The visualization of molecularly labeled structures within large intact tissues in three dimensions is an area of intense focus. We describe a simple, rapid, and inexpensive method, iDISCO, that ...permits whole-mount immunolabeling with volume imaging of large cleared samples ranging from perinatal mouse embryos to adult organs, such as brains or kidneys. iDISCO is modeled on classical histology techniques, facilitating translation of section staining assays to intact tissues, as evidenced by compatibility with 28 antibodies to both endogenous antigens and transgenic reporters like GFP. When applied to degenerating neurons, iDISCO revealed unexpected variability in number of apoptotic neurons within individual sensory ganglia despite tight control of total number in all ganglia. It also permitted imaging of single degenerating axons in adult brain and the first visualization of cleaved Caspase-3 in degenerating embryonic sensory axons in vivo, even single axons. iDISCO enables facile volume imaging of immunolabeled structures in complex tissues. PAPERCLIP:
This chapter reviews current thinking about environment-development issues in the transitional zones between distinctly urban and unambiguously rural areas, known variously as rural-urban ...fringes/transition zones, or peri-urban zones/areas or interfaces (PUI). Such concerns reflect the growing real-world limitations of traditional concepts of a simple rural-urban dichotomy. Moreover, recent archaeological research suggests that these phenomena may have ancient antecedents. Present-day fringes/interfaces have become intimately bound up with notions of (more) sustainable urbanization and urban development, with different issues and agendas manifested in different geohistorical zones of urbanization. Following an overview of planning issues in (post)industrial societies, the chapter addresses the complexities of changing peri-urban production and livelihood systems in the context of rapid urbanization in poorer countries, distinctive peri-urban challenges of appropriate and flexible planning and development, and the future prospects for enhanced sustainability in this most challenging category of development-environment interfaces. Possibilities for mutual learning between geohistorical regions are also raised.
Evidence suggests that excise taxes on tobacco improve fetal health. However, it remains unknown if smoke exposure in early life causes lasting harm to children. I find that in utero exposure to a ...dollar increase in the state cigarette tax causes a 10 percent decrease in sick days from school and a 4.7 percent decrease in having two or more doctor visits. I present additional evidence for decreases in hospitalizations and asthma. This supports the hypothesis that exposure to cigarette smoke in utero and infancy carries significant medium-term costs, and that excise taxes can lead to lasting intergenerational improvements in well-being.
The microbiome is known to play an important role in the development and maintenance of human health. During early childhood the gut microbiome undergoes a rapid evolution, making this developmental ...window most susceptible to microbial manipulation and, therefore, most vulnerable to environmental stimuli. Such stimuli may induce persistent alterations (or dysbiosis) in microbiome and/or host physiology, thereby resulting in susceptibility to subsequent disease development. This phenomenon is frequently described as “the microbial developmental origins of disease.” In this topic of the month, we call attention to the microbial developmental origins of disease by examining the potential for childhood antibiotic exposures and appendectomy (ie, inducers of dysbiosis) to influence the pathogenesis of certain multifactorial, common diseases (eg, celiac disease, inflammatory bowel disease, obesity), especially those with increasing incidence worldwide. We conclude that fully appreciating the critical components in the microbial developmental origins of common chronic disorders is a major task ahead of pediatric gastroenterologists in the 21st century. Such information will be key in working to prevent numerous common and emerging disorders.
Axonal death disrupts functional connectivity of neural circuits and is a critical feature of many neurodegenerative disorders. Pathological axon degeneration often occurs independently of known ...programmed death pathways, but the underlying molecular mechanisms remain largely unknown. Using traumatic injury as a model, we systematically investigate mitogen-activated protein kinase (MAPK) families and delineate a MAPK cascade that represents the early degenerative response to axonal injury. The adaptor protein Sarm1 is required for activation of this MAPK cascade, and this Sarm1-MAPK pathway disrupts axonal energy homeostasis, leading to ATP depletion before physical breakdown of damaged axons. The protective cytoNmnat1/Wlds protein inhibits activation of this MAPK cascade. Further, MKK4, a key component in the Sarm1-MAPK pathway, is antagonized by AKT signaling, which modulates the degenerative response by limiting activation of downstream JNK signaling. Our results reveal a regulatory mechanism that integrates distinct signals to instruct pathological axon degeneration.
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•A MAPK cascade is a central pathway underlying pathological axon degeneration•Sarm1 is required for activation of the MAPK cascade in this degenerative response•Sarm1-MAPK pathway triggers a local energy deficit in axons leading to degeneration•CytoNmnat1/Wlds and AKT converge on the MAPK cascade to regulate axon degeneration
This study delineates a MAPK cascade as the central pathway downstream of the adaptor protein Sarm1 in promoting pathological axonal death after injury. Early activation of the Sarm1-MAPK pathway in response to axonal damage triggers a local energy deficit that leads to final activation of calpains and breakdown of axonal.
