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Background: Inflammation is a central process of many neurological diseases, and a growing number of studies suggest that non-brain-resident immune cells may contribute to this neuroinflammation. However, the unique contributions of specific immune cell subsets to neuroinflammation are presently unknown, and it is unclear how communication between brain-resident and non-resident immune cells underlies peripheral immune cell involvement in neuroinflammation. Methods: In this study, we employed the well-established model of lipopolysaccharide (LPS)-induced neuroinflammation and captured brain-resident and non-resident immune cells from the brain and its vasculature by magnetically enriching cell suspensions from the non-perfused brain for CD45 + cells. Then, we identified immune subtype-specific neuroinflammatory processes using single-cell genomics and predicted the crosstalk between immune cell subtypes by analyzing the simultaneous expression of ligands and receptors. Results: We observed a greater abundance of peripheral phagocytes associated with the brain in this model of neuroinflammation, and report that these professional phagocytes activated similar transcriptional profiles to microglia during LPS-induced neuroinflammation. And, we observed that the probable crosstalk between microglia and peripheral phagocytes was activated in this model while homotypic microglial communication was likely to be decreased. Conclusions: Our novel findings reveal that microglia signaling to non-brain-resident peripheral phagocytes is preferentially triggered by peripheral inflammation, which is associated with brain infiltration of peripheral cells. Overall, our study supports the involvement of peripheral immune cells in neuroinflammation and suggests several possible molecular signaling pathways between microglia and peripheral cells that may facilitate central-peripheral crosstalk during inflammation. Examining these molecular mediators in human disease and other rodent models may reveal novel targets that modify brain health, especially in comorbidities characterized by peripheral inflammation.

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Dragged-fovea diplopia syndrome (DFDS) is a type of binocular double vision caused by a displacement of the fovea in one or both eyes due to retinal disorders including epiretinal membranes or other maculopathies. DFDS induces diplopia through a mismatch between peripheral motor fusion and central (foveal) fusion. It can be diagnosed by utilizing the Lights on - Lights off test. While there is no cure, there are treatments for DFDS including monocular occlusion or blurring (tape, lenses, IOL), Bangerter filter, and Fresnel prisms. While this syndrome has been identified in the literature by multiple names including central-peripheral Rivalry (CPR)-type diplopia, macular diplopia, and foveal displacement syndrome, this article works to summarize the current known characteristics, diagnostic tests, and treatment for this syndrome.

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Typically, searching for a target among uniformly tilted non-targets is easier when this target is perpendicular, rather than parallel, to the non-targets. The V1 Saliency Hypothesis (V1SH) - that V1 creates a saliency map to guide attention exogenously - predicts exactly the opposite in a special case: each target or non-target is a pair of equally-sized disks, a homo-pair of two disks of the same color, black or white, or a hetero-pair of two disks of the opposite color; the inter-disk displacement defines its orientation. This prediction - parallel advantage - was supported by the finding that parallel targets require shorter reaction times (RTs) to report targets' locations. Furthermore, it is stronger for targets further from the center of search images, as predicted by the Central-peripheral Dichotomy (CPD) theory entailing that saliency effects are stronger in peripheral than in central vision. However, the parallel advantage could arise from a shorter time required to recognize - rather than to shift attention to - the parallel target. By gaze tracking, the present study confirms that the parallel advantage is solely due to the RTs for the gaze to reach the target. Furthermore, when the gaze is sufficiently far from the target during search, saccade to a parallel, rather than perpendicular, target is more likely, demonstrating the Central-peripheral Dichotomy more directly. Parallel advantage is stronger among observers encouraged to let their search be guided by spontaneous gaze shifts, which are presumably guided by bottom-up saliency rather than top-down factors.

