Zfp697 is an RNA-binding protein that regulates skeletal muscle inflammation and remodeling.

Skeletal muscle atrophy is a morbidity and mortality risk factor that happens with disuse, chronic disease, and aging. The tissue remodeling that happens during recovery from atrophy or injury involves changes in different cell types such as muscle fibers, and satellite and immune cells. Here, we show that the previously uncharacterized gene and protein Zfp697 is a damage-induced regulator of muscle remodeling.

Mustn1 is a smooth muscle cell-secreted microprotein that modulates skeletal muscle extracellular matrix composition.

Objective: Skeletal muscle plasticity and remodeling are critical for adapting tissue function to use, disuse, and regeneration. The aim of this study was to identify genes and molecular pathways that regulate the transition from atrophy to compensatory hypertrophy or recovery from injury. Here, we have used a mouse model of hindlimb unloading and reloading, which causes skeletal muscle atrophy, and compensatory regeneration and hypertrophy, respectively.

Multivalent insulin receptor activation using insulin-DNA origami nanostructures.

Insulin binds the insulin receptor (IR) and regulates anabolic processes in target tissues. Impaired IR signalling is associated with multiple diseases, including diabetes, cancer and neurodegenerative disorders. IRs have been reported to form nanoclusters at the cell membrane in several cell types, even in the absence of insulin binding.

Robust derivation of transplantable dopamine neurons from human pluripotent stem cells by timed retinoic acid delivery.

Stem cell therapies for Parkinson's disease (PD) have entered first-in-human clinical trials using a set of technically related methods to produce mesencephalic dopamine (mDA) neurons from human pluripotent stem cells (hPSCs). Here, we outline an approach for high-yield derivation of mDA neurons that principally differs from alternative technologies by utilizing retinoic acid (RA) signaling, instead of WNT and FGF8 signaling, to specify mesencephalic fate. Unlike most morphogen signals, where precise concentration determines cell fate, it is the duration of RA exposure that is the key-parameter for mesencephalic specification.

A Shh/Gli-driven three-node timer motif controls temporal identity and fate of neural stem cells.

How time is measured by neural stem cells during temporal neurogenesis has remained unresolved. By combining experiments and computational modeling, we define a Shh/Gli-driven three-node timer underlying the sequential generation of motor neurons (MNs) and serotonergic neurons in the brainstem. The timer is founded on temporal decline of Gli-activator and Gli-repressor activities established through down-regulation of Gli transcription.

Modeling the transport of nuclear proteins along single skeletal muscle cells.

Skeletal muscle cells contain hundreds of myonuclei within a shared cytoplasm, presenting unique challenges for regulating gene expression. Certain transcriptional programs (e.g.

EviNet: a web platform for network enrichment analysis with flexible definition of gene sets.

The new web resource EviNet provides an easily run interface to network enrichment analysis for exploration of novel, experimentally defined gene sets. The major advantages of this analysis are (i) applicability to any genes found in the global network rather than only to those with pathway/ontology term annotations, (ii) ability to connect genes via different molecular mechanisms rather than within one high-throughput platform, and (iii) statistical power sufficient to detect enrichment of very small sets, down to individual genes. The users' gene sets are either defined prior to upload or derived interactively from an uploaded file by differential expression criteria.

Characterization of association of human mitochondrial lysyl-tRNA synthetase with HIV-1 Pol and tRNA.

Background: An important step in human immunodeficiency virus type 1 (HIV-1) replication is the packaging of tRNA from the host cell, which plays the role of primer RNA in the process of initiation of reverse transcription. The viral GagPol polyprotein precursor, and the human mitochondrial lysyl-tRNA synthetase (mLysRS) from the host cell, have been proposed to be involved in the packaging process. More specifically, the catalytic domain of mLysRS is supposed to interact with the transframe (TF or p6*) and integrase (IN) domains of the Pol region of the GagPol polyprotein.

Differential requirement of SUFU in tissue development discovered in a hypomorphic mouse model.

