Brains, genes, and primates Izpisua Belmonte, Juan Carlos; Callaway, Edward M; Caddick, Sarah J ...
Neuron,
05/2015, Letnik:
86, Številka:
3
Journal Article
Recenzirano
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One of the great strengths of the mouse model is the wide array of genetic tools that have been developed. Striking examples include methods for directed modification of the genome, and for regulated ...expression or inactivation of genes. Within neuroscience, it is now routine to express reporter genes, neuronal activity indicators, and opsins in specific neuronal types in the mouse. However, there are considerable anatomical, physiological, cognitive, and behavioral differences between the mouse and the human that, in some areas of inquiry, limit the degree to which insights derived from the mouse can be applied to understanding human neurobiology. Several recent advances have now brought into reach the goal of applying these tools to understanding the primate brain. Here we describe these advances, consider their potential to advance our understanding of the human brain and brain disorders, discuss bioethical considerations, and describe what will be needed to move forward.
Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also ...associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.
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•Type 2 cytokines directly activate both mouse and human sensory neurons•IL-4 enhances neuronal responsiveness to multiple pruritogens•Sensory neuron-specific deletion of IL-4Rα or JAK1 reduces chronic itch•Clinical studies demonstrate that JAK inhibitors relieve chronic itch
Type 2 cytokines directly stimulate itch-sensory neurons, and blocking this pathway is effective in a proof-of-concept study in patients with recalcitrant chronic itch.
The relationship between gastrointestinal (GI) bacteria and the response to anti-CTLA-4 and anti-PD-1 immunotherapy in the treatment of cancer can potentially be enhanced to allow patients to ...maximally respond to these treatments. Insight into the complex interaction between gut microbiota and the human adaptive immune system will help guide future immunotherapeutic cancer treatments to allow a more robust clinical response and fewer adverse effects in patients requiring these drugs. This review highlights these interactions as well as the potential for the creation of "oncomicrobiotics" that would selectively tailor one's GI bacteria to maximally respond to anti-CTLA-4 and anti-PD-1 treatments will fewer adverse effects.
CTLA-4 is an antigen on the surface of T cells which, upon stimulation, leads to inhibition of activated T cells to terminate the immune response. However, many types of tumor cells can upregulate CTLA-4 in the tumor microenvironment, allowing these cells to evade targeting and destruction by the body's immune system by prematurely inhibiting T cells. Increased representation of
,
and the
in the GI tract of patients receiving CTLA-4-based immunotherapy led to a stronger therapeutic effect while minimizing adverse side effects such as colitis. In addition, by introducing bacteria involved in vitamin B and polyamine transport to the GI tracts of patients treated with anti-CTLA-4 drugs led to increased resistance to colitis while maintaining therapeutic efficacy. PD-1 is another molecule upregulated in many tumor microenvironments which acts in a similar manner to CTLA-4 to tone down the anti-neoplastic actions of T cells. Antibodies to PD-1 have shown promise to help allow the body's natural immune response to appropriately target and destroy tumor cells. The presence of
and
,
and
in the GI tracts of cancer patients has the potential to create a more robust immune response to anti-PD-1 drugs and prolonged survival. The development of "oncomicrobiotics" has the potential to help tailor one's gut microbiota to allow patients to maximally respond to immunotherapy without sacrificing increases in toxicity. These oncomicrobiotics may possibly include antibiotics, probiotics, postbiotics and/or prebiotics. However, many challenges lie ahead in the creation of oncomicrobiotics.
The creation of oncomicrobiotics may allow many patients receiving anti-CTLA-4 and PD-1 immunotherapy to experience prolonged survival and a better quality of life.
1. Marine mammals may be negatively affected by anthropogenic noise. Behavioural response studies (BRS) aim to establish a relationship between noise exposure conditions (dose) from a potential ...Stressor and associated behavioural responses of animals. A recent series of BRS have focused on the effects of naval sonar sounds on cetaceans. Here, we review the current state of understanding of naval sonar impact on marine mammals and highlight knowledge gaps and future research priorities. 2. Many marine mammal species exhibit responses to naval sonar sounds. However, responses vary between and within individuals and populations, highlighting the importance of exposure context in modulating dose-response relationships. 3. There is increasing support from both terrestrial and marine systems for the risk-disturbance hypothesis as an explanation for underlying response processes. This proposes that sonar sounds may be perceived by animals as a threat, evoking a response shaped by the underlying species-specific risk of predation and antipredator strategy. An understanding of responses within both the dose-response and risk-disturbance frameworks may enhance our ability to predict responsiveness for unstudied species and populations. 4. Many observed behavioural responses are energetically costly, but the way that these responses may lead to long-term individual and population-level impacts is poorly understood. 5. Synthesis and applications. Behavioural response studies have greatly improved our understanding of the potential effects of naval sonar on marine mammals. Despite data gaps, we believe a dose-response approach within a risk-disturbance framework will enhance our ability to predict responsiveness for unstudied species and populations. W e advocate for (1) regulatory frameworks to utilize peer-reviewed research findings when making predictions of impact, (2) regulatory frameworks to account for the inherent uncertainty in predictions of impact and (3) investment in monitoring programmes that are both directed by recent research and offer opportunities for validation of predictions at the individual and population level.
