Although, rare  and common (sporadic) forms can occur for the same disease, it is unclear whether this reflects several distinct pathogenic pathways or the convergence of different causes into a common form of nerve cell death. Remarkably, neurodegenerative diseases are increasingly found to be accompanied by activation of the innate immune surveillance system normally associated with pathogen recognition and response. Innate surveillance is the cell's quality control system for the purpose of detecting such danger signals and responding in an appropriate manner. Innate surveillance is an “intelligent system,” in that the manner of response is relevant to the magnitude and duration of the threat. If possible, the threat is dealt with within the cell in which it is detected, by degrading the danger signal(s) and restoring homeostasis. If this is not successful then an inflammatory response is instigated that is aimed at restricting the spread of the threat by elevating degradative pathways, sensitizing neighboring cells, and recruiting specialized cell types to the site. If the danger signal persists, then the ultimate response can include not only the programmed cell death of the original cell, but the contents of this dead cell can also bring about the death of adjacent sensitized cells. These responses are clearly aimed at destroying the ability of the detected pathogen to propagate and spread. Innate surveillance comprises intracellular, extracellular, non-cell autonomous and systemic processes. Recent studies have revealed how multiple steps in these processes involve proteins that, through their mutation, have been linked to many familial forms of neurodegenerative disease. This suggests that individuals harboring these mutations may have an amplified response to innate-mediated damage in neural tissues, and renders innate surveillance mediated cell death a plausible common pathogenic pathway responsible for neurodegenerative diseases, in both familial and sporadic forms. Here we have assembled evidence in favor of the hypothesis that neurodegenerative disease is the cumulative result of chronic activation of the innate surveillance pathway, triggered by endogenous or environmental  Different chronic neurodegenerative diseases are distinguished by the type of neurons and the regions of the brain that are first affected. In each case the different initial symptoms and functions lost are due to the progressive death of specific neurons. Neurodegenerative diseases also tend to be diverse in their timing, with some being congenital whereas others are late age-at-onset. Those that progress, gradually exhibit commonalities. A large number and wide variety of causes of neurodegeneration have been identified. These range from inherited single gene mutation effects, to environmental factors or complex mixtures of both. It has been difficult to establish cause and effect pathways and to reconcile how so many apparently disparate conditions all result in similar outcomes. Either the diverse causes trigger multiple pathogenic pathways, or alternatively they must converge into a common mechanism of cell death and tissue damage. Familial cases of neurodegeneration, while typically less frequent than sporadic cases, have provided opportunities to gain insight into the genetic factors and thereby the underlying biological processes.In this review we present evidence to support the hypothesis that a common pathogenic mechanism for neurodegenerative disease exists, and is mediated by innate surveillance-cell death.defense strategy in combating infection. Where cells harbor and are unable to destroy pathogens then cell death is a means to limit propagation and spread of the pathogen. Similarly, if a cell has acquired somatic mutations that predispose to tumorigenesis, then elimination by cell death is a means to neutralize the threat. In each of these situations the innate immune surveillance system programs the appropriate cell death pathways.Cell death is vital in the biology of multicellular organisms. It is integral to tissue remodeling during development, where programmed cell death is required to deconstruct, remove and replace tissues. Cell death is also a vital In the last few years, a growing body of literature has appeared, pointing to innate surveillance system activity being an early, elemental and consistent hallmark of neurodegenerative disease. In particular recent genome wide association studies in Alzheimer's disease  that detect trigger molecules—foreign Pathogen Associated Molecular Patterns (PAMPs) or endogenous Danger Associated Molecular Patterns (DAMPs), the latter typically being elevated in response to perturbation of homeostasis. The immediate response is an escalation of appropriate degradation pathways  in order to eliminate the intruder and/or restore homeostasis. Persistence of trigger signal molecules provokes the production and release of pro-inflammatory and anti-inflammatory cytokines, which sensitize adjacent cells. This is followed by programmed death (by necroptosis) of cells in which trigger molecules are detected  by adjacent sensitized cells . At least some of this modification appears devoid of function, other than to identify nucleic acids as belonging to the host. Indeed, such modifications are required for exogenous mRNA to avoid stimulating the innate surveillance response, even when its sequence is identical to that of the endogenous mRNA  interacts dynamically with membranous structures in the cell including the Golgi apparatus, mitochondria, peroxisomes, endosomes, lysosomes, and autophagosomes. The ER plays a key role in protein biosynthesis of cellular components and therefore it is a target for pathogens seeking to co-opt this capacity for replication, as well as being a risk site for the synthesis of aberrant proteins that can contribute to tumourigenesis. Newly synthesized proteins entering the ER are either folded into their required conformation for targeting to organelles or identified as unfolded and are then destined for degradation.The unfolded protein response (UPR) monitors and maintains protein-folding homeostasis within the ER  implicating defects in this pathway, in the pathogenesis of this form of neurodegeneration.A distinct system of unfolded protein response in the mitochondria is best characterized in The host defense system operates in an environment comprising a complex mixture of molecules - some pose a threat while others are either harmless or beneficial. Recognition of threatening molecules occurs on the basis of their molecular pattern Figure .Molecular patterns exhibited by a diverse array of exogenous, foreign pathogen molecules of viral, bacterial and fungal origin are recognized by the innate immune surveillance system and trigger an inflammatory response. Some “non-pathogenic” molecules also act as trigger molecules, invoking a sterile inflammatory response. Such molecules may be threatening, such as asbestos . In an effort to distinguish these, we have used “D” for danger and “d” for damage.While labeled in the literature with common and therefore confusing acronyms, two types of molecular patterns factor in the innate surveillance system—those that signal Pathogen Associated Molecular Patterns (PAMPs) can be molecules derived from pathogens that either contain recognizable patterns or are devoid of modifications that would otherwise mask their recognition. Pathogen RNAs will not have been exposed to the same post-transcriptional modifications as host RNAs and can be distinguished on this basis  and utilized as intracellular danger signaling molecules. Ribonuclease IRE-1 cleavage produces a pool of RNA products with unusual 3′ cyclic phosphates, that are recognized by Pattern Recognition Receptors.Pattern recognition is a major element of innate surveillance. While the host needs to be able to distinguish “self” from “non-self,” and do so in a manner uncorrupted by pathogen mimicry, it also needs to monitor endogenous trigger molecules—those that act as sentinels of a developmental switch or a perturbation in homeostasis. Post-transcriptional modification of RNA and post-translational modification of proteins are processes that cells utilize to either mask or unmask molecular patterns that trigger recognition. dAMPs)—damage Associated Molecular Patterns  can thereby activate the innate surveillance response. Forms of programmed cell death (such as necroptosis) facilitate the release of dAMPs that are recognized by PRRs on adjacent cells. Sensitized adjacent cells can have elevated levels of PRRs thereby mediating their non-cell autonomous death. In this manner dAMPs act as extracellular signaling molecules.Cell death comes in various forms, certain types of which lead to the extracellular appearance of normally intracellular molecules. Some of these cell damage molecules—spätzle is an extracellular ligand for the cell surface receptor Toll, is indicative of cell-cell signaling in the system  can include environmental causes . TLRs have, at least in some cases, been induced in the cells adjacent to the primary cell undergoing an inflammatory response, by virtue of the cytokines that the primary response cell produces  in vertebrates and Toll-related receptors (TRRs) in Drosophila. Functional relationships are likely based on their cellular localization, some common pattern recognition and inter-connected signal transduction pathways  and restoring homeostasis by reprogramming gene expression. In some cases this includes the cessation of processes that contribute to the trigger signal and increasing the activity of degradative pathways. A diverse array of such degradative processes are activated Box .Box 2Pathways responsible for proteostasis and RNAstasis in the event of stress responseUnfolded Protein Response (UPR)—integrated pathway for sensing and overcoming the accumulation of unfolded or mis-folded proteins within the ER, or in the event of persistent accumulation, to induce innate surveillance-mediated cell death —pathway is modulated by the UPR and targets misfolded proteins to the cytosol for their ubiquitination and subsequent proteosomal degradation.Autophagy—degradation of macromolecular complexes including protein aggregates and RNA granules, as well as damaged organelles through fusion with lysosomes.Granulophagy—in response to stress polysomes disassociate and their mRNAs form granules (stress granules or P-bodies) with specific RNA binding proteins (including TDP43 and FUS). These stress granules hold the RNAs until the stress is relieved or failing this are transported (by VCP) to autophagosomes that then fuse with lysosomes (regulated by the inhibitor CHMP2B) for degradation and subsequent recycling.Mitochondrial Unfolded Protein Response (UPRmt)—the location of activating transcription factor associated with stress-1 (ATFS-1) is sensitive to unfolded protein stress inside the mitochondria. Stress restricts mitochondrial importation of ATFS-1 resulting in higher cytosolic level, that in turn leads to its nuclear localization where it activates target genes, the products of which act to protect the mitochondria. Failure to resolve the mitochondrial stress leads to autophagy  of the damaged mitochondria.Heat Shock Response (HSR)—includes dissociation of heat shock factor-1 (HSF1) from inhibitory binding with heat shock factor 90 (HSP90). HSF-1 induces heat shock target genes that in turn mediate protein quality control pathways.Nonsense Mediated Decay (NMD)—a highly conserved RNA integrity surveillance pathway that not only leads to the elimination of faulty endogenous transcripts and viral RNAs, but also regulates levels of ~10% of normal