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The ribosome plays a central role in translation of the genetic code into amino acid sequences during synthesis of polypeptides. During each cycle of peptide elongation, the ribosome must discriminate between correct and incorrect aminoacyl-tRNAs according to the codon present in its A-site. Ribosomes rely on a complex sequence of proofreading mechanisms to minimize erroneous selection of incorrect aminoacyl-tRNAs that would lead to mistakes in translation. These mechanisms have been studied extensively in prokaryotic organisms, but eukaryotic elongation is less well understood. Here, we use single-molecule fluorescence resonance energy transfer (smFRET) with an in vitro eukaryotic translation system to investigate tRNA selection and subsequent steps during peptide elongation. We compared accommodation of a tryptophan-aminoacyl-tRNA into the ribosomal A-site containing either a cognate or near-cognate codon and unexpectedly found that, following an initial slow sampling event, subsequent near-cognate sampling events proceeded more rapidly than the initial event. Further, we found a strong negative correlation between the concentration of near-cognate aminoacyl-tRNA and the efficiency of tRNA accommodation. These novel characteristics of near-cognate interaction with the eukaryotic ribosome suggest that rejection of a near-cognate tRNAs leads to formation of an altered ribosomal conformation that assists in rejecting subsequent incorrect tRNA interactions., Competing Interests: Conflict of interest statement. None declared.

In recent years, much of the emphasis for transformation of introductory STEM courses has focused on "active learning", and while this approach has been shown to produce more equitable outcomes for students, the construct of "active learning" is somewhat ill-defined and is often used as a "catch-all" that can encompass a wide range of pedagogical techniques. Here we present an alternative approach for how to think about the transformation of STEM courses that focuses instead on what students should know and what they can do with that knowledge. This approach, known as three-dimensional learning (3DL), emerged from the National Academy's "A Framework for K-12 Science Education", which describes a vision for science education that centers the role of constructing productive causal accounts for phenomena. Over the past 10 years, we have collected data from introductory biology, chemistry, and physics courses to assess the impact of such a transformation on higher education courses. Here we report on an analysis of video data of class sessions that allows us to characterize these sessions as active, 3D, neither, or both 3D and active. We find that 3D classes are likely to also involve student engagement (i.e. be active), but the reverse is not necessarily true. That is, focusing on transformations involving 3DL also tends to increase student engagement, whereas focusing solely on student engagement might result in courses where students are engaged in activities that do not involve meaningful engagement with core ideas of the discipline., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Cooper et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Visual acuity (VA) testing is a vital screening tool for the assessment of ocular function. The coronavirus 2019 pandemic has caused an immediate need for synchronous telemedicine in all specialties, including ophthalmology. While a plethora of mobile VA applications exist, there is no consensus as to what technology can accurately and reproducibly measure a patient's vision at home., Methods: A systematic literature search was performed in April 2020 using PubMed, Embase and Medline, identifying English publications from 2010 to 2020 on remote VA tests: 4338 articles were identified and 14 were ultimately included in the review., Results: Of those 14, the highest quality studies, best reproducibility and correlation with in-clinic acuities measured were found using the Peek Acuity application. The studies included patients throughout the world aged 3-97, with and without correction, with known ocular pathology.The Peek Acuity studies measured distance vision on a Samsung Galaxy S3 with a mean difference of 0.055 Logarithm of the Minimum Angle of Resolution (LogMAR) for home testing compared with the Early Treatment Diabetic Retinopathy Study (ETDRS). Test-retest variability was ±0.029 LogMAR for 95% confidence interval limits., Discussion: There can be one or more lines of variability in vision testing in a clinical setting using reference standard ETDRS and clinical standard Snellen charts. Test-retest reliability is not perfect even on standard clinical charts (variation up to 0.48 LogMAR). Of the technologies reviewed, Peek Acuity home testing had the greatest correlation with ETDRS clinical vision and high test-retest reliability. Peek Acuity performed no worse than Snellen and ETDRS charts.

Introduction: More than 400 million people suffer from visual impairment globally, with more than half due to uncorrected refractive error. Autorefraction (AR) is the most common examination performed prior to prescribing glasses. As technology advances, so has the accuracy and number of portable autorefractors available. Portable technology has become acutely important with the coronavirus disease 2019 pandemic and the conversion of in-person clinical evaluations to remote telemedicine encounters. Patients and providers want to do as much as possible remotely. The aim of this study was to conduct a systematic literature review of the accuracy and effectiveness of available portable automated refractors compared to the current standard of care, subjective refraction (SR)., Methods: A literature search of PubMED, Embase and ClinicalTrials.gov 97 unique publications in English on portable autorefractors. Twelve studies comparing a portable AR device to at least one form of SR were systematically included in this review., Results: There were four portable autorefractors (Netra, Quicksee, Retinomax and SVOne) studied against SR. There was high patient acceptance of glasses prescriptions by the Quicksee alone, with 87% subjects seeing the same or better than SR. Quicksee was more accurate than Netra and Retinomax. SVOne was preferred over Netra and outperformed Retinomax in multiple measures, despite Retinomax being the fastest test., Discussion: There are numerous portable autorefractors available, but few were compared against SR. Quicksee and SVOne are the most accurate and patient-preferred devices. Quicksee was the most accurate, and it performed clinically the same as SR in some reports.

Drug discovery for diseases such as Parkinson's disease are impeded by the lack of screenable cellular phenotypes. We present an unbiased phenotypic profiling platform that combines automated cell culture, high-content imaging, Cell Painting, and deep learning. We applied this platform to primary fibroblasts from 91 Parkinson's disease patients and matched healthy controls, creating the largest publicly available Cell Painting image dataset to date at 48 terabytes. We use fixed weights from a convolutional deep neural network trained on ImageNet to generate deep embeddings from each image and train machine learning models to detect morphological disease phenotypes. Our platform's robustness and sensitivity allow the detection of individual-specific variation with high fidelity across batches and plate layouts. Lastly, our models confidently separate LRRK2 and sporadic Parkinson's disease lines from healthy controls (receiver operating characteristic area under curve 0.79 (0.08 standard deviation)), supporting the capacity of this platform for complex disease modeling and drug screening applications., (© 2022. The Author(s).)

