Pax7 is back

Two recent studies have reinvigorated the conversation regarding the role of Pax7 in adult satellite. Studies by Gunther et al (Cell Stem Cell 13:590–601, 2013) and Von Maltzhen et al (Proc Natl Acad Sci U S A 110:16474–16479) show that Pax7 is critical for adult satellite cell function and their contribution to muscle repair. Previously, Lepper et al (Nature 460:627–631, 2009) demonstrated that Pax7 was dispensable for adult muscle repair. In this commentary I have summarized the results from these studies, focusing on the differences in experimental paradigms that led the authors to different conclusions. I also take this opportunity to discuss the potential limitations and hurdles of Cre-lox technology that are responsible for the discrepant results

ISSCR 2013: Back to Bean Town

The International Society for Stem Cell Research 11th Annual Meeting was held in Boston in June 2013, bringing together just over 4000 attendees. An emphasis on therapeutic applications in many talks reflected the maturation of the stem cell field from its origins in basic science to one that is beginning to show therapeutic promise

Sprouty1 regulates reversible quiescence of a self-renewing adult muscle stem cell pool during regeneration.

Satellite cells are skeletal muscle stem cells capable of self-renewal and differentiation after transplantation, but whether they contribute to endogenous muscle fiber repair has been unclear. The transcription factor Pax7 marks satellite cells and is critical for establishing the adult satellite cell pool. By using a lineage tracing approach, we show that after injury, quiescent adult Pax7(+) cells enter the cell cycle; a subpopulation returns to quiescence to replenish the satellite cell compartment, while others contribute to muscle fiber formation. We demonstrate that Sprouty1 (Spry1), a receptor tyrosine kinase signaling inhibitor, is expressed in quiescent Pax7(+) satellite cells in uninjured muscle, downregulated in proliferating myogenic cells after injury, and reinduced as Pax7(+) cells re-enter quiescence. We show that Spry1 is required for the return to quiescence and homeostasis of the satellite cell pool during repair. Our results therefore define a role for Spry1 in adult muscle stem cell biology and tissue repair

MyoD- and nerve-dependent maintenance of MyoD expression in mature muscle fibres acts through the DRR/PRR element

<p>Abstract</p> <p>Background</p> <p>MyoD is a transcription factor implicated in the regulation of adult muscle gene expression. Distinguishing the expression of <it>MyoD </it>in satellite myoblasts and muscle fibres has proved difficult <it>in vivo </it>leading to controversy over the significance of <it>MyoD </it>expression within adult innervated muscle fibres. Here we employ the <it>MD6.0-lacZ </it>transgenic mouse, in which the 6 kb proximal enhancer/promoter (DRR/PRR) of <it>MyoD </it>drives <it>lacZ</it>, to show that MyoD is present and transcriptionally active in many adult muscle fibres.</p> <p>Results</p> <p>In culture, <it>MD6.0-lacZ </it>expresses in myotubes but not myogenic cells, unlike endogenous <it>MyoD</it>. Reporter expression <it>in vivo </it>is in muscle fibre nuclei and is reduced in <it>MyoD </it>null mice. The <it>MD6.0-lacZ </it>reporter is down-regulated both in adult muscle fibres by denervation or muscle disuse and in cultured myotubes by inhibition of activity. Activity induces and represses <it>MyoD </it>through the DRR and PRR, respectively. During the postnatal period, accumulation of β-galactosidase correlates with maturation of innervation. Strikingly, endogenous <it>MyoD </it>expression is up-regulated in fibres by complete denervation, arguing for a separate activity-dependent suppression of <it>MyoD </it>requiring regulatory elements outside the DRR/PRR.</p> <p>Conclusion</p> <p>The data show that <it>MyoD </it>regulation is more complex than previously supposed. Two factors, MyoD protein itself and fibre activity are required for essentially all expression of the 6 kb proximal enhancer/promoter (DRR/PRR) of <it>MyoD </it>in adult fibres. We propose that modulation of MyoD positive feedback by electrical activity determines the set point of <it>MyoD </it>expression in innervated fibres through the DRR/PRR element.</p

Occurrence and distribution of resistance to QoI fungicides in populations of Podosphaera fusca in south central Spain