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Cigarette smoking has long been recognized as a risk factor for type 2 diabetes (T2D), although the precise causal mechanisms underlying this relationship remain poorly understood. Recent evidence suggests that nicotine, the primary reinforcing component in tobacco, may play a pivotal role in connecting cigarette smoking and T2D. Extensive research conducted in both humans and animals has demonstrated that nicotine can elevate blood glucose levels, disrupt glucose homeostasis, and induce insulin resistance. The review aims to elucidate the genetic variants of nicotinic acetylcholine receptors associated with diabetes risk and provide a comprehensive overview of the available data on the mechanisms through which nicotine influences blood glucose homeostasis and the development of diabetes. Here we emphasize the central and peripheral actions of nicotine on the release of glucoregulatory hormones, as well as its effects on glucose tolerance and insulin sensitivity. Notably, the central actions of nicotine within the brain, which encompass both insulin-dependent and independent mechanisms, are highlighted as potential targets for intervention strategies in diabetes management.

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Stroke is a major cause of disability because of its motor and cognitive sequelae even when the acute phase of stabilization of vital parameters is overcome. The most important improvements occur in the first 8-12 weeks after stroke, indicating that it is crucial to improve our understanding of the dynamics of phenomena occurring in this time window to prospectively target rehabilitation procedures from the earliest stages after the event. Here, we studied the intracortical excitability properties of delivering transcranial magnetic stimulation (TMS) to the primary motor cortex (M1) of left and right hemispheres in 17 stroke patients who suffered a mono-lateral left hemispheric stroke, excluding pure cortical damage. All patients were studied within 10 days of symptom onset. TMS-evoked potentials (TEPs) were collected via a TMS-compatible electroencephalogram system (TMS-EEG) concurrently with motor-evoked responses (MEPs) induced in the contralateral first dorsal interosseous muscle. Comparison with age-matched healthy volunteers was made by collecting the same bilateral-stimulation data in nine healthy volunteers as controls. Excitability in the acute phase revealed relevant changes in the relationship between left lesioned and contralesionally right hemispheric homologous areas both for TEPs and MEPs. While the paretic hand displayed reduced MEPs compared to the non-paretic hand and to healthy volunteers, TEPs revealed an overexcitable lesioned hemisphere with respect to both healthy volunteers and the contra-lesion side. Our quantitative results advance the understanding of the impairment of intracortical inhibitory networks. The neuronal dysfunction most probably changes the excitatory/inhibitory on-center off-surround organization that supports already acquired learning and reorganization phenomena that support recovery from stroke sequelae.

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Central and peripheral interventions for brain injury rehabilitation have been widely employed. However, as patients' requirements and expectations for stroke rehabilitation have gradually increased, the limitations of simple central intervention or peripheral intervention in the rehabilitation application of stroke patients' function have gradually emerged. Studies have suggested that central intervention promotes the activation of functional brain regions and improves neural plasticity, whereas peripheral intervention enhances the positive feedback and input of sensory and motor control modes to the central nervous system, thereby promoting the remodeling of brain function. Based on the model of a central-peripheral-central (CPC) closed loop, the integration of center and peripheral interventions was effectively completed to form "closed-loop" information feedback, which could be applied to specific brain areas or function-related brain regions of patients. Notably, the closed loop can also be extended to central and peripheral immune systems as well as central and peripheral organs such as the brain-gut axis and lung-brain axis. In this review article, the model of CPC closed-loop rehabilitation and the potential neuroimmunological mechanisms of a closed-loop approach will be discussed. Further, we highlight critical questions about the neuroimmunological aspects of the closed-loop technique that merit future research attention.

