Bioengineered human myobundles mimic clinical responses of skeletal muscle to drugs.

Existing in vitro models of human skeletal muscle cannot recapitulate the organization and function of native muscle, limiting their use in physiological and pharmacological studies. Here, we demonstrate engineering of electrically and chemically responsive, contractile human muscle tissues ('myobundles') using primary myogenic cells. These biomimetic constructs exhibit aligned architecture, multinucleated and striated myofibers, and a Pax7(+) cell pool. They contract spontaneously and respond to electrical stimuli with twitch and tetanic contractions. Positive correlation between contractile force and GCaMP6-reported calcium responses enables non-invasive tracking of myobundle function and drug response. During culture, myobundles maintain functional acetylcholine receptors and structurally and functionally mature, evidenced by increased myofiber diameter and improved calcium handling and contractile strength. In response to diversely acting drugs, myobundles undergo dose-dependent hypertrophy or toxic myopathy similar to clinical outcomes. Human myobundles provide an enabling platform for predictive drug and toxicology screening and development of novel therapeutics for muscle-related disorders.

The reminiscence bump in the temporal distribution of the best football players of all time: Pelé, Cruijff or Maradona?

The reminiscence bump is the tendency to recall more autobiographical memories from adolescence and early adulthood than from adjacent lifetime periods. In this online study, the robustness of the reminiscence bump was examined by looking at participants' judgements about the quality of football players. Dutch participants (N = 619) were asked who they thought the five best players of all time were. The participants could select the names from a list or enter the names when their favourite players were not on the list. Johan Cruijff, Pelé, and Diego Maradona were the three most often mentioned players. Participants frequently named football players who reached the midpoint of their career when the participants were adolescents (mode = 17). The results indicate that the reminiscence bump can also be identified outside the autobiographical memory domain.

The temporal distribution of autobiographical memory: changes in reliving and vividness over the life span do not explain the reminiscence bump.

When autobiographical memories are elicited with word cues, personal events from middle childhood to early adulthood are overrepresented compared to events from other periods. It is, however, unclear whether these memories are also associated with greater recollection. In this online study, we examined whether autobiographical memories from adolescence and early adulthood are recollected more than memories from other lifetime periods. Participants rated personal events that were elicited with cue words on reliving or vividness. Consistent with previous studies, most memories came from the period in which the participants were between 6 and 20 years old. The memories from this period were not relived more or recalled more vividly than memories from other lifetime periods, suggesting that they do not involve more recollection. Recent events had higher levels of reliving and vividness than remote events, and older adults reported a stronger recollective experience than younger adults.

The short and long of it: neural correlates of temporal-order memory for autobiographical events.

Previous functional neuroimaging studies of temporal-order memory have investigated memory for laboratory stimuli that are causally unrelated and poor in sensory detail. In contrast, the present functional magnetic resonance imaging (fMRI) study investigated temporal-order memory for autobiographical events that were causally interconnected and rich in sensory detail. Participants took photographs at many campus locations over a period of several hours, and the following day they were scanned while making temporal-order judgments to pairs of photographs from different locations. By manipulating the temporal lag between the two locations in each trial, we compared the neural correlates associated with reconstruction processes, which we hypothesized depended on recollection and contribute mainly to short lags, and distance processes, which we hypothesized to depend on familiarity and contribute mainly to longer lags. Consistent with our hypotheses, parametric fMRI analyses linked shorter lags to activations in regions previously associated with recollection (left prefrontal, parahippocampal, precuneus, and visual cortices), and longer lags with regions previously associated with familiarity (right prefrontal cortex). The hemispheric asymmetry in prefrontal cortex activity fits very well with evidence and theories regarding the contributions of the left versus right prefrontal cortex to memory (recollection vs. familiarity processes) and cognition (systematic vs. heuristic processes). In sum, using a novel photo-paradigm, this study provided the first evidence regarding the neural correlates of temporal-order for autobiographical events.

Spatial imagery preserves temporal order.

Line drawings were presented in either a spatial or a nonspatial format. Subjects recalled each of four sets of 24 items in serial order. Amount recalled in the correct serial order and sequencing errors were scored. In Experiment 1 items appeared either in consecutive locations of a matrix or in one central location. Subjects who saw the items in different locations made fewer sequencing errors than those who saw each item in a central location, but serial recall levels for these two conditions did not differ. When items appeared in nonconsecutive locations in Experiment 2, the advantage of the spatial presentation on sequencing errors disappeared. Experiment 3 included conditions in which both the consecutive and nonconsecutive spatial formats were paired with retrieval cues that either did or did not indicate the sequence of locations in which the items had appeared. Spatial imagery aided sequencing when, and only when, the order of locations in which the stimuli appeared could be reconstructed at retrieval.

