Transected axons fail to regrow in the mature central nervous system. Astrocytic scars are widely regarded as causal in this failure. Here, using three genetically targeted loss-of-function ...manipulations in adult mice, we show that preventing astrocyte scar formation, attenuating scar-forming astrocytes, or ablating chronic astrocytic scars all failed to result in spontaneous regrowth of transected corticospinal, sensory or serotonergic axons through severe spinal cord injury (SCI) lesions. By contrast, sustained local delivery via hydrogel depots of required axon-specific growth factors not present in SCI lesions, plus growth-activating priming injuries, stimulated robust, laminin-dependent sensory axon regrowth past scar-forming astrocytes and inhibitory molecules in SCI lesions. Preventing astrocytic scar formation significantly reduced this stimulated axon regrowth. RNA sequencing revealed that astrocytes and non-astrocyte cells in SCI lesions express multiple axon-growth-supporting molecules. Our findings show that contrary to the prevailing dogma, astrocyte scar formation aids rather than prevents central nervous system axon regeneration.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Evolving resistance to arte misi ni n-based compounds threatens to derail attempts to control malaria. Resistance has been confirmed in western Cambodia and has recently emerged in western Thailand, ...but is absent from neighboring Laos. Artemisinin resistance results in reduced parasite clearance rates (CRs) after treatment. We used a two-phase strategy to identify genome region(s) underlying this ongoing selective event. Geographical differentiation and haplotype structure at 6969 polymorphic single-nucleotide polymorphisms (SNPs) in 91 parasites from Cambodia, Thailand, and Laos identified 33 genome regions under strong selection. We screened SNPs and microsatellites within these regions in 715 parasites from Thailand, identifying a selective sweep on chromosome 13 that shows strong association (P = 10⁻⁶ to 10⁻¹²) with slow CRs, illustrating the efficacy of targeted association for identifying the genetic basis of adaptive traits.
Reductive electrosynthesis has faced long-standing challenges in applications to complex organic substrates at scale. Here, we show how decades of research in lithium-ion battery materials, ...electrolytes, and additives can serve as an inspiration for achieving practically scalable reductive electrosynthetic conditions for the Birch reduction. Specifically, we demonstrate that using a sacrificial anode material (magnesium or aluminum), combined with a cheap, nontoxic, and water-soluble proton source (dimethylurea), and an overcharge protectant inspired by battery technology tris(pyrrolidino)phosphoramide can allow for multigram-scale synthesis of pharmaceutically relevant building blocks. We show how these conditions have a very high level of functional-group tolerance relative to classical electrochemical and chemical dissolving-metal reductions. Finally, we demonstrate that the same electrochemical conditions can be applied to other dissolving metal-type reductive transformations, including McMurry couplings, reductive ketone deoxygenations, and epoxide openings.
Transected axons fail to regrow across anatomically complete spinal cord injuries (SCI) in adults. Diverse molecules can partially facilitate or attenuate axon growth during development or after ...injury
, but efficient reversal of this regrowth failure remains elusive
. Here we show that three factors that are essential for axon growth during development but are attenuated or lacking in adults-(i) neuron intrinsic growth capacity
, (ii) growth-supportive substrate
and (iii) chemoattraction
-are all individually required and, in combination, are sufficient to stimulate robust axon regrowth across anatomically complete SCI lesions in adult rodents. We reactivated the growth capacity of mature descending propriospinal neurons with osteopontin, insulin-like growth factor 1 and ciliary-derived neurotrophic factor before SCI
; induced growth-supportive substrates with fibroblast growth factor 2 and epidermal growth factor; and chemoattracted propriospinal axons with glial-derived neurotrophic factor
delivered via spatially and temporally controlled release from biomaterial depots
, placed sequentially after SCI. We show in both mice and rats that providing these three mechanisms in combination, but not individually, stimulated robust propriospinal axon regrowth through astrocyte scar borders and across lesion cores of non-neural tissue that was over 100-fold greater than controls. Stimulated, supported and chemoattracted propriospinal axons regrew a full spinal segment beyond lesion centres, passed well into spared neural tissue, formed terminal-like contacts exhibiting synaptic markers and conveyed a significant return of electrophysiological conduction capacity across lesions. Thus, overcoming the failure of axon regrowth across anatomically complete SCI lesions after maturity required the combined sequential reinstatement of several developmentally essential mechanisms that facilitate axon growth. These findings identify a mechanism-based biological repair strategy for complete SCI lesions that could be suitable to use with rehabilitation models designed to augment the functional recovery of remodelling circuits.
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KISLJ, NUK, SBMB, UL, UM, UPUK
With the rapidly increasing abundance and accessibility of genomic data, there is a growing interest in using population genetic approaches to characterize fine-scale dispersal of organisms, ...providing insight into biological processes across a broad range of fields including ecology, evolution and epidemiology. For sexually recombining haploid organisms such as the human malaria parasite P. falciparum, however, there have been no systematic assessments of the type of data and methods required to resolve fine scale connectivity. This analytical gap hinders the use of genomics for understanding local transmission patterns, a crucial goal for policy makers charged with eliminating this important human pathogen. Here we use data collected from four clinics with a catchment area spanning approximately 120 km of the Thai-Myanmar border to compare the ability of divergence (FST) and relatedness based on identity by descent (IBD) to resolve spatial connectivity between malaria parasites collected from proximal clinics. We found no relationship between inter-clinic distance and FST, likely due to sampling of highly related parasites within clinics, but a significant decline in IBD-based relatedness with increasing inter-clinic distance. This association was contingent upon the data set type and size. We estimated that approximately 147 single-infection whole genome sequenced parasite samples or 222 single-infection parasite samples genotyped at 93 single nucleotide polymorphisms (SNPs) were sufficient to recover a robust spatial trend estimate at this scale. In summary, surveillance efforts cannot rely on classical measures of genetic divergence to measure P. falciparum transmission on a local scale. Given adequate sampling, IBD-based relatedness provides a useful alternative, and robust trends can be obtained from parasite samples genotyped at approximately 100 SNPs.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Artemisinin-based combination therapies are the first line of treatment for Plasmodium falciparum infections worldwide, but artemisinin resistance has risen rapidly in Southeast Asia over the past ...decade. Mutations in the kelch13 gene have been implicated in this resistance. We used longitudinal genomic surveillance to detect signals in kelch13 and other loci that contribute to artemisinin or partner drug resistance. We retrospectively sequenced the genomes of 194 P. falciparum isolates from five sites in Northwest Thailand, over the period of a rapid increase in the emergence of artemisinin resistance (2001-2014).
