Tobacco smoke condensate-induced senescence in endothelial cells was ameliorated by colchicine treatment via suppression of NF-κB and MAPKs P38 and ERK pathways activation.

Smoking is the major cause of cardiovascular diseases and cancer. It induces oxidative stress, leading to DNA damage and cellular senescence. Senescent cells increase the expression and release of pro-inflammatory molecules and matrix metalloproteinase, which are known to play a vital role in the initiation and progression of cardiovascular diseases and metastasis in cancer. The current study investigated the smoking induced cellular senescence and employed colchicine that blocked senescence in endothelial cells exposed to tobacco smoke condensate. Colchicine prevented oxidative stress and DNA damage in tobacco smoke-condensate-treated endothelial cells. Colchicin reduced ß-gal activity, improved Lamin B1, and attenuated cell growth arrest markers P21 and P53. Colchicine also ameliorated the expression of SASP factors and inhibited the activation of NF-kB and MAPKs P38 and ERK. In summary, colchicine inhibited tobacco smoke condensate-induced senescence in endothelial cells by blocking the activation of NF-kB and MAPKs P38 and ERK.

Mutational bias in spermatogonia impacts the anatomy of regulatory sites in the human genome.

Mutation in the germline is the ultimate source of genetic variation, but little is known about the influence of germline chromatin structure on mutational processes. Using ATAC-seq, we profile the open chromatin landscape of human spermatogonia, the most proliferative cell type of the germline, identifying transcription factor binding sites (TFBSs) and PRDM9 binding sites, a subset of which will initiate meiotic recombination. We observe an increase in rare structural variant (SV) breakpoints at PRDM9-bound sites, implicating meiotic recombination in the generation of structural variation. Many germline TFBSs, such as NRF1, are also associated with increased rates of SV breakpoints, apparently independent of recombination. Singleton short insertions (≥5 bp) are highly enriched at TFBSs, particularly at sites bound by testis active TFs, and their rates correlate with those of structural variant breakpoints. Short insertions often duplicate the TFBS motif, leading to clustering of motif sites near regulatory regions in this male-driven evolutionary process. Increased mutation loads at germline TFBSs disproportionately affect neural enhancers with activity in spermatogonia, potentially altering neurodevelopmental regulatory architecture. Local chromatin structure in spermatogonia is thus pervasive in shaping both evolution and disease.

Pervasive lesion segregation shapes cancer genome evolution.

Cancers arise through the acquisition of oncogenic mutations and grow by clonal expansion1,2. Here we reveal that most mutagenic DNA lesions are not resolved into a mutated DNA base pair within a single cell cycle. Instead, DNA lesions segregate, unrepaired, into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterize this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can produce multiple alternative alleles in successive cell divisions, thereby generating both multiallelic and combinatorial genetic diversity. The phasing of lesions enables accurate measurement of strand-biased repair processes, quantification of oncogenic selection and fine mapping of sister-chromatid-exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes.

Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline.

BACKGROUND: Chromatin loops form a basic unit of interphase nuclear organization, with chromatin loop anchor points providing contacts between regulatory regions and promoters. However, the mutational landscape at these anchor points remains under-studied. Here, we describe the unusual patterns of somatic mutations and germline variation associated with loop anchor points and explore the underlying features influencing these patterns. RESULTS: Analyses of whole genome sequencing datasets reveal that anchor points are strongly depleted for single nucleotide variants (SNVs) in tumours. Despite low SNV rates in their genomic neighbourhood, anchor points emerge as sites of evolutionary innovation, showing enrichment for structural variant (SV) breakpoints and a peak of SNVs at focal CTCF sites within the anchor points. Both CTCF-bound and non-CTCF anchor points harbour an excess of SV breakpoints in multiple tumour types and are prone to double-strand breaks in cell lines. Common fragile sites, which are hotspots for genome instability, also show elevated numbers of intersecting loop anchor points. Recurrently disrupted anchor points are enriched for genes with functions in cell cycle transitions and regions associated with predisposition to cancer. We also discover a novel class of CTCF-bound anchor points which overlap meiotic recombination hotspots and are enriched for the core PRDM9 binding motif, suggesting that the anchor points have been foci for diversity generated during recent human evolution. CONCLUSIONS: We suggest that the unusual chromatin environment at loop anchor points underlies the elevated rates of variation observed, marking them as sites of regulatory importance but also genomic fragility.

Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations.

The immune system plays a major role in human health and disease, and understanding genetic causes of interindividual variability of immune responses is vital. Here, we isolate monocytes from 134 genotyped individuals, stimulate these cells with three defined microbe-associated molecular patterns (LPS, MDP, and 5'-ppp-dsRNA), and profile the transcriptomes at three time points. Mapping expression quantitative trait loci (eQTL), we identify 417 response eQTLs (reQTLs) with varying effects between conditions. We characterize the dynamics of genetic regulation on early and late immune response and observe an enrichment of reQTLs in distal cis-regulatory elements. In addition, reQTLs are enriched for recent positive selection with an evolutionary trend towards enhanced immune response. Finally, we uncover reQTL effects in multiple GWAS loci and show a stronger enrichment for response than constant eQTLs in GWAS signals of several autoimmune diseases. This demonstrates the importance of infectious stimuli in modifying genetic predisposition to disease.Insight into the genetic influence on the immune response is important for the understanding of interindividual variability in human pathologies. Here, the authors generate transcriptome data from human blood monocytes stimulated with various immune stimuli and provide a time-resolved response eQTL map.

When TADs go bad: chromatin structure and nuclear organisation in human disease.

Chromatin in the interphase nucleus is organised as a hierarchical series of structural domains, including self-interacting domains called topologically associating domains (TADs). This arrangement is thought to bring enhancers into closer physical proximity with their target genes, which often are located hundreds of kilobases away in linear genomic distance. TADs are demarcated by boundary regions bound by architectural proteins, such as CTCF and cohesin, although much remains to be discovered about the structure and function of these domains. Recent studies of TAD boundaries disrupted in engineered mouse models show that boundary mutations can recapitulate human developmental disorders as a result of aberrant promoter-enhancer interactions in the affected TADs. Similar boundary disruptions in certain cancers can result in oncogene overexpression, and CTCF binding sites at boundaries appear to be hyper-mutated across cancers. Further insights into chromatin organisation, in parallel with accumulating whole genome sequence data for disease cohorts, are likely to yield additional valuable insights into the roles of noncoding sequence variation in human disease.

Mutational Biases Drive Elevated Rates of Substitution at Regulatory Sites across Cancer Types.

Disruption of gene regulation is known to play major roles in carcinogenesis and tumour progression. Here, we comprehensively characterize the mutational profiles of diverse transcription factor binding sites (TFBSs) across 1,574 completely sequenced cancer genomes encompassing 11 tumour types. We assess the relative rates and impact of the mutational burden at the binding sites of 81 transcription factors (TFs), by comparing the abundance and patterns of single base substitutions within putatively functional binding sites to control sites with matched sequence composition. There is a strong (1.43-fold) and significant excess of mutations at functional binding sites across TFs, and the mutations that accumulate in cancers are typically more disruptive than variants tolerated in extant human populations at the same sites. CTCF binding sites suffer an exceptionally high mutational load in cancer (3.31-fold excess) relative to control sites, and we demonstrate for the first time that this effect is seen in essentially all cancer types with sufficient data. The sub-set of CTCF sites involved in higher order chromatin structures has the highest mutational burden, suggesting a widespread breakdown of chromatin organization. However, we find no evidence for selection driving these distinctive patterns of mutation. The mutational load at CTCF-binding sites is substantially determined by replication timing and the mutational signature of the tumor in question, suggesting that selectively neutral processes underlie the unusual mutation patterns. Pervasive hyper-mutation within transcription factor binding sites rewires the regulatory landscape of the cancer genome, but it is dominated by mutational processes rather than selection.

Homozygous loss-of-function variants in European cosmopolitan and isolate populations.