Impact assessments for sonar operations typically use received sound levels to predict behavioural disturbance in marine mammals. However, there are indications that cetaceans may learn to associate ...exposures from distant sound sources with lower perceived risk. To investigate the roles of source distance and received level in an area without frequent sonar activity, we conducted multi-scale controlled exposure experiments ( n = 3) with 12 northern bottlenose whales near Jan Mayen, Norway. Animals were tagged with high-resolution archival tags ( n = 1 per experiment) or medium-resolution satellite tags ( n = 9 in total) and subsequently exposed to sonar. We also deployed bottom-moored recorders to acoustically monitor for whales in the exposed area. Tagged whales initiated avoidance of the sound source over a wide range of distances (0.8-28 km), with responses characteristic of beaked whales. Both onset and intensity of response were better predicted by received sound pressure level (SPL) than by source distance. Avoidance threshold SPLs estimated for each whale ranged from 117-126 dB re 1 µPa, comparable to those of other tagged beaked whales. In this pristine underwater acoustic environment, we found no indication that the source distances tested in our experiments modulated the behavioural effects of sonar, as has been suggested for locations where whales are frequently exposed to sonar.
Many ecosystems around the world are rapidly deteriorating due to both local and global pressures, and perhaps none so precipitously as coral reefs. Management of coral reefs through maintenance ...(e.g., marine‐protected areas, catchment management to improve water quality), restoration, as well as global and national governmental agreements to reduce greenhouse gas emissions (e.g., the 2015 Paris Agreement) is critical for the persistence of coral reefs. Despite these initiatives, the health and abundance of corals reefs are rapidly declining and other solutions will soon be required. We have recently discussed options for using assisted evolution (i.e., selective breeding, assisted gene flow, conditioning or epigenetic programming, and the manipulation of the coral microbiome) as a means to enhance environmental stress tolerance of corals and the success of coral reef restoration efforts. The 2014–2016 global coral bleaching event has sharpened the focus on such interventionist approaches. We highlight the necessity for consideration of alternative (e.g., hybrid) ecosystem states, discuss traits of resilient corals and coral reef ecosystems, and propose a decision tree for incorporating assisted evolution into restoration initiatives to enhance climate resilience of coral reefs.
Many ecosystems around the world are rapidly deteriorating due to both local and global pressures including climate change, and perhaps none so precipitously as coral reefs. While root causes of human‐driven climate change should be addressed, additional solutions are urgently required to ensure coral reefs persist into the future. In this Opinion piece, we address how breeding coral stock with enhanced environmental stress tolerance (assisted evolution) can increase reef resilience and contribute to the success of coral reef restoration efforts. We discuss traits of resilient corals and coral reef ecosystems, and provide guidelines for incorporating assisted evolution into restoration initiatives.
Wildlife populations and their habitats are exposed to an expanding diversity and intensity of stressors caused by human activities, within the broader context of natural processes and increasing ...pressure from climate change. Estimating how these multiple stressors affect individuals, populations, and ecosystems is thus of growing importance. However, their combined effects often cannot be predicted reliably from the individual effects of each stressor, and we lack the mechanistic understanding and analytical tools to predict their joint outcomes. We review the science of multiple stressors and present a conceptual framework that captures and reconciles the variety of existing approaches for assessing combined effects. Specifically, we show that all approaches lie along a spectrum, reflecting increasing assumptions about the mechanisms that regulate the action of single stressors and their combined effects. An emphasis on mechanisms improves analytical precision and predictive power but could introduce bias if the underlying assumptions are incorrect. A purely empirical approach has less risk of bias but requires adequate data on the effects of the full range of anticipated combinations of stressor types and magnitudes. We illustrate how this spectrum can be formalised into specific analytical methods, using an example of North Atlantic right whales feeding on limited prey resources while simultaneously being affected by entanglement in fishing gear. In practice, case-specific management needs and data availability will guide the exploration of the stressor combinations of interest and the selection of a suitable trade-off between precision and bias. We argue that the primary goal for adaptive management should be to identify the most practical and effective ways to remove or reduce specific combinations of stressors, bringing the risk of adverse impacts on populations and ecosystems below acceptable thresholds.
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•Assessing the combined effects of stressors is a primary multidisciplinary goal.•We review the science of multiple stressors and inconsistencies across disciplines.•We present a conceptual framework encompassing existing analytical approaches.•We reinforce the centrality of management in guiding analysis and interpretation.•Our approach reconciles cross-disciplinary differences and supports management.