•Altered sensory and perceptual function is recognized as an important characteristic of Autism Spectrum Disorder (ASD).•Disrupted oscillatory synchronization in ASD is observable in numerous sensory ...and perceptual tasks and in multiple frequency bands of the oscillatory hierarchy.•Oscillatory changes in ASD are consistent with a disturbance in the balance of excitation and inhibition, as well as disruption of thalamic function.•Altered network synchronization makes contributions to both perceptual enhancement and impairment in ASD.
Autism Spectrum Disorder (ASD) is a highly prevalent developmental disability characterized by deficits in social communication and interaction, restricted interests, and repetitive behaviors. Recently, anomalous sensory and perceptual function has gained an increased level of recognition as an important feature of ASD. A specific impairment in the ability to integrate information across brain networks has been proposed to contribute to these disruptions. A crucial mechanism for these integrative processes is the rhythmic synchronization of neuronal excitability across neural populations; collectively known as oscillations. In ASD there is believed to be a deficit in the ability to efficiently couple functional neural networks using these oscillations. This review discusses evidence for disruptions in oscillatory synchronization in ASD, and how disturbance of this neural mechanism contributes to alterations in sensory and perceptual function. The review also frames oscillatory data from the perspective of prevailing neurobiologically-inspired theories of ASD.
Temperature fields provide a noninvasive approach for manipulating individual macromolecules in solution. Utilizing thermophoresis and other secondary effects resulting from the inhomogeneous ...distribution of crowding agents, one may gain valuable insights into the interactions of molecular mixtures. In this report, we examine the steady-state concentration distribution and dynamics of DNA molecules in a poly(ethylene glycol) (PEG)/water solution when exposed to localized temperature gradients generated by optical heating of a thin chrome layer at a liquid–solid boundary. This allowed us to experimentally investigate the interplay between DNA thermophoresis and PEG-induced entropic depletion effects. Our quantitative analysis demonstrates that the depletion effects dominate over DNA thermophoresis, causing the DNA polymers to migrate toward the heat source. Additionally, we explore the transient stretching of individual DNA molecules in thermally induced PEG gradients and estimate the contributing forces.
ABSTRACT
The massive elliptical galaxy M87 has been the subject of several supermassive black hole mass measurements from stellar dynamics, gas dynamics, and recently the black hole shadow by the ...Event Horizon Telescope. This uniquely positions M87 as a benchmark for alternative black hole mass determination methods. Here, we use stellar kinematics extracted from integral-field spectroscopy observations with adaptive optics using Multi Unit Spectroscopic Explorer (MUSE) and Optically Adaptive System for Imaging Spectroscopy (OASIS). We exploit our high-resolution integral field spectroscopy to spectrally decompose the central actice galactic nuclei (AGNs) from the stars. We derive an accurate inner stellar-density profile and find it is flatter than previously assumed. We also use the spectrally extracted AGNs as a reference to accurately determine the observed MUSE and OASIS AO PSF. We then perform Jeans anisotropic modelling, with a new flexible spatially variable anisotropy, and measure the anisotropy profile, stellar mass-to-light variations, inner dark matter fraction, and black hole mass. Our preferred black hole mass is MBH = (8.7 ± 1.2random ± 1.3systematic) × 109 M⊙. However, using the inner stellar density from previous studies, we find a preferred black hole mass of $M_{\rm BH} = (5.5^{+0.5}_{-0.3}) \times 10^9 \ M_\odot$, consistent with previous work. We find that this is the primary cause of the difference between our results and previous work, in addition to smaller contributions due to kinematics and modelling method. We conduct numerous systematic tests of the kinematics and model assumptions and conclude that uncertainties in the black hole mass of M87 from previous determinations may have been underestimated and further analyses are needed.
The outdated and discredited notion of a binary urban–rural divide remains stubbornly widely used. However, it both sets up and reflects oppositional politics and processes between the two supposedly ...mutually exclusive categories of space and place, which hamper urban–rural partnerships. Empirical reality on the ground is far more complex. Just as more appropriate conceptualisations and approaches have evolved, so new research methods and tools have been developed to overcome the different institutional barriers and stakeholder priorities in the face of contemporary real-world complexities and the urgency of tackling the ‘wicked’ challenges of sustainability, which also underpin the New Leipzig Charter. The focus here is on co-production and related methods, which can be considered as representing the top-most rungs of Arnstein’s (1969) Ladder of Participation. The relevance and application of these methods are exemplified from the work of Mistra Urban Futures in relation to transcending conventional European urban–rural divisions and forming partnerships, with due attention to problems and limitations. Such methods have considerable potential, including for addressing unequal power relations, but are time-consuming and require careful adaptation to each situation.
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