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1.
Mol Biol Evol ; 38(9): 3497-3511, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34129037

RESUMO

Ancient genomes anchor genealogies in directly observed historical genetic variation and contextualize ancestral lineages with archaeological insights into their geography and cultural associations. However, the majority of ancient genomes are of lower coverage and cannot be directly built into genealogies. Here, we present a fast and scalable method, Colate, the first approach for inferring ancestral relationships through time between low-coverage genomes without requiring phasing or imputation. Our approach leverages sharing patterns of mutations dated using a genealogy to infer coalescence rates. For deeply sequenced ancient genomes, we additionally introduce an extension of the Relate algorithm for joint inference of genealogies incorporating such genomes. Application to 278 present-day and 430 ancient DNA samples of >0.5x mean coverage allows us to identify dynamic population structure and directional gene flow between early farmer and European hunter-gatherer groups. We further show that the previously reported, but still unexplained, increase in the TCC/TTC mutation rate, which is strongest in West Eurasia today, was already present at similar strength and widespread in the Late Glacial Period ~10k-15k years ago, but is not observed in samples >30k years old. It is strongest in Neolithic farmers, and highly correlated with recent coalescence rates between other genomes and a 10,000-year-old Anatolian hunter-gatherer. This suggests gene-flow among ancient peoples postdating the last glacial maximum as widespread and localizes the driver of this mutational signal in both time and geography in that region. Our approach should be widely applicable in future for addressing other evolutionary questions, and in other species.


Assuntos
DNA Antigo , Genoma , Fluxo Gênico , Genética Populacional , Geografia , História Antiga , Dinâmica Populacional
2.
Nature ; 530(7589): 171-176, 2016 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-26840484

RESUMO

The DNA-binding protein PRDM9 directs positioning of the double-strand breaks (DSBs) that initiate meiotic recombination in mice and humans. Prdm9 is the only mammalian speciation gene yet identified and is responsible for sterility phenotypes in male hybrids of certain mouse subspecies. To investigate PRDM9 binding and its role in fertility and meiotic recombination, we humanized the DNA-binding domain of PRDM9 in C57BL/6 mice. This change repositions DSB hotspots and completely restores fertility in male hybrids. Here we show that alteration of one Prdm9 allele impacts the behaviour of DSBs controlled by the other allele at chromosome-wide scales. These effects correlate strongly with the degree to which each PRDM9 variant binds both homologues at the DSB sites it controls. Furthermore, higher genome-wide levels of such 'symmetric' PRDM9 binding associate with increasing fertility measures, and comparisons of individual hotspots suggest binding symmetry plays a downstream role in the recombination process. These findings reveal that subspecies-specific degradation of PRDM9 binding sites by meiotic drive, which steadily increases asymmetric PRDM9 binding, has impacts beyond simply changing hotspot positions, and strongly support a direct involvement in hybrid infertility. Because such meiotic drive occurs across mammals, PRDM9 may play a wider, yet transient, role in the early stages of speciation.


Assuntos
Especiação Genética , Histona-Lisina N-Metiltransferase/química , Histona-Lisina N-Metiltransferase/metabolismo , Hibridização Genética/genética , Infertilidade/genética , Engenharia de Proteínas , Dedos de Zinco/genética , Alelos , Animais , Sítios de Ligação , Pareamento Cromossômico/genética , Cromossomos de Mamíferos/genética , Cromossomos de Mamíferos/metabolismo , Quebras de DNA de Cadeia Dupla , Feminino , Histona-Lisina N-Metiltransferase/genética , Humanos , Masculino , Meiose/genética , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Estrutura Terciária de Proteína/genética , Recombinação Genética/genética
3.
PLoS Genet ; 10(7): e1004503, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25033397

