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1.
Cell Syst ; 12(2): 128-140.e4, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33373583

RESUMO

Systematic perturbation of cells followed by comprehensive measurements of molecular and phenotypic responses provides informative data resources for constructing computational models of cell biology. Models that generalize well beyond training data can be used to identify combinatorial perturbations of potential therapeutic interest. Major challenges for machine learning on large biological datasets are to find global optima in a complex multidimensional space and mechanistically interpret the solutions. To address these challenges, we introduce a hybrid approach that combines explicit mathematical models of cell dynamics with a machine-learning framework, implemented in TensorFlow. We tested the modeling framework on a perturbation-response dataset of a melanoma cell line after drug treatments. The models can be efficiently trained to describe cellular behavior accurately. Even though completely data driven and independent of prior knowledge, the resulting de novo network models recapitulate some known interactions. The approach is readily applicable to various kinetic models of cell biology. A record of this paper's Transparent Peer Review process is included in the Supplemental Information.

2.
Phys Chem Chem Phys ; 22(41): 23618-23626, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33112304

RESUMO

Lack of quality data and difficulty generating these data hinder quantitative understanding of reaction kinetics. Specifically, conventional methods to generate transition state structures are deficient in speed, accuracy, or scope. We describe a novel method to generate three-dimensional transition state structures for isomerization reactions using reactant and product geometries. Our approach relies on a graph neural network to predict the transition state distance matrix and a least squares optimization to reconstruct the coordinates based on which entries of the distance matrix the model perceives to be important. We feed the structures generated by our algorithm through a rigorous quantum mechanics workflow to ensure the predicted transition state corresponds to the ground truth reactant and product. In both generating viable geometries and predicting accurate transition states, our method achieves excellent results. We envision workflows like this, which combine neural networks and quantum chemistry calculations, will become the preferred methods for computing chemical reactions.

3.
Hand (N Y) ; 15(1): 97-102, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30043624

RESUMO

Background: Indication for intervention in Dupuytren disease is influenced by many factors, including location and extent of disease, surgeon preference, and comfort level with different treatment techniques. The aim of this study was to determine current Dupuytren disease management trends. Methods: A questionnaire was sent through the American Society for Surgery of the Hand to all members. In addition to demographic data, questions focused on indications for different procedural interventions based on location of disease, age, and activity level of the patient. Results: Approximately 24% of respondents completed the survey. Respondents were mostly orthopedic surgeons in private practice who do not work with residents or fellows. Respondents preferred collagenase over needle aponeurotomy and limited fasciectomy for primary Dupuytren disease involving only the metacarpophalangeal (MCP) joint. Limited fasciectomy was the preferred treatment for primary Dupuytren disease involving the MCP and proximal interphalangeal joints. For a patient amenable to any treatment option, the majority would use collagenase, although 87.1% felt that fasciectomy offered the longest disease-free interval. Furthermore, given the option of a young, working patient, 42.7% would use collagenase, while plastic and general surgeons were more likely to treat this patient with limited fasciectomy. More plastic surgeons (vs orthopedic) believe that limited fasciectomy yields the longest disease-free interval. For a patient amenable to any surgical option, orthopedic surgeons prefer collagenase, whereas plastic hand surgeons prefer a limited fasciectomy. Conclusion: There are several procedural options for the treatment of Dupuytren disease. This study details current practice patterns among hand surgeons and reveals the increasingly prevalent use of collagenase.

4.
Bioinformatics ; 35(9): 1582-1584, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30304492

RESUMO

SUMMARY: Coevolutionary sequence analysis has become a commonly used technique for de novo prediction of the structure and function of proteins, RNA, and protein complexes. We present the EVcouplings framework, a fully integrated open-source application and Python package for coevolutionary analysis. The framework enables generation of sequence alignments, calculation and evaluation of evolutionary couplings (ECs), and de novo prediction of structure and mutation effects. The combination of an easy to use, flexible command line interface and an underlying modular Python package makes the full power of coevolutionary analyses available to entry-level and advanced users. AVAILABILITY AND IMPLEMENTATION: https://github.com/debbiemarkslab/evcouplings.