Objective: The increase in smartphone usage has enabled the possibility of more accessible ways to conduct neuropsychological evaluations. The objective of this study was to determine the feasibility of using smartphone typing dynamics with mood scores to supplement cognitive assessment through trail making tests., Methods: Using a custom-built keyboard, naturalistic keypress dynamics were unobtrusively recorded in individuals with bipolar disorder (n = 11) and nonbipolar controls (n = 8) on an Android smartphone. Keypresses were matched to digital trail making tests part B (dTMT-B) administered daily in two periods and weekly mood assessments. Following comparison of dTMT-Bs to the pencil-and-paper equivalent, longitudinal mixed-effects models were used to analyze daily dTMT-B performance as a function of typing and mood., Results: Comparison of the first dTMT-B to paper TMT-B showed adequate reliability (intraclass correlations = 0.74). In our model, we observed that participants who typed slower took longer to complete dTMT-B (b = 0.189, p < .001). This trend was also seen in individual fluctuations in typing speed and dTMT-B performance (b = 0.032, p = .004). Moreover, participants who were more depressed completed the dTMT-B slower than less depressed participants (b = 0.189, p < .001). A practice effect was observed for the dTMT-Bs., Conclusion: Typing speed in combination with depression scores has the potential to infer aspects of cognition (visual attention, processing speed, and task switching) in people's natural environment to complement formal in-person neuropsychological assessments that commonly include the trail making test., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

The coronavirus disease 2019 pandemic created unprecedented challenges for the health care system. To meet capacity demands, hospitals around the world suspended surgeries deemed to be elective. In hand surgery, numerous pathologies are treated on an elective basis, but a delay or absence of care may result in poorer outcomes. Here, we present an ethical framework for prioritizing elective surgery during a period of resource scarcity. Instead of using the term "elective," we define procedures that can be safely delayed on the basis of 3 considerations. First, a safe delay is possible only if deferral will not result in permanent injury. Second, a delay in care will come with tolerable costs and impositions that can be appropriately managed in the future. Third, a safe delay will preserve the bioethical principle of patient autonomy. In considering these criteria, 3 case examples are discussed considering individual patient characteristics and the pathophysiology of the condition. This framework design is applicable to ambulatory surgery in any period of crisis that may strain resources, but further considerations may be important if an operation requires hospital admission., (Copyright © 2021 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Objective : To explore relationships between PET/CT characteristics of cold-activated brown adipose tissue (BAT), measures of adiposity and metabolic markers. Methods : We conducted a post-hoc analysis of a study which utilized PET/CT to characterize BAT. 25 men ages 18-24 (BMI 19.4 to 35.9 kg/m 2 ) were studied. Fasting blood samples were collected. Body composition was measured using DXA. An individualized cooling protocol was utilized to activate BAT prior to imaging with PET/CT. Results : There was an inverse relationship between fasting serum glucose and BAT volume (r = -0.40, p = 0.048). A marginally significant inverse relationship was also noted between fasting glucose and total BAT activity (r = -0.40, p = 0.05). In addition, a positive correlation was observed between serum FGF21 and SUV max (r = 0.51, p = 0.01). No significant correlations were noted for measures of BAT activity or volume and other indicators of adiposity or glucose metabolism. Conclusions : The presence of active BAT may be associated with lower fasting glucose in young men. BAT activity may also be correlated with levels of FGF21, suggesting that BAT may lower glucose levels via an FGF21 dependent pathway. Further studies are needed to clarify mechanisms by which BAT may impact glucose metabolism.

Purpose: Healthcare costs are a continual concern. To improve our cost-efficiency we must identify the direct costs of ocular injuries requiring hospitalization. The purpose of this study was to evaluate the direct costs of hospitalized ocular injuries in Texas., Methods: Retrospective cohort study using the Texas Hospital Inpatient Discharge Public Use Data File, 2013-2014. Persons hospitalized for ocular trauma were identified using ICD-9-CM codes. Injuries were subcategorized as ocular adnexal, open globe, or closed globe based on diagnosis and procedure codes and analyzed across three age groups: 18-44, 45-64, and >65 years., Results: From 2013 to 2014, 1498 patients were hospitalized with ocular adnexal injuries, 644 with open globe injuries, and 2877 with closed globe injuries. Length of stay ranged from 2 to 4 days. The median total charges ranged between $34,576 and $55,409 across all injuries and groups. The largest portion of medical costs were due to radiology in the ocular adnexal and closed globe groups, and operating room charges in the open globe group., Conclusions: Median hospitalization costs for ocular injuries were between $34,576 and $55,409 for a 2-4 day length of stay. Open globe injuries had the shortest median lengths of stay, 2-3 days, and lower median total costs. Only in the open globe group were operative costs higher than radiology costs. Operative charges were lowest in the oldest age group, who also had longer lengths of stay. Our reported costs were lower than other nationally reported ocular injury costs for similar lengths of hospital stay.

Objective: Ubiquitous technologies can be leveraged to construct ecologically relevant metrics that complement traditional psychological assessments. This study aims to determine the feasibility of smartphone-derived real-world keyboard metadata to serve as digital biomarkers of mood., Materials and Methods: BiAffect, a real-world observation study based on a freely available iPhone app, allowed the unobtrusive collection of typing metadata through a custom virtual keyboard that replaces the default keyboard. User demographics and self-reports for depression severity (Patient Health Questionnaire-8) were also collected. Using >14 million keypresses from 250 users who reported demographic information and a subset of 147 users who additionally completed at least 1 Patient Health Questionnaire, we employed hierarchical growth curve mixed-effects models to capture the effects of mood, demographics, and time of day on keyboard metadata., Results: We analyzed 86 541 typing sessions associated with a total of 543 Patient Health Questionnaires. Results showed that more severe depression relates to more variable typing speed (P < .001), shorter session duration (P < .001), and lower accuracy (P < .05). Additionally, typing speed and variability exhibit a diurnal pattern, being fastest and least variable at midday. Older users exhibit slower and more variable typing, as well as more pronounced slowing in the evening. The effects of aging and time of day did not impact the relationship of mood to typing variables and were recapitulated in the 250-user group., Conclusions: Keystroke dynamics, unobtrusively collected in the real world, are significantly associated with mood despite diurnal patterns and effects of age, and thus could serve as a foundation for constructing digital biomarkers., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The importance of improving STEM education is of perennial interest, and to this end, the education community needs ways to characterize transformation efforts. Three-dimensional learning (3DL) is one such approach to transformation, in which core ideas of the discipline, scientific practices, and crosscutting concepts are combined to support student development of disciplinary expertise. We have previously reported on an approach to the characterization of assessments, the Three-Dimensional Learning Assessment Protocol (3D-LAP), that can be used to identify whether assessments have the potential to engage students in 3DL. Here we present the development of a companion, the Three-Dimensional Learning Observation Protocol (3D-LOP), an observation protocol that can reliably distinguish between instruction that has potential for engagement with 3DL and instruction that does not. The 3D-LOP goes beyond other observation protocols, because it is intended not only to characterize the pedagogical approaches being used in the instructional environment, but also to identify whether students are being asked to engage with scientific practices, core ideas, and crosscutting concepts. We demonstrate herein that the 3D-LOP can be used reliably to code for the presence of 3DL; further, we present data that show the utility of the 3D-LOP in differentiating between instruction that has the potential to promote 3DL from instruction that does not. Our team plans to continue using this protocol to evaluate outcomes of instructional transformation projects. We also propose that the 3D-LOP can be used to support practitioners in developing curricular materials and selecting instructional strategies to promote engagement in three-dimensional instruction., Competing Interests: The authors have declared that no competing interests exist.