RESUMO

The pseudoautosomal region (PAR) is a short region of homology between the mammalian X and Y chromosomes, which has undergone rapid evolution. A crossover in the PAR is essential for the proper disjunction of X and Y chromosomes in male meiosis, and PAR deletion results in male sterility. This leads the human PAR with the obligatory crossover, PAR1, to having an exceptionally high male crossover rate, which is 17-fold higher than the genome-wide average. However, the mechanism by which this obligatory crossover occurs remains unknown, as does the fine-scale positioning of crossovers across this region. Recent research in mice has suggested that crossovers in PAR may be mediated independently of the protein PRDM9, which localises virtually all crossovers in the autosomes. To investigate recombination in this region, we construct the most fine-scale genetic map containing directly observed crossovers to date using African-American pedigrees. We leverage recombination rates inferred from the breakdown of linkage disequilibrium in human populations and investigate the signatures of DNA evolution due to recombination. Further, we identify direct PRDM9 binding sites using ChIP-seq in human cells. Using these independent lines of evidence, we show that, in contrast with mouse, PRDM9 does localise peaks of recombination in the human PAR1. We find that recombination is a far more rapid and intense driver of sequence evolution in PAR1 than it is on the autosomes. We also show that PAR1 hotspot activities differ significantly among human populations. Finally, we find evidence that PAR1 hotspot positions have changed between human and chimpanzee, with no evidence of sharing among the hottest hotspots. We anticipate that the genetic maps built and validated in this work will aid research on this vital and fascinating region of the genome.


Assuntos
Troca Genética , Histona-Lisina N-Metiltransferase/genética , Infertilidade Masculina/genética , Recombinação Genética , Cromossomos Humanos X/genética , Cromossomos Humanos Y/genética , Feminino , Genética Populacional , Projeto HapMap , Humanos , Desequilíbrio de Ligação , Masculino , Meiose/genética
4.
Aesthetic Plast Surg ; 41(1): 81-89, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28032159

RESUMO

BACKGROUND: The aim of this paper is to analyze the aesthetic characteristics of the human females' gaze using anthropometry and to present an artistic model to represent it: "The Frame Concept." In this model, the eye fissure represents a painting, and the most peripheral shadows around it represent the frame of this painting. The narrower the frame, the more aesthetically pleasing and youthful the gaze appears. MATERIALS AND METHOD: This study included a literature review of the features that make the gaze appear attractive. Photographs of models with attractive gazes were examined, and old photographs of patients were compared to recent photographs. The frame ratio was defined by anthropometric measurements of modern portraits of twenty consecutive Miss World winners. The concept was then validated for age and attractiveness across centuries by analysis of modern female photographs and works of art acknowledged for portraying beautiful young and older women in classical paintings. RESULTS: The frame height inversely correlated with attractiveness in modern female portrait photographs. The eye fissure frame ratio of modern idealized female portraits was similar to that of beautiful female portraits idealized by classical artists. In contrast, the eye fissure frames of classical artists' mothers' portraits were significantly wider than those of beautiful younger women. CONCLUSION: The Frame Concept is a valid artistic tool that provides an understanding of both the aesthetic and aging characteristics of the female periorbital region, enabling the practitioner to plan appropriate aesthetic interventions. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the A3 online Instructions to Authors. www.springer.com/00266 .


Assuntos
Beleza , Olho , Expressão Facial , Retratos como Assunto/história , Feminino , História do Século XVII , História do Século XVIII , História do Século XIX , Humanos , Medicina nas Artes , Pinturas/história , Cirurgia Plástica/história , Cirurgia Plástica/métodos
5.
Med Teach ; 38(9): 872-8, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27071862

RESUMO

Microsurgery is used in a variety of surgical specialties, including Plastic Surgery, Maxillofacial Surgery, Ophthalmic Surgery, Otolaryngology and Neurosurgery. It is considered one of the most technically challenging fields of surgery. Microsurgical skills demand fine, precise and controlled movements, and microsurgical skill acquisition has a steep initial learning curve. Microsurgical simulation provides a safe environment for skill acquisition before operating clinically. The traditional starting point for anyone wanting to pursue microsurgery is a basic simulation training course. We present twelve tips for postgraduate and undergraduate medics on how to set up and run a basic ex-vivo microsurgery simulation training course suitable for their peers.