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Background: Dyskinesia is a common manifestation after stroke. Motor functional rehabilitation after stroke is of great significance to the maintenance of national health. Ocular Acupuncture Kinesitherapy (OAKT) can repair nerve injuries, improve motor function, reduce rehabilitation time, and promote dyskinesia recovery after stroke. The mechanism, however, remains a mystery, necessitating urgent research. The M1-thalamus-spinal cord neural signaling pathway is linked to limb motor function. Bold-fMRI can represent the cerebral functional state, and TMS-MEP is of certain practical utility for assessing motor neural function and prognosis. Combining fMRI scanning with TMS-MEP detection is predicted to advance brain-spinal cord regulation and muscle response linkage control mechanism research, as well as completely investigate the central-peripheral coupling effect of Ocular Acupuncture Kinesitherapy on dyskinesia after stroke (PSD). Methods: This is a prospective functional neuroimaging and neurotic electrophysiological study with a case-control design between the PSD with the HC groups and a randomized controlled design within the 3 PSD groups (OAKT group, ocular acupuncture group, and kinesitherapy group). Using fMRI scans and TMS-MEP approach, we will assess the central-peripheral neural function alterations in PSD as well as the coupling effects of OAKT on PSD. We plan to enroll 90 participants at the Hospital of Chengdu University of Traditional Chinese Medicine from Aug 31, 2022, to Dec 31, 2023, including 45 PSD and 45 HC subjects. After enrollment and on the last day after 4-weeks of waiting (HC subjects) or intervention (PSD subjects), all eligible subjects will be evaluated using fMRI scanning, TMS-MEP detection, and the MMT and Fugl-Mayer scales assessment. The MMT and Fugl-Meyer scores will be recorded, and a Pearson correlation analysis will be performed to assess the correlation between clinical and imaging outcomes. Discussion: Findings of this study will help to explain the central-peripheral coupling effect of OAKT on PSD and to further provide the neural processing of acupuncture kinesitherapy covering the entire pathway from peripheral to central nervous system. Clinical trial registration: This study is registered with an identifier (ChiCTR2200060483) at the Chinese Clinical Trial Registry in June 2022. http://www.chictr.org.cn/index.aspx.

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Microglia are tissue-resident macrophages of the central nervous system (CNS). In the CNS, microglia play an important role in the monitoring and intervention of synaptic and neuron-level activities. Interventions targeting microglia have been shown to improve the prognosis of various neurological diseases. Recently, studies have observed the activation of microglia in different cardiovascular diseases. In addition, different approaches that regulate the activity of microglia have been shown to modulate the incidence and progression of cardiovascular diseases. The change in autonomic nervous system activity after neuroinflammation may be a potential intermediate link between microglia and cardiovascular diseases. Here, in this review, we will discuss recent updates on the regulatory role of microglia in hypertension, myocardial infarction and ischemia/reperfusion injury. We propose that microglia serve as neuroimmune modulators and potential targets for cardiovascular diseases.

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Recently a theory (Zhaoping, Vision Research, 136, 32-49, 2017) proposed that top-down feedback from higher to lower visual cortical areas, to aid visual recognition, is stronger in the central than in the peripheral visual fields. Since top-down feedback helps feature binding, a critical visual recognition process, this theory predicts that insufficient feedback in the periphery should make feature misbinding more likely. To test this prediction, this study assessed binding between color and motion features, or between luminance and motion features, at different visual field eccentricities. We first used color-motion stimuli containing equiluminant red and green dots moving in opposite directions, for example, red dots moved leftward while green dots moved rightward. Such stimuli were shown in both a central reference strip and a peripheral test strip; participants reported whether it was the first or second interval in a trial in which the dots of each color moved in the opposite directions between the two strips. The center of the test strip was at 4° or 15° away from the gaze fixation. Participants' performance was much worse when the test strip was more peripheral, suggesting that feature misbinding occurred more frequently there. This held even when the size and density of the dots were adjusted by eccentricity-dependent cortical magnification factors, and even when red/green dots were replaced by yellow/blue dots or black/white dots to suit the retinal input sampling peripherally. Our findings support that top-down feedback is more directed to central vision, which can resolve ambiguities in feature binding at more central visual locations.

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In a random-dot stereogram (RDS), the spatial disparities between the interocularly corresponding black and white random dots determine the depths of object surfaces. If a black dot in one monocular image corresponds to a white dot in the other, disparity-tuned neurons in primary visual cortex (V1) respond as if their preferred disparities become non-preferred and vice versa, reversing the disparity sign reported to higher visual areas. Reversed depth is perceptible in the peripheral but not the central visual field. This study demonstrates that, in central vision, adding contrast-reversed dots to a noisy RDS (containing the normal contrast-matched dots) can augment or degrade depth perception. Augmentation occurs when the reversed depth signals are congruent with the normal depth signals to report the same disparity sign, and occurs regardless of the viewing duration. Degradation occurs when the reversed and normal depth signals are incongruent with each other and when the RDS is viewed briefly. These phenomena reflect the Feedforward-Feedback-Verify-and-reWeight (FFVW) process for visual inference in central vision, and are consistent with the central-peripheral dichotomy that central vision has a stronger top-down feedback from higher to lower brain areas to disambiguate noisy and ambiguous inputs from V1. When a RDS is viewed too briefly for feedback, augmentation and degradation work by adding the reversed depth signals from contrast-reversed dots to the feedforward, normal, depth signals. With a sufficiently long viewing duration, the feedback vetoes incongruent reversed depth signals and amends or completes the imperfect, but congruent, reversed depth signals by analysis-by-synthesis computation.