cellular transcripts —the major pathway for non-lysosomal degradation of proteins.RNA exosome (SKIV2L)—an exoribonuclease complex for RNA processing, quality control and turnover regulation. In low stress environments it efficiently digests mRNAs including those encoding cytokines. It is negatively regulated by stress, resulting in greater stability of cytokine mRNAs (and therefore elevated cytokine levels) as well as incomplete removal of IRE1 RNA digestion products that are recognized by RIG-Like Receptors (RLRs) of the innate surveillance system  resulting in its activation  have mutations in various familial cases of the neurodegenerative diseases fronto-temporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). While TDP43 and FUS have multiple functions, both have been found in RNA stress granules  as a regulator of the trafficking of these aggregates for degradation . This clustering of mutations around the autophagy function implies that defective stress granule metabolism has a causal role to play in neurodegenerative disease.In response to stress, cells reprogram translation—they disassociate polysomes from mRNA and specific proteins are aggregated into granules , whereas oxidative phosphorylation in the mitochondria produces energy (ATP). Once cells cease dividing and differentiate they have reduced biosynthetic requirements and shift to mainly utilizing glucose as an energy source for cell function. Since pathogens strive to replicate themselves, their biosynthesis requires structural components and therefore a reduction in mitochondrial metabolism, in favor of glycolysis, facilitates their replication. Similarly cancer cells favor glycolysis as it facilitates cell division. The state of the mitochondria and its perturbation is therefore closely monitored, including the mechanism of mitochondrial unfolded protein response (described above). The functional integrity of the mitochondria is maintained by mitophagy, a specific form of autophagy. Damaged or dysfunctional mitochondria are recognized as such and shunted into the autophagy process, for recycling and regeneration. Defects in this process are detected by PRRs to trigger alarm in the cell, resulting in an elevated response to the danger, including increased mitophagy . These molecules have been identified in different cell types and model organisms and likely vary in composition and function in different circumstances  those that do not release dAMPs, and thereby limit and contain the response.Given the importance of programmed cell death as a defense mechanism and the intense selective pressure this system faces from rapidly evolving pathogens, it is hardly surprising that multiple forms of programmed cell death have evolved. There appear to be two functionally distinct forms with respect to the innate surveillance system—(1) those that release Apoptosis is a well-characterized form of programmed cell death , effector  or inflammatory . The intrinsic pathway of caspase activation involves mitochondria. A variety of stimuli cause mitochondria to release cytochrome c, that in turn binds to and sequesters the adaptor protein Apaf-1. Apaf-1 binds, aggregates and cleaves procaspase-9 molecules, to trigger a caspase cascade , the nuclear protein HMGB1, F-Actin, RNA, and DNA  yet they do exhibit Toll-like receptor mediated cell death. This is due to the expression of intracellular dAMPs  Polymerase (PARP-1)  and frontotemporal dementia (FTD) exhibit overlap in both clinical and genetic features. They share multiple common genetic causes and can be found separately or co-incidentally in different members of the same family  are in genes that encode RNA-metabolizing proteins. The remaining two genes that have been identified (TREX1 and SAMHD1) also encode enzymes that have roles in nucleic acid metabolism, and have recently both been shown to also have ribonuclease activity . AGS is a genetically heterogeneous autosomal recessive encephalopathy characterized in its most severe form by cerebral atrophy, leukodystrophy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon (IFNA1), and negative serologic investigations for common prenatal infections. AGS is phenotypically similar to Therefore, loss-of-function mutations in a variety of proteins that are required for the degradation of RNA identify the accumulation of specific RNA danger molecules that trigger innate surveillance activation as a common causal mechanism through which neurodegeneration is initiated.Gain-of-function mutations in neurodegenerative diseases have generally proven more difficult to attribute. In a few cases the gain-of-function can be an enhancement of the normal function of the relevant protein and a plausible pathway to neurodegeneration is evident. For example, CHMP2B is an inhibitor of autophagosome-lysosome fusion . This disease is due to expansion of either of two repeat sequences. These repeats are transcribed as either 3′ untranslated RNA (CUG in DM1) or intronic RNA (CCUG in DM2). Both of these expanded repeat RNAs bind and sequester the alternative splicing factor Drosophila models where RNA in various forms has been tested for its ability to initiate cell death . These hallmark pathogen response changes in Drosophila are consistent with observations of immune pathway activation  before clinical onset in Huntington's disease Bjorkqvist et al.  exhibits a phenotype consistent with the symptoms of the human disease. The survival of SODG93A mice is extended by genetic removal of the TLR4 pattern recognition receptor, indicating a role for innate surveillance in the pathogenesis  is a progressive neurodegenerative disease that is thought to have both genetic and environmental causes. Certain chemicals in the environment are strongly associated with PD. These include the herbicides rotenone and paraquat  or PINK1 cause early onset recessive PD, with both proteins having important roles to play in mitophagy (as described earlier). Drosophila models reveal that mitochondrial dysfunction in PINK1 mutants is complemented by parkin , indicating the activation of innate surveillance , a distinct compartment of the endoplasmic reticulum  occurs in both sporadic and familial forms, with genetic causes or contributions to each form. Familial forms are earlier onset, with mutations found in genes that encode the amyloid precursor protein (APP) and two components of its cleavage (presenilin 1 and 2) to amyloid beta protein, a major component of amyloid plaques found in AD brain. These findings led to the amyloid cascade hypothesis—in essence that fragments of APP cause AD . Pathogens either directly or indirectly generate such signaling molecules, that the systemic component of innate surveillance then utilizes to communicate the presence of infection and primes the body to prepare for its potential spread. While such sensitization provokes host cells to then actively restrict infection, it also appears to increase susceptibility to other processes mediated by innate surveillance—including neurodegeneration. A very clear illustration of this phenomenon occurs following sepsis. Long-term cognitive impairment and functional disability are frequent consequences among survivors of severe sepsis  to the site of activation . The same ADAR1 mutation can cause differing symptoms  of the defined genetic causes of neurodegeneration in humans, are therefore a key strategy in establishing cause and effect relationships in the pathophysiology of neurodegenerative disease.Drosophila; commented and provided intellectual input into several manuscript drafts. DF conducted literature searches on RNA based pathology, particularly the distinction between “self” and “non-self” RNAs and contributed Figure RR conceived the hypothesis, initiated the assembly of supporting data, and wrote the first and final drafts following input from each of the co-authors. SR contributed material on the molecular and cellular components of inflammatory pathways, their roles in combating infection and their dysfunction in disease; intellectual contributions to both the formulation of the hypothesis and the form and content of the manuscript. LO contributed material on animals models, particularly This research is funded in part by Project Grant (APP1069348) from the National Health and Medical Research Council of Australia and a grant from the National Ataxia Foundation (USA).RR has previously been a consultant for Glaxo-Wellcome (later GlaxoSmithKline), but is not currently and was not during the preparation of this manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We find infant faces highly attractive as a result of specific features which Konrad Lorenz termed “Kindchenschema” or “baby schema,” and this is considered to be an important adaptive trait for promoting protective and caregiving behaviors in adults, thereby increasing the chances of infant survival. This review first examines the behavioral support for this effect and physical and behavioral factors which can influence it. It then provides details of the increasing number of neuroimaging and electrophysiological studies investigating the neural circuitry underlying this baby schema effect in parents and non-parents of both sexes. Next it considers potential hormonal contributions to the baby schema effect in both sexes and the neural effects associated with reduced responses to infant cues in post-partum depression, anxiety and drug taking. Overall the findings reviewed reveal a very extensive neural circuitry involved in our perception of cuteness in infant faces, with enhanced activation compared to adult faces being found in brain regions involved in face perception, attention, emotion, empathy, memory, reward and attachment, theory of mind and also control of motor responses. Both mothers and fathers also show evidence for enhanced responses in these same neural systems when viewing their own as opposed to another child. Furthermore, responses to infant cues in many of these neural systems are reduced in mothers with post-partum depression or anxiety or have taken addictive drugs throughout pregnancy. In general reproductively active women tend to rate infant faces as cuter than men, which may reflect both heightened attention to relevant cues and a stronger activation in their brain reward circuitry. Perception of infant cuteness may also be influenced by reproductive hormones with the hypothalamic neuropeptide oxytocin being most strongly associated to date with increased attention and attraction to infant cues in both sexes. The faces of both infants and young children are potent cross-cultural emotive stimuli that adults find both very cute and highly likeable and evoke feelings of protectiveness and care which thereby serve to aid survival of these vulnerable individuals , have shown that there is a degree of overlap in neural processing of infant and adult faces since both activate primary visual processing areas as well as those more specifically associated with face perception, such as the fusiform face area (FFA)   and children (low baby schema) or through direct manipulation of baby schema features in specific face stimuli. From these studies there is evidence that intensity of baby schema does influence neural responses in visual and face processing regions as well as in regions controlling emotional responses, attention and memory, theory of mind and reward. An ERP study found that N1 amplitude localized in the FFG was increased in response to infant faces compared to adult, although not child faces, in both males and females. On the other hand N2 amplitude localized in the medial occipital cortex and FFG, uncus and medial OFC was increased in response