Assuntos
Internato e Residência , Microcirurgia/educação , Microcirurgia/normas , Desenvolvimento de Programas/métodos , Treinamento por Simulação/organização & administração , Competência Clínica , Currículo , Guias como Assunto
6.
Nat Genet ; 39(5): 638-44, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17401364

RESUMO

After the recent discovery that common genetic variation in 8q24 influences inherited risk of prostate cancer, we genotyped 2,973 SNPs in up to 7,518 men with and without prostate cancer from five populations. We identified seven risk variants, five of them previously undescribed, spanning 430 kb and each independently predicting risk for prostate cancer (P = 7.9 x 10(-19) for the strongest association, and P < 1.5 x 10(-4) for five of the variants, after controlling for each of the others). The variants define common genotypes that span a more than fivefold range of susceptibility to cancer in some populations. None of the prostate cancer risk variants aligns to a known gene or alters the coding sequence of an encoded protein.


Assuntos
Cromossomos Humanos Par 8/genética , Predisposição Genética para Doença/genética , Variação Genética , Neoplasias da Próstata/genética , Negro ou Afro-Americano , Etnicidade/genética , Genômica/métodos , Genótipo , Haplótipos/genética , Humanos , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Estados Unidos , População Branca
7.
J Reconstr Microsurg ; 32(7): 556-61, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27303937

RESUMO

Background The aim of this article is to evaluate the difference in skills acquisition of two end-to-end microvascular anastomosis techniques-the triangulation and biangulation-in early microsurgery training. Method In this study, 32 candidates ranging from medical students to higher surgical trainees underwent a 5-day basic microsurgery course. On days 3 and 5 of the course, candidates performed two end-to-end anastomoses on cryopreserved rat aortas. One anastomosis was performed using the biangulation technique and the other using the triangulation technique. Candidates were randomized to the order of technique performed. Structural patency, errors performed, and suture distribution were evaluated randomly by a blinded reviewer using the anastomosis lapse index score and ImageJ (U.S. National Institutes of Health, Bethesda, MD) Software. Results A total of 128 anastomoses were evaluated during the study period. A total of six anastomoses performed with the biangulation technique, and four anastomoses with the triangulation technique, were physically occluded on day 3 of the course. On day 5, two biangulation technique anastomoses and one triangulation technique produced a nonpatent outcome. There was a statistically significant difference of patency rate between the 2 days of evaluation confirming evidence of skill acquisition but no statistically significant difference between the two techniques in relation to anastomotic patency, errors performed, or suture placement quality. Conclusion The biangulation and triangulation techniques of microvascular anastomosis produce similar outcomes in relation to vessel structural patency and quality of anastomosis when taught in early stages of microsurgery training. Our results suggest that both techniques are equally suitable in training novices, basic microsurgical skills.


Assuntos
Anastomose Cirúrgica/métodos , Competência Clínica/normas , Microcirurgia , Treinamento por Simulação , Técnicas de Sutura/normas , Grau de Desobstrução Vascular/fisiologia , Procedimentos Cirúrgicos Vasculares , Animais , Modelos Animais de Doenças , Método Duplo-Cego , Humanos , Microcirurgia/educação , Microcirurgia/normas , Estudos Prospectivos , Ratos , Análise e Desempenho de Tarefas , Procedimentos Cirúrgicos Vasculares/educação , Procedimentos Cirúrgicos Vasculares/normas
8.
Microsurgery ; 33(5): 406-15, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23712917

RESUMO

In the last decade surgical training is being revolutionized by two novel concepts that have been introduced to almost all branches of surgery including and most recently to microsurgery. These two concepts are: objective assessments of surgical skills and the nurturing of surgical skills in a simulation laboratory setting. Acquiring surgical skills in the laboratory setting can help move the microsurgical learning curve from the patient to the laboratory and this will in turn improve patient safety. In order to optimize microsurgical training through a competency based training programme, it is imperative for microsurgical educators to understand microsurgical skill acquisition. This requires accurate objective assessment tools that can define and quantify microsurgical competency. This article aims to review the current literature on the various objective assessment tools adapted for microsurgery and attempt to identify the gaps that need to be addressed by research in microsurgical education to establish the ideal objective assessment tool.