Cucurbit powdery mildew caused by Podosphaera fusca limits crop production in Spain. Since its management is strongly dependent on chemicals, the rational design of control programmes requires a good understanding of the fungicide resistance phenomenon in field populations. Fifty single-spore isolates of P. fusca were tested for sensitivity to three quinone-outside inhibiting (QoI) fungicides: azoxystrobin, kresoxim-methyl and trifloxystrobin. Minimum inhibitory concentration (MIC) values for QoI-sensitive isolates were found to range from 0.25 to 10 μg ml−1 for azoxystrobin to 5–25 μg ml−1 for kresoxim-methyl, using a leaf disc-based bioassay. High levels of cross-resistance to QoI fungicides were found. Eleven isolates showed resistance to the three QoI fungicides tested with MIC and EC50 values >500 μg ml−1 resulting in RF values as high as >715 and >1000 for trifloxystrobin and azoxystrobin, respectively. A survey of P. fusca QoI resistance was carried out in different provinces located in the south central area of Spain during the cucurbit growing seasons in 2002, 2003 and 2004. Examination of a collection of 250 isolates for QoI resistance revealed that 32% were resistant to the three fungicides tested; the provinces of Ciudad Real, Córdoba and Murcia being the locations with the highest frequencies of resistance (44–74%). By contrast, no resistance was found in Badajoz, and relatively low frequencies were observed in Almería and Valencia (10–13%). Nearly 50% of resistant isolates were collected from melon plants. Based on these data, recommendations about the use of QoI fungicides for cucurbit powdery mildew management in the sampled areas are made.Estación Experimental “La Mayora” (CSIC), Algarrobo-Costa, E-29750 Málaga, Spain Grupo de Microbiología y Patología Vegetal-Unidad Asociada a CSIC, Departamento de Microbiología, Facultad de Ciencias, Universidad de Málaga, E-29071 Málaga, SpainPeer reviewe

Aerosol-assisted CVD of bismuth vanadate thin films and their photoelectrochemical properties

Thin film bismuth vanadate (BiVO4) photoelectrodes are prepared by aerosol-assisted (AA)CVD for the first time on fluorine-doped tin oxide (FTO) glass substrates. The BiVO4 photoelectrodes are characterised by X-ray diffraction (XRD), Raman spectroscopy (RS), and energy-dispersive X-ray (EDX) spectroscopy and are found to consist of phase-pure monoclinic BiVO4. Scanning electron microscopy (SEM) analysis shows that the thin film is uniform with a porous structure, and consists of particles approximately 75-125nm in diameter. The photoelectrochemical (PEC) properties of the BiVO4 photoelectrodes are studied in aqueous 1M Na2SO4 and show photocurrent densities of 0.4mAcm-2, and a maximum incident-photon-to-electron conversion efficiency (IPCE) of 19% at 1.23V vs. the reversible hydrogen electrode (RHE). BiVO4 photoelectrodes prepared by this method are thus highly promising for use in PEC water-splitting cells. Thin film bismuth vanadate (BiVO4) photoelectrodes are prepared by AACVD for the first time on fluorine-doped tin oxide (FTO) glass substrates. The photoelectrochemical (PEC) properties of the BiVO4 photoelectrodes are studied in aqueous 1M Na2SO4 and show photocurrent densities of 0.4mAcm-2 and a maximum incident-photon-to-electron conversion efficiency (IPCE) of 19% at 1.23V vs. RHE. BiVO4 photoelectrodes prepared by this method are highly promising for use in PEC water-splitting cells

MultiFusion: Fusing Pre-Trained Models for Multi-Lingual, Multi-Modal Image Generation

The recent popularity of text-to-image diffusion models (DM) can largely be attributed to the intuitive interface they provide to users. The intended generation can be expressed in natural language, with the model producing faithful interpretations of text prompts. However, expressing complex or nuanced ideas in text alone can be difficult. To ease image generation, we propose MultiFusion that allows one to express complex and nuanced concepts with arbitrarily interleaved inputs of multiple modalities and languages. MutliFusion leverages pre-trained models and aligns them for integration into a cohesive system, thereby avoiding the need for extensive training from scratch. Our experimental results demonstrate the efficient transfer of capabilities from individual modules to the downstream model. Specifically, the fusion of all independent components allows the image generation module to utilize multilingual, interleaved multimodal inputs despite being trained solely on monomodal data in a single language

Control of ventricular excitability by neurons of the dorsal motor nucleus of the vagus nerve