Assuntos
Análise de Sequência , Software , Proteínas , RNA , Alinhamento de Sequência
5.
Nat Methods ; 15(10): 816-822, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30250057

RESUMO

The functions of proteins and RNAs are defined by the collective interactions of many residues, and yet most statistical models of biological sequences consider sites nearly independently. Recent approaches have demonstrated benefits of including interactions to capture pairwise covariation, but leave higher-order dependencies out of reach. Here we show how it is possible to capture higher-order, context-dependent constraints in biological sequences via latent variable models with nonlinear dependencies. We found that DeepSequence ( https://github.com/debbiemarkslab/DeepSequence ), a probabilistic model for sequence families, predicted the effects of mutations across a variety of deep mutational scanning experiments substantially better than existing methods based on the same evolutionary data. The model, learned in an unsupervised manner solely on the basis of sequence information, is grounded with biologically motivated priors, reveals the latent organization of sequence families, and can be used to explore new parts of sequence space.


Assuntos
Biologia Computacional/métodos , Evolução Molecular , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Modelos Teóricos , Mutação , Algoritmos , Humanos
6.
Hand (N Y) ; 12(4): 325-326, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28644931

RESUMO

Financial productivity in academic surgery is important and deserves great emphasis, yet it is but one of many vital elements of a healthy practice. Productivity must be carefully balanced with many other vital goals such as maximizing patient safety, maintaining excellent outcomes, optimizing resident and medical student education, and earning outstanding patient feedback. The following editorial explores this elusive balance and the importance of not swaying too far in the direction of revenue.


Assuntos
Eficiência Organizacional , Docentes de Medicina , Cirurgiões , Humanos
8.
Nat Biotechnol ; 35(2): 128-135, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28092658

RESUMO

Many high-throughput experimental technologies have been developed to assess the effects of large numbers of mutations (variation) on phenotypes. However, designing functional assays for these methods is challenging, and systematic testing of all combinations is impossible, so robust methods to predict the effects of genetic variation are needed. Most prediction methods exploit evolutionary sequence conservation but do not consider the interdependencies of residues or bases. We present EVmutation, an unsupervised statistical method for predicting the effects of mutations that explicitly captures residue dependencies between positions. We validate EVmutation by comparing its predictions with outcomes of high-throughput mutagenesis experiments and measurements of human disease mutations and show that it outperforms methods that do not account for epistasis. EVmutation can be used to assess the quantitative effects of mutations in genes of any organism. We provide pre-computed predictions for ∼7,000 human proteins at http://evmutation.org/.


Assuntos
Sequência Conservada/genética , Análise Mutacional de DNA/métodos , Epistasia Genética/genética , Variação Genética/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Proteoma/genética , Sequência de Aminoácidos/genética , Evolução Molecular , Humanos , Dados de Sequência Molecular , Mutação/genética , Proteoma/química
9.
Ann Plast Surg ; 78(5): 552-556, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27750269

RESUMO

BACKGROUND: The ethical practice of medicine has always been of utmost importance, and plastic surgery is no exception. The literature is devoid of information on the teaching of ethics and professionalism in plastic surgery. In light of this, a survey was sent to ascertain the status of ethics training in plastic surgery residencies. METHODS: A 21-question survey was sent from the American Council of Academic Plastic Surgeons meeting to 180 plastic surgery program directors and coordinators via email. Survey questions inquired about practice environment, number of residents, presence of a formal ethics training program, among others. Binary regression was used to determine if any relationships existed between categorical variables, and Poisson linear regression was used to assess relationships between continuous variables. Statistical significance was set at a P value of 0.05. RESULTS: A total of 104 members responded to the survey (58% response rate). Sixty-three percent were program directors, and most (89%) practiced in academic settings. Sixty-two percent in academics reported having a formal training program, and 60% in private practice reported having one. Only 40% of programs with fewer than 10 residents had ethics training, whereas 78% of programs with more than 20 residents did. The odds of having a training program were slightly higher (odds ratio, 1.1) with more residents (P = 0.17). CONCLUSIONS: Despite the lack of information in the literature, formal ethics and professionalism training does exist in many plastic surgery residencies, although barriers to implementation do exist. Plastic surgery leadership should be involved in the development of standardized curricula to help overcome these barriers.