Assuntos
Competência Clínica , Microcirurgia/normas , Lista de Checagem , Simulação por Computador , Humanos , Microcirurgia/educação , Microcirurgia/métodos , Modelos Anatômicos , Modelos Educacionais , Ontário , Reino Unido , Interface Usuário-Computador
9.
Elife ; 122023 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-36648429

RESUMO

Causal loss-of-function (LOF) variants for Mendelian and severe complex diseases are enriched in 'mutation intolerant' genes. We show how such observations can be interpreted in light of a model of mutation-selection balance and use the model to relate the pathogenic consequences of LOF mutations at present to their evolutionary fitness effects. To this end, we first infer posterior distributions for the fitness costs of LOF mutations in 17,318 autosomal and 679 X-linked genes from exome sequences in 56,855 individuals. Estimated fitness costs for the loss of a gene copy are typically above 1%; they tend to be largest for X-linked genes, whether or not they have a Y homolog, followed by autosomal genes and genes in the pseudoautosomal region. We compare inferred fitness effects for all possible de novo LOF mutations to those of de novo mutations identified in individuals diagnosed with one of six severe, complex diseases or developmental disorders. Probands carry an excess of mutations with estimated fitness effects above 10%; as we show by simulation, when sampled in the population, such highly deleterious mutations are typically only a couple of generations old. Moreover, the proportion of highly deleterious mutations carried by probands reflects the typical age of onset of the disease. The study design also has a discernible influence: a greater proportion of highly deleterious mutations is detected in pedigree than case-control studies, and for autism, in simplex than multiplex families and in female versus male probands. Thus, anchoring observations in human genetics to a population genetic model allows us to learn about the fitness effects of mutations identified by different mapping strategies and for different traits.


Assuntos
Transtorno Autístico , Mutação com Perda de Função , Humanos , Masculino , Feminino , Mutação , Transtorno Autístico/genética , Fenótipo , Estudos de Casos e Controles
10.
PLoS Genet ; 3(3): e35, 2007 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-17352536

RESUMO

There is strong evidence that hotspots of meiotic recombination in humans are transient features of the genome. For example, hotspot locations are not shared between human and chimpanzee. Biased gene conversion in favor of alleles that locally disrupt hotspots is a possible explanation of the short lifespan of hotspots. We investigate the implications of such a bias on human hotspots and their evolution. Our results demonstrate that gene conversion bias is a sufficiently strong force to produce the observed lack of sharing of intense hotspots between species, although sharing may be much more common for weaker hotspots. We investigate models of how hotspots arise, and find that only models in which hotspot alleles do not initially experience drive are consistent with observations of rather hot hotspots in the human genome. Mutations acting against drive cannot successfully introduce such hotspots into the population, even if there is direct selection for higher recombination rates, such as to ensure correct segregation during meiosis. We explore the impact of hotspot alleles on patterns of haplotype variation, and show that such alleles mask their presence in population genetic data, making them difficult to detect.


Assuntos
Evolução Molecular , Recombinação Genética/genética , Alelos , Animais , Segregação de Cromossomos/genética , Quebras de DNA de Cadeia Dupla , Conversão Gênica/genética , Frequência do Gene , Genética Populacional , Humanos , Modelos Genéticos , Pan troglodytes/genética , Especificidade da Espécie
12.
Elife ; 92020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32744506

RESUMO

During meiosis, homologous chromosomes pair and recombine, enabling balanced segregation and generating genetic diversity. In many vertebrates, double-strand breaks (DSBs) initiate recombination within hotspots where PRDM9 binds, and deposits H3K4me3 and H3K36me3. However, no protein(s) recognising this unique combination of histone marks have been identified. We identified Zcwpw1, containing H3K4me3 and H3K36me3 recognition domains, as having highly correlated expression with Prdm9. Here, we show that ZCWPW1 has co-evolved with PRDM9 and, in human cells, is strongly and specifically recruited to PRDM9 binding sites, with higher affinity than sites possessing H3K4me3 alone. Surprisingly, ZCWPW1 also recognises CpG dinucleotides. Male Zcwpw1 knockout mice show completely normal DSB positioning, but persistent DMC1 foci, severe DSB repair and synapsis defects, and downstream sterility. Our findings suggest ZCWPW1 recognition of PRDM9-bound sites at DSB hotspots is critical for synapsis, and hence fertility.