to infant compared with child and adult faces, although only in females   and adolescence (11–15 years) females exhibited the highest preference, but that this declined thereafter during early (19–35 years) and later (46–75 years) adulthood. Interestingly males showed a relatively constant preference across all four age groups  are more sensitive compared to those who do not  and its effects on trust, cooperation, face emotion recognition, empathy, in-group preferences and also on social bonds and maternal attachment  or an unfamiliar vs. familiar child. Oxytocin also decreased functional connectivity within a fronto-pallido-hippocampal network for own vs. unfamiliar child  in 2007 found that 5.2% of pregnant women reported using illicit drugs during pregnancy; and an additional 11.6% reported using alcohol and 16.4% tobacco. Mothers using cocaine during pregnancy have been found to respond more passively and in a more disengaged way to their babies (Gottwald and Thurman, In line with the potent impact of facial baby schema on adult attraction, protection and caregiving behaviors, neuroimaging and electrophysiological studies reveal an extensive neural circuitry involved in our perception of infant faces. Enhanced activation in response to infant compared to adult faces is found in cortical and sub-cortical brain regions involved in face perception, attention, emotion, empathy, memory, reward and attachment, theory of mind and also control of motor responses. Both mothers and fathers also show evidence for enhanced responses in these same neural systems when viewing their own as opposed to another child. Importantly post-partum depression, anxiety and drug-taking all tend to reduce responsivity in this neural circuitry involved in processing and responding to infant face cues, with the most extensive changes in this respect appearing to occur in women taking addictive drugs during pregnancy.Reproductively active women tend to rate infant faces as cuter than men and this may be mainly a reflection of both heightened attention to relevant cues and a stronger activation in their brain reward circuitry. In both sexes perceived cuteness of infant faces is influenced by reproductive hormones, with women in particular showing an ovulatory peak in interest during their cycle and an apparent decline post-menopause. To date evidence does not support major roles for the gonadal hormones estradiol, progesterone and testosterone in influencing responsivity to infant faces, although there is increasing evidence linking oxytocin with facilitation of attention toward and attractiveness of infant cues in both sexes.Future studies need to explore in more detail the functional relevance of specific components of the widespread neural circuitry associated with the enhanced responses to infant faces. To date, for example, only one study has demonstrated the functional importance of the dorsolateral prefrontal cortex in the processing of emotional baby faces using rTMS (Baeken et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Synaptic communication requires constant adjustments of pre- and postsynaptic efficacies. In addition to synaptic long term plasticity, the presynaptic machinery underlies homeostatic regulations which prevent out of range transmitter release. In this minireview we will discuss the relevance of selected presynaptic mechanisms to epilepsy including voltage- and ligand-gated ion channels as well as cannabinoid and adenosine receptor signaling. Many studies highlighted the importance of homeostasis in neuronal signaling either within neurons, then called “intrinsic plasticity” or between neurons, referred to as “synaptic scaling”  and K+ (Kv) channels can be shifted along the axon , when seizures invade the hippocampus and feedforward inhibition of CA3 pyramidal cells via interneurons is compromised -triggered calcium influx in the synaptic terminal, regulation of ion channels which shape the axonal AP and terminal depolarization is an effective mechanism of presynaptic plasticity. With this definition, the AP initiation zone (AIZ) could be viewed as part of the presynaptic equipment. A striking form of homeostatic plasticity has been documented for the AIZ: this entire subcellular structure including voltage-gated Nan Figure , therebyn Figure . Such axn Figure . Other i in vivo and, depending on the type of neuron, triggered cognitive dysfunction or anxiety in our mouse model of epilepsy  currents  is released from astrocytes and can enhance neuronal excitability through its direct action onto purinergic receptors. However, ATP can also exert indirect effects upon its enzymatic conversion to adenosine and signaling through adenosine A1 receptors, which reduces synaptic glutamate release , likely act primarily in axons (Stefani et al., In agreement with the proposed critical role of presynaptic compartments in the regulation of neural network homeostasis, diverse pharmacological agents with a presynaptic mode of action were reported to be effective in the treatment of epilepsy. In particular drugs which provide rapid adaptation against excessive excitation, e.g., via use-dependent inhibition of NaThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The lifespan of fast-cycling roots is a critical parameter determining a large flux of plant carbon into soil through root turnover and is a biological feature regulating the capacity of a plant to capture soil water and nutrients via root-age-related physiological processes. While the importance of root lifespan to whole-plant and ecosystem processes is increasingly recognized, robust descriptions of this dynamic process and its response to changes in climatic and edaphic factors are lacking. Here we synthesize available information and propose testable hypotheses using conceptual models to describe how changes in temperature, water, nitrogen (N), and phosphorus (P) availability impact fine root lifespan within a species. Each model is based on intrinsic responses including root physiological activity and alteration of carbohydrate allocation at the whole-plant level as well as extrinsic factors including mycorrhizal fungi and pressure from pathogens, herbivores, and other microbes. Simplifying interactions among these factors, we propose three general principles describing fine root responses to complex environmental gradients. First, increases in a factor that strongly constrains plant growth  should result in increased fine root lifespan. Second, increases in a factor that exceeds plant demand or tolerance should result in decreased lifespan. Third, as multiple factors interact fine root responses should be determined by the most dominant factor controlling plant growth. Moving forward, field experiments should determine which types of species  will express greater plasticity in response to environmental gradients while ecosystem models may begin to incorporate more detailed descriptions of root lifespan and turnover. Together these efforts will improve quantitative understanding of root dynamics and help to identify areas where future research should be focused. Describing and predicting patterns of plant traits and growth strategies has long attracted attention from plant and ecosystem ecologists . While aThe lifespan of fast-cycling, absorptive roots determines root turnover, and consequently impacts carbon (C), nutrient, and water cycles for plants and whole-ecosystems. While estimates vary, between 10 and 40% of net primary productivity is likely allocated to the production and turnover of fine roots , with muBased on current evidence, it is clear that root lifespan and turnover are highly variable in both space and time, with a wide range of estimates reported across biomes , within Pinus palustris and Pinus taeda across sites in the southeastern United States , soil moisture, temperature, N availability, and phosphorus (P) availability. First, we focus on as trees . Additiovice versa.Second, we primarily refer to root lifespan rather than root turnover because lifespan is a simple parameter that can be directly measured and its variation can be related to environmental factors. By contrast, variation in root turnover can be difficult to interpret as shifts in turnover result from various combinations of increasing or decreasing root production, standing biomass, and mortality. Lifespan can be used to estimate turnover  which alFigure 1). Pathways 1 and 2 represent potential increases in root lifespan through increased allocation of plant resources to absorptive fine roots under favorable growing conditions and increased carbohydrate supply (Pathway 1) or by colonization of roots by beneficial organisms including some mycorrhizal fungi and root endophytes which can provide direct protection from pathogens and saprotrophs or improve whole-plant nutrient balance (Pathway 2). Pathways 3 and 4 reduce lifespan through increased pressure from soil pathogens, saprophytic fungi, and herbivores (Pathway 3) or by physiological stress within the root resulting from poor growing conditions, high respiration, and buildup of free radicals (Pathway 4). Pathways 1 and 4 can generally be considered intrinsic plant responses while 2 and 3 are more extrinsic. Of particular importance will be determining if and where different environmental factors transition from being resource factors benefitting plant health and root lifespan to becoming stress factors impairing root function and reducing lifespan.In this framework, we propose a set of four broad pathways through which root lifespan is either reduced or extended along environmental gradients . Roots growing at lower temperatures tend to have lower respiration rates . Furthermore, increased temperature variability may limit the ability of roots to acclimate to increased temperatures and exacerbate the effects of temperature change. However, there are likely to be complex interactions between temperature and plant productivity, nutrient mineralization rates, and water use (see discussions below).Based on these observations, it appears that under most circumstances root lifespan will decrease with increasing temperature and with increasing temperature variability .Variation in the response of root lifespan to changes in water availability likely depends on whether water strongly limits root or whole-plant growth. On one side, adding water and alleviating drought should increase whole-plant productivity and increase root lifespan . Higher Importantly, as water availability can vary dramatically across a site with changes in soil characteristics and topographic position, so too might the response of individual roots to changes in soil moisture. Perhaps reflecting within-site variability, root responses to patch-level water additions may differ from those at the whole plot level. Hydraulic redistribution may also play a role in mediating responses of fine roots to drought. In a study by The effect of N addition on root dynamics has perhaps received more attention than any other environmental factor, yet, little broad consensus has been found. Studies directly observing root dynamics have variably reported increased, no change, and decreased fine root lifespan see . AdditioFigure 4). By contrast, whole-plot level N additions may decrease root lifespan if the treatments saturate plant demand and result in damage to root tissues as the costs of N uptake and storage  but no change in lifespan for two others  following patch additions of N. After whole-plot fertilizations, M. Coleman  observed a decrease in lifespan for Pinus taeda and a slight increase in lifespan for Populus deltoids. These mixed responses echo those found by Intrinsic species