Characterization of B cells in muscle-specific kinase antibody myasthenia gravis.

OBJECTIVE: To characterize B-cell subsets in patients with muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG). METHODS: In accordance with Human Immunology Project Consortium guidelines, we performed polychromatic flow cytometry and ELISA assays in peripheral blood samples from 18 patients with MuSK MG and 9 healthy controls. To complement a B-cell phenotype assay that evaluated maturational subsets, we measured B10 cell percentages, plasma B cell-activating factor (BAFF) levels, and MuSK antibody titers. Immunologic variables were compared with healthy controls and clinical outcome measures. RESULTS: As expected, patients treated with rituximab had high percentages of transitional B cells and plasmablasts and thus were excluded from subsequent analysis. The remaining patients with MuSK MG and controls had similar percentages of total B cells and naïve, memory, isotype-switched, plasmablast, and transitional B-cell subsets. However, patients with MuSK MG had higher BAFF levels and lower percentages of B10 cells. In addition, we observed an increase in MuSK antibody levels with more severe disease. CONCLUSIONS: We found prominent B-cell pathology in the distinct form of MG with MuSK autoantibodies. Increased BAFF levels have been described in other autoimmune diseases, including acetylcholine receptor antibody-positive MG. This finding suggests a role for BAFF in the survival of B cells in MuSK MG, which has important therapeutic implications. B10 cells, a recently described rare regulatory B-cell subset that potently blocks Th1 and Th17 responses, were reduced, which suggests a potential mechanism for the breakdown in immune tolerance in patients with MuSK MG.

Spatial and temporal scales of neuronal correlation in visual area V4.

The spiking activity of nearby cortical neurons is correlated on both short and long time scales. Understanding this shared variability in firing patterns is critical for appreciating the representation of sensory stimuli in ensembles of neurons, the coincident influences of neurons on common targets, and the functional implications of microcircuitry. Our knowledge about neuronal correlations, however, derives largely from experiments that used different recording methods, analysis techniques, and cortical regions. Here we studied the structure of neuronal correlation in area V4 of alert macaques using recording and analysis procedures designed to match those used previously in primary visual cortex (V1), the major input to V4. We found that the spatial and temporal properties of correlations in V4 were remarkably similar to those of V1, with two notable differences: correlated variability in V4 was approximately one-third the magnitude of that in V1 and synchrony in V4 was less temporally precise than in V1. In both areas, spontaneous activity (measured during fixation while viewing a blank screen) was approximately twice as correlated as visual-evoked activity. The results provide a foundation for understanding how the structure of neuronal correlation differs among brain regions and stages in cortical processing and suggest that it is likely governed by features of neuronal circuits that are shared across the visual cortex.

Magnetic resonance imaging of graded skeletal muscle injury in live rats.

INTRODUCTION: Increasing number of stretch-shortening contractions (SSCs) results in increased muscle injury. METHODS: Fischer Hybrid rats were acutely exposed to an increasing number of SSCs in vivo using a custom-designed dynamometer. Magnetic resonance imaging (MRI) imaging was conducted 72 hours after exposure when rats were infused with Prohance and imaged using a 7T rodent MRI system (GE Epic 12.0). Images were acquired in the transverse plane with typically 60 total slices acquired covering the entire length of the hind legs. Rats were euthanized after MRI, the lower limbs removed, and tibialis anterior muscles were prepared for histology and quantified stereology. RESULTS: Stereological analyses showed myofiber degeneration, and cellular infiltrates significantly increased following 70 and 150 SSC exposure compared to controls. MRI images revealed that the percent affected area significantly increased with exposure in all SSC groups in a graded fashion. Signal intensity also significantly increased with increasing SSC repetitions. DISCUSSION: These results suggest that contrast-enhanced MRI has the sensitivity to differentiate specific degrees of skeletal muscle strain injury, and imaging data are specifically representative of cellular histopathology quantified via stereological analyses.

Botulinum toxin type A injections for the management of muscle tightness following total hip arthroplasty: a case series.

