Sensitive and objective biomarkers of neuronal injury, degeneration, and regeneration can help facilitate translation of experimental findings into clinical testing. Whereas measures of upper motor ...neuron connectivity have been readily established, functional assessments of lower motor neuron (LMN) innervation of forelimb muscles are lacking. Compound muscle action potential (CMAP) and motor unit (MU) number estimation (MUNE) are well-established methods that allow longitudinal MU integrity monitoring in patients. In analogy we refined CMAP and MUNE methods for assessing spinal MU input in the rat forelimb and hindlimb. Repeated CMAP and MUNE recordings are robust (coefficients of variability: 4.5-11.3%), and MUNE measurements from forelimb wrist flexor muscles (415 ± 8 SEM) align with back-traced anatomical LMN counts (336 ± 16 SEM). For disease validation, cross-sectional blinded electrophysiological and muscle contractility measurements were obtained in a cohort of G93A SOD1 mutant overexpressing rats and compared with controls. Longitudinal assessment of mutant animals demonstrated progressive motor unit decline in the hindlimb to a greater extent than the forelimb. Hindlimb CMAP and MUNE demonstrated strong correlations with plantarflexion muscle contractility. Cross-species assessment of upper/fore- limb and lower/hind- limb motor units using objective electrophysiological CMAP and MUNE values as biomarkers will guide and improve bi-directional translation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Formation of bony fusion after arthrodesis depends on osteoinduction, osteoconduction, and osteogenesis. Traditionally, the patient's own bone, or autograft, has been used to provide biological ...material necessary for these steps. However, the amount of autograft obtainable is often inadequate. Modern spine surgery has adopted the use of many autograft extenders or replacements, such as demineralized bone matrix or fibers. The present article covers the history of bone grafting, the production and technical details of demineralized bone matrix, and the evidence supporting its use in spine fusions.
Mesodermal cells signal to neighboring epithelial cells to modulate their proliferation in both normal and disease states. We adapted a Caenorhabditis elegans organogenesis model to enable ...a genome-wide mesodermal-specific RNAi screen and discovered 39 factors in mesodermal cells that suppress the proliferation of adjacent Ras pathway-sensitized epithelial cells. These candidates encode components of protein complexes and signaling pathways that converge on the control of chromatin dynamics, cytoplasmic polyadenylation, and translation. Stromal fibroblast-specific deletion of mouse orthologs of several candidates resulted in the hyper-proliferation of mammary gland epithelium. Furthermore, a 33-gene signature of human orthologs was selectively enriched in the tumor stroma of breast cancer patients, and depletion of these factors from normal human breast fibroblasts increased proliferation of co-cultured breast cancer cells. This cross-species approach identified unanticipated regulatory networks in mesodermal cells with growth-suppressive function, exposing the conserved and selective nature of mesodermal-epithelial communication in development and cancer.
•Mesodermal suppressors of epithelial proliferation identified in C. elegans•Mesoderm-epithelial signaling components are highly conserved across species•Depletion of candidates in murine fibroblasts causes mammary hyper-proliferation•Human orthologs of identified genes are altered in breast cancer stroma
Liu, Dowdle, Khurshid, Sullivan et al. identify mesodermal factors in C. elegans that suppress growth of adjacent epithelial cells. These candidates are shown to have conserved function in murine contexts and to be altered in human breast cancer stroma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pathological age-related loss of skeletal muscle strength and mass contribute to impaired physical function in older adults. Factors that promote the development of these conditions remain ...incompletely understood, impeding development of effective and specific diagnostic and therapeutic approaches. Inconclusive evidence across species suggests disruption of action potential signal transmission at the neuromuscular junction (NMJ), the crucial connection between the nervous and muscular systems, as a possible contributor to age-related muscle dysfunction. Here we investigated age-related loss of NMJ function using clinically relevant, electrophysiological measures (single-fiber electromyography (SFEMG) and repetitive nerve stimulation (RNS)) in aged (26 months) versus young (6 months) F344 rats. Measures of muscle function (e.g., grip strength, peak plantarflexion contractility torque) and mass were assessed for correlations with physiological measures (e.g., indices of NMJ transmission). Other outcomes also included plantarflexion muscle contractility tetanic torque fade during 1-s trains of stimulation as well as gastrocnemius motor unit size and number. Profiling NMJ function in aged rats identified significant declines in NMJ transmission stability and reliability. Further, NMJ deficits were tightly correlated with hindlimb grip strength, gastrocnemius muscle weight, loss of peak contractility torque, degree of tetanic fade, and motor unit loss. Thus, these findings provide direct evidence for NMJ dysfunction as a potential mechanism of age-related muscle dysfunction pathogenesis and severity. These findings also suggest that NMJ transmission modulation may serve as a target for therapeutic development for age-related loss of physical function.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Practical quantum computing will require error rates well below those achievable with physical qubits. Quantum error correction
offers a path to algorithmically relevant error rates by encoding ...logical qubits within many physical qubits, for which increasing the number of physical qubits enhances protection against physical errors. However, introducing more qubits also increases the number of error sources, so the density of errors must be sufficiently low for logical performance to improve with increasing code size. Here we report the measurement of logical qubit performance scaling across several code sizes, and demonstrate that our system of superconducting qubits has sufficient performance to overcome the additional errors from increasing qubit number. We find that our distance-5 surface code logical qubit modestly outperforms an ensemble of distance-3 logical qubits on average, in terms of both logical error probability over 25 cycles and logical error per cycle ((2.914 ± 0.016)% compared to (3.028 ± 0.023)%). To investigate damaging, low-probability error sources, we run a distance-25 repetition code and observe a 1.7 × 10
logical error per cycle floor set by a single high-energy event (1.6 × 10
excluding this event). We accurately model our experiment, extracting error budgets that highlight the biggest challenges for future systems. These results mark an experimental demonstration in which quantum error correction begins to improve performance with increasing qubit number, illuminating the path to reaching the logical error rates required for computation.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
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