differences may also have a role to play in defining fine root responses to increases in N availability . Though The addition of N in terrestrial ecosystems also interacts with the biotic and abiotic soil environment, thus, its impact on root growth and lifespan may go beyond simple alterations in mineral nutrition . SmithwiFigure 4). However, it is also possible that lifespan may increase with decreasing N availability in some circumstances, particularly in cases where N exists in mobile forms . Here, old roots may be retained to minimize resource loss through turnover of root tissue . Because excessive P levels rarely occur in nature, root lifespan does not show a drop at relatively high P levels as in the case of excessive N . These predictions may be altered by mediations from mycorrhizal fungi, which respond strongly to alterations in soil fertility . First, when plant growth is strongly limited by a given factor or resource, increases in that factor should result in increased lifespan . This occurs as stress is relieved, first at the root level , and later at the whole-plant level as growing conditions improve, carbohydrate reserves increase, and plants can allocate additional resources to maintain root performance or distribute resources to root symbionts . Second, when a given factor or resource is in excess of plant need or demand, further increases should result in a decline in root lifespan . This occurs as stress factors at the root level increase  and whole-plant growth is again impaired. Based on these two assertions the longest fine root lifespan for a given species should be found in locations with average climate levels for a given species and moderate to high, but not excessive fertility levels.Given current limitations in observing the belowground component of natural ecosystems, it is often difficult to predict changes in root dynamics in relation to broader changes in climate or fertility. As a first approximation, a few general principles may be drawn .Key to understanding variation in root lifespan within a species is to determine which species or what types of species are likely to be most plastic when facing changes in temperature, water availability, and soil fertility. The degree to which environmental factors impact root lifespan may be related to root morphology and chemistry, whole-plant growth strategies , or the type and intensity of mycorrhizal association. While direct comparisons here are few, some evidence of systematic differences among species has emerged. Currently, the role that mycorrhizal fungi play in modulating root responses to environmental variability remains largely unknown. A wide taxonomic array of fungi form intimate relationships with the majority of terrestrial plant roots , and simFigure 1). Regardless, the specific effects are likely to depend on the strength of the stress as well as the fungal and plant species involved.While the direct effects of fungal colonization on root lifespan remain elusive, several studies have found that different mycorrhizal fungi can confer resistance to various environmental stress factors including drought , temperaIn the previous sections, we have alluded to the role that soils play in modulating root responses to environmental factors. Highly complex, soils have the capacity to enhance or buffer plant responses to changes in climate and soil fertility through varied physical and chemical properties. For example, though the frequency and intensity of water stress is certainly defined in part by precipitation, physical properties of soil largely determine the total water storage capacity of an ecosystem and the amount of water available for plant uptake . As a re3+) are likely to greatly improve our understanding of root responses to environmental factors at scales ranging from individual roots and species to whole-ecosystems and communities.Beyond primarily physical properties, soils also play a large role mediating elemental cycles in a system. Interactions between soil cation exchange capacity, acidity, and the movement of anions and cations can be vital in determining root responses to environmental factors. The effects of soil exchange and buffering capacities may indeed be key determinates of root responses to N fertilization . More atlikely responses through sensitivity analyses, models can help to (1) focus field efforts on the relationships with greatest uncertainty and impact on model outputs . For example, root lifespan/turnover varies as a function of annual N mineralization in PnET-CN , as a fu outputs  and (2) average conditions so that we can better appreciate when increases or decreases in a given environmental factor will move fine roots toward or away from their maximum lifespan . Additionally, modeling work defining which factors are likely to be most limiting or constraining for a given site may help to predict changes in root dynamics in response to multiple, interacting factors.Based on current evidence, it seems reasonable for models to assume decreasing lifespan with increased temperature and water stress, though the specific rate of change in lifespan with a unit increase in temperature or water is more difficult to set. Given the often contradictory reports in the literature, approaches modulating root lifespan based on N mineralization rates may be more tenuous when applied beyond the original ecosystems where the turnover-N mineralization relationships are developed. However, this too is likely a useful approach that can be used to further test relationships between root dynamics, background site conditions, and nutrient additions. Future efforts may link root lifespan-N relationships with more complex functions including additional soil factors  pending development of more clear relationships among them. In all cases, more work is needed to observe and define Figures 2–5 represent testable hypotheses. Each model is based on empirical data when possible along with a simple logical framework . Though simple in their presentation here, patterns of root responses to environmental changes are likely to be complex and contingent at least in part on prevailing climatic conditions across biomes, specific climate and background soil conditions within a site, and interactions with mycorrhizal fungi. While it is likely that further study may amend or even change the specific predictions entirely, these conceptual models offer a reference against which field experiments and modeling work can be compared. In near term, we may test the predictions from these conceptual models at selected, individual sites and manipulative studies to gain a baseline understanding of root lifespan–environment relationship. However, observations of fine root lifespan along natural environmental gradients across sites are also much needed and may provide the most useful information regarding within species variation. Efforts should also be made to better appreciate fundamental differences in plasticity among different species in response to environmental factors so that regions/species likely to have the greatest variation and the largest uncertainty can be expressly targeted (Table 2).The conceptual models presented in Over the long run, the goal should be to rigorously test predictions across a range of plant species and biomes. Additionally, building a greater research portfolio investigating multifactor effects on fine root lifespan and determining under which conditions each factor will be the dominant driver of altered fine root lifespan will be a tremendous improvement predicting and modeling root dynamics. Given the difficulty and long-term (>5 year) commitment required to observe and assess root dynamics, we may not be able to rapidly address many of the recommendations. However, linking the currently disparate observations of root dynamics spread across the globe into more cohesive networks with greater similarity in methodology will likely serve as an efficient path toward greater predictability and deeper understanding of fine root and ecosystem processes.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Inequitable distribution of the medical workforce is an international problem that undermines universal access to healthcare. Governments in many countries have invested in rural-focused medical education programs to increase the supply of rural doctors.Using a structured five-step approach, a scoping review was conducted to map the existing evidence on the relationship between professional entry-level, pre-vocational medical education delivered in rural settings and rural workforce outcomes. Key search terms were developed, with database searches yielding 37 relevant articles. During data charting, a set of types of studies emerged, and we developed a typology to assist with article sorting and information structuring.Medical students attending a rural campus or spending time in a rural area are more likely to practise in non-metropolitan areas upon graduation than students studying at a city campus. In many cases, these positive findings could be confounded by students having a rural origin or being predisposed to want rural work. There is some evidence to suggest that the longer a person spends time as a medical student in a rural area, the more likely they are to work rurally following graduation. Overall, the articles located had limitations related to small sample size, inconsistent definition of rurality and lack of attention to controlling for variables that might influence rural practice decision, for example, rural background. Comparative data were lacking, and most studies were conducted by staff from the medical schools that were the focus of the research. There was no consideration given in any study found to the cost-effectiveness of entry-level medical education delivered in rural settings versus other ways of producing rural practitioners.Given limitations, available evidence suggests that medical education in a rural location does increase the number of medical graduates that will work in a rural place. There are indications of a gradient effect where increased rural practice exposure during medical education leads to more rurally located graduates; however, robust studies are needed to verify this finding. Given the significant funding being directed to universities to increase graduates that will work rurally, appropriate future research is recommended. In this article, we review what is known about an association between professional entry-level, pre-vocational medical education in rural areas and rural medical practice location following graduation. We address two research questions: does medical education in a rural place produce rural doctors? And, is there a gradient relationship between time spent in rural-based medical education and likelihood of working in rural practice? For the purposes of this review, our interest was rural practice following graduation from a medical school, so we did not include the impact of postgraduate study. We acknowledge that there exists evidence indicating diverse factors associated with practising rurally. In this article, our specific interest is in studies that explored associations between rural medical education and rural practice location of doctors.Internationally, there is significant funding invested in initiatives to increase the numbers of medical graduates choosing rural practice. While there is a body of evidence that suggests rural upbringing as a predictor of rural medical practice -3, less Especially in a constrained financial environment, funding decisions about medical student programs should be based on sound evidence. The purpose of our review is to map