BACKGROUND: Development of hip adductor, tensor fascia lata, and rectus femoris muscle contractures following total hip arthroplasties are quite common, with some patients failing to improve despite treatment with a variety of non-operative modalities. The purpose of the present study was to describe the use of and patient outcomes of botulinum toxin injections as an adjunctive treatment for muscle tightness following total hip arthroplasty. METHODS: Ten patients (14 hips) who had hip adductor, abductor, and/or flexor muscle contractures following total arthroplasty and had been refractory to physical therapeutic efforts were treated with injection of botulinum toxin A. Eight limbs received injections into the adductor muscle, 8 limbs received injections into the tensor fascia lata muscle, and 2 limbs received injection into the rectus femoris muscle, followed by intensive physical therapy for 6 weeks. RESULTS: At a mean final follow-up of 20 months, all 14 hips had increased range in the affected arc of motion, with a mean improvement of 23 degrees (range, 10 to 45 degrees). Additionally all hips had an improvement in hip scores, with a significant increase in mean score from 74 points (range, 57 to 91 points) prior to injection to a mean of 96 points (range, 93 to 98) at final follow-up. There were no serious treatment-related adverse events. CONCLUSION: Botulinum toxin A injections combined with intensive physical therapy may be considered as a potential treatment modality, especially in difficult cases of muscle tightness that are refractory to standard therapy.

Temporal Stability of Molecular Diversity Measures in Natural Populations of Drosophila pseudoobscura and Drosophila persimilis

Many molecular ecological and evolutionary studies sample wild populations at a single point in time, failing to consider that data they collect represents genetic variation from a potentially unrepresentative snapshot in time. Variation across time in genetic parameters may occur quickly in species that produce multiple generations of offspring per year. However, many studies of rapid contemporary microevolution examine phenotypic trait divergence as opposed to molecular evolutionary divergence. Here, we compare genetic diversity in wild caught populations of Drosophila persimilis and D. pseudoobscura collected 16 years apart at the same time of year and same site at four X-linked and two mitochondrial loci to assess genetic stability. We found no major changes in nucleotide diversity in either species, but we observed a drastic shift in Tajima’s D between D. pseudoobscura timepoints at one locus associated with the increased abundance of a set of related haplotypes. Our data also suggests that D. persimilis may have recently accelerated its demographic expansion. While the changes we observed were modest, this study reinforces the importance of considering potential temporal variation in genetic parameters within single populations over short evolutionary timescales.

Muscle Logic: New Knowledge Resource for Anatomy Enables Comprehensive Searches of the Literature on the Feeding Muscles of Mammals.

BACKGROUND: In recent years large bibliographic databases have made much of the published literature of biology available for searches. However, the capabilities of the search engines integrated into these databases for text-based bibliographic searches are limited. To enable searches that deliver the results expected by comparative anatomists, an underlying logical structure known as an ontology is required. DEVELOPMENT AND TESTING OF THE ONTOLOGY: Here we present the Mammalian Feeding Muscle Ontology (MFMO), a multi-species ontology focused on anatomical structures that participate in feeding and other oral/pharyngeal behaviors. A unique feature of the MFMO is that a simple, computable, definition of each muscle, which includes its attachments and innervation, is true across mammals. This construction mirrors the logical foundation of comparative anatomy and permits searches using language familiar to biologists. Further, it provides a template for muscles that will be useful in extending any anatomy ontology. The MFMO is developed to support the Feeding Experiments End-User Database Project (FEED, https://feedexp.org/), a publicly-available, online repository for physiological data collected from in vivo studies of feeding (e.g., mastication, biting, swallowing) in mammals. Currently the MFMO is integrated into FEED and also into two literature-specific implementations of Textpresso, a text-mining system that facilitates powerful searches of a corpus of scientific publications. We evaluate the MFMO by asking questions that test the ability of the ontology to return appropriate answers (competency questions). We compare the results of queries of the MFMO to results from similar searches in PubMed and Google Scholar. RESULTS AND SIGNIFICANCE: Our tests demonstrate that the MFMO is competent to answer queries formed in the common language of comparative anatomy, but PubMed and Google Scholar are not. Overall, our results show that by incorporating anatomical ontologies into searches, an expanded and anatomically comprehensive set of results can be obtained. The broader scientific and publishing communities should consider taking up the challenge of semantically enabled search capabilities.

The temporal dynamics of metacognition: Dissociating task-related activity from later metacognitive processes

In recent years, neuroscience research spent much effort in revealing brain activity related to metacognition. Despite this endeavor, it remains unclear exactly when metacognitive experiences develop during task performance. To investigate this, the current study used EEG to temporally and spatially dissociate task-related activity from metacognitive activity. In a masked priming paradigm, metacognitive experiences of difficulty were induced by manipulating congruency between prime and target. As expected, participants more frequently rated incongruent trials as difficult and congruent trials as easy, while being completely unable to perceive the masked primes. Results showed that both the N2 and the P3 ERP components were modulated by congruency, but that only the P3 modulation interacted with metacognitive experiences. Single-trial analysis additionally showed that the magnitude of the P3 modulation by congruency accurately predicted the metacognitive response. Source localization indicated that the N2 task-related activity originated in the ACC, whereas the P3-interplay between task-related activation and metacognitive experiences originated from the precuneus. We conclude that task-related activity can be dissociated from later metacognitive processing.