Suppressor of Fused (SUFU) is an essential negative regulator of the Hedgehog (HH) pathway and involved in GLI transcription factor regulation. Due to early embryonic lethality of Sufu mice, investigations of SUFU's role later in development are limited to conditional, tissue-specific knockout models. In this study we developed a mouse model (Sufu) with hypomorphic features where embryos were viable up to E18.

The novel enterochromaffin marker Lmx1a regulates serotonin biosynthesis in enteroendocrine cell lineages downstream of Nkx2.2.

Intestinal hormone-producing cells represent the largest endocrine system in the body, but remarkably little is known about enteroendocrine cell type specification in the embryo and adult. We analyzed stage- and cell type-specific deletions of Nkx2.2 and its functional domains in order to characterize its role in the development and maintenance of enteroendocrine cell lineages in the mouse duodenum and colon.

Nkx2.2 and Nkx2.9 are the key regulators to determine cell fate of branchial and visceral motor neurons in caudal hindbrain.

Cranial motor nerves in vertebrates are comprised of the three principal subtypes of branchial, visceral, and somatic motor neurons, which develop in typical patterns along the anteroposterior and dorsoventral axes of hindbrain. Here we demonstrate that the formation of branchial and visceral motor neurons critically depends on the transcription factors Nkx2.2 and Nkx2.

Tgfβ signaling regulates temporal neurogenesis and potency of neural stem cells in the CNS.

How the sequential specification of neurons and progressive loss of potency associated with aging neural progenitors are regulated in vertebrate brain development is poorly understood. By examining a temporal differentiation lineage in the hindbrain, we here identify Tgfβ as a switch signal that executes the transition between early and late phases of neurogenesis and concurrently constrains progenitor potency. Young progenitors have inherent competence to produce late-born neurons, but implementation of late-differentiation programs requires suppression of early identity genes achieved through temporally programmed activation of Tgfβ downstream of Shh signaling.

CtBPs sense microenvironmental oxygen levels to regulate neural stem cell state.

Bone morphogenetic proteins (BMPs) secreted by the dorsal neural tube and overlying ectoderm are key signals for the specification of the roof plate and dorsal interneuron populations. However, the signals that confer nonneurogenic character to the roof plate region are largely unknown. We report that the roof plate region shows elevated oxygen levels compared to neurogenic regions of the neural tube.

Mechanistic differences in the transcriptional interpretation of local and long-range Shh morphogen signaling.

Morphogens orchestrate tissue patterning in a concentration-dependent fashion during vertebrate embryogenesis, yet little is known of how positional information provided by such signals is translated into discrete transcriptional outputs. Here we have identified and characterized cis-regulatory modules (CRMs) of genes operating downstream of graded Shh signaling and bifunctional Gli proteins in neural patterning. Unexpectedly, we find that Gli activators have a noninstructive role in long-range patterning and cooperate with SoxB1 proteins to facilitate a largely concentration-independent mode of gene activation.

Metastatic cutaneous Crohn's disease of the face: a case report and review of the literature.

Metastatic cutaneous Crohn's disease is one of the most uncommon cutaneous extraintestinal manifestations. The face is the rarest location, with only eight cases described in the literature. We report a rare case of a young man with Crohn's disease and two granulomatous lesions on the face in a nodular form.

A homeodomain feedback circuit underlies step-function interpretation of a Shh morphogen gradient during ventral neural patterning.

The deployment of morphogen gradients is a core strategy to establish cell diversity in developing tissues, but little is known about how small differences in the concentration of extracellular signals are translated into robust patterning output in responding cells. We have examined the activity of homeodomain proteins, which are presumed to operate downstream of graded Shh signaling in neural patterning, and describe a feedback circuit between the Shh pathway and homeodomain transcription factors that establishes non-graded regulation of Shh signaling activity. Nkx2 proteins intrinsically strengthen Shh responses in a feed-forward amplification and are required for ventral floor plate and p3 progenitor fates.

Effects of small molecule modulators on ATP binding to skeletal ryanodine receptor.