the evidence and summarise what is known about relationships between entry-level, pre-vocational medical education delivered in rural places and rural work outcomes. Rural as a spatial categorisation is a contested concept and, internationally, is subject to multiple definitions . For theInequitable distribution of the medical workforce is an international problem that undermines universal access to health services ,6. AlthoEvidence shows that physician assistants, nurse practitioners and community health workers can substitute for high proportions of medical practitioner competencies , but medInequities in doctor distribution are most significant when rural–urban comparisons are made . Per 100…[a] broad generalist set of skills, knowledge and attitudes…practiced at a distance from comprehensive specialist medical and surgical services and investigations. [gations. The rural general medical practitioner (GP) is skilled to deal with diverse encounters and contexts, clinical procedures, after-hours work, emergencies, complex care, public health issues and Indigenous peoples’ needs . PractisHistorically, attracting rural medical staff to improve health and social conditions is a government concern. For example, the 1912 Dewar Report established the Scottish Highlands and Islands Medical Service, precursor to the UK National Health Service (NHS), to address poor rural health outcomes and a dearth of rural doctors .Attracting medical graduates to work in rural areas is challenging, with recent United States (USA) research indicating only 3% of medical school entrants planned to practise in rural areas , compareTo grow rural doctor supply from domestic students, a strong focus of Australian investment has been the funding of city-based medical schools to develop rural components in degree programs. In the Australian context, initial medical education typically lasts from 4 to 6 years. Students enter undergraduate programs direct from secondary school, or graduate entry programs, where students are admitted on the basis of completing an earlier undergraduate degree. The rural component of Australian programs tends to be delivered largely through rural clinical schools. The University Departments of Rural Health and Rural Clinical School (UDRH/RCS) programme began in 1994 . The AusNoting proliferation of initiatives to encourage rural working, an Australian government review  identifiIn an era of fiscal constraint, Australian universities have attracted funding for new medical programmes built on a case of addressing rural disadvantage. ‘Rural’ medical schools have been developed in Geelong and Wollongong, although both are categorised as ‘major cities’ using the Australian Standard Geographical Classification . James CEstablishing medical programmes in rural places is not a purely Australian phenomenon. The Northern Ontario School of Medicine was established in 2005 as a ‘rural, distributed community-based medical school’ recruiting students from Canadian northern, rural, remote, Aboriginal or Francophone backgrounds . Exeter An evidence base exists that identifies predictors for medical graduates choosing to practise rurally. Rural background and duration of time spent living in a rural place, prior to medical education, have been consistently described as strong predictors -28.Considering associations between experience of living rurally and rural practice following graduation, Farmer et al.  use BourBuilding on evidence of associations between time residing rurally and eventual work outcomes, some argue that the key to increasing rural practitioners is to develop medical schools where all education is delivered in a rural place. The success of such programmes, for example, that of James Cook University, where 59% of 2005–2011 graduates primarily worked outside of major cities postgraduation , has fueThere is vigorous debate about the need for new medical programmes located wholly in rural locations. Proponents argue rural location is a key feature for addressing workforce disparity, while metropolitan-based medical schools argue their programmes with rural components are effective and increasing medical student places is unnecessary . The issWith increasing higher education marketisation, the debate intensifies. Medical schools are attractive for universities in any country . UniversIn an environment characterised by these debates, having good, independent, evidence to inform funding decisions about medical school places would be useful. While the weight of evidence shows an association between rural upbringing and practising rurally -28, the A scoping review was undertaken to identify what was known about the impact of professional entry medical education in rural places on rural medical practice location following graduation. Scoping reviews are an effective, robust approach to map, collate and summarise literature . This tyConsistent with Arksey and O’Malley’s  recommenIn designing scoping reviews, there is a need to establish key search terms to achieve a balance between a rigorous review and practicalities such as time and cost . Here, wA preliminary search of Google Scholar showed the likely extent of findings and relevance of terms selected and helped to refine inclusion and exclusion criteria. The search results are not included due to the inability to accurately replicate Google Scholar searches . InclusiA search of the Cochrane Library identified no systematic reviews that were directly relevant to our research question. Databases searched included Medline, CINAHL, Proquest, Expanded Academic and Informit.Using the developed search terms, 274 articles were identified, and after removal of duplicates, 202 remained. The title and keywords of the articles were compared with the inclusion and exclusion criteria, with the research team agreeing and confirming the elimination of irrelevant studies. Of the 157 articles that remained, the full-text versions of the articles were read by a minimum of three researchers. Through a process of matching against inclusion and exclusion criteria, 127 references were excluded. Primary reasons for exclusion were the following: literature review or commentary, the dependent variable was not rural practice, the authors did not quantify the time spent in rural areas or the authors considered intention rather than actual practice. The 30 identified articles that matched our inclusion and exclusion criteria were deemed directly relevant to our research question. We hand-searched reference lists from these articles and checked citations and identified seven further relevant articles. A total of 37 articles were included in our final review. To ensure that we had captured all articles, we completed an additional hand search of the reference lists of all articles that had been extracted for full-text review. No further articles were identified. The process of article selection is outlined in Figure Consistent with the fourth stage of Arksey and O’Malley’s framework, the following is reported for each article: author, publication year, location, sample, method, major findings, discussion points and limitations. During data charting, a set of types of studies emerged, and we developed a typology  compared rural campuses with the main campus of the same university and appeared to show that rural campuses produce higher percentages of rural workers. Typology category 2 examined studies of the impact of medical schools providing education wholly in rural places. From the studies, we conclude that percentages working rurally appear high when compared with available national data. Typology category 3 would ideally have provided evidence about gradient effects as it unites 17 studies each defining lengths of time medical students spent in rural places during their undergraduate degrees. Three studies considered different lengths of time spent in rural education, concluding an association between longer time in a rural clinical school or GP attachment and greater likelihood of rural working. Most included studies showed associations between time spent in rural programmes, clinical schools or attachments and rural work outcomes. Typology category 4 considered first years of employment in internships. Again, evidence indicates a relationship between experiences of medical education in a rural place and rural working. The most striking finding is from Sen Gupta et al.  of arounper se but, rather, the ‘package’ of experience provided, including ‘hard to measure’ factors like the enthusiasm of educators and mentors for rural working. None of the associations linking place of education with place of employment are therefore independent of other factors. Invariably, the studies of medical school students’ conversion to rural practice, following the range of rural education durations and types, were conducted by teams involving researchers from the medical schools concerned.Overall, we found some studies confusingly written, particularly around identifying numbers of students or practitioners included in analyses relating to our research question. Considering the impact of place was often not the papers’ focus but was explored alongside other variables and relationships. Some studies had very small sample sizes. Some lacked transparency, for example, by not reporting original sample size or methods. Several studies had to be excluded from our review, as they did not quantify precise periods of rural exposure. Some studies combined (and in some cases conflated) intentions to work rurally with actual rural work. With studies considering programmes, GP attachments or time spent at rural clinical schools, it might be argued that what is being measured is not simply the effect of rural education location There was considerable variety in the ways rural was discussed and defined. This is a regular challenge when comparing studies in rural health. We included studies where authors specifically stated they were considering rural working as an outcome; that is, they specifically used the term rural , and they specifically defined or described what was meant. For example, Inoue et al.  note theGiven the caveats outlined, there is evidence (lacking in robustness though it is) that does suggest that medical education in a rural place may positively affect production of rural doctors. Additionally, there is some evidence to suggest a gradient effect, with increasing duration of educational experiences in rural settings, although the number of studies is small and limited to evaluating single programmes.A key challenge to having these findings acknowledged as interesting and worthy of further exploration is the regular reporting that the findings are likely confounded by students’ having a rural background or pre-existing propensity to choose rural work. This is often suggested to influence their initial choice of a rural-based medical programme, special programme or attendance at a rural clinical school.While rural background is influential, its inclusion as a problematical confounding factor, detrimental to considering the value of rural medical education, raises questions. The success of rural medical schools such as Jichi, Tromso and James Cook University in producing high proportions of rural doctors prompts consideration of a counterfactual. Put simply, what happened to these rural-origin students before the rural programmes existed? Did the students attend city universities and become converted to urban work? Or, did they not attend medical school at all? Are rural medical programmes, therefore, simply efficiently finding those with a propensity to rural work and converting them into rural doctors? It is an intriguing, but