Homozygous loss of function (HLOF) variants provide a valuable window on gene function in humans, as well as an inventory of the human genes that are not essential for survival and reproduction. All humans carry at least a few HLOF variants, but the exact number of inactivated genes that can be tolerated is currently unknown­as are the phenotypic effects of losing function for most human genes. Here, we make use of 1432 whole exome sequences from five European populations to expand the catalogue of known human HLOF mutations; after stringent filtering of variants in our dataset, we identify a total of 173 HLOF mutations, 76 (44%) of which have not been observed previously. We find that population isolates are particularly well suited to surveys of novel HLOF genes because individuals in such populations carry extensive runs of homozygosity, which we show are enriched for novel, rare HLOF variants. Further, we make use of extensive phenotypic data to show that most HLOFs, ascertained in population-based samples, appear to have little detectable effect on the phenotype. On the contrary, we document several genes directly implicated in disease that seem to tolerate HLOF variants. Overall HLOF genes are enriched for olfactory receptor function and are expressed in testes more often than expected, consistent with reduced purifying selection and incipient pseudogenisation.

Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes.

Toll-like receptors (TLRs) play a key role in innate immunity. Apart from their function in host defense, dysregulation in TLR signalling can confer risk to autoimmune diseases, septic shock or cancer. Here we report genetic variants and transcripts that are active only during TLR signalling and contribute to interindividual differences in immune response. Comparing unstimulated versus TLR4-stimulated monocytes reveals 1,471 expression quantitative trait loci (eQTLs) that are unique to TLR4 stimulation. Among these we find functional SNPs for the expression of NEU4, CCL14, CBX3 and IRF5 on TLR4 activation. Furthermore, we show that SNPs conferring risk to primary biliary cirrhosis (PBC), inflammatory bowel disease (IBD) and celiac disease are immune response eQTLs for PDGFB and IL18R1. Thus, PDGFB and IL18R1 represent plausible candidates for studying the pathophysiology of these disorders in the context of TLR4 activation. In summary, this study presents novel insights into the genetic basis of the innate immune response and exemplifies the value of eQTL studies in the context of exogenous cell stimulation.

De novo transcriptome assembly reveals sex-specific selection acting on evolving neo-sex chromosomes in Drosophila miranda.

BACKGROUND: The Drosophila miranda neo-sex chromosome system is a useful resource for studying recently evolved sex chromosomes. However, the neo-Y genomic assembly is fragmented due to the accumulation of repetitive sequence. Furthermore, the separate assembly of the neo-X and neo-Y chromosomes into genomic scaffolds has proven to be difficult, due to their low level of sequence divergence, which in coding regions is about 1.5%. Here, we de novo assemble the transcriptome of D. miranda using RNA-seq data from several male and female tissues, and develop a bioinformatic pipeline to separately reconstruct neo-X and neo-Y transcripts. RESULTS: We obtain 2,141 transcripts from the neo-X and 1,863 from the neo-Y. Neo-Y transcripts are generally shorter than their homologous neo-X transcripts (N50 of 2,048-bp vs. 2,775-bp) and expressed at lower levels. We find that 24% of expressed neo-Y transcripts harbor nonsense mutation within their open reading frames, yet most non-functional neo-Y genes are expressed throughout all of their length. We find evidence of gene loss of male-specific genes on the neo-X chromosome, and transcriptional silencing of testis-specific genes from the neo-X. CONCLUSIONS: Nonsense mediated decay (NMD) has been implicated to degrade transcripts containing pre-mature termination codons (PTC) in Drosophila, but rampant description of neo-Y genes with pre-mature stop codons suggests that it does not play a major role in down-regulating transcripts from the neo-Y. Loss or transcriptional down-regulation of genes from the neo-X with male-biased function provides evidence for beginning demasculinization of the neo-X. Thus, evolving sex chromosomes can rapidly shift their gene content or patterns of gene expression in response to their sex-biased transmission, supporting the idea that sex-specific or sexually antagonistic selection plays a major role in the evolution of heteromorphic sex chromosomes.

Self-priming determines high type I IFN production by plasmacytoid dendritic cells.