Background: Mood disorders are common and associated with significant morbidity and mortality. Better tools are needed for their diagnosis and treatment. Deeper phenotypic understanding of these disorders is integral to the development of such tools. This study is the first effort to use passively collected mobile phone keyboard activity to build deep digital phenotypes of depression and mania., Objective: The objective of our study was to investigate the relationship between mobile phone keyboard activity and mood disturbance in subjects with bipolar disorders and to demonstrate the feasibility of using passively collected mobile phone keyboard metadata features to predict manic and depressive signs and symptoms as measured via clinician-administered rating scales., Methods: Using a within-subject design of 8 weeks, subjects were provided a mobile phone loaded with a customized keyboard that passively collected keystroke metadata. Subjects were administered the Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) weekly. Linear mixed-effects models were created to predict HDRS and YMRS scores. The total number of keystrokes was 626,641, with a weekly average of 9791 (7861), and that of accelerometer readings was 6,660,890, with a weekly average 104,076 (68,912)., Results: A statistically significant mixed-effects regression model for the prediction of HDRS-17 item scores was created: conditional R 2 =.63, P=.01. A mixed-effects regression model for YMRS scores showed the variance accounted for by random effect was zero, and so an ordinary least squares linear regression model was created: R 2 =.34, P=.001. Multiple significant variables were demonstrated for each measure., Conclusions: Mood states in bipolar disorder appear to correlate with specific changes in mobile phone usage. The creation of these models provides evidence for the feasibility of using passively collected keyboard metadata to detect and monitor mood disturbances., (©John Zulueta, Andrea Piscitello, Mladen Rasic, Rebecca Easter, Pallavi Babu, Scott A Langenecker, Melvin McInnis, Olusola Ajilore, Peter C Nelson, Kelly Ryan, Alex Leow. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 20.07.2018.)

Resonance energy transfer has become an indispensable experimental tool for single-molecule and single-cell biophysics. Its physical underpinnings, however, are subtle: it involves a discrete jump of excitation from one molecule to another, and so we regard it as a strongly quantum-mechanical process. And yet its kinetics differ from what many of us were taught about two-state quantum systems, quantum superpositions of the states do not seem to arise, and so on. Although J. R. Oppenheimer and T. Förster navigated these subtleties successfully, it remains hard to find an elementary derivation in modern language. The key step involves acknowledging quantum decoherence. Appreciating that aspect can be helpful when we attempt to extend our understanding to situations in which Förster's original analysis is not applicable., (Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To implement quantitative Dixon magnetic resonance imaging (MRI) methods for brown adipose tissue (BAT) characterization at inactive and cold-activated states in normal weight, overweight, and obese subjects. The hypotheses are that MRI characteristics of BAT would differentiate between nonobese and obese subjects, and activation of BAT in response to thermal challenges that are detected by MRI would be correlated with BAT activity measured by positron emission tomography / computed tomography (PET/CT)., Materials and Methods: Fifteen male subjects (20.7 ± 1.5 years old) including six normal weight, five overweight, and four obese subjects participated in the study. A multiecho Dixon MRI sequence was performed on a 1.5T scanner. MRI was acquired under thermoneutral, nonshivering thermogenesis, and subsequent warm-up conditions. Fat fraction (FF), R2*, and the number of double bonds (ndb) were measured by solving an optimization problem that fits in- and out-of-phase MR signal intensities to the fat-water interference models. Imaging acquisition and postprocessing were performed by two MRI physicists. In each subject, Dixon MRI measurements of FF, R2*, and ndb were calculated for each voxel within all BAT regions of interest (ROIs) under each thermal condition. Mean FF, R2*, and ndb were compared between nonobese (ie, normal-weight/overweight) and obese subjects using the two-sample t-test. Receiver operating characteristic (ROC) analyses were performed to differentiate nonobese vs. obese subjects. BAT MRI measurement changes in response to thermal condition changes were compared with hypermetabolic BAT volume/activity measured by PET/CT using the Pearson's correlation. In addition, BAT MRI measurements were compared with body adiposity using the Pearson's correlation. P < 0.05 was considered statistically significant., Results: Obese subjects showed higher FF and lower R2* than nonobese subjects under all three thermal conditions (P < 0.01). ROC analyses demonstrated that FF and R2* were excellent predictors for the differentiation of nonobese from obese subjects (100% specificity and 100% sensitivity). FF changes under thermal challenges were correlated with hypermetabolic BAT volume (r = -0.55, P = 0.04 during activation, and r = 0.72, P = 0.003 during deactivation), and with BAT activity (r = 0.69, P = 0.006 during deactivation), as measured by PET/CT. FF and R2* under all three thermal conditions were highly correlated with body adiposity (P ≤ 0.002)., Conclusion: MRI characteristics of BAT differentiated between nonobese and obese subjects in both inactivated and activated states. BAT activation detected by Dixon MRI in response to thermal challenges were correlated with glucose uptake of metabolically active BAT., Level of Evidence: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:936-947., (© 2017 International Society for Magnetic Resonance in Medicine.)