Sexual reproduction ­ that is, the combination of sex cells from two different individuals to produce an embryo ­ is one of the many mechanisms that have evolved to maintain genetic diversity. Most human cells contain 23 pairs of chromosomes, with each chromosome in a pair carrying either a paternal or maternal copy of the same gene. To form an embryo with the right number of chromosomes, each sex cell (the egg or sperm cell) must only contain one chromosome from each pair. Sex cells are produced from parent cells containing two sets of paternal and maternal chromosomes: these cells then divide twice to form four sex cells which contain only one chromosome from each pair. Before the parent cell divides, a process known as 'recombination' takes place, which allows chromosomes in a pair to exchange bits of genetic information. This reshuffling ensures that each chromosome in a sex cell is unique. A protein called PRDM9 helps control which sections of genetic information are recombined by modifying proteins attached to the chromosomes, marking them as locations for exchange. The DNA at each of these sites is then broken and repaired using the genetic sequence of the chromosome it is paired with as a template, thus causing the two chromosomes to swap genes. In 2019, a group of researchers found a set of genes in the testis of mice that are expressed at the same time as the gene for PRDM9. This suggested that another protein called ZCWPW1 is likely involved in recombination, but the precise role of this protein was unclear. To answer this question, Wells, Bitoun et al. ­ including many of the researchers involved in the 2019 study ­ examined human cells grown in the laboratory to determine where ZCWPW1 binds to in the chromosome. This revealed that ZCWPW1 can be found at the same sites as PRDM9, which is responsible for bringing it there. Furthermore, cells from male mice lacking the gene for ZCWPW1 cannot complete the exchange of genetic information between chromosomes, meaning that the mice are infertile. As such, ZCWPW1 seems to connect location selection by PRDM9 to the DNA repair mechanisms needed for gene exchange between chromosomes. Infertility is a significant issue for humans affecting as many as one in every six couples. Fertility is complex and many of the biological mechanisms involved are not fully understood. This work suggests that both PRDM9 and ZCWPW1 are key to the production of sex cells and may be worth investigating as factors that affect fertility in humans.


Assuntos
Proteínas de Ciclo Celular/genética , Quebras de DNA de Cadeia Dupla , Reparo do DNA/genética , Histona-Lisina N-Metiltransferase/genética , Meiose/genética , Animais , Proteínas de Ciclo Celular/metabolismo , Feminino , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Masculino , Camundongos , Camundongos Knockout , Recombinação Genética
13.
Nat Genet ; 51(9): 1321-1329, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31477933

RESUMO

Knowledge of genome-wide genealogies for thousands of individuals would simplify most evolutionary analyses for humans and other species, but has remained computationally infeasible. We have developed a method, Relate, scaling to >10,000 sequences while simultaneously estimating branch lengths, mutational ages and variable historical population sizes, as well as allowing for data errors. Application to 1,000 Genomes Project haplotypes produces joint genealogical histories for 26 human populations. Highly diverged lineages are present in all groups, but most frequent in Africa. Outside Africa, these mainly reflect ancient introgression from groups related to Neanderthals and Denisovans, while African signals instead reflect unknown events unique to that continent. Our approach allows more powerful inferences of natural selection than has previously been possible. We identify multiple regions under strong positive selection, and multi-allelic traits including hair color, body mass index and blood pressure, showing strong evidence of directional selection, varying among human groups.


Assuntos
Evolução Molecular , Genética Populacional , Genoma Humano , Estudo de Associação Genômica Ampla/métodos , Linhagem , Seleção Genética , Animais , Haplótipos , Humanos , Mutação , Homem de Neandertal , Polimorfismo de Nucleotídeo Único , Densidade Demográfica
14.
Nat Commun ; 10(1): 3900, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467277

RESUMO

During meiotic recombination, homologue-templated repair of programmed DNA double-strand breaks (DSBs) produces relatively few crossovers and many difficult-to-detect non-crossovers. By intercrossing two diverged mouse subspecies over five generations and deep-sequencing 119 offspring, we detect thousands of crossover and non-crossover events genome-wide with unprecedented power and spatial resolution. We find that both crossovers and non-crossovers are strongly depleted at DSB hotspots where the DSB-positioning protein PRDM9 fails to bind to the unbroken homologous chromosome, revealing that PRDM9 also functions to promote homologue-templated repair. Our results show that complex non-crossovers are much rarer in mice than humans, consistent with complex events arising from accumulated non-programmed DNA damage. Unexpectedly, we also find that GC-biased gene conversion is restricted to non-crossover tracts containing only one mismatch. These results demonstrate that local genetic diversity profoundly alters meiotic repair pathway decisions via at least two distinct mechanisms, impacting genome evolution and Prdm9-related hybrid infertility.