Plasmacytoid dendritic cells (pDCs) are responsible for the robust and immediate production of type I IFNs during viral infection. pDCs employ TLR7 and TLR9 to detect RNA and CpG motifs present in microbial genomes. CpG-A was the first synthetic stimulus available that induced large amounts of IFN-α (type I IFN) in pDCs. CpG-B, however, only weakly activates pDCs to produce IFN-α. Here, we demonstrate that differences in the kinetics of TLR9 activation in human pDCs are essential for the understanding of the functional difference between CpG-A and CpG-B. While CpG-B quickly induces IFN-α production in pDCs, CpG-A stimulation results in delayed yet maximal IFN-α induction. Constitutive production of low levels of type I IFN in pDCs, acting in a paracrine and autocrine fashion, turned out to be the key mechanism responsible for this phenomenon. At high cell density, pDC-derived, constitutive type I IFN production primes pDCs for maximal TLR responsiveness. This accounts for the high activity of higher structured TLR agonists that trigger type I IFN production in a delayed fashion. Altogether, these data demonstrate that high type I IFN production by pDCs cannot be simply ascribed to cell-autonomous mechanisms, yet critically depends on the local immune context.

Cortical effects of user training in a motor imagery based brain-computer interface measured by fNIRS and EEG.

The present study aims to gain insights into the effects of training with a motor imagery (MI)-based brain-computer interface (BCI) on activation patterns of the sensorimotor cortex. We used functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG) to investigate long-term training effects across 10 sessions using a 2-class (right hand and feet) MI-based BCI in fifteen subjects. In the course of the training a significant enhancement of activation pattern emerges, represented by an [oxy-Hb] increase in fNIRS and a stronger event-related desynchronization in the upper ß-frequency band in the EEG. These effects were only visible in participants with relatively low BCI performance (mean accuracy ≤ 70%). We found that training with an MI-based BCI affects cortical activation patterns especially in users with low BCI performance. Our results may serve as a valuable contribution to the field of BCI research and provide information about the effects that training with an MI-based BCI has on cortical activation patterns. This might be useful for clinical applications of BCI which aim at promoting and guiding neuroplasticity.

The epigenome of evolving Drosophila neo-sex chromosomes: dosage compensation and heterochromatin formation.

Sex chromosomes originated from autosomes but have evolved a highly specialized chromatin structure. Drosophila Y chromosomes are composed entirely of silent heterochromatin, while male X chromosomes have highly accessible chromatin and are hypertranscribed as a result of dosage compensation. Here, we dissect the molecular mechanisms and functional pressures driving heterochromatin formation and dosage compensation of the recently formed neo-sex chromosomes of Drosophila miranda. We show that the onset of heterochromatin formation on the neo-Y is triggered by an accumulation of repetitive DNA. The neo-X has evolved partial dosage compensation and we find that diverse mutational paths have been utilized to establish several dozen novel binding consensus motifs for the dosage compensation complex on the neo-X, including simple point mutations at pre-binding sites, insertion and deletion mutations, microsatellite expansions, or tandem amplification of weak binding sites. Spreading of these silencing or activating chromatin modifications to adjacent regions results in massive mis-expression of neo-sex linked genes, and little correspondence between functionality of genes and their silencing on the neo-Y or dosage compensation on the neo-X. Intriguingly, the genomic regions being targeted by the dosage compensation complex on the neo-X and those becoming heterochromatic on the neo-Y show little overlap, possibly reflecting different propensities along the ancestral chromosome that formed the sex chromosome to adopt active or repressive chromatin configurations. Our findings have broad implications for current models of sex chromosome evolution, and demonstrate how mechanistic constraints can limit evolutionary adaptations. Our study also highlights how evolution can follow predictable genetic trajectories, by repeatedly acquiring the same 21-bp consensus motif for recruitment of the dosage compensation complex, yet utilizing a diverse array of random mutational changes to attain the same phenotypic outcome.

Hybrid brain-computer interfaces and hybrid neuroprostheses for restoration of upper limb functions in individuals with high-level spinal cord injury.

