Deletion of Tsc2 in nociceptors reduces target innervation, ion channel expression, and sensitivity to heat

AbstractThe mechanistic target of rapamycin complex 1 (mTORC1) is known to regulate cellular growth pathways, and its genetic activation is sufficient to enhance regenerative axon growth following injury to the central or peripheral nervous systems. However, excess mTORC1 activation may promote innervation defects, and mTORC1 activity mediates injury-induced hypersensitivity, reducing enthusiasm for the pathway as a therapeutic target. While mTORC1 activity is required for full expression of some pain modalities, the effects of pathway activation on nociceptor phenotypes and sensory behaviors are currently unknown. To address this, we genetically activated mTORC1 in mouse peripheral sensory neurons by conditional deletion of its negative regulator Tuberous Sclerosis Complex 2 (Tsc2). Consistent with the well-known role of mTORC1 in regulating cell size, soma size and axon diameter of C-nociceptors were increased in Tsc2-deleted mice. Glabrous skin and spinal cord innervation by C-fiber neurons were also disrupted. Transcriptional profiling of nociceptors enriched by fluorescence-associated cell sorting (FACS) revealed downregulation of multiple classes of ion channels as well as reduced expression of markers for peptidergic nociceptors in Tsc2-deleted mice. In addition to these changes in innervation and gene expression, Tsc2-deleted mice exhibited reduced noxious heat sensitivity and decreased injury-induced cold hypersensitivity, but normal baseline sensitivity to cold and mechanical stimuli. Together, these data show that excess mTORC1 activity in sensory neurons produces changes in gene expression, neuron morphology and sensory behavior.</jats:p

Gpr126/Adgrg6 has Schwann cell autonomous and nonautonomous functions in peripheral nerve injury and repair

Schwann cells (SCs) are essential for proper peripheral nerve development and repair, although the mechanisms regulating these processes are incompletely understood. We previously showed that the adhesion G protein-coupled receptor Gpr126/Adgrg6 is essential for SC development and myelination. Interestingly, the expression of Gpr126 is maintained in adult SCs, suggestive of a function in the mature nerve. We therefore investigated the role of Gpr126 in nerve repair by studying an inducible SC-specific Gpr126 knock-out mouse model. Here, we show that remyelination is severely delayed after nerve-crush injury. Moreover, we also observe noncell-autonomous defects in macrophage recruitment and axon regeneration in injured nerves following loss of Gpr126 in SCs. This work demonstrates that Gpr126 has critical SC-autonomous and SC-nonautonomous functions in remyelination and peripheral nerve repair. SIGNIFICANCE STATEMENT Lack of robust remyelination represents one of the major barriers to recovery of neurological functions in disease or following injury in many disorders of the nervous system. Here we show that the adhesion class G protein-coupled receptor (GPCR) Gpr126/Adgrg6 is required for remyelination, macrophage recruitment, and axon regeneration following nerve injury. At least 30% of all approved drugs target GPCRs; thus, Gpr126 represents an attractive potential target to stimulate repair in myelin disease or following nerve injury

On Black Fundamental Strings

We study aspects of four dimensional black holes with two electric charges, corresponding to fundamental strings with generic momentum and winding on an internal circle. The perturbative \alpha' correction to such black holes and their gravitational thermodynamics is obtained.Comment: 17 pages, v2: published versio

Developing a pressure ulcer risk factor minimum data set and risk assessment framework

AIM: To agree a draft pressure ulcer risk factor Minimum Data Set to underpin the development of a new evidenced-based Risk Assessment Framework.BACKGROUND: A recent systematic review identified the need for a pressure ulcer risk factor Minimum Data Set and development and validation of an evidenced-