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The peripheral (axonal) neuropathy associated with repeated exposure to aliphatic and aromatic solvents that form protein-reactive γ-diketones shares some clinical and neuropathological features with certain metabolic neuropathies, including type-II diabetic neuropathy and uremic neuropathy, and with the largely sub-clinical nerve damage associated with old age. These conditions may be linked by metabolites that adduct and cross-link neuroproteins required for the maintenance of axonal transport and nerve fiber integrity in the peripheral and central nervous system.

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Plant meristems are self-renewing groups of pluripotent stem cells that produce lateral organs in a stereotypical pattern. Of interest is how the radially symmetrical meristem produces laminar lateral organs. Both the male and female inflorescence meristems of the dominant Fascicled ear (Fas1) mutant fail to grow as a single point and instead show deep branching. Positional cloning of two independent Fas1 alleles identified an ∼160 kb region containing two floral genes, the MADS-box gene, zmm8, and the YABBY gene, drooping leaf2 (drl2). Both genes are duplicated within the Fas1 locus and spatiotemporally misexpressed in the mutant inflorescence meristems. Increased zmm8 expression alone does not affect inflorescence development; however, combined misexpression of zmm8, drl2, and their syntenic paralogs zmm14 and drl1, perturbs meristem organization. We hypothesize that misexpression of the floral genes in the inflorescence and their potential interaction cause ectopic activation of a laminar program, thereby disrupting signaling necessary for maintenance of radially symmetrical inflorescence meristems. Consistent with this hypothesis, RNA sequencing and in situ analysis reveal altered expression patterns of genes that define distinct zones of the meristem and developing leaf. Our findings highlight the importance of strict spatiotemporal patterns of expression for both zmm8 and drl2 and provide an example of phenotypes arising from tandem gene duplications.

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Consider a gray field comprising pairs of vertically aligned dots; in each pair, one dot is white the other black. When viewed in a peripheral visual field, these pairs appear horizontally aligned. By the Central-Peripheral Dichotomy, this flip tilt illusion arises because top-down feedback from higher to lower visual cortical areas is too weak or absent in the periphery to veto confounded feedforward signals from the primary visual cortex (V1). The white and black dots in each pair activate, respectively, on and off subfields of V1 neural receptive fields. However, the sub-fields' orientations, and the preferred orientations, of the most activated neurons are orthogonal to the dot alignment. Hence, V1 reports the flip tilt to higher visual areas. Top-down feedback vetoes such misleading reports, but only in the central visual field.

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The central nervous system controls the activity states of the peripheral organs in response to various environmental changes. However, the physiological interactions across multiple organs remain largely unknown. Recently, we have developed an electrophysiological recording system that simultaneously captures neuronal population activity patterns in the brain, heartbeat signals, muscle contraction signals, respiratory signals, and vagus nerve action potentials in freely moving rodents. This paper summarizes several recent insights obtained from this recording system, including the observations that some but not all brain activity patterns are associated with peripheral organ activity in a behavioral test, and that functions across cortical networks can predict stress-induced changes in cardiac function in rats. The evidence suggests that adding information on peripheral physiological signals to behavioral data assists in a more accurate estimation of animals' mental states. The concept of such a research approach opens a new field of large-scale analysis of systemic physiological signals, termed "physiolomics," which is expected to unveil further physiological issues involving mind-body associations in health and disease.