For almost two decades, equations that use serum creatinine, age, sex, and race to eGFR have included "race" as Black or non-Black. Given considerable evidence of disparities in health and healthcare ...delivery in African American communities, some regard keeping a race term in GFR equations as a practice that differentially influences access to care and kidney transplantation. Others assert that race captures important non GFR determinants of serum creatinine and its removal from the calculation may perpetuate other disparities. The National Kidney Foundation (NKF) and American Society of Nephrology (ASN) established a task force in 2020 to reassess the inclusion of race in the estimation of GFR in the United States and its implications for diagnosis and subsequent management of patients with, or at risk for, kidney diseases. This interim report details the process, initial assessment of evidence, and values defined regarding the use of race to estimate GFR. We organized activities in phases: (
) clarify the problem and examine evidence, (
) evaluate different approaches to address use of race in GFR estimation, and (
) make recommendations. In phase one, we constructed statements about the evidence and defined values regarding equity and disparities; race and racism; GFR measurement, estimation, and equation performance; laboratory standardization; and patient perspectives. We also identified several approaches to estimate GFR and a set of attributes to evaluate these approaches. Building on evidence and values, the attributes of alternative approaches to estimate GFR will be evaluated in the next phases and recommendations will be made.
For almost 2 decades, equations that use serum creatinine, age, sex, and race to estimate glomerular filtration rate (GFR) have included “race” as Black or non-Black. Given considerable evidence of ...disparities in health and health care delivery in African American communities, some regard keeping a race term in GFR equations as a practice that differentially influences access to care and kidney transplantation. Others assert that race captures important non-GFR determinants of serum creatinine and its removal from the calculation may perpetuate other disparities. The National Kidney Foundation (NKF) and American Society of Nephrology (ASN) established a task force in 2020 to reassess the inclusion of race in the estimation of GFR in the United States and its implications for diagnosis and subsequent management of patients with, or at risk for, kidney diseases. This interim report details the process, initial assessment of evidence, and values defined regarding the use of race to estimate GFR. We organized activities in phases: (1) clarify the problem and examine evidence, (2) evaluate different approaches to address use of race in GFR estimation, and (3) make recommendations. In phase 1, we constructed statements about the evidence and defined values regarding equity and disparities; race and racism; GFR measurement, estimation, and equation performance; laboratory standardization; and patient perspectives. We also identified several approaches to estimate GFR and a set of attributes to evaluate these approaches. Building on evidence and values, the attributes of alternative approaches to estimate GFR will be evaluated in the next phases and recommendations will be made.
Use of indentation to study the degradation of photovoltaic backsheets Miller, David C.; Owen-Bellini, Michael; Hacke, Peter L.
Solar energy materials & solar cells/Solar energy materials and solar cells,
October 2019, 2019-10-00, 20191001, 2019-10-01, Letnik:
201, Številka:
C
Journal Article
Recenzirano
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The ability of electrical insulating materials within a module to act as insulators is a key safety requirement for photovoltaic (PV) technology. Presently, however, the durability of backsheets may ...not be readily assessed. For example, the mechanical tensile test continues to be developed, and its use has not been validated such that a technically based pass/fail criteria may be established. This study examines the use of simple indentation methods, including durometer hardness and instrumented indentation, as a means to quantitively assess the degradation of PV backsheets. Characteristics including: hardness, modulus, load/displacement profile, creep hold response, and residual impression are explored in an empirical study. Glass/encapsulant/backsheet mini-modules constructed using backsheets including: polyamide (specifically the AAA backsheet product), poly(ethylene terephthalate) (PET), polyvinyl fluoride (PVF) laminate (“TPE”), and polyvinylidene fluoride (PVDF) were examined. An M-type durometer as well as Berkovich and cube-corner tips were used in the indentation experiments. Additional characterizations were performed to interpret the indentation measurements including: surface roughness measurements using atomic force microscopy (AFM), a chemical structure study using Fourier-transform infrared spectroscopy (FTIR), and phase-transition measurements using differential scanning calorimetry (DSC). The results are analyzed in the context of the combined accelerated stress test (C-AST) also explored in this study. Instrumented indentation (i.e., using a Berkovich tip) was able to distinguish between backsheets and quantify the effects of accelerated testing (including up to 60%, 25%, and 20% change in hardness, modulus, and creep displacement, respectively). The embrittlement of the backsheets was not readily assessable using cube-corner indentation. Cracking of the known-bad polyamide backsheet was observed from the C-AST, which was not observed to result from steady state UV weathering.
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•Instrumented indentation (i.e., using a Berkovich tip) readily distinguished the mechanical responce of unaged backsheets.•Instrumented indentation readily distinguished the effects of accelerated stress testing, e.g., in a reliability study.•The fracture toughness of the backsheets could not be determined from the cracks at the corners of the indent impression.•The combined accelerated stress test (C-AST) in this study was able to cause cracking in known-bad AAA backsheet.
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