Contribution of non-extensor muscles of the leg to maximal-effort countermovement jumping

BACKGROUND: The purpose of this study was to determine the effects of non-extensor muscles of the leg (i.e., muscles whose primary function is not leg extension) on the kinematics and kinetics of human maximal-effort countermovement jumping. Although it is difficult to address this type of question through experimental procedures, the methodology of computer simulation can be a powerful tool. METHODS: A skeletal model that has nine rigid body segments and twenty degrees of freedom was developed. Two sets of muscle models were attached to this skeletal model: all (most of) major muscles in the leg ("All Muscles" model) and major extensor muscles in the leg (i.e., muscles whose primary function is leg extension; "Extensors Only" model). Neural activation input signal was represented by a series of step functions with a step duration of 0.05 s. Simulations were started from an identical upright standing posture. The optimal pattern of the activation input signal was searched through extensive random-search numerical optimization with a goal of maximizing the height reached by the mass centre of the body after jumping up. RESULTS: The simulated kinematics was almost two-dimensional, suggesting the validity of two-dimensional analyses when evaluating net mechanical outputs around the joints using inverse dynamics. A greater jumping height was obtained for the "All Muscles" model (0.386 m) than for the "Extensors Only" model (0.301 m). For the "All Muscles" model, flexor muscles developed force in the beginning of the countermovement. For the "All Muscles" model, the sum of the work outputs from non-extensor muscles was 47.0 J, which was 13% of the total amount (359.9 J). The quantitative distribution of the work outputs from individual muscles was markedly different between these two models. CONCLUSION: It was suggested that the contribution of non-extensor muscles in maximal-effort countermovement jumping is substantial. The use of a computer simulation model that includes non-extensor muscles seems to be more desirable for the assessment of muscular outputs during jumping

The Novel Mouse Mutation Oblivion Inactivates the PMCA2 Pump and Causes Progressive Hearing Loss

Progressive hearing loss is common in the human population, but we have few clues to the molecular basis. Mouse mutants with progressive hearing loss offer valuable insights, and ENU (N-ethyl-N-nitrosourea) mutagenesis is a useful way of generating models. We have characterised a new ENU-induced mouse mutant, Oblivion (allele symbol Obl), showing semi-dominant inheritance of hearing impairment. Obl/+ mutants showed increasing hearing impairment from post-natal day (P)20 to P90, and loss of auditory function was followed by a corresponding base to apex progression of hair cell degeneration. Obl/Obl mutants were small, showed severe vestibular dysfunction by 2 weeks of age, and were completely deaf from birth; sensory hair cells were completely degenerate in the basal turn of the cochlea, although hair cells appeared normal in the apex. We mapped the mutation to Chromosome 6. Mutation analysis of Atp2b2 showed a missense mutation (2630C→T) in exon 15, causing a serine to phenylalanine substitution (S877F) in transmembrane domain 6 of the PMCA2 pump, the resident Ca2+ pump of hair cell stereocilia. Transmembrane domain mutations in these pumps generally are believed to be incompatible with normal targeting of the protein to the plasma membrane. However, analyses of hair cells in cultured utricular maculae of Obl/Obl mice and of the mutant Obl pump in model cells showed that the protein was correctly targeted to the plasma membrane. Biochemical and biophysical characterisation showed that the pump had lost a significant portion of its non-stimulated Ca2+ exporting ability. These findings can explain the progressive loss of auditory function, and indicate the limits in our ability to predict mechanism from sequence alone

Lobe Specific Ca2+-Calmodulin Nano-Domain in Neuronal Spines: A Single Molecule Level Analysis

Calmodulin (CaM) is a ubiquitous Ca2+ buffer and second messenger that affects cellular function as diverse as cardiac excitability, synaptic plasticity, and gene transcription. In CA1 pyramidal neurons, CaM regulates two opposing Ca2+-dependent processes that underlie memory formation: long-term potentiation (LTP) and long-term depression (LTD). Induction of LTP and LTD require activation of Ca2+-CaM-dependent enzymes: Ca2+/CaM-dependent kinase II (CaMKII) and calcineurin, respectively. Yet, it remains unclear as to how Ca2+ and CaM produce these two opposing effects, LTP and LTD. CaM binds 4 Ca2+ ions: two in its N-terminal lobe and two in its C-terminal lobe. Experimental studies have shown that the N- and C-terminal lobes of CaM have different binding kinetics toward Ca2+ and its downstream targets. This may suggest that each lobe of CaM differentially responds to Ca2+ signal patterns. Here, we use a novel event-driven particle-based Monte Carlo simulation and statistical point pattern analysis to explore the spatial and temporal dynamics of lobe-specific Ca2+-CaM interaction at the single molecule level. We show that the N-lobe of CaM, but not the C-lobe, exhibits a nano-scale domain of activation that is highly sensitive to the location of Ca2+ channels, and to the microscopic injection rate of Ca2+ ions. We also demonstrate that Ca2+ saturation takes place via two different pathways depending on the Ca2+ injection rate, one dominated by the N-terminal lobe, and the other one by the C-terminal lobe. Taken together, these results suggest that the two lobes of CaM function as distinct Ca2+ sensors that can differentially transduce Ca2+ influx to downstream targets. We discuss a possible role of the N-terminal lobe-specific Ca2+-CaM nano-domain in CaMKII activation required for the induction of synaptic plasticity

