 expression is very high on T cells in the tumor microenvironment, and PD-L1, its primary ligand, is variably expressed on tumor cells and antigen-presenting cells within tumors, providing a potent inhibitory influence within the tumor microenvironment. While PD-L1 expression on tumors is often regarded as a negative prognostic factor, it is clearly associated with a positive outcome for treatment with PD-1/PD-L1 blocking antibodies, and has been used to select patients for this therapy. Responses of long duration, a minority of patients with atypical responses in which progression may precede tumor shrinkage, and a pattern of autoimmune side effects often seen with this class of drugs characterize therapy with PD-1/PD-L1 blocking drugs. While excellent efficacy has been seen with a limited number of tumor types, most epithelial cancers do not show responses of long duration with these agents. In the current review, we will briefly summarize the scientific background data supporting the development of PD-1/PD-L1 blockade, and then describe the track record of these antibodies in multiple different histologies ranging from melanoma and lung cancer to less common tumor types as well as discuss biomarkers that may assist in patient selection.
This article explores the links between social media and public space within the #Occupy Everywhere movements. Whereas listservs and websites helped give rise to a widespread logic of networking ...within the movements for global justice of the 1990s–2000s, I argue that social media have contributed to an emerging logic of aggregation in the more recent #Occupy movements—one that involves the assembling of masses of individuals from diverse backgrounds within physical spaces. However, the recent shift toward more decentralized forms of organizing and networking may help to ensure the sustainability of the #Occupy movements in a posteviction phase.
When one brings “polymeric materials” and “mechanical action” into the same conversation, the topic of this discussion might naturally focus on everyday circumstances such as failure of fibers, ...fatigue of composites, abrasion of coatings, etc. This intuitive viewpoint reflects the historic consensus in both academia and industry that mechanically induced chemical changes are destructive, leading to polymer degradation that limits materials lifetime on both macroscopic and molecular levels. In the 1930s, Staudinger observed mechanical degradation of polymers, and Melville later discovered that polymer chain scission caused the degradation. Inspired by these historical observations, we sought to redirect the destructive mechanical energy to a productive form that enables mechanoresponsive functions. In this Account, we provide a personal perspective on the origin, barriers, developments, and key advancements of polymer mechanochemistry. We revisit the seminal events that offered molecular-level insights into the mechanochemical behavior of polymers and influenced our thinking. We also highlight the milestones achieved by our group along with the contributions from key comrades at the frontier of this field. We present a workflow for the design, evaluation, and development of new “mechanophores”, a term that has come to mean a molecular unit that chemically responds in a selective manner to a mechanical perturbation. We discuss the significance of computation in identifying pairs of points on the mechanophore that promote stretch-induced activation. Attaching polymer chains to the mechanophore at the most sensitive pair and locating the mechanophore near the center of a linear polymer are thought to maximize the efficiency of mechanical-to-chemical energy transduction. We also emphasize the importance of control experiments to validate mechanochemical transformations, both in solution and in the solid state, to differentiate “mechanical” from “thermal” activation. This Account offers our first-hand perspective of the change-in-thinking in polymer mechanochemistry from “destructive” to “productive” and looks at future advances that will stimulate this growing field.
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