BACKGROUND: The bilateral loss of the grasp function associated with a lesion of the cervical spinal cord severely limits the affected individuals' ability to live independently and return to gainful employment after sustaining a spinal cord injury (SCI). Any improvement in lost or limited grasp function is highly desirable. With current neuroprostheses, relevant improvements can be achieved in end users with preserved shoulder and elbow, but missing hand function. OBJECTIVE: The aim of this single case study is to show that (1) with the support of hybrid neuroprostheses combining functional electrical stimulation (FES) with orthoses, restoration of hand, finger and elbow function is possible in users with high-level SCI and (2) shared control principles can be effectively used to allow for a brain-computer interface (BCI) control, even if only moderate BCI performance is achieved after extensive training. PATIENT AND METHODS: The individual in this study is a right-handed 41-year-old man who sustained a traumatic SCI in 2009 and has a complete motor and sensory lesion at the level of C4. He is unable to generate functionally relevant movements of the elbow, hand and fingers on either side. He underwent extensive FES training (30-45min, 2-3 times per week for 6 months) and motor imagery (MI) BCI training (415 runs in 43 sessions over 12 months). To meet individual needs, the system was designed in a modular fashion including an intelligent control approach encompassing two input modalities, namely an MI-BCI and shoulder movements. RESULTS: After one year of training, the end user's MI-BCI performance ranged from 50% to 93% (average: 70.5%). The performance of the hybrid system was evaluated with different functional assessments. The user was able to transfer objects of the grasp-and-release-test and he succeeded in eating a pretzel stick, signing a document and eating an ice cream cone, which he was unable to do without the system. CONCLUSION: This proof-of-concept study has demonstrated that with the support of hybrid FES systems consisting of FES and a semiactive orthosis, restoring hand, finger and elbow function is possible in a tetraplegic end-user. Remarkably, even after one year of training and 415 MI-BCI runs, the end user's average BCI performance remained at about 70%. This supports the view that in high-level tetraplegic subjects, an initially moderate BCI performance cannot be improved by extensive training. However, this aspect has to be validated in future studies with a larger population.

Conservation and de novo acquisition of dosage compensation on newly evolved sex chromosomes in Drosophila.

Dosage compensation has arisen in response to the evolution of distinct male (XY) and female (XX) karyotypes. In Drosophila melanogaster, the MSL complex increases male X transcription approximately twofold. X-specific targeting is thought to occur through sequence-dependent binding to chromatin entry sites (CESs), followed by spreading in cis to active genes. We tested this model by asking how newly evolving sex chromosome arms in Drosophila miranda acquired dosage compensation. We found evidence for the creation of new CESs, with the analogous sequence and spacing as in D. melanogaster, providing strong support for the spreading model in the establishment of dosage compensation.

Sex-biased gene expression at homomorphic sex chromosomes in emus and its implication for sex chromosome evolution.

Sex chromosomes originate from autosomes. The accumulation of sexually antagonistic mutations on protosex chromosomes selects for a loss of recombination and sets in motion the evolutionary processes generating heteromorphic sex chromosomes. Recombination suppression and differentiation are generally viewed as the default path of sex chromosome evolution, and the occurrence of old, homomorphic sex chromosomes, such as those of ratite birds, has remained a mystery. Here, we analyze the genome and transcriptome of emu (Dromaius novaehollandiae) and confirm that most genes on the sex chromosome are shared between the Z and W. Surprisingly, however, levels of gene expression are generally sex-biased for all sex-linked genes relative to autosomes, including those in the pseudoautosomal region, and the male-bias increases after gonad formation. This expression bias suggests that the emu sex chromosomes have become masculinized, even in the absence of ZW differentiation. Thus, birds may have taken different evolutionary solutions to minimize the deleterious effects imposed by sexually antagonistic mutations: some lineages eliminate recombination along the protosex chromosomes to physically restrict sexually antagonistic alleles to one sex, whereas ratites evolved sex-biased expression to confine the product of a sexually antagonistic allele to the sex it benefits. This difference in conflict resolution may explain the preservation of recombining, homomorphic sex chromosomes in other lineages and illustrates the importance of sexually antagonistic mutations driving the evolution of sex chromosomes.

A ligation-independent cloning technique for high-throughput assembly of transcription activator­like effector genes.

Transcription activator­like (TAL) effector proteins derived from Xanthomonas species have emerged as versatile scaffolds for engineering DNA-binding proteins of user-defined specificity and functionality. Here we describe a rapid, simple, ligation-independent cloning (LIC) technique for synthesis of TAL effector genes. Our approach is based on a library of DNA constructs encoding individual TAL effector repeat unit combinations that can be processed to contain long, unique single-stranded DNA overhangs suitable for LIC. Assembly of TAL effector arrays requires only the combinatorial mixing of fluids and has exceptional fidelity. TAL effector nucleases (TALENs) produced by this method had high genome-editing activity at endogenous loci in HEK 293T cells (64% were active). To maximize throughput, we generated a comprehensive 5-mer TAL effector repeat unit fragment library that allows automated assembly of >600 TALEN genes in a single day. Given its simplicity, throughput and fidelity, LIC assembly will permit the generation of TAL effector gene libraries for large-scale functional genomics studies.