Assuntos
Ética Médica/educação , Profissionalismo/educação , Profissionalismo/ética , Cirurgia Plástica/educação , Cirurgia Plástica/ética , Estudos Transversais , Educação de Pós-Graduação em Medicina , Humanos , Internato e Residência , Inquéritos e Questionários , Estados Unidos
10.
Cell ; 167(1): 158-170.e12, 2016 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-27662088

RESUMO

Protein flexibility ranges from simple hinge movements to functional disorder. Around half of all human proteins contain apparently disordered regions with little 3D or functional information, and many of these proteins are associated with disease. Building on the evolutionary couplings approach previously successful in predicting 3D states of ordered proteins and RNA, we developed a method to predict the potential for ordered states for all apparently disordered proteins with sufficiently rich evolutionary information. The approach is highly accurate (79%) for residue interactions as tested in more than 60 known disordered regions captured in a bound or specific condition. Assessing the potential for structure of more than 1,000 apparently disordered regions of human proteins reveals a continuum of structural order with at least 50% with clear propensity for three- or two-dimensional states. Co-evolutionary constraints reveal hitherto unseen structures of functional importance in apparently disordered proteins.


Assuntos
Proteínas Intrinsicamente Desordenadas/química , Evolução Molecular Direcionada/métodos , Genômica , Humanos , Proteínas Intrinsicamente Desordenadas/genética , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Proteoma/química , Proteoma/genética
11.
Cell ; 165(4): 963-75, 2016 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-27087444

RESUMO

Non-coding RNAs are ubiquitous, but the discovery of new RNA gene sequences far outpaces the research on the structure and functional interactions of these RNA gene sequences. We mine the evolutionary sequence record to derive precise information about the function and structure of RNAs and RNA-protein complexes. As in protein structure prediction, we use maximum entropy global probability models of sequence co-variation to infer evolutionarily constrained nucleotide-nucleotide interactions within RNA molecules and nucleotide-amino acid interactions in RNA-protein complexes. The predicted contacts allow all-atom blinded 3D structure prediction at good accuracy for several known RNA structures and RNA-protein complexes. For unknown structures, we predict contacts in 160 non-coding RNA families. Beyond 3D structure prediction, evolutionary couplings help identify important functional interactions-e.g., at switch points in riboswitches and at a complex nucleation site in HIV. Aided by increasing sequence accumulation, evolutionary coupling analysis can accelerate the discovery of functional interactions and 3D structures involving RNA.


Assuntos
Conformação de Ácido Nucleico , RNA não Traduzido/química , Entropia , Evolução Molecular , Modelos Moleculares , Dobramento de RNA , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Ribossomos/metabolismo
12.
Hand (N Y) ; 10(3): 574-7, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26330800

RESUMO

BACKGROUND: The most common compressive neuropathy affects the median nerve in the carpal tunnel; it is typically chronic and progressive. Acute carpal tunnel syndrome (ACTS), on the other hand, is a less frequently encountered surgical emergency that usually occurs in the setting of trauma, such as a displaced fracture of the distal radius or carpal dislocation. To our knowledge, there are only two cases of acute carpal tunnel secondary to gout reported in the literature, with both being outside of the USA and the last case being over 20 years ago. We reviewed the literature describing acute carpal tunnel syndrome (ACTS) caused by gout and present a recent case of atraumatic ACTS caused, in part, by a tophaceous gouty mass. METHODS: Review of the literature consisted of a PubMed search of all articles in the English language using the following keywords: "Acute Carpal Tunnel Syndrome" and "Tophaceous Gout" and "Gout." RESULTS: We present the youngest reported case of atraumatic ACTS caused by tophaceous gout and the only reported case with a documented history of gout being actively medically managed with a uric acid lowering agent. This was successfully treated with an emergent extended carpal tunnel release, a complete flexor synovectomy, and excision of a gouty mass adhered to the carpal tunnel floor. CONCLUSIONS: Atraumatic ACTS secondary to gout is rare and has never been reported in a patient already being managed with uric acid lowering agents. Such a presentation requires rapid surgical exploration with release of the carpal tunnel, debridement of all gouty tissue, and increasingly aggressive adjuvant medical therapy.