Variación espacial y temporal de la producción primaria neta aérea y secundaria neta

Las actividades humanas impactan fuertemente sobre los procesos de los ecosistemas. En los sistemas ganaderos, las actividades humanas intentan maximizar el flujo de energía hacia la productividad secundaria. Las consecuencias sobre la transferencia de energía desde la productividad primaria neta aérea (PPNA) a la producción secundaria neta no están totalmente establecidas. Varios estudios describieron la relación entre la carga animal y la PPNA a lo largo de gradientes regionales de recursos, tanto en sistemas naturales como ganaderos. Pero persisten al menos tres vacíos de conocimiento sobre los sistemas ganaderos que fueron abordados en esta tesis. En primer lugar, no se conocía la relación entre la producción secundaria neta y la PPNA, a lo largo de un gradiente regional de recursos y se desconocía la medida en que la actividad humana afectaba diferencialmente a los procesos parciales entre la PPNA y la producción secundaria : la eficiencia de cosecha (consumo / PPNA) y la eficiencia de producción (producción secundaria / consumo). En segundo lugar, no se conocía la relación entre la variabilidad interanual del flujo de entrada de energía, la PPNA, y el de salida, la producción secundaria neta, entre sitios que difieren por la disponibilidad de recursos o por el impacto humano. Asociado a esto existían escasos antecedentes sobre la relación entre producción secundaria, o algún determinante de esta, y la disponibilidad de recursos a través del tiempo. En particular, no existían evidencias de si esta relación temporal cambiaba a lo largo de un gradiente espacial y regional de recursos. En tercer lugar, eran muy escasos los antecedentes sobre las variaciones estacionales del índice de cosecha, y la incidencia de la carga y la PPNA sobre tales variaciones. Para abordar los primeros dos vacíos de conocimiento se compiló información de precipitación, carga animal y producción secundaria, tanto de sistemas naturales como de sistemas ganaderos. La información de sistemas naturales se obtuvo de búsquedas bibliográficas y compilaciones a nivel mundial ya publicadas. La de los sistemas ganaderos se obtuvo de dos fuentes. La primera, contempló información de 113 establecimientos ubicados a lo largo de un amplio gradiente de precipitación regional el de Argentina, pertencecientes en su mayoría la movimiento CREA. La segunda, se realizó a partir de la información brindada por el plan nacional de vacunación de aftosa para departamentos ubicados al norte del río Colorado. Para este último análisis, se estimó la PPNA a partir de información satelital, usando la lógica del modelo propuesto por Monteith (...) Para abordar el tercer vacío de conocimiento, se llevó adelante un ensayo en el que se manipularon la PPNA y su calidad, a través de dos comunidades vegetales diferentes, y la carga animal, a través de tres niveles. Este ensayo se condujo a lo largo de un año para evaluar la dinámica estacional del índice de cosecha, y al mismo tiempo identificar los factores que la regulan. En relación al primer vacío, la relación entre la producción secundaria neta y la PPNA mostró un patrón unimodal. A su vez se observó que a igual PPNA la producción secundaria neta de los sistemas ganaderos fue mayor a la de los naturales. Este incremento de la producción secundaria se debió en mayor medida a un aumento del índice de cosecha y en menor medida a un aumento en la eficiencia de producción. En relación al segundo vacío, la variabilidad interanual de la lluvia, principal control abiótico del flujo de entrada, no se relacionó significativamente con la variabilidad de un componente del siguiente nivel trófico, la carga animal, tanto en sistemas naturales como ganaderos. Sin embargo, la variabilidad de la carga animal de los naturales fue mayor que la de los ganaderos. En estos últimos la variabilidad de la PPNA, fue el doble que la de la carga animal (...) En relación al tercer vacío, se mostró que el principal control de la variación estacional del índice de cosecha fue la PPNA. Esta tesis representa la primera evidencia del impacto de la introducción de herbívoros exóticos a lo largo de un gradiente regional sobre el flujo desde la PPNA a la producción secundaria neta y brinda una de las pocas evaluaciones sobre el impacto humano sobre la estabilidad de este flujo. Finalmente, se desarrolló un modelo que permitiría mejorar las estimaciones de carga animal al relacionar la dinámica del índice de cosecha con la biomasa acumulada estimada a partir de la PPNA acumulada por estación del año.