Standard pedagogy introduces optics as though it were a consequence of Maxwell's equations and only grudgingly admits, usually in a rushed aside, that light has a particulate character that can somehow be reconciled with the wave picture. Recent revolutionary advances in optical imaging, however, make this approach more and more unhelpful: How are we to describe two-photon imaging, FRET, localization microscopy, and a host of related techniques to students who think of light primarily as a wave? I was surprised to find that everything I wanted my biophysics students to know about light, including image formation, x-ray diffraction, and even Bessel beams, could be expressed as well (or better) from the quantum viewpoint pioneered by Richard Feynman. Even my undergraduate students grasp this viewpoint as well as (or better than) the traditional one, and by mid-semester they are already well positioned to integrate the latest advances into their understanding. Moreover, I have found that this approach clarifies my own understanding of new techniques., (Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to examine advanced diffusion-weighted magnetic resonance imaging (DW-MRI) models for differentiation of low- and high-grade tumors in the diagnosis of pediatric brain neoplasms., Methods: Sixty-two pediatric patients with various types and grades of brain tumors were evaluated in a retrospective study. Tumor type and grade were classified using the World Health Organization classification (WHO I-IV) and confirmed by pathological analysis. Patients underwent DW-MRI before treatment. Diffusion-weighted images with 16 b-values (0-3500 s/mm 2 ) were acquired. Averaged signal intensity decay within solid tumor regions was fitted using two-compartment and anomalous diffusion models. Intracellular and extracellular diffusion coefficients (D slow and D fast ), fractional volumes (V slow and V fast ), generalized diffusion coefficient (D), spatial constant (μ), heterogeneity index (β), and a diffusion index (index&#95;diff = μ × V slow /β) were calculated. Multivariate logistic regression models with stepwise model selection algorithm and receiver operating characteristic (ROC) analyses were performed to evaluate the ability of each diffusion parameter to distinguish tumor grade., Results: Among all parameter combinations, D and index&#95;diff jointly provided the best predictor for tumor grades, where lower D (p = 0.03) and higher index&#95;diff (p = 0.009) were significantly associated with higher tumor grades. In ROC analyses of differentiating low-grade (I-II) and high-grade (III-IV) tumors, index&#95;diff provided the highest specificity of 0.97 and D provided the highest sensitivity of 0.96., Conclusions: Multi-parametric diffusion measurements using two-compartment and anomalous diffusion models were found to be significant discriminants of tumor grading in pediatric brain neoplasms.

Importance: Deep learning is a family of computational methods that allow an algorithm to program itself by learning from a large set of examples that demonstrate the desired behavior, removing the need to specify rules explicitly. Application of these methods to medical imaging requires further assessment and validation., Objective: To apply deep learning to create an algorithm for automated detection of diabetic retinopathy and diabetic macular edema in retinal fundus photographs., Design and Setting: A specific type of neural network optimized for image classification called a deep convolutional neural network was trained using a retrospective development data set of 128 175 retinal images, which were graded 3 to 7 times for diabetic retinopathy, diabetic macular edema, and image gradability by a panel of 54 US licensed ophthalmologists and ophthalmology senior residents between May and December 2015. The resultant algorithm was validated in January and February 2016 using 2 separate data sets, both graded by at least 7 US board-certified ophthalmologists with high intragrader consistency., Exposure: Deep learning-trained algorithm., Main Outcomes and Measures: The sensitivity and specificity of the algorithm for detecting referable diabetic retinopathy (RDR), defined as moderate and worse diabetic retinopathy, referable diabetic macular edema, or both, were generated based on the reference standard of the majority decision of the ophthalmologist panel. The algorithm was evaluated at 2 operating points selected from the development set, one selected for high specificity and another for high sensitivity., Results: The EyePACS-1 data set consisted of 9963 images from 4997 patients (mean age, 54.4 years; 62.2% women; prevalence of RDR, 683/8878 fully gradable images [7.8%]); the Messidor-2 data set had 1748 images from 874 patients (mean age, 57.6 years; 42.6% women; prevalence of RDR, 254/1745 fully gradable images [14.6%]). For detecting RDR, the algorithm had an area under the receiver operating curve of 0.991 (95% CI, 0.988-0.993) for EyePACS-1 and 0.990 (95% CI, 0.986-0.995) for Messidor-2. Using the first operating cut point with high specificity, for EyePACS-1, the sensitivity was 90.3% (95% CI, 87.5%-92.7%) and the specificity was 98.1% (95% CI, 97.8%-98.5%). For Messidor-2, the sensitivity was 87.0% (95% CI, 81.1%-91.0%) and the specificity was 98.5% (95% CI, 97.7%-99.1%). Using a second operating point with high sensitivity in the development set, for EyePACS-1 the sensitivity was 97.5% and specificity was 93.4% and for Messidor-2 the sensitivity was 96.1% and specificity was 93.9%., Conclusions and Relevance: In this evaluation of retinal fundus photographs from adults with diabetes, an algorithm based on deep machine learning had high sensitivity and specificity for detecting referable diabetic retinopathy. Further research is necessary to determine the feasibility of applying this algorithm in the clinical setting and to determine whether use of the algorithm could lead to improved care and outcomes compared with current ophthalmologic assessment.

It is sometimes said that 'our eyes can see single photons'. This article begins by finding a more precise version of that claim and reviewing evidence gathered for it up to around 1985 in two distinct realms, those of human psychophysics and single-cell physiology. Finding a single framework that accommodates both kinds of result is then a nontrivial challenge, and one that sets severe quantitative constraints on any model of dim-light visual processing. This article presents one such model and compares it to a recent experiment.

Mitosis in the early syncytial Drosophila embryo is highly correlated in space and time, as manifested in mitotic wavefronts that propagate across the embryo. In this paper we investigate the idea that the embryo can be considered a mechanically-excitable medium, and that mitotic wavefronts can be understood as nonlinear wavefronts that propagate through this medium. We study the wavefronts via both image analysis of confocal microscopy videos and theoretical models. We find that the mitotic waves travel across the embryo at a well-defined speed that decreases with replication cycle. We find two markers of the wavefront in each cycle, corresponding to the onsets of metaphase and anaphase. Each of these onsets is followed by displacements of the nuclei that obey the same wavefront pattern. To understand the mitotic wavefronts theoretically we analyze wavefront propagation in excitable media. We study two classes of models, one with biochemical signaling and one with mechanical signaling. We find that the dependence of wavefront speed on cycle number is most naturally explained by mechanical signaling, and that the entire process suggests a scenario in which biochemical and mechanical signaling are coupled.