Calcium release for muscle contraction in skeletal muscle is mediated in part by the ryanodine receptor 1, RyR1, Ca2+-channel and is strongly affected by intrinsic modulators like Ca2+, Mg2+ and ATP. We showed differential effects on ATP binding in the presence of Ca2+ or Mg2+ ions using ESR spectroscopy and a spin-labeled ATP analog, SL-ATP (Dias et al. Biochemistry 45: 9408-9415, 2006).

Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways.

Cells adapt to hypoxia by a cellular response, where hypoxia-inducible factor 1alpha (HIF-1alpha) becomes stabilized and directly activates transcription of downstream genes. In addition to this "canonical" response, certain aspects of the pathway require integration with Notch signaling, i.e.

The ZpiM algorithm: a method for interferometric image reconstruction in SAR/SAS.

This paper presents an effective algorithm for absolute phase (not simply modulo-2-pi) estimation from incomplete, noisy and modulo-2pi observations in interferometric aperture radar and sonar (InSAR/InSAS). The adopted framework is also representative of other applications such as optical interferometry, magnetic resonance imaging and diffraction tomography. The Bayesian viewpoint is adopted; the observation density is 2-pi-periodic and accounts for the interferometric pair decorrelation and system noise; the a priori probability of the absolute phase is modeled by a compound Gauss-Markov random field (CGMRF) tailored to piecewise smooth absolute phase images.

Insights into the regulation of the ryanodine receptor: differential effects of Mg2+ and Ca2+ on ATP binding.

Calcium ions are frequently used second messengers in most living organisms. Members of the family of ryanodine sensitive calcium channels (ryanodine receptors, RyRs) are responsible for many important Ca(2+) signaling events in both excitable and nonexcitable cells. The biological activity of these membrane proteins is modulated and regulated by a great variety of different cellular and extracellular effectors, proteins, and small molecules.

Tbx20 is essential for cardiac chamber differentiation and repression of Tbx2.

Tbx20, a member of the T-box family of transcriptional regulators, shows evolutionary conserved expression in the developing heart. In the mouse, Tbx20 is expressed in the cardiac crescent, then in the endocardium and myocardium of the linear and looped heart tube before it is restricted to the atrioventricular canal and outflow tract in the multi-chambered heart. Here, we show that Tbx20 is required for progression from the linear heart tube to a multi-chambered heart.

Different spindle checkpoint proteins monitor microtubule attachment and tension at kinetochores in Drosophila cells.

The spindle assembly checkpoint detects errors in kinetochore attachment to the spindle including insufficient microtubule occupancy and absence of tension across bi-oriented kinetochore pairs. Here, we analyse how the kinetochore localization of the Drosophila spindle checkpoint proteins Bub1, Mad2, Bub3 and BubR1, behave in response to alterations in microtubule binding or tension. To analyse the behaviour in the absence of tension, we treated S2 cells with low doses of taxol to disrupt microtubule dynamics and tension, but not kinetochore-microtubule occupancy.

Complementary roles for Nkx6 and Nkx2 class proteins in the establishment of motoneuron identity in the hindbrain.

The genetic program that underlies the generation of visceral motoneurons in the developing hindbrain remains poorly defined. We have examined the role of Nkx6 and Nkx2 class homeodomain proteins in this process, and provide evidence that these proteins mediate complementary roles in the specification of visceral motoneuron fate. The expression of Nkx2.

Coordinated temporal and spatial control of motor neuron and serotonergic neuron generation from a common pool of CNS progenitors.

Neural progenitor cells often produce distinct types of neurons in a specific order, but the determinants that control the sequential generation of distinct neuronal subclasses in the vertebrate CNS remain poorly defined. We examined the sequential generation of visceral motor neurons and serotonergic neurons from a common pool of neural progenitors located in the ventral hindbrain. We found that the temporal specification of these neurons varies along the anterior-posterior axis of the hindbrain, and that the timing of their generation critically depends on the integrated activities of Nkx- and Hox-class homeodomain proteins.