13.
J Craniofac Surg ; 26(4): 1088-90, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26080132

RESUMO

OBJECTIVE: The present status of global mission trips of all of the academic Plastic Surgery programs was surveyed. We aimed to provide information and guidelines for other interested programs on creating a global health elective in compliance with American Board of Plastic Surgery (ABPS) and Accreditation Council for Graduate Medical Education Residency Review Committee (ACGME/RRC) requirements. DESIGN: A free-response survey was sent to all of the Plastic Surgery Residency program directors inquiring about their present policy on international mission trips for residents and faculty. Questions included time spent in mission, cases performed, sponsoring organizations, and whether cases are being counted in their resident Plastic Surgery Operative Logs (PSOL). RESULTS: Thirty-one programs responded, with 23 programs presently sponsoring international mission trips. Thirteen programs support residents going on nonprogram-sponsored trips where the majority of these programs partner with outside organizations. Many programs do not count cases performed on mission trips as part of ACGME index case requirement. Application templates for international rotations to comply with ABPS and ACGME/RRC requirements were created to facilitate the participation of interested programs. CONCLUSIONS: Many Plastic Surgery Residency programs are sponsoring international mission trips for their residents; however, there is a lack of uniformity and administrative support in pursuing these humanitarian efforts. The creation of a dynamic centralized database will help interested programs and residents seek out the global health experience they desire and ensure standardization of the educational experience they obtain during these trips.


Assuntos
Acreditação , Educação de Pós-Graduação em Medicina/métodos , Internato e Residência/organização & administração , Missões Médicas/organização & administração , Cirurgia Plástica/organização & administração , Humanos
14.
Proc Natl Acad Sci U S A ; 112(5): 1636-41, 2015 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-25605920

RESUMO

Natural environments are filled with multiple, often competing, signals. In contrast, biological systems are often studied in "well-controlled" environments where only a single input is varied, potentially missing important interactions between signals. Catabolite repression of galactose by glucose is one of the best-studied eukaryotic signal integration systems. In this system, it is believed that galactose metabolic (GAL) genes are induced only when glucose levels drop below a threshold. In contrast, we show that GAL gene induction occurs at a constant external galactose:glucose ratio across a wide range of sugar concentrations. We systematically perturbed the components of the canonical galactose/glucose signaling pathways and found that these components do not account for ratio sensing. Instead we provide evidence that ratio sensing occurs upstream of the canonical signaling pathway and results from the competitive binding of the two sugars to hexose transporters. We show that a mutant that behaves as the classical model expects (i.e., cannot use galactose above a glucose threshold) has a fitness disadvantage compared with wild type. A number of common biological signaling motifs can give rise to ratio sensing, typically through negative interactions between opposing signaling molecules. We therefore suspect that this previously unidentified nutrient sensing paradigm may be common and overlooked in biology.


Assuntos
Galactose/metabolismo , Glucose/metabolismo , Saccharomyces cerevisiae/genética , Meios de Cultura , Genes Fúngicos , Microscopia de Fluorescência , Saccharomyces cerevisiae/metabolismo , Transdução de Sinais
15.
PLoS One ; 9(4): e95315, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24736608

RESUMO

The spectral properties of pulses transmitted by three commercially available 200 kHz echo sounders were measured to assess the possibility that marine mammals might hear sound energy below the center (carrier) frequency that may be generated by transmitting short rectangular pulses. All three sounders were found to generate sound at frequencies below the center frequency and within the hearing range of some marine mammals, e.g. killer whales, false killer whales, beluga whales, Atlantic bottlenose dolphins, harbor porpoises, and others. The frequencies of these sub-harmonic sounds ranged from 90 to 130 kHz. These sounds were likely detectable by the animals over distances up to several hundred meters but were well below potentially harmful levels. The sounds generated by the sounders could potentially affect the behavior of marine mammals within fairly close proximity to the sources and therefore the exclusion of echo sounders from environmental impact analysis based solely on the center frequency output in relation to the range of marine mammal hearing should be reconsidered.