Assuntos
Quebras de DNA de Cadeia Dupla , Variação Genética , Recombinação Homóloga , Alelos , Animais , Proteínas de Ciclo Celular/genética , Cromossomos , Troca Genética , Dano ao DNA , Reparo de Erro de Pareamento de DNA , Feminino , Conversão Gênica , Histona-Lisina N-Metiltransferase/genética , Histonas/genética , Humanos , Hibridização Genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Genéticos , Proteínas de Ligação a Fosfato/genética , Polimorfismo de Nucleotídeo Único , Reparo de DNA por Recombinação
15.
Elife ; 82019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31237565

RESUMO

To fully exploit the potential of single-cell functional genomics in the study of development and disease, robust methods are needed to simplify the analysis of data across samples, time-points and individuals. Here we introduce a model-based factor analysis method, SDA, to analyze a novel 57,600 cell dataset from the testes of wild-type mice and mice with gonadal defects due to disruption of the genes Mlh3, Hormad1, Cul4a or Cnp. By jointly analyzing mutant and wild-type cells we decomposed our data into 46 components that identify novel meiotic gene-regulatory programs, mutant-specific pathological processes, and technical effects, and provide a framework for imputation. We identify, de novo, DNA sequence motifs associated with individual components that define temporally varying modes of gene expression control. Analysis of SDA components also led us to identify a rare population of macrophages within the seminiferous tubules of Mlh3-/- and Hormad1-/- mice, an area typically associated with immune privilege.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas MutL/genética , Espermatogênese/genética , Testículo/metabolismo , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/genética , Animais , Proteínas de Ciclo Celular/imunologia , Proteínas Culina/genética , Regulação da Expressão Gênica/genética , Genômica , Masculino , Meiose/genética , Camundongos , Camundongos Knockout , Proteínas MutL/imunologia , Motivos de Nucleotídeos/genética , Células de Sertoli/metabolismo , Análise de Célula Única , Espermatogênese/imunologia , Testículo/crescimento & desenvolvimento , Testículo/imunologia
16.
Eplasty ; 18: e25, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30338013

RESUMO

Objective: Microsurgical education is an integral aspect of plastic surgery training. Like most traditional surgical education models, microsurgical skills are taught on an apprenticeship model. This study aims at evaluating microsurgery skill acquisition within an integrated plastic surgery residency using electromagnetic hand-motion analysis and a global rating scale. Methods: This is a cross-sectional study of an integrated plastic surgery residency program. Participants performed microsurgical arterial anastomoses on cryopreserved rat aortas. Hand-motion analysis was recorded using a trakSTAR hand-motion tracker. Total time to complete the task, number of hand movements, and path length (mm) were recorded. Participant videos were graded using a subjective global rating scale (scored 0-100). Results: The data demonstrated construct validity, as hand-motion analysis outcome measures statistically varied according to the level of skill. Mean global rating scale scores increased with level of experience but lacked statistical significance. Conclusions: These data suggest that the objective assessment of hand motion is a valid tool for the evaluation of microsurgical skill. It is more accurate and reflective of the level of skill than a global rating scale. Identifying the predictive validity of hand-motion analysis will be a useful tool to establish clinical safe training and practice thresholds, and the application of both assessment tools simultaneously can yield better evaluation.