Myosin V is biomolecular motor with two actin-binding domains (heads) that take multiple steps along actin by a hand-over-hand mechanism. We used high-speed polarized total internal reflection fluorescence (polTIRF) microscopy to study the structural dynamics of single myosin V molecules that had been labeled with bifunctional rhodamine linked to one of the calmodulins along the lever arm. With the use of time-correlated single-photon counting technology, the temporal resolution of the polTIRF microscope was improved ~50-fold relative to earlier studies, and a maximum-likelihood, multitrace change-point algorithm was used to objectively determine the times when structural changes occurred. Short-lived substeps that displayed an abrupt increase in rotational mobility were detected during stepping, likely corresponding to random thermal fluctuations of the stepping head while it searched for its next actin-binding site. Thus, myosin V harnesses its fluctuating environment to extend its reach. Additional, less frequent angle changes, probably not directly associated with steps, were detected in both leading and trailing heads. The high-speed polTIRF method and change-point analysis may be applicable to single-molecule studies of other biological systems., (Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Redundancies and correlations in the responses of sensory neurons may seem to waste neural resources, but they can also carry cues about structured stimuli and may help the brain to correct for response errors. To investigate the effect of stimulus structure on redundancy in retina, we measured simultaneous responses from populations of retinal ganglion cells presented with natural and artificial stimuli that varied greatly in correlation structure; these stimuli and recordings are publicly available online. Responding to spatio-temporally structured stimuli such as natural movies, pairs of ganglion cells were modestly more correlated than in response to white noise checkerboards, but they were much less correlated than predicted by a non-adapting functional model of retinal response. Meanwhile, responding to stimuli with purely spatial correlations, pairs of ganglion cells showed increased correlations consistent with a static, non-adapting receptive field and nonlinearity. We found that in response to spatio-temporally correlated stimuli, ganglion cells had faster temporal kernels and tended to have stronger surrounds. These properties of individual cells, along with gain changes that opposed changes in effective contrast at the ganglion cell input, largely explained the pattern of pairwise correlations across stimuli where receptive field measurements were possible.

Wojtczak and Viemeister (J Acoust Soc Am 118:3198-3210, 2005) demonstrated forward masking in the amplitude-modulation (AM) domain. The present study examined whether this effect has correlates in physiological responses to AM at the level of the auditory midbrain. The human psychophysical experiment used 40-Hz, 100% AM (masker AM) that was imposed on a 5.5-kHz carrier during the first 150 ms of its duration. The masker AM was followed by a 50-ms burst of AM of the same rate (signal AM) imposed on the same (uninterrupted) carrier, either immediately after the masker or with a delay. In the physiological experiment, single-unit extracellular recordings in the awake rabbit inferior colliculus (IC) were obtained for stimuli designed to be similar to the uninterrupted-carrier conditions used in the psychophysics. The masker AM was longer (500 ms compared with 150 ms in the psychophysical experiment), and the carrier and modulation rate were chosen based on each neuron's audio- and envelope-frequency selectivity. Based on the average discharge rates of the responses or on the temporal correlation between neural responses to masked and unmasked stimuli, only a small subset of the population of IC cells exhibited suppression of signal AM following the masker. In contrast, changes in the discharge rates between the temporal segments of the carrier immediately preceding the signal AM and during the signal AM varied as a function of masker-signal delay with a trend that matched the psychophysical results. Unless the physiological observations were caused by species differences, they suggest that stages of processing higher than the IC must be considered to account for the AM-processing time constants measured perceptually in humans.

We present an algorithm to identify individual neural spikes observed on high-density multi-electrode arrays (MEAs). Our method can distinguish large numbers of distinct neural units, even when spikes overlap, and accounts for intrinsic variability of spikes from each unit. As MEAs grow larger, it is important to find spike-identification methods that are scalable, that is, the computational cost of spike fitting should scale well with the number of units observed. Our algorithm accomplishes this goal, and is fast, because it exploits the spatial locality of each unit and the basic biophysics of extracellular signal propagation. Human interaction plays a key role in our method; but effort is minimized and streamlined via a graphical interface. We illustrate our method on data from guinea pig retinal ganglion cells and document its performance on simulated data consisting of spikes added to experimentally measured background noise. We present several tests demonstrating that the algorithm is highly accurate: it exhibits low error rates on fits to synthetic data, low refractory violation rates, good receptive field coverage, and consistency across users.

The experimental study of individual macromolecules has opened a door to determining the details of their mechanochemical operation. Motor enzymes such as the myosin family have been particularly attractive targets for such study, in part because some of them are highly processive and their "product" is spatial motion. But single-molecule resolution comes with its own costs and limitations. Often, the observations rest on single fluorescent dye molecules, which emit a limited number of photons before photobleaching and are subject to complex internal dynamics. Thus, it is important to develop methods that extract the maximum useful information from a finite set of detected photons. We have extended an experimental technique, multiple polarization illumination in total internal reflection fluorescence microscopy (polTIRF), to record the arrival time and polarization state of each individual detected photon. We also extended an analysis technique, previously applied to FRET experiments, that optimally determines times of changes in photon emission rates. Combining these improvements allows us to identify the structural dynamics of a molecular motor (myosin V) with unprecedented detail and temporal resolution., (© 2011 Elsevier Inc. All rights reserved.)

In certain situations, preceding auditory stimulation can actually result in heightened sensitivity to subsequent sounds. Many of these phenomena appear to be generated in the brain as reflections of central computations. One example is the robust perceptual enhancement (or "pop out") of a probe signal within a broadband sound whose onset time is delayed relative to the remainder of a mixture of tones. Here we show that the neural representation of such stimuli undergoes a dramatic transformation as the pathway is ascended, from an implicit and distributed peripheral code to explicitly facilitated single-neuron responses at the level of the inferior colliculus (IC) of two awake and passively listening female marmoset monkeys (Callithrix jacchus). Many key features of the IC responses directly parallel psychophysical measures of enhancement, including the dependence on the width of a spectral notch surrounding the probe, the overall level of the complex, and the duration of the preceding sound (referred to as the conditioner). Neural detection thresholds for the probe with and without the conditioner were also in qualitative agreement with analogous psychoacoustic measures. Response characteristics during the conditioners were predictive of the enhancement or suppression of the ensuing probe response: buildup responses were associated with enhancement, whereas adapting conditioner responses were more likely to result in suppression. These data can be primarily explained by a phenomenological computational model using dynamic (adapting) inhibition as a necessary ingredient in the generation of neural enhancement.