inherently un-researchable, question to compare the situation now with the past.Our interest in conducting this review was focused on exploring an association between rural medical education and rural working. We were specifically interested in rural practice following medical school, so we did not include the impact of postgraduate study. A review that considers studies reporting work location following the completion of all postgraduate education would have a different purpose to ours.Confounding factors feature in discussions considering the relationship between rural medical education and rural practice location—most notably the effect of rural background. Due to varying reporting in the studies we reviewed, we made the early decision not to divide studies into those that stated they had controlled for rural background and those that did not state this. Put simply, we did not have the consistent information for every study about whether or not they had controlled for rural background, so it would be misleading of us to attempt to divide. Of the few studies that stated they had accounted for rural background, the strongest predictors for practising rurally, following graduation, were location of the medical school and time spent gaining experience in rural practices during medical education. There is a gap in robust studies which allow for distinction of the effects of different variables on rural practice outcomes.We believe that the reporting typology that we developed provides a useful, if pragmatic, structure for reporting about a relatively large group of articles. Providing an overview of studies from different countries, and typologising them, given variable coverage in reporting is inevitably challenging. Consistent with scoping review methods, the purpose was to map the nature and extent of existing international published evidence.The WHO  recommenFor countries that lack access to well-constructed longitudinal medical workforce databases, there is a dearth of quality comparative statistics. International collaborations that collect comparative data would strengthen the evidence base. Findings from independent, international, robust, studies would be valuable because rural advocacy groups continue to state rural doctor deficits, while city-based medical schools continue to provide small-scale evidence that their programmes are working.Given the considerable public finance invested in schemes to generate rural doctors, including bonded student places, clinical schools, workforce agencies and work incentives , indepenpost hoc approaches. Ideally, a study would include the following: rural and urban medical schools; apply a practical, but meaningful, classification of rural; include data on students’ rural/urban background on entering medical school ; apply a measure of rural work outcome ; and identify per capita costs of producing a medical graduate in a rural or urban area.Studies to address the question—does medical education in a rural area most effectively produce rural doctors?—might adopt modelling or prospective or A study to establish whether there is a gradient in rural work outcomes in relation to time spent in rural places during medical education would ideally include the following: several rural- and urban-based medical schools; use data on students’ rural/urban background on entering medical school; identify number of weeks spent located in a rural place, as part of entry-level medical education for each student; apply a measure of rural work outcome; and identify costs associated with different numbers of weeks in rural places.While such studies might be dismissed as unfeasibly complex or large and thus expensive, the ongoing cost, internationally, of medical workforce incentives and payments to universities to produce rural practitioners is considerable. The question is perhaps whether enough of the powerful stakeholders want to know the answers.Technology should make education of all types more readily available in future, regardless of location, but there will always be a strong element of medical education that involves hands-on work with patients and learning from skilled role models. The location where these experiences take place may be important, and it seems only just that rural populations, national governments and international agencies should have the best evidence so they can fund the best methods of producing rural doctors. Some of the significant international spending applied to getting doctors to work rurally could be diverted to finding out what works. In the short term, an outlay of resources to identify what works best could lead to considerable long-term gains in healthcare accessibility and ultimately to a cost-effective contribution to improving rural health outcomes.


This theory is about early developmental mechanisms, nevertheless impaired oscillatory sampling in auditory cortex could, over developmental time, lead to atypical functioning of the left-lateralized “reading network” identified in many fMRI studies of older children . The TSF proposed that atypical oscillatory entrainment at The aim of this special issue, however, was to simultaneously invite colleagues who work on visual sensory processing to consider whether atypical oscillatory “temporal sampling” may explain the pervasive visual processing deficits in dyslexia reported in many orthographies  in predictable waysreading skills are matched with the dyslexics the sensory/neural deficit can be demonstrated when children with dyslexia are compared to younger children whose developmental trajectories are followed in longitudinal studies, exploring the complex interplay of auditory and visual sensory/neural and cognitive processes during the development of reading, thereby establishing the developmental primacy of the candidate deficitthe sensory/neural deficit is consistent across different languages and orthographiestraining the candidate deficit has demonstrable effects upon subsequent reading developmentAt minimum, evidence is required that:manifest differently in different languages, for example as a consequence of factors such as orthographic grain size  or phonology . Reading difficulties may be comorbid with other difficulties such as attention-deficit-hyperactivity disorder (ADHD); the possible effects of co-morbid disorders on sensory processing must be taken into account (Thaler et al., Longitudinal studies, beginning before reading is taught and carried out across languages, are enormously important to the field (e.g., Boets et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Cortical networks and quantitative measures of connectivity are integral to the study of brain function. Despite lack of direct connections between left and right subthalamic nuclei (STN), there are apparent physiological connections. During clinical examination of patients with Parkinson’s disease (PD), this connectivity is exploited to enhance signs of PD, yet our understanding of this connectivity is limited. We hypothesized that movement leads to synchronization of neural oscillations in bilateral STN, and we implemented phase coherence, a measure of phase-locking between cortical sites in a narrow frequency band, to demonstrate this synchronization. We analyzed task specific phase synchronization and causality between left and right STN local field potentials (LFPs) recorded from both hemispheres simultaneously during a cued movement task in four subjects with PD who underwent Deep Brain Stimulation (DBS) surgery. We used a data driven approach to determine inter-hemispheric channel pairs and frequencies with a task specific increase in phase locking.We found significant phase locking between hemispheres in alpha frequency (8–12 Hz) in all subjects concurrent with movement of either hand. In all subjects, phase synchronization increased over baseline upon or prior to hand movement onset and lasted until the motion ceased. Left and right hand movement showed similar patterns. Granger causality (GC) at the phase-locking frequencies between synchronized electrodes revealed a unidirectional causality from right to left STN regardless of which side was moved.Phase synchronization across hemispheres between basal ganglia supports existence of a bilateral network having lateralized regions of specialization for motor processing. Our results suggest this bilateral network is activated by a unilateral motor program. Understanding phase synchronization in natural brain functions is critical to development of future DBS systems that augment goal directed behavioral function. Neuronal assemblies are rhythmically activated and inhibited through the influence of an oscillatory extracellular local field potentials (LFPs). This phenomenon has been demonstrated in neocortex  that can generate spurious results. Therefore data driven applications of phase synchrony have a high computational demand, and require applied statistical approaches that capture only genuine synchrony across distinct brain regions.As the phase of the LFP influences the probability of neuronal firing, phase locking of specific frequencies in distant regions of the brain implies connectivity between these regions for the transfer of information  in patients suffering from Parkinson’s disease (PD) during awake-surgery present a unique opportunity to test for functional synchronization. Despite the lack of direct anatomical connections between left and right STN, there is evidence for physiological connectivity or synchrony  as standard of care for treatment of idiopathic PD were enrolled in this study. All subjects provided informed consent for participation in this research study, in a manner approved by the internal review board of the University of Washington. Details of the DBS surgery have previously been published in Hebb et al. .The motor task in this study consisted of cued button presses using the thumb of each hand. Each task block consisted of 15 presses and was performed with the same hand, alternating right and left sides for successive blocks. Speech and speech/motor combination tasks were also performed but not analyzed for this study. A detailed description of the entire paradigm has been previously published  biosignal amplifier. LFP recordings were referenced to a linked-mastoid ear reference. For each STN  data was recorded from the four contacts of the DBS lead  in each STN. While the STN was the target of the DBS electrode, the total physical electrode span is greater than the anatomical span of the STN. For the purpose of this analysis, the placement with respect to specific STN regions was considered arbitrary and hence a direct comparison of electrode pairs across subjects was not possible. Therefore, to determine task specific interactions we considered all pairs in our analysis. Given the low number of available subjects (four) and the spatial incongruence between montages across subjects, analysis aimed to identify significant common task related features in each subject.We used the phase locking value , , and , where the order of the hemispheres is irrelevant in calculating the PLV measure, e.g., PLV = PLV. Such symmetry does not exist for GC analysis.We computed the PLV using a complex Morlet wavelet transform to determine the time-varying phase and amplitude for each STN inter-hemispheric LFP pair and for each trial. This method has been shown to be equivalent to phase extraction use the Hilbert transform on band-pass filtered signals , using the CCA Matlab toolbox Seth, , betweenLike the PLV, GC is sensitive to trial order, so significance can be established based on a trial shuffling permutation scheme. We computed GC over short time