17.
Tissue Eng ; 13(11): 2733-41, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17880270

RESUMO

Keratinocyte stem cell technology provides at least an adjuvant therapy to clinically close large cutaneous wounds (e.g., burn wounds). Here, the performance of keratinocyte cultures depends primarily on the quality of the bed to which they are applied. Clinical take rates for cultured keratinocyte grafts are optimal when applied to a vascularized dermal bed with minimal bacterial colonization. In the absence of autologous dermis, staged reconstruction with a dermal equivalent or dermal regeneration template is required. A novel product, Hyalomatrix, is a bilayer of an esterified hyaluronan scaffold beneath a silicone membrane. The scaffold delivers hyaluronan to the wound bed, and the silicone membrane acts as a temporary epidermal barrier. The product has been investigated in a controlled, porcine, acute full-thickness excisional wound model. Cultured autologous keratinocytes (CAKs) were delivered on Laserskin to acute full-thickness wounds treated with Hyalomatrix within chambers, and graft take rates were assessed longitudinally using image analysis. In the absence of chambers, wound contraction was assessed. Clinical CAK take rates fall sequentially with delay in application post-Hyalomatrix pre-treatment, but repeated pre-treatment removed this, with maximal take of 57.2% at 5 weeks post-wounding. In the absence of chambers, more-complete wound closure resulted from edge re-epithelialization and contraction, by a factor of 5 at 1 month, and was achieved at least 2 weeks sooner in the gold standard controls of split-thickness autograft to an acute or pre-treated wound bed. Wound contraction and late neodermal morphology (1 year) were similar in pre-treated CAKs and split-thickness autograft wounds. In this model, the Hyalomatrix wound bed pre-treatment increase in CAK take appeared to be dose dependent. The product appeared to act as a hyaluronan delivery system rather than a dermal regeneration template. The silicone membrane may limit wound bed colonization, and the combination of this temporary barrier with hyaluronan delivery and neodermis induction has been termed a barrier-delivery-induction system. The development of similar systems for serial application offers an alternative to a dermal regeneration template when CAKs are engrafted in the hostile, colonized environment of large burn wounds.


Assuntos
Ácido Hialurônico , Queratinócitos/transplante , Pele Artificial , Células-Tronco/citologia , Cicatrização , Animais , Células Cultivadas , Modelos Animais de Doenças , Células Epidérmicas , Masculino , Transplante de Pele , Suínos , Porco Miniatura , Fatores de Tempo , Transplante Autólogo , Resultado do Tratamento
18.
Elife ; 62017 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-29072575

RESUMO

PRDM9 binding localizes almost all meiotic recombination sites in humans and mice. However, most PRDM9-bound loci do not become recombination hotspots. To explore factors that affect binding and subsequent recombination outcomes, we mapped human PRDM9 binding sites in a transfected human cell line and measured PRDM9-induced histone modifications. These data reveal varied DNA-binding modalities of PRDM9. We also find that human PRDM9 frequently binds promoters, despite their low recombination rates, and it can activate expression of a small number of genes including CTCFL and VCX. Furthermore, we identify specific sequence motifs that predict consistent, localized meiotic recombination suppression around a subset of PRDM9 binding sites. These motifs strongly associate with KRAB-ZNF protein binding, TRIM28 recruitment, and specific histone modifications. Finally, we demonstrate that, in addition to binding DNA, PRDM9's zinc fingers also mediate its multimerization, and we show that a pair of highly diverged alleles preferentially form homo-multimers.


Assuntos
DNA/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Recombinação Homóloga , Meiose , Sítios de Ligação , Mapeamento Cromossômico , Células HEK293 , Humanos , Ligação Proteica , Multimerização Proteica
20.
Br J Oral Maxillofac Surg ; 54(9): 1025-1027, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26867483

RESUMO

We investigated the effect of physical activity on microsurgical performance. Forty novice candidates and 6 expert controls did a series of consecutive end-to-end microvascular anastomoses. To assess performance, we did a hand motion analysis and correlated the results with levels of habitual physical activity. Higher levels of activity in the novice candidates correlated with slower completion of anastomosis for medical students on day 1 (p=0.0035) and day 5 (p=0.0003). The same pattern was seen for postgraduate trainees on day 1 (p=0.024) and day 5 (p=0.0063). Higher level of activity also correlated with an increase in path length (total distance travelled and direction of travel) and in total movements on day 1 for medical students (p=0.016 and p=0.0021, respectively), and in total path length on day 1 for postgraduate trainees (p=0.0305).


Assuntos
Competência Clínica , Exercício Físico , Microcirurgia , Anastomose Cirúrgica , Humanos , Estudantes de Medicina
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