Mechanisms of human telomerase reverse transcriptase (hTERT) regulation: clinical impacts in cancer

Background Limitless self-renewal is one of the hallmarks of cancer and is attained by telomere maintenance, essentially through telomerase (hTERT) activation. Transcriptional regulation of hTERT is believed to play a major role in telomerase activation in human cancers. Main body The dominant interest in telomerase results from its role in cancer. The role of telomeres and telomere maintenance mechanisms is well established as a major driving force in generating chromosomal and genomic instability. Cancer cells have acquired the ability to overcome their fate of senescence via telomere length maintenance mechanisms, mainly by telomerase activation. hTERT expression is up-regulated in tumors via multiple genetic and epigenetic mechanisms including hTERT amplifications, hTERT structural variants, hTERT promoter mutations and epigenetic modifications through hTERT promoter methylation. Genetic (hTERT promoter mutations) and epigenetic (hTERT promoter methylation and miRNAs) events were shown to have clinical implications in cancers that depend on hTERT activation. Knowing that telomeres are crucial for cellular self-renewal, the mechanisms responsible for telomere maintenance have a crucial role in cancer diseases and might be important oncological biomarkers. Thus, rather than quantifying TERT expression and its correlation with telomerase activation, the discovery and the assessment of the mechanisms responsible for TERT upregulation offers important information that may be used for diagnosis, prognosis, and treatment monitoring in oncology. Furthermore, a better understanding of these mechanisms may promote their translation into effective targeted cancer therapies. Conclusion Herein, we reviewed the underlying mechanisms of hTERT regulation, their role in oncogenesis, and the potential clinical applications in telomerase-dependent cancers.info:eu-repo/semantics/publishedVersio

Sediment characteristics and internal architecture of offshore sand ridges on a tideless continental shelf (western Mediterranean)

15 pages, 13 figuresAn integrated approach combining swath bathymetry, an extensive dataset of vibrocores and high‐resolution seismic reflection data was used to assess the origin and evolution of offshore sand ridges on a tideless continental shelf (Gulf of Valencia, western Mediterranean). The sand ridges are located in the mid‐outer shelf at 55–85 m water depth, obliquely oriented to the shoreline. They are 1.5 to 7 m high, with a wavelength between 600 and 1,100 m and a mean height‐to‐wavelength ratio of 0.004. The sand ridges are composed of well‐sorted medium sand and are partially covered by a mud layer, evidencing a moribund stage. They overlie an erosion surface that locally crops out at the seafloor and is interpreted as the Holocene wave‐ravinement surface. In the sediment cores, this surface corresponds to an erosional lag composed of coarse sand and gravel with pebbles. Small topographic irregularities on this surface are interpreted as shoreline‐associated features that may act as the precursor for ridge development. Their preservation within the sand ridges could be related to the hardness of these features. Internally, the sand ridges display high‐angle dipping reflections, indicating ridge migration towards the southeast in the direction of the present‐day sediment transport direction. The presence of interbedded mud layers, associated with these reflections, indicates intermittent episodes of mud deposition when active. The internal architecture of some small ridges also provides new insights into their transition from an active to moribund state, as evidenced by a change in the geometry of the internal units from progradational to aggradational, finally being overlain by onlapping finer deposits over the flanks and in the troughs. The Gulf of Valencia sand ridge field constitutes a valuable potential sand resource of 22 million m3 of well‐sorted medium and coarse sand with limited mud content, which must be preserved as a strategic sand reservoir. © 2020 John Wiley & Sons, LtdThis research was supported by the projects FORMED (CGL2012-33989) and COSTEM (CTM2009-07806). [...] R. Durán is supported by the Ocean and Littoral Sedimentary Process Consolidated http://mc.manuscriptcentral.com/esp Earth Surface Processes and Landforms For Peer Review Research Group by the Generalitat de Catalunya grant (2017 SGR-863)With the funding support of the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S), of the Spanish Research Agency (AEI)Peer reviewe

Structural Insight into the Binding Mode of FXR and GPBAR1 Modulators

In this chapter we provide an exhaustive overview of the binding modes of bile acid (BA) and non-BA ligands to the nuclear farnesoid X receptor (FXR) and the G-protein bile acid receptor 1 (GPBAR1). These two receptors play a key role in many diseases related to lipid and glucose disorders, thus representing promising pharmacological targets. We pay particular attention to the chemical and structural features of the ligand-receptor interaction, providing guidelines to achieve ligands endowed with selective or dual activity towards the receptor and paving the way to future drug design studies