We evaluate statistical metrics for temporal change in the frequency of individual SNPs, assuming that SNPs associated with resistance increase in frequency over this period. After Kelch13-C580Y, the strongest temporal change is seen at a SNP in phosphatidylinositol 4-kinase, which is involved in a pathway recently implicated in artemisinin resistance. Furthermore, other loci exhibit strong temporal signatures which warrant further investigation for involvement in artemisinin resistance evolution. Through genome-wide association analysis we identify a variant in a kelch domain-containing gene on chromosome 10 that may epistatically modulate artemisinin resistance.
This analysis demonstrates the potential of a longitudinal genomic surveillance approach to detect resistance-associated gene loci to improve our mechanistic understanding of how resistance develops. Evidence for additional genomic regions outside of the kelch13 locus associated with artemisinin-resistant parasites may yield new molecular markers for resistance surveillance, which may be useful in efforts to reduce the emergence or spread of artemisinin resistance in African parasite populations.
Abstract Objective To describe the design and ongoing conduct of the Million Veteran Program (MVP), as an observational cohort study and mega-biobank in the Department of Veterans Affairs (VA) health ...care system. Study Design and Setting Data are being collected from participants using questionnaires, the VA electronic health record, and a blood sample for genomic and other testing. Several ongoing projects are linked to MVP, both as peer-reviewed research studies and as activities to help develop an infrastructure for future, broad-based research uses. Results Formal planning for MVP commenced in 2009; the protocol was approved in 2010, and enrollment began in 2011. As of August 3, 2015, and with a steady state of ≈50 recruiting sites nationwide, N = 397,104 veterans have been enrolled. Among N = 199,348 with currently available genotyping data, most participants (as expected) are male (92.0%) between the ages of 50 and 69 years (55.0%). On the basis of self-reported race, white (77.2%) and African American (13.5%) populations are well represented. Conclusions By helping to promote the future integration of genetic testing in health care delivery, including clinical decision making, the MVP is designed to contribute to the development of precision medicine.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
We investigated the relationship between individual subjects' functional connectomes and 280 behavioral and demographic measures in a single holistic multivariate analysis relating imaging to ...non-imaging data from 461 subjects in the Human Connectome Project. We identified one strong mode of population co-variation: subjects were predominantly spread along a single 'positive-negative' axis linking lifestyle, demographic and psychometric measures to each other and to a specific pattern of brain connectivity.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
The fundamental properties of organisms—what they are, how and where they live, and the biotic and abiotic interactions that link them to communities and ecosystems—are the domain of natural history. ...We provide examples illustrating the vital importance of natural history knowledge to many disciplines, from human health and food security to conservation, management, and recreation. We then present several lines of evidence showing that traditional approaches to and support for natural history in developed economies has declined significantly over the past 40 years. Finally, we argue that a revitalization of the practice of natural history—one that is focused on new frontiers in a rapidly changing world and that incorporates new technologies—would provide significant benefits for both science and society.
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BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Characterising connectivity between geographically separated biological populations is a common goal in many fields. Recent approaches to understanding connectivity between malaria parasite ...populations, with implications for disease control efforts, have used estimates of relatedness based on identity-by-descent (IBD). However, uncertainty around estimated relatedness has not been accounted for. IBD-based relatedness estimates with uncertainty were computed for pairs of monoclonal Plasmodium falciparum samples collected from five cities on the Colombian-Pacific coast where long-term clonal propagation of P. falciparum is frequent. The cities include two official ports, Buenaventura and Tumaco, that are separated geographically but connected by frequent marine traffic. Fractions of highly-related sample pairs (whose classification using a threshold accounts for uncertainty) were greater within cities versus between. However, based on both highly-related fractions and on a threshold-free approach (Wasserstein distances between parasite populations) connectivity between Buenaventura and Tumaco was disproportionally high. Buenaventura-Tumaco connectivity was consistent with transmission events involving parasites from five clonal components (groups of statistically indistinguishable parasites identified under a graph theoretic framework). To conclude, P. falciparum population connectivity on the Colombian-Pacific coast abides by accessibility not isolation-by-distance, potentially implicating marine traffic in malaria transmission with opportunities for targeted intervention. Further investigations are required to test this hypothesis. For the first time in malaria epidemiology (and to our knowledge in ecological and epidemiological studies more generally), we account for uncertainty around estimated relatedness (an important consideration for studies that plan to use genotype versus whole genome sequence data to estimate IBD-based relatedness); we also use threshold-free methods to compare parasite populations and identify clonal components. Threshold-free methods are especially important in analyses of malaria parasites and other recombining organisms with mixed mating systems where thresholds do not have clear interpretation (e.g. due to clonal propagation) and thus undermine the cross-comparison of studies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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