Assuntos
Acústica , Organismos Aquáticos , Percepção Auditiva , Orca/fisiologia , Animais , Navegação Espacial
16.
Sci Rep ; 4: 4090, 2014 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-24522516

RESUMO

The Juvenile Salmon Acoustic Telemetry System (JSATS) has been used at many dams but has never been deployed in the near-dam tailrace environment. The use of JSATS in the tailrace is of interest to fishery managers to evaluate downstream passage behavior of juvenile salmonids and dam approach behavior of upstream migrating adult salmon and lamprey. The acoustic noise level and detection range of JSATS were studied to determine the feasibility of deploying JSATS in the Ice Harbor Dam tailrace. The noise level measured from the powerhouse deck was less than 104 dB re 1 µPa except for the turbine outlet near the spillway, and 350 m downstream of the dam, the noise level was less than 106 dB. The measured noise levels would allow a theoretical detection range of 100 m to 350 m and 85 m to 320 m, respectively. Validation experiments showed that the detection range is 113 to 184 m using hydrophones deployed from the powerhouse deck and 148 m using hydrophones deployed 500 m downstream of the dam.


Assuntos
Salmão/fisiologia , Telemetria/métodos , Acústica , Migração Animal , Animais , Rios , Telemetria/instrumentação
17.
PLoS One ; 7(11): e47445, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23139744

RESUMO

We asked how team dynamics can be captured in relation to function by considering games in the first round of the NBA 2010 play-offs as networks. Defining players as nodes and ball movements as links, we analyzed the network properties of degree centrality, clustering, entropy and flow centrality across teams and positions, to characterize the game from a network perspective and to determine whether we can assess differences in team offensive strategy by their network properties. The compiled network structure across teams reflected a fundamental attribute of basketball strategy. They primarily showed a centralized ball distribution pattern with the point guard in a leadership role. However, individual play-off teams showed variation in their relative involvement of other players/positions in ball distribution, reflected quantitatively by differences in clustering and degree centrality. We also characterized two potential alternate offensive strategies by associated variation in network structure: (1) whether teams consistently moved the ball towards their shooting specialists, measured as "uphill/downhill" flux, and (2) whether they distributed the ball in a way that reduced predictability, measured as team entropy. These network metrics quantified different aspects of team strategy, with no single metric wholly predictive of success. However, in the context of the 2010 play-offs, the values of clustering (connectedness across players) and network entropy (unpredictability of ball movement) had the most consistent association with team advancement. Our analyses demonstrate the utility of network approaches in quantifying team strategy and show that testable hypotheses can be evaluated using this approach. These analyses also highlight the richness of basketball networks as a dataset for exploring the relationships between network structure and dynamics with team organization and effectiveness.


Assuntos
Atletas , Basquetebol , Logro , Desempenho Atlético , Análise por Conglomerados , Entropia , Humanos
18.
Microsurgery ; 31(4): 318-22, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21500276

RESUMO

Esophageal strictures may be caused by many etiologies. Patients suffer from dysphagia and many are tube-feed dependent. Cervical esophageal reconstruction is challenging for the plastic surgeon, and although there are reports utilizing chest wall flaps or even free flaps, the use of a sternocleidomastoid (SCM) myocutaneous flap provides an ideal reconstruction in select patients who require noncircumferential "patch" cervical esophagoplasty. We present two cases of esophageal reconstruction in which we demonstrate our technique for harvesting and insetting the SCM flap, with particular emphasis on design of the skin paddle and elucidation of the vascular anatomy. We believe that the SCM flap is simple, reliable, convenient, and technically easy to perform. There is minimal donor site morbidity with no functional loss. The SCM myocutaneous flap is a viable option for reconstructing partial esophageal defects and obviates the need to perform staged procedures or more extensive operations such as free tissue transfer.


Assuntos
Estenose Esofágica/cirurgia , Esôfago/cirurgia , Músculo Esquelético/transplante , Procedimentos Cirúrgicos Reconstrutivos/métodos , Retalhos Cirúrgicos , Estenose Esofágica/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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