There is growing evidence that the dynamics of biological systems that appear to be exponential over short time courses are in some cases better described over the long-term by power-law dynamics. A model of rate adaptation at the synapse between inner hair cells and auditory-nerve (AN) fibers that includes both exponential and power-law dynamics is presented here. Exponentially adapting components with rapid and short-term time constants, which are mainly responsible for shaping onset responses, are followed by two parallel paths with power-law adaptation that provide slowly and rapidly adapting responses. The slowly adapting power-law component significantly improves predictions of the recovery of the AN response after stimulus offset. The faster power-law adaptation is necessary to account for the "additivity" of rate in response to stimuli with amplitude increments. The proposed model is capable of accurately predicting several sets of AN data, including amplitude-modulation transfer functions, long-term adaptation, forward masking, and adaptation to increments and decrements in the amplitude of an ongoing stimulus.

We calculate the probability of DNA loop formation mediated by regulatory proteins such as Lac repressor (LacI), using a mathematical model of DNA elasticity. Our model is adapted to calculating quantities directly observable in tethered particle motion (TPM) experiments, and it accounts for all the entropic forces present in such experiments. Our model has no free parameters; it characterizes DNA elasticity using information obtained in other kinds of experiments. It assumes a harmonic elastic energy function (or wormlike chain type elasticity), but our Monte Carlo calculation scheme is flexible enough to accommodate arbitrary elastic energy functions. We show how to compute both the 'looping J factor' (or equivalently, the looping free energy) for various DNA construct geometries and LacI concentrations, as well as the detailed probability density function of bead excursions. We also show how to extract the same quantities from recent experimental data on TPM, and then compare to our model's predictions. In particular, we present a new method to correct observed data for finite camera shutter time and other experimental effects. Although the currently available experimental data give large uncertainties, our first-principles predictions for the looping free energy change are confirmed to within about 1 k(B)T, for loops of length around 300 basepairs. More significantly, our model successfully reproduces the detailed distributions of bead excursion, including their surprising three-peak structure, without any fit parameters and without invoking any alternative conformation of the LacI tetramer. Indeed, the model qualitatively reproduces the observed dependence of these distributions on tether length (e.g., phasing) and on LacI concentration (titration). However, for short DNA loops (around 95 basepairs) the experiments show more looping than is predicted by the harmonic-elasticity model, echoing other recent experimental results. Because the experiments we study are done in vitro, this anomalously high looping cannot be rationalized as resulting from the presence of DNA-bending proteins or other cellular machinery. We also show that it is unlikely to be the result of a hypothetical 'open' conformation of the LacI tetramer.

In many cases, transcriptional regulation involves the binding of transcription factors at sites on the DNA that are not immediately adjacent to the promoter of interest. This action at a distance is often mediated by the formation of DNA loops: Binding at two or more sites on the DNA results in the formation of a loop, which can bring the transcription factor into the immediate neighborhood of the relevant promoter. These processes are important in settings ranging from the historic bacterial examples (bacterial metabolism and the lytic-lysogeny decision in bacteriophage), to the modern concept of gene regulation to regulatory processes central to pattern formation during development of multicellular organisms. Though there have been a variety of insights into the combinatorial aspects of transcriptional control, the mechanism of DNA looping as an agent of combinatorial control in both prokaryotes and eukaryotes remains unclear. We use single-molecule techniques to dissect DNA looping in the lac operon. In particular, we measure the propensity for DNA looping by the Lac repressor as a function of the concentration of repressor protein and as a function of the distance between repressor binding sites. As with earlier single-molecule studies, we find (at least) two distinct looped states and demonstrate that the presence of these two states depends both upon the concentration of repressor protein and the distance between the two repressor binding sites. We find that loops form even at interoperator spacings considerably shorter than the DNA persistence length, without the intervention of any other proteins to prebend the DNA. The concentration measurements also permit us to use a simple statistical mechanical model of DNA loop formation to determine the free energy of DNA looping, or equivalently, the for looping.

An organism's ability to detect and discriminate sensory inputs depends on the recent stimulus history. For example, perceptual detection thresholds for a brief tone can be elevated by as much as 50 dB when following a masking stimulus. Previous work suggests that such forward masking is not a direct result of peripheral neural adaptation; the central pathway apparently modifies the representation in a way that further attenuates the input's response to short probe signals. Here, we show that much of this transformation is complete by the level of the inferior colliculus (IC). Single-neuron extracellular responses were recorded in the central nucleus of the awake marmoset IC. The threshold for a 20 ms probe tone presented at best frequency was determined for various masker-probe delays, over a range of masker sound pressure levels (SPLs) and frequencies. The most striking aspect of the data was the increased potency of forward maskers as their SPL was increased, despite the fact that the excitatory response to the masker was often saturating or nonmonotonic over the same range of levels. This led to probe thresholds at high masker levels that were almost always higher than those observed in the auditory nerve. Probe threshold shifts were not usually caused by a persistent excitatory response to the masker; instead we propose a wide-dynamic-range inhibitory mechanism locked to sound offset as an explanation for several key aspects of the data. These findings further delineate the role of subcortical auditory processing in the generation of a context-dependent representation of ongoing acoustic scenes.

The force generated between actin and myosin acts predominantly along the direction of the actin filament, resulting in relative sliding of the thick and thin filaments in muscle or transport of myosin cargos along actin tracks. Previous studies have also detected lateral forces or torques that are generated between actin and myosin, but the origin and biological role of these sideways forces is not known. Here we adapt an actin gliding filament assay to measure the rotation of an actin filament about its axis ("twirling") as it is translocated by myosin. We quantify the rotation by determining the orientation of sparsely incorporated rhodamine-labeled actin monomers, using polarized total internal reflection microscopy. To determine the handedness of the filament rotation, linear incident polarizations in between the standard s- and p-polarizations were generated, decreasing the ambiguity of our probe orientation measurement fourfold. We found that whole myosin II and myosin V both twirl actin with a relatively long (approximately 1 microm), left-handed pitch that is insensitive to myosin concentration, filament length, and filament velocity.

We study the role of microtubule movement in bidirectional organelle transport in Drosophila S2 cells and show that EGFP-tagged peroxisomes in cells serve as sensitive probes of motor induced, noisy cytoskeletal motions. Multiple peroxisomes move in unison over large time windows and show correlations with microtubule tip positions, indicating rapid microtubule fluctuations in the longitudinal direction. We report the first high-resolution measurement of longitudinal microtubule fluctuations performed by tracing such pairs of co-moving peroxisomes. The resulting picture shows that motor-dependent longitudinal microtubule oscillations contribute significantly to cargo movement along microtubules. Thus, contrary to the conventional view, organelle transport cannot be described solely in terms of cargo movement along stationary microtubule tracks, but instead includes a strong contribution from the movement of the tracks.