Relationship between electrical brain responses to motor imagery and motor impairment in stroke.

BACKGROUND AND PURPOSE: New strategies like motor imagery based brain-computer interfaces, which use brain signals such as event-related desynchronization (ERD) or event-related synchronization (ERS) for motor rehabilitation after a stroke, are undergoing investigation. However, little is known about the relationship between ERD and ERS patterns and the degree of stroke impairment. The aim of this work was to clarify this relationship. METHODS: EEG during motor imagery and execution were measured in 29 patients with first-ever monolateral stroke causing any degree of motor deficit in the upper limb. The strength and laterality of the ERD or ERS patterns were correlated with the scores of the European Stroke Scale, the Medical Research Council, and the Modified Ashworth Scale. RESULTS: Mean age of the patients was 58 ± 15 years; mean time from the incident was 4 ± 4 months. Stroke lesions were cortical (n=8), subcortical (n=11), or mixed (n=10), attributable to either an ischemic event (n=26) or a hemorrhage (n=3), affecting the right (n=16) or left (n=13) hemisphere. Higher impairment was related to stronger ERD in the unaffected hemisphere and higher spasticity was related to stronger ERD in the affected hemisphere. Both were related to a relatively stronger ERS in the affected hemisphere. CONCLUSIONS: The results of this study may have implications for the design of potential poststroke rehabilitation interventions based on brain-computer interface technologies that use neurophysiological signals like ERD or ERS as neural substrates for the mutual interaction between brain and machine and, ultimately, help stroke patients to regain motor control.

Stability and distribution of steady-state somatosensory evoked potentials elicited by vibro-tactile stimulation.

Steady-state somatosensory evoked potentials (SSSEPs) have been elicited applying vibro-tactile stimulation to all fingertips of the right hand. Nine healthy subjects participated in two sessions within this study. All fingers were stimulated 40 times with a 200-Hz carrier frequency modulated with a rectangular signal. The frequencies of the rectangular signal ranged between 17 and 35 Hz in 2 Hz steps. Relative band power tuning curves were calculated, introducing two different methods. Person-specific resonance-like frequencies were selected based on the data from the first session. The selected resonance-like frequencies were compared with the second session using an ANOVA for repeated measures to investigate the stability of SSSEPs over time. To determine, if SSSEPs can be classified with a classifier based on unseen data, an LDA classifier was trained with data from the first and applied to data from the second session. Person-specific resonance-like frequencies within a range from 19 to 29 Hz were found. The relative band power of the resonance-like frequencies did not differ significantly between the two sessions. Significant differences were found for the two methods and the used channels. SSSEPs were classified with a hit rate from 51 to 96 %.

Development of a non-invasive, multifunctional grasp neuroprosthesis and its evaluation in an individual with a high spinal cord injury.

Over the last decade the improvement of a missing hand function by application of neuroprostheses in particular the implantable Freehand system has been successfully shown in high spinal cord injured individuals. The clinically proven advantages of the Freehand system is its ease of use, the reproducible generation of two distinct functional grasp patterns and an analog control scheme based on movements of the contralateral shoulder. However, after the Freehand system is not commercially available for more than ten years, alternative grasp neuroprosthesis with a comparable functionality are still missing. Therefore, the aim of this study was to develop a non-invasive neuroprosthesis and to show that a degree of functional restoration can be provided to end users comparable to implanted devices. By introduction of an easy to handle forearm electrode sleeve the reproducible generation of two grasp patterns has been achieved. Generated grasp forces of the palmar grasp are in the range of the implanted system. Though pinch force of the lateral grasp is significantly lower, it can effectively used by a tetraplegic subject to perform functional tasks. The non-invasive grasp neuroprosthesis developed in this work may serve as an easy to apply and inexpensive way to restore a missing hand and finger function at any time after spinal cord injury.