Background The central nervous origins of functional parasympathetic innervation of cardiac ventricles remain controversial. Objective This study aimed to identify a population of vagal preganglionic neurons that contribute to the control of ventricular excitability. An animal model of synuclein pathology relevant to Parkinson’s disease was used to determine whether age-related loss of the activity of the identified group of neurons is associated with changes in ventricular electrophysiology. Methods In vivo cardiac electrophysiology was performed in anesthetized rats in conditions of selective inhibition of the dorsal vagal motor nucleus (DVMN) neurons by pharmacogenetic approach and in mice with global genetic deletion of all family members of the synuclein protein. Results In rats anesthetized with urethane (in conditions of systemic beta-adrenoceptor blockade), muscarinic and neuronal nitric oxide synthase blockade confirmed the existence of a tonic parasympathetic control of cardiac excitability mediated by the actions of acetylcholine and nitric oxide. Acute DVMN silencing led to shortening of the ventricular effective refractory period (vERP), a lowering of the threshold for triggered ventricular tachycardia, and prolongation of the corrected QT (QTc) interval. Lower resting activity of the DVMN neurons in aging synuclein-deficient mice was found to be associated with vERP shortening and QTc interval prolongation. Conclusion Activity of the DVMN vagal preganglionic neurons is responsible for tonic parasympathetic control of ventricular excitability, likely to be mediated by nitric oxide. These findings provide the first insight into the central nervous substrate that underlies functional parasympathetic innervation of the ventricles and highlight its vulnerability in neurodegenerative diseases

Dynamical Evolution of Simulated Particles Ejected from Asteroid Bennu

In early 2019, the OSIRIS‐REx spacecraft discovered small particles being ejected from the surface of the near‐Earth asteroid Bennu. Although they were seen to be ejected at slow speeds, on the order of tens of cm/s, a number of particles were surprisingly seen to orbit for multiple revolutions and days, which requires a dynamical mechanism to quickly and substantially modify the orbit to prevent re‐impact upon their first periapse passage. This paper demonstrates that, based on simulations constrained by the conditions of the observed events, the combined effects of gravity, solar radiation pressure, and thermal radiation pressure from Bennu can produce many sustained orbits for ejected particles. Furthermore, the simulated populations exhibit two interesting phenomena that could play an important role in the geophysical evolution of bodies such as Bennu. First, small particles (<1 cm radius) are preferentially removed from the system, which could lead to a deficit of such particles on the surface. Second, re‐impacting particles preferentially land near or on the equatorial bulge of Bennu. Over time, this can lead to crater in‐filling and growth of the equatorial radius without requiring landslides

The effect of statins on muscle symptoms in primary care:the StatinWISE series of 200 N-of-1 RCTs

Background: Uncertainty persists about whether or not statins cause symptomatic muscle adverse effects (e.g. pain, stiffness and weakness) in the absence of severe myositis.Objectives: To establish the effect of statins on all muscle symptoms, and the effect of statins on muscle symptoms that are perceived to be statin related.Design: A series of 200 double-blinded N-of-1 trials.Setting: Participants were recruited from 50 general practices in England and Wales.Participants: Patients who were considering discontinuing statin use and those who had discontinued statin use in the last 3 years because of perceived muscle symptoms.Interventions: Participants were randomised to a sequence of six 2-month treatment periods during which they received 20 mg of atorvastatin daily or a matched placebo.Main outcome measures: The primary outcome was self-reported muscle symptoms rated using a visual analogue scale on the last week of each treatment period. Secondary outcomes included the participant's belief about the cause of their muscle symptoms, the site of muscle symptoms, how the muscle symptoms affected the participant, any other symptoms they experienced, adherence to medication, the participant's decision about statin treatment following the trial, and whether or not they found their own trial result helpful.Results: A total of 151 out of 200 (75.5%) randomised participants provided one or more visual analogue scale measurements in a placebo period and one or more measurements in a statin period, and were included in the primary analysis. There was no evidence of a difference in muscle symptom scores between statin and placebo periods (mean difference statin minus placebo -0.11, 95% confidence interval -0.36 to 0.14; p = 0.398). Withdrawals, adherence and missing data were similar during the statin periods and the placebo periods.Conclusions: Among people who previously reported severe muscle symptoms while taking statins, this series of randomised N-of-1 trials found no overall effect of statins on muscle symptoms compared with the placebo. The slight difference in withdrawals due to muscle symptoms suggests that statins may contribute to symptoms in a small number of patients. The results are generalisable to patients who are considering discontinuing or have already discontinued statins because of muscle symptoms, and who are willing to re-challenge or participate in their own N-of-1 trial.Future work: We recommend that additional statins and doses are explored using N-of-1 trials. More broadly, N-of-1 trials present a useful tool for exploring transient symptoms with other medications.Limitations: This study used 20-mg doses of atorvastatin only. Furthermore, a dropout rate of 43% was observed, but this was accounted for in the power calculations.Trial registration: Current Controlled Trials ISRCTN30952488 and EudraCT 2016-000141-31.</p