windows to determine the time course of causality.All subjects exhibited movement dependent suppression in the alpha and beta band followed by a beta rebound at the end of the movement, a finding described previously . This resting state oscillation may serve to end motor programs and suppress involuntary movements, and acute damage to key regions may lead to undesired movements . Phase synchrony is likely to have multiple roles, and these roles may be dependent on frequency and the distance spanned.Rhythmic oscillations of the LFP may to arise from a closed loop network system between member nuclei with inherent delays in their connections that define natural resonant frequencies  applied to cortical input signals may provide a basis for describing this functionality. Briefly, SR counter-intuitively increases the signal to noise ratio of neural information by adding an optimal level of noise . However, as depicted in Figure Phase synchronization between bilateral STN has been previously reported. Cross hemispheric STN Beta frequency coherence in the off medication state was reported by de Solages et al. with a peak coupling frequency of 27 Hz (de Solages et al., Given no direct anatomical connection between left and right STN, the current findings imply the existence of a closed STN-cortex-STN loop or parallel connections from cortex to bilateral STN through which synchronization occurs across hemispheres (Carpenter and Strominger, Several studies have shown movement-dependent frontal cortex to STN synchronization within a range of specific frequency bands. These studies used computational techniques that combine both the phase and amplitude of oscillations. In combined MEG and STN LFP recordings, resting baseline has been characterized by beta frequency STN-cortex coherence with M1 to STN directionality, whereas motor activity was characterized by gamma frequency STN to M1 directional coherence (Litvak et al., Phase synchronization between bilateral basal ganglia structures supports the existence of an inter-hemispheric network with lateralized regions specialized for motor processing. Our results suggest that a simple unilateral motor program activates this bilateral network. Understanding phase synchronization in natural brain functions will be critical for the development of the next generation of DBS systems that minimize the negative impact on, and potentially augment, goal directed behaviors.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


As Caixia Gao and Dan Voytas explain, new techniques make it possible to precisely edit plant genomic DNA, providing opportunities to create crop varieties that will help meet the challenges facing agriculture, including an expanding world population and environmental change. Plant agriculture is poised at a technological inflection point. Recent advances in genome engineering make it possible to precisely alter DNA sequences in living cells, providing unprecedented control over a plant's genetic material. Potential future crops derived through genome engineering include those that better withstand pests, that have enhanced nutritional value, and that are able to grow on marginal lands. In many instances, crops with such traits will be created by altering only a few nucleotides among the billions that comprise plant genomes. As such, and with the appropriate regulatory structures in place, crops created through genome engineering might prove to be more acceptable to the public than plants that carry foreign DNA in their genomes. Public perception and the performance of the engineered crop varieties will determine the extent to which this powerful technology contributes towards securing the world's food supply. PLOS Biology Collection “The Promise of Plant Translational Research.”This article is part of the Over the past 100 years, technological advances have resulted in remarkable increases in agricultural productivity. Such advances include the production of hybrid plants and the use of the genes of the Green Revolution—genes that alter plant stature and thereby increase productivity The tools of genome engineering allow DNA in living cells to be precisely manipulated , transcription activator-like effector nucleases (TALENs), and clustered regularly interspersed short palindromic repeats (CRISPR)/Cas9 reagents . MeganucHow do targeted DSBs enable precise genome modifications? After breaks are introduced into the chromosome, one mechanism for break repair is non-homologous end-joining (NHEJ)  [16],,[19The promise of genome engineering for crop improvement is only just beginning to be realized. Because targeted modifications through NHEJ are relatively simple to achieve—requiring only expression of the SSN —most pubIPK1), an enzyme that catalyzes the final step in phytate biosynthesis In terms of trait development, the elimination of gene function through knockout mutations might seem to have limited utility. However, plants produce many products that negatively impact food quality, storage, and processing. Anti-nutritionals, such as glucosinolates, are produced by some plants to thwart insect pests, but they also have toxic effects when consumed by animals at high dose Whereas gene knockouts can remove unwanted metabolites, they also make it possible to create plants that accumulate metabolites of value. For example, in the biosynthesis of fatty acids, loss of certain fatty acid desaturases in seeds allows monounsaturated fats to accumulate Xanthomonas oryzae, is the causal agent of a blight that affects rice in both temperate and tropical climates and causes significant annual losses in rice productivity. During infection, the pathogen secretes effector proteins into rice cells that bind to the promoter region of the rice sucrose-efflux transporter gene (OsSWEET14). The binding of these effectors activates OsSWEET14 transcription, which contributes to pathogen survival and virulence. TALENs were used to create a mutation in the effector binding site in the promoter of OsSWEET14, thereby eliminating the transcriptional induction of this gene by effectors and consequently reducing the pathogen's virulence.An excellent example of how NHEJ can be used to create a trait of value has recently been demonstrated in rice Whereas plants with genomes altered via NHEJ are only just beginning to be reported, there are even fewer published examples of plants modified by HR. This is because HR is more challenging to implement The real potential of HR for crop improvement, namely targeted gene replacement, remains to be fully realized. In one example, HR was used to introduce amino acid changes in a plant gene encoding acetolactate synthase (ALS)—an enzyme involved in branched-chain amino acid biosynthesis How will new crop varieties with precisely modified genomes be regulated? This question is currently being grappled with by regulatory authorities worldwide. The framework for making such decisions is the existing regulations covering transgenic crops, and different countries generally follow one of two approaches—process-based regulation considers whether biotechnology was used to create the crop, and product-based regulation considers attributes of the new variety itself . The amoProcess based regulatory frameworks consider the techniques used to create new crop plant varieties. In general, if nucleic acids are introduced into plants or recombinant DNA technologies are deployed in the development of a crop, then regulation is triggered. The definitions and guidelines for regulation are based on those stipulated by organizations such as the United Nations Food and Agricultural Organization and treaties such as the Cartagena protocol. Process-based regulation is followed by the EU, Argentina, Brazil, and several other countries.Product-based regulatory frameworks focus less on the technology used to develop the crop and more on the inherent risk of the final product; that is, the potential risk the new trait or attributes introduced into the plant poses to the public or the environment. The US and Canada use product-based regulation.For crop varieties created by NHEJ, the issues under deliberation are somewhat straightforward. Mutations created with SSNs are often indistinguishable from those that occur naturally or that are created by conventional chemical, X- or gamma-ray mutagenesis. Furthermore, targeted modification can be achieved without incorporating foreign DNA into the plant's genome: mutagenesis using NHEJ is possible by transiently expressing the SSN within a plant cell . TransieIntegration of SSN constructs into plant genomes. SSNs are expressed from the integrated DNA, and they act at a distal site. The SSN construct is then segregated away by crossing to obtain a plant with the mutation but no transgene.Transient delivery of SSNs to plant cells as DNA using Agrobacterium, biolistics, or protoplast transformation. SSNs are expressed from DNA constructs transiently before the DNA is degraded.Transient delivery of SSNs to plant cells as proteins or mRNAs. Since DNA is not delivered, no foreign DNA is incorporated into the plant genome.Transient delivery of SSNs using viral vectors. As viral vectors typically do not integrate into the plant genome, mutated plants are not transgenic.Regulatory authorities have recently published preliminary opinions on the use of SSNs to create new crop varieties. In the US, the US Department of Agriculture (USDA) has recently stated that some NHEJ-induced mutations made by meganucleases and ZFNs fall outside their regulatory authority Other statements made recently by the USDA may impact certain approaches for mutant plant production. At least three recent rulings have indicated that the offspring of transgenic plant parents, which themselves lack a transgene, would not fall under the USDA's regulatory authority Plants modified by HR warrant different consideration. Because a DNA template is required to copy information into a chromosomal locus, nucleic acids must necessarily be delivered to a plant cell to create the targeted modification. As mentioned above, for those countries that adhere to process-based regulation, this would likely trigger regulation of crop varieties made through HR. Consider, however, a situation where a plant gene is altered to have the same DNA sequence as an orthologous gene in another variety or species. Pathogen resistance, for example, might be achieved by identifying a disease resistance gene in a wild species and using it as a template in HR to replace a non-effective ortholog in a susceptible cultivar. Whereas such a cultivar could also be attained through conventional breeding, this is time-consuming. Furthermore, the resistance gene could have tight genetic linkage to unwanted loci that compromise fitness . It is our opinion that a different regulatory consideration should be given to cases where naturally occurring genetic variation is introduced.For other types of genetic variation created by HR, it is likely that some threshold will have to be established as to the amount of variation that triggers regulation. Will it be the number of bases modified? The distribution of base changes over a certain length of DNA? Such distinctions seem rather arbitrary. It may be that plants engineered through HR will have to be considered on a case-by-case basis. Although determining the best means to regulate plants created by HR may prove challenging, such guidance is urgently needed.The ability to modify genomes through HR makes it possible to generate crop varieties that have whole suites of genes altered to produce needed metabolites and to provide resistance to biotic and abiotic stresses. In plant synthetic biology, genome engineering through HR will likely become a cornerstone for this rapidly emerging field. Precise DNA sequence alterations will be important to realize opportunities in synthetic biology, such as increasing photosynthetic efficiency to attain higher yields  Public acceptance will ultimately impact how widely genome engineering is deployed in agriculture: the public may simply not want products of genome engineering in the food supply, regardless of what different regulatory authorities decide. In Europe, for example, transgenic varieties are not cultivated, even those, such as Monsanto's YieldGard maize, which have received regulatory approval elsewhere. Similarly, Calgene's Flavr Savr tomato—engineered to remain firm after ripening—was approved in 1994 for release but failed in the supermarket for a variety of reasons including public acceptance