The wormlike chain (WLC) model currently provides the best description of double-stranded DNA elasticity for micron-sized molecules. This theory requires two intrinsic material parameters-the contour length L and the persistence length p. We measured and then analyzed the elasticity of double-stranded DNA as a function of L (632 nm-7.03 microm) using the classic solution to the WLC model. When the elasticity data were analyzed using this solution, the resulting fitted value for the persistence length p(wlc) depended on L; even for moderately long DNA molecules (L = 1300 nm), this apparent persistence length was 10% smaller than its limiting value for long DNA. Because p is a material parameter, and cannot depend on length, we sought a new solution to the WLC model, which we call the "finite wormlike chain (FWLC)," to account for effects not considered in the classic solution. Specifically we accounted for the finite chain length, the chain-end boundary conditions, and the bead rotational fluctuations inherent in optical trapping assays where beads are used to apply the force. After incorporating these corrections, we used our FWLC solution to generate force-extension curves, and then fit those curves with the classic WLC solution, as done in the standard experimental analysis. These results qualitatively reproduced the apparent dependence of p(wlc) on L seen in experimental data when analyzed with the classic WLC solution. Directly fitting experimental data to the FWLC solution reduces the apparent dependence of p(fwlc) on L by a factor of 3. Thus, the FWLC solution provides a significantly improved theoretical framework in which to analyze single-molecule experiments over a broad range of experimentally accessible DNA lengths, including both short (a few hundred nanometers in contour length) and very long (microns in contour length) molecules.

In many biochemical processes, proteins bound to DNA at distant sites are brought into close proximity by loops in the underlying DNA. For example, the function of some gene-regulatory proteins depends on such 'DNA looping' interactions. We present a new technique for characterizing the kinetics of loop formation in vitro, as observed using the tethered particle method, and apply it to experimental data on looping induced by lambda repressor. Our method uses a modified ('diffusive') hidden Markov analysis that directly incorporates the Brownian motion of the observed tethered bead. We compare looping lifetimes found with our method (which we find are consistent over a range of sampling frequencies) to those obtained via the traditional threshold-crossing analysis (which can vary depending on how the raw data are filtered in the time domain). Our method does not involve any time filtering and can detect sudden changes in looping behavior. For example, we show how our method can identify transitions between long-lived, kinetically distinct states that would otherwise be difficult to discern.

In general, the temporal structure of stimuli must be considered to account for certain observations made in detection and masking experiments in the audio-frequency domain. Two such phenomena are (1) a heightened sensitivity to amplitude increments with a temporal fringe compared to gated level discrimination performance and (2) lower tone-in-noise detection thresholds using a modulated masker compared to those using an unmodulated masker. In the current study, translations of these two experiments were carried out to test the hypothesis that analogous cues might be used in the envelope-frequency domain. Pure-tone carrier amplitude-modulation (AM) depth-discrimination thresholds were found to be similar using both traditional gated stimuli and using a temporally modulated fringe for a fixed standard depth (ms = 0.25) and a range of AM frequencies (4-64 Hz). In a second experiment, masked sinusoidal AM detection thresholds were compared in conditions with and without slow and regular fluctuations imposed on the instantaneous masker AM depth. Release from masking was obtained only for very slow masker fluctuations (less than 2 Hz). A physiologically motivated model that effectively acts as a first-order envelope change detector accounted for several, but not all, of the key aspects of the data.

The mechanical properties of DNA play a critical role in many biological functions. For example, DNA packing in viruses involves confining the viral genome in a volume (the viral capsid) with dimensions that are comparable to the DNA persistence length. Similarly, eukaryotic DNA is packed in DNA-protein complexes (nucleosomes), in which DNA is tightly bent around protein spools. DNA is also tightly bent by many proteins that regulate transcription, resulting in a variation in gene expression that is amenable to quantitative analysis. In these cases, DNA loops are formed with lengths that are comparable to or smaller than the DNA persistence length. The aim of this review is to describe the physical forces associated with tightly bent DNA in all of these settings and to explore the biological consequences of such bending, as increasingly accessible by single-molecule techniques., ((c) 2006 Wiley Periodicals, Inc.)

Neural responses to amplitude-modulated (AM) tones in the unanesthetized rabbit inferior colliculus (IC) were studied in an effort to establish explicit relationships between physiological and psychophysical measures of temporal envelope processing. Specifically, responses to variations in modulation depth (m) at the cell's best modulation frequency, with and without modulation maskers, were quantified in terms of average rate and synchronization to the envelope over the entire perceptual dynamic range of depths. Statistically significant variations in the metrics were used to define neural AM detection and discrimination thresholds. Synchrony emerged at modulation depths comparable with psychophysical AM detection sensitivities in some neurons, whereas the lowest rate-based neural thresholds could not account for psychoacoustical thresholds. The majority of rate thresholds (85%) were -10 dB or higher (in 20 log m), and 16% of the population exhibited no systematic dependence of average rate on m. Neural thresholds for AM detection did not decrease systematically at higher SPLs (as observed psychophysically): thresholds remained constant or increased with level for most cells tested at multiple sound-pressure levels (SPLs). At depths higher than the rate-based detection threshold, some rate modulation-depth functions were sufficiently steep with respect to the across-trial variability of the rate to predict depth discrimination thresholds as low as 1 dB (comparable with the psychophysics). Synchrony, on the other hand, did not vary systematically with m in many cells at high modulation depths. A simple computational model was extended to reproduce several features of the modulation frequency and depth dependence of both transient and sustained pure-tone responders.

DNA loop formation is one of several mechanisms used by organisms to regulate genes. The free energy of forming a loop is an important factor in determining whether the associated gene is switched on or off. In this paper we use an elastic rod model of DNA to determine the free energy of forming short (50-100 basepair), protein mediated DNA loops. Superhelical stress in the DNA of living cells is a critical factor determining the energetics of loop formation, and we explicitly account for it in our calculations. The repressor protein itself is regarded as a rigid coupler; its geometry enters the problem through the boundary conditions it applies on the DNA. We show that a theory with these ingredients is sufficient to explain certain features observed in modulation of in vivo gene activity as a function of the distance between operator sites for the lac repressor. We also use our theory to make quantitative predictions for the dependence of looping on superhelical stress, which may be testable both in vivo and in single-molecule experiments such as the tethered particle assay and the magnetic bead assay.

The mechanics of DNA bending on intermediate length scales (5-100 nm) plays a key role in many cellular processes, and is also important in the fabrication of artificial DNA structures, but previous experimental studies of DNA mechanics have focused on longer length scales than these. We use high-resolution atomic force microscopy on individual DNA molecules to obtain a direct measurement of the bending energy function appropriate for scales down to 5 nm. Our measurements imply that the elastic energy of highly bent DNA conformations is lower than predicted by classical elasticity models such as the worm-like chain (WLC) model. For example, we found that on short length scales, spontaneous large-angle bends are many times more prevalent than predicted by the WLC model. We test our data and model with an interlocking set of consistency checks. Our analysis also shows how our model is compatible with previous experiments, which have sometimes been viewed as confirming the WLC.

The tethered particle motion (TPM) technique involves an analysis of the Brownian motion of a bead tethered to a slide by a single DNA molecule. We describe an improved experimental protocol with which to form the tethers, an algorithm for analyzing bead motion visualized using differential interference contrast microscopy, and a physical model with which we have successfully simulated such DNA tethers. Both experiment and theory show that the statistics of the bead motion are quite different from those of a free semiflexible polymer. Our experimental data for chain extension versus tether length fit our model over a range of tether lengths from 109 to 3477 base pairs, using a value for the DNA persistence length that is consistent with those obtained under similar solution conditions by other methods. Moreover, we present the first experimental determination of the full probability distribution function of bead displacements and find excellent agreement with our theoretical prediction. Our results show that TPM is a useful tool for monitoring large conformational changes such as DNA looping.

The ability of psychoacoustic models to predict listeners' performance depends on two key stages: preprocessing and the generation of a decision variable. The goal of the current study was to determine the perceptually relevant decision variables in masked amplitude-modulation detection tasks in which the modulation depth of the masker was systematically varied. Potential cues were made unreliable by roving the overall modulation depth from trial to trial or were reduced in salience by equalizing the envelope energy of the standard and target after the signal was added. Listeners' performance was significantly degraded in both paradigms compared to the baseline (fixed-level modulation masker) condition, which was similar to those used in previous studies of masking in the envelope-frequency domain. Although this observation was broadly consistent with a simple long-term envelope power-spectrum model, there were several aspects of the data that were not. For example, the steep rate of change in threshold with masker depth and the fact that an optimal amount of envelope noise could enhance performance were not predicted by decision variables calculated directly from the stimulus envelope. A physiologically based processing model suggested a realistic nonlinear mechanism that could give rise to these second-order features of the data.

We give a theoretical analysis of bead motion in tethered-particle experiments, a single-molecule technique that has been used to explore the dynamics of a variety of macromolecules of biological interest. Our analysis reveals that the proximity of the tethered bead to a nearby surface gives rise to a volume-exclusion effect, resulting in an entropic stretching-force on the molecule that changes its statistical properties. In addition, volume exclusion brings about intriguing scaling relations between key observables (statistical moments of the bead) and parameters such as bead size and contour length of the molecule. We present analytic and numerical results for these effects in both flexible and semiflexible tethers. Finally, our results give a precise, experimentally testable prediction for the probability distribution of the bead center measured from the polymer attachment point.

DNA bending on length scales shorter than a persistence length plays an integral role in the translation of genetic information from DNA to cellular function. Quantitative experimental studies of these biological systems have led to a renewed interest in the polymer mechanics relevant for describing the conformational free energy of DNA bending induced by protein-DNA complexes. Recent experimental results from DNA cyclization studies have cast doubt on the applicability of the canonical semiflexible polymer theory, the wormlike chain (WLC) model, to DNA bending on biologically relevant length scales. This paper develops a theory of the chain statistics of a class of generalized semiflexible polymer models. Our focus is on the theoretical development of these models and the calculation of experimental observables. To illustrate our methods, we focus on a specific, illustrative model of DNA bending. We show that the WLC model generically describes the long-length-scale chain statistics of semiflexible polymers, as predicted by renormalization group arguments. In particular, we show that either the WLC or our present model adequately describes force-extension, solution scattering, and long-contour-length cyclization experiments, regardless of the details of DNA bend elasticity. In contrast, experiments sensitive to short-length-scale chain behavior can in principle reveal dramatic departures from the linear elastic behavior assumed in the WLC model. We demonstrate this explicitly by showing that our toy model can reproduce the anomalously large short-contour-length cyclization factors recently measured by Cloutier and Widom. Finally, we discuss the applicability of these models to DNA chain statistics in the context of future experiments.

The importance of nonlinearities in material constitutive relations has long been appreciated in the continuum mechanics of macroscopic rods. Although the moment (torque) response to bending is almost universally linear for small deflection angles, many rod systems exhibit a high-curvature softening. The signature behavior of these rod systems is a kinking transition in which the bending is localized. Recent DNA cyclization experiments by Cloutier and Widom have offered evidence that the linear-elastic bending theory fails to describe the high-curvature mechanics of DNA. Motivated by this recent experimental work, we develop a simple and exact theory of the statistical mechanics of linear-elastic polymer chains that can undergo a kinking transition. We characterize the kinking behavior with a single parameter and show that the resulting theory reproduces both the low-curvature linear-elastic behavior which is already well described by the worm-like chain model, as well as the high-curvature softening observed in recent cyclization experiments.

A phenomenological model with time-varying excitation and inhibition was developed to study possible neural mechanisms underlying changes in the representation of temporal envelopes along the auditory pathway. A modified version of an existing auditory-nerve model [Zhang et al., J. Acoust. Soc. Am. 109, 648-670 (2001)] was used to provide inputs to higher hypothetical processing centers. Model responses were compared directly to published physiological data at three levels: the auditory nerve, ventral cochlear nucleus, and inferior colliculus. Trends and absolute values of both average firing rate and synchrony to the modulation period were accurately predicted at each level for a wide range of stimulus modulation depths and modulation frequencies. The diversity of central physiological responses was accounted for with realistic variations of model parameters. Specifically, enhanced synchrony in the cochlear nucleus and rate-tuning to modulation frequency in the inferior colliculus were predicted by choosing appropriate relative strengths and time courses of excitatory and inhibitory inputs to postsynaptic model cells. The proposed model is fundamentally different than others that have been used to explain the representation of envelopes in the mammalian midbrain, and it provides a computational tool for testing hypothesized relationships between physiology and psychophysics.