Variación espacial y temporal de la producción primaria neta aérea y secundaria neta

Las actividades humanas impactan fuertemente sobre los procesos de los ecosistemas. En los sistemas ganaderos, las actividades humanas intentan maximizar el flujo de energía hacia la productividad secundaria. Las consecuencias sobre la transferencia de energía desde la productividad primaria neta aérea (PPNA)a la producción secundaria neta no están totalmente establecidas. Varios estudios describieron la relación entre la carga animal y la PPNA a lo largo de gradientes regionales de recursos, tanto en sistemas naturales como ganaderos. Pero persisten al menos tres vacíos de conocimiento sobre los sistemas ganaderos que fueron abordados en esta tesis. En primer lugar, no se conocía la relación entre la producción secundaria neta y la PPNA, a lo largo de un gradiente regional de recursos y se desconocía la medida en que la actividad humana afectaba diferencialmente a los procesos parciales entre la PPNA y la producción secundaria : la eficiencia de cosecha (consumo / PPNA)y la eficiencia de producción (producción secundaria / consumo). En segundo lugar, no se conocía la relación entre la variabilidad interanual del flujo de entrada de energía, la PPNA, y el de salida, la producción secundaria neta, entre sitios que difieren por la disponibilidad de recursos o por el impacto humano. Asociado a esto existían escasos antecedentes sobre la relación entre producción secundaria, o algún determinante de esta, y la disponibilidad de recursos a través del tiempo. En particular, no existían evidencias de si esta relación temporal cambiaba a lo largo de un gradiente espacial y regional de recursos. En tercer lugar, eran muy escasos los antecedentes sobre las variaciones estacionales del índice de cosecha, y la incidencia de la carga y la PPNA sobre tales variaciones. Para abordar los primeros dos vacíos de conocimiento se compiló información de precipitación, carga animal y producción secundaria, tanto de sistemas naturales como de sistemas ganaderos. La información de sistemas naturales se obtuvo de búsquedas bibliográficas y compilaciones a nivel mundial ya publicadas. La de los sistemas ganaderos se obtuvo de dos fuentes. La primera, contempló información de 113 establecimientos ubicados a lo largo de un amplio gradiente de precipitación regional el de Argentina, pertencecientes en su mayoría la movimiento CREA. La segunda, se realizó a partir de la información brindada por el plan nacional de vacunación de aftosa para departamentos ubicados al norte del río Colorado. Para este último análisis, se estimó la PPNA a partir de información satelital, usando la lógica del modelo propuesto por Monteith (...)Para abordar el tercer vacío de conocimiento, se llevó adelante un ensayo en el que se manipularon la PPNA y su calidad, a través de dos comunidades vegetales diferentes, y la carga animal, a través de tres niveles. Este ensayo se condujo a lo largo de un año para evaluar la dinámica estacional del índice de cosecha, y al mismo tiempo identificar los factores que la regulan. En relación al primer vacío, la relación entre la producción secundaria neta y la PPNA mostró un patrón unimodal. A su vez se observó que a igual PPNA la producción secundaria neta de los sistemas ganaderos fue mayor a la de los naturales. Este incremento de la producción secundaria se debió en mayor medida a un aumento del índice de cosecha y en menor medida a un aumento en la eficiencia de producción. En relación al segundo vacío, la variabilidad interanual de la lluvia, principal control abiótico del flujo de entrada, no se relacionó significativamente con la variabilidad de un componente del siguiente nivel trófico, la carga animal, tanto en sistemas naturales como ganaderos. Sin embargo, la variabilidad de la carga animal de los naturales fue mayor que la de los ganaderos. En estos últimos la variabilidad de la PPNA, fue el doble que la de la carga animal (...)En relación al tercer vacío, se mostró que el principal control de la variación estacional del índice de cosecha fue la PPNA. Esta tesis representa la primera evidencia del impacto de la introducción de herbívoros exóticos a lo largo de un gradiente regional sobre el flujo desde la PPNA a la producción secundaria neta y brinda una de las pocas evaluaciones sobre el impacto humano sobre la estabilidad de este flujo. Finalmente, se desarrolló un modelo que permitiría mejorar las estimaciones de carga animal al relacionar la dinámica del índice de cosecha con la biomasa acumulada estimada a partir de la PPNA acumulada por estación del año.