Considerable progress has been made recently in the understanding of how best to accomplish safe and effective ventilation of patients with acute lung injury. Mechanical and nonmechanical factors contribute to causation of ventilator-associated lung injury. Intervention timing helps determine the therapeutic efficacy and outcome, and the stage and severity of the disease process may determine the patient's vulnerability as well as an intervention's value. Reducing oxygen consumption and ventilatory demands are key to a successful strategy for respiratory support of acute respiratory distress syndrome. Results from major clinical trials can be understood against the background of the complex physiology of ventilator-induced lung injury. In recent years physicians have learned to care better for their patients with acute respiratory failure. For no condition has this improvement become more evident than in the treatment of acute respiratory distress syndrome (ARDS), a signature problem of intensive care. Over time, we have learned important lessons. We know from research and experience that despite well-intentioned attempts at revision, our clinical definition for ARDS still needs work. We are now also aware that many factors--mechanical and nonmechanical--contribute to ventilator-induced lung injury (VILI). Timing has proven key to the efficacy of several important ventilation-related therapeutic interventions. Moreover, the stage and severity of disease determine an intervention's potential value or harm. A collective implication of the growing evidence base related to respiratory failure is that reducing oxygen consumption and ventilator demands is a rational point of focus and high priority when attempting to optimize respiratory support for the individual patient.When ARDS was first defined by Ashbaugh, Bigelow, and Petty in 1967  stated iFrom that early time to this we have continued to espouse the concept that different insults lead to a shared pathophysiology which defines a clinical syndrome that justifies a unified clinical approach. It is interesting, however, that the original 12-patient cohort Petty and colleagues described might not have initially had ARDS as we currently understand it to be. Five of the 12 original patients were managed with nasal oxygen, room air, or low-flow oxygen masks ,4. Like Debate regarding the concept that a unifying entity of ARDS even exists was conducted throughout the 1970s and into the 1980s ,6. DurinWith guidance from such imprecise definitions, most trials undertaken for therapy of ARDS have failed to demonstrate new interventions, pathways, and strategies that consistently improve care . Yet, dePerhaps because we have used imprecise definitions, we are left at the bedside with long simmering questions related to the mechanical ventilation and ventilatory support of patients with lung injury. For the individual patient, these questions include: which tidal volume should we use? Which PEEP should we use? Should we employ recruiting maneuvers? Should prone positioning be routine? Is high-frequency ventilation lung protective or damaging? Should we encourage spontaneous breathing in the early stage of illness, or take control of the breathing pattern? Should we use corticosteroids in our patients with inflammatory lung disease? Should we embrace extrapulmonary gas exchange technology, and if so, in whom? The list of unsettled questions can be made longer.2/pH [2 [Management principles derived from laboratory results appear much clearer. Experimental evidence provides consistent laboratory observations regarding what is needed to avoid inflicting VILI. Adverse patterns of ventilation injure both airways and alveoli, causing damage that prevails in anatomically dependent zones. Laboratory experiments have shown that adverse patterns of ventilation apply large tidal volumes with high driving pressures, low levels of PEEP, high inspiratory flows, and elevated minute ventilations. Nonmechanical background factors are also important in the process of VILI generation and, for any given ventilation pattern that applies potentially damaging stress, may determine whether or not VILI is expressed. These background factors, which may synergize with each other, include the preinjury and inflammatory state, the temperature at which the experiment is conducted , the amp2/pH , and FiO2/pH [2 . The mecThe interplay of mechanical stressors that determine whether or not tissues are injured by the ventilation pattern involves an interaction between driving pressure, defined as the difference between plateau pressure and PEEP, and the number of lung units at higher risk for stress amplification; that is, those at the junctions of open and closed lung tissue. Although dynamic characteristics are less well studied as provocative influences, the rate at which the lungs are expanded, determined by the amplitude and pattern of airflow delivery, may be an important determinant of the ventilator-associated damage that results from the tidal excursion. The focus of investigative attention regarding VILI has been on the individual tidal cycle--as defined by PEEP and tidal volume. However, it stands to reason that the number of damaging cycles delivered per unit time  would accentuate the injury inflicted by the individual tidal cycle . PEEP teWhile the use of the esophageal balloon catheter as a sensor of intrapleural pressure is helpful and offers a definite clinical advantage over airway pressures alone for some purposes , esophageal pressure (Pes) measurements are not entirely representative of all transalveolar environments encountered locally (site to site) throughout the lung . For exaThere are several theoretical advantages of using an esophageal balloon catheter in our most seriously lung-injured patients. The balloon catheter is a relatively noninvasive probe that helps monitor transpulmonary static and dynamic pressures under both active and passive conditions. Furthermore, the balloon catheter samples pleural pressure in an important "interface" (mid-lung) zone that is highly predisposed to VILI. Lung units at the interface between open and closed tissue undergo regional stress focusing and force amplification that may incite inflammation or overtly tear microvessels and alveolar epithelium. The damaging energy delivered to lung tissue per unit time (power) is locally higher there.Esophageal pressures must be carefully recorded and interpreted. Calculations based on Pes are not always representative of true risk and Pes is susceptible to artifacts from its own local environment and from the weight of the structures that lie above it. Transpulmonary pressure may increase either if the lung volume changes or if compliance declines. In part for this reason, transpulmonary pressure does not closely track absolute lung volume changes that result from rising intra-abdominal pressure at end expiration (when the circuit is open and the lung is free to lose or gain units). The Pes-determined estimate of pleural pressure may not reflect those lung units that are most stretched or those already collapsed, as the Pes-based trans-pulmonary pressure (Ptp) is only regionally valid and tracks only the aerated compartment of the lung . These wGiven the advantages and disadvantages, the key uses for Pes determinations are to: set an effective PEEP level that maintains the lung less de-recruited ; to bett2 elimination, clinical data that demonstrate a strong correlation between alveolar dead space and mortality risk would seem consistent with the admonition to reduce the vigor of ventilation support by reducing demands [2 and oxygenate the venous blood has offered long-awaited and much-needed assistance in accomplishing this objective.When the mechanical stresses of the tidal cycle are high, experiments have shown that an increase in precapillary vascular pressure or a reduction in postcapillary vascular pressure each accentuate VILI . These o demands . In recePerhaps no issue has been more troublesome to the physician attempting to select and regulate the ventilator's prescription than selecting the appropriate level of PEEP. Insufficient PEEP allows unnecessary collapse of recruitable tissue, whereas excessive PEEP promotes tissue stretch and dead space generation while elevating the mean airway pressure and right ventricular afterload. Unless the tidal volume is simultaneously reduced, increasing PEEP also elevates the plateau pressure. When the overstretching of open lung tissue outweighs the benefit from recruitment, PEEP redirects pulmonary blood flow and accentuates mechanical heterogeneity within the acutely injured lung. Although either respiratory system compliance or oxygenation can be used as the criterion target for PEEP selection with good physiological justification, it appears as if oxygenation response best parallels stabilized recruitment of collapsed lung units, which is the primary objective for PEEP employment .Recruitment of lung tissue can be attained without increasing PEEP by prone positioning. Because modifications of the chest wall that result from prone positioning help even the distribution of transpulmonary pressures, several of the important disadvantages of PEEP just enumerated can be avoided. Prone positioning tends to recruit selectively in dorsal regions that are gravitationally dependent when supine. Airway secretion drainage is also promoted.2 removal upstream from the lungs themselves, offloading much of the dynamic burdens of ventilation.A key lesson learned from investigations conducted over the past three decades is that excessive stress and strain are essential prerequisites for inflicting lung damage, but are only the preconditions to VILI Figure . As alreFor more than two decades, clinicians have used standardized definitions of ARDS in RCTs of interventions aimed at learning what physicians can do to stop VILI ,10. UnfoA recent bright spot in trials of ventilation strategy was the demonstration that prone positioning could help very severely ill patients early in the course of illness when recruitability was presumably higher . As the Another positive trial that relates to mechanical ventilation, the Neromuscular Blockers in Early Acute Respiratory Distress Syndrome (ACURASYS) study found benefit from the use of muscle relaxants early in the disease course . This fiAs noted at the beginning of this discussion, we have learned some hard won lessons Figure . Among tAECC, American-European Consensus Committee; ARDS, Acute respiratory distress syndrome; EBM, Evidence-based medicine; HFO, High-frequency oscillatory ventilation; IRDS, Infant respiratory distress syndrome; PEEP, Positive end-expiratory pressure; RCT, Randomized clinical trial; VILI, Ventilator-induced lung injury.The author declares that he has no competing interests.