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The anterior pituitary gland is a key organ involved in the control of multiple physiological functions including growth, reproduction, metabolism and stress. These functions are controlled by five distinct hormone-producing pituitary cell types that produce growth hormone (somatotropes), prolactin (lactotropes), adrenocorticotropin (corticotropes), thyrotropin (thyrotropes) and follicle stimulating hormone/luteinizing hormone (gonadotropes). Classically, the synthesis and release of pituitary hormones was thought to be primarily regulated by central (neuroendocrine) signals. However, it is now becoming apparent that factors produced by pituitary hormone targets (endocrine and non-endocrine organs) can feedback directly to the pituitary to adjust pituitary hormone synthesis and release. Therefore, pituitary cells serve as sensors to integrate central and peripheral signals in order to fine-tune whole-body homeostasis, although it is clear that pituitary cell regulation is species-, age- and sex-dependent. The purpose of this review is to provide a comprehensive, general overview of our current knowledge of both central and peripheral regulators of pituitary cell function and associated intracellular mechanisms, focusing on human and non-human primates.

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Brain tryptophan and its neuroactive metabolites play key roles in central fatigue. However, previous brain function analysis targets may have included both glia and neurons together. Here, we clarified the fatigue-cognitive circuit of the central-peripheral linkage, including the role of glial-neuronal interaction in cognition. Using a rat model of central fatigue induced by chronic sleep disorder (CFSD), we isolated presynaptic terminals and oligodendrocytes. Results showed that compared to control group, presynaptic levels of tryptophan, kynurenine, and kynurenic acid, but not serotonin, in the CFSD group were higher in the hypothalamus and hippocampus. Moreover, CFSD group had higher oligodendrocytic levels of tryptophan, and impaired spatial cognitive memory accuracy and increased hyperactivity and impulsivity. These findings suggest that dynamic change in glial-neuronal interactions within the hypothalamus-hippocampal circuit causes central fatigue, and increased tryptophan-kynurenic acid pathway activity in this circuit causes reduced cognitive function. Additionally, CFSD group had 1.5 times higher plasma levels of tryptophan and kynurenine. Furthermore, in rats undergoing intraperitoneal administration of kynurenine (100mg/kg) versus vehicle, kynurenine-treated rats showed enhanced production of kynurenic acid in the hippocampus, with suppressed recall of retained spatial cognitive memory. The study revealed that uptake of periphery-derived kynurenine and tryptophan into the brain enhances kynurenic acid production in the brain, and the three factors produce amplification effect involved in the role of central-peripheral linkage in central fatigue, triggering cognitive dysfunction.

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AIMS: The study investigated the association between clinical symptoms and late-onset sepsis (LOS) in preterm infants with the aim of identifying a non-invasive tool for the early detection of LOS. METHODS: This was a prospective study of 83 episodes of suspected LOS in 67 preterm infants. At the time LOS was suspected, we recorded a standardized set of clinical symptoms. A diagnosis of "clinical LOS" (Clin-LOS), "culture-proven LOS" (Prov-LOS) or "LOS not present" (No-LOS) was made on the basis of C-reactive protein (CrP) and blood culture results where Clin-LOS was defined as CrP>10mg/l, Prov-LOS was defined as CrP>10mg/l AND positive blood cultures, or it was established that there was no sepsis present (No-LOS). We examined univariable associations between clinical signs and LOS using odds ratio (OR) analysis and then adjusted the odds ratio (adOR) through binary regression analysis. RESULTS: Clin-LOS was diagnosed in 20/83 episodes, 19 cases were found to have Prov-LOS. Clinical signs which had a significant association with Clin-LOS were capillary refill time >2s (OR 2.9) and decreased responsiveness (OR 5.2), whereas there was a negative association between gastric residuals and LOS (OR 0.35). However, the most marked association was found for a greater central-peripheral temperature difference (cpTD) >2°C (OR 9). In Prov-LOS an increased heart rate (OR 3.1), prolonged capillary refill time (OR 3.3) and again an increased cpTD (OR 16) had a significant association with LOS, whereas gastric residuals were negatively associated (OR 0.29). Regression analysis showed that cpTD was the most striking clinical sign associated with both Clin- (adOR 6.3) and Prov-LOS (adOR 10.5). CONCLUSIONS: Prolonged capillary refill time and - more impressive - elevated cpTD were the most useful clinical symptoms for detection of LOS in preterm infants. We especially suggest using cpTD as a predictor of LOS. It is a cheap, non-invasive and readily available tool for daily routines.

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OBJECT Correct diagnosis and precise localization of adenomas in patients with Cushing's disease are essential for avoiding unsuccessful transsphenoidal pituitary exploration. In addition to the well-established inferior petrosal sinus sampling, preoperative cavernous sinus sampling (CSS) was introduced as a potentially improved way to predict adenoma lateralization. The authors present their results with CSS in a consecutive series of patients with Cushing's disease. METHODS During 1999-2014, transsphenoidal surgeries were consecutively performed in 510 patients with Cushing's disease. For most patients, suppression of cortisol in high-dose dexamethasone tests and stimulation of adrenocorticotropic hormone and cortisol after administration of corticotropin-releasing hormone were sufficient to prove the diagnosis of adrenocorticotropic hormone-dependent hypercortisolism. Of the 510 patients, 67 (13%) were referred to the department of neuroradiology for CSS according to the technique of Teramoto. The indications for CSS were unclear endocrine test results or negative MRI results. Data for all patients were retrospectively analyzed. RESULTS A central/peripheral gradient was found in 59 patients; lateralization to the left or right side was found in 51. For 8 patients with a central/peripheral gradient, no left/right gradient could be determined. For another 8 patients with equivocal test results, no central/peripheral gradient was found. No severe CSS-associated complications were encountered. Of the 51 patients who underwent transsphenoidal surgery, the predicted lateralization was proven correct for 42 (82%). CONCLUSIONS As MRI techniques have improved, the number of potential candidates for this invasive method has decreased in the past decade. However, because detecting minute adenomas remains problematic, CSS remains a useful diagnostic tool for patients with Cushing's disease.

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2,5-Hexanedione (HD) and acrylamide (ACR) are considered to be prototypical among chemical toxicants that cause central-peripheral axonopathies characterized by distal axon swelling and degeneration. Because the demise of distal regions was assumed to be causally related to the onset of neurotoxicity, substantial effort was devoted to deciphering the respective mechanisms. Continued research, however, revealed that expression of the presumed hallmark morphological features was dependent upon the daily rate of toxicant exposure. Indeed, many studies reported that the corresponding axonopathic changes were late developing effects that occurred independent of behavioral and/or functional neurotoxicity. This suggested that the toxic axonopathy classification might be based on epiphenomena related to dose-rate. Therefore, the goal of this mini-review is to discuss how quantitative morphometric analyses and the establishment of dose-dependent relationships helped distinguish primary, mechanistically relevant toxicant effects from non-specific consequences. Perhaps more importantly, we will discuss how knowledge of neurotoxicant chemical nature can guide molecular-level research toward a better, more rational understanding of mechanism. Our discussion will focus on HD, the neurotoxic γ-diketone metabolite of the industrial solvents n-hexane and methyl-n-butyl ketone. Early investigations suggested that HD caused giant neurofilamentous axonal swellings and eventual degeneration in CNS and PNS. However, as our review will point out, this interpretation underwent several iterations as the understanding of γ-diketone chemistry improved and more quantitative experimental approaches were implemented. The chemical concepts and design strategies discussed in this mini-review are broadly applicable to the mechanistic studies of other chemicals (e.g., n-propyl bromine, methyl methacrylate) that cause toxic neuropathies.

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The distribution of genetic diversity within and among populations in relation to species' geographic ranges is important to understanding processes of evolution, speciation, and biogeography. One hypothesis predicts that natural populations at geographic range margins will have lower genetic diversity relative to those located centrally in species' distributions owing to a link between geographic and environmental marginality; alternatively, genetic variation may be unrelated with geographic marginality via decoupling of geographic and environmental marginality. We investigate the predictivity of geographic patterns of genetic variation based on geographic and environmental marginality using published genetic diversity data for 40 species (insects, plants, birds, mammals, worms). Only about half of species showed positive relationships between geographic and environmental marginality. Three analyses (sign test, multiple linear regression, and meta-analysis of correlation effect sizes) showed a negative relationship between genetic diversity and distance to environmental niche centroid, but no consistent relationship of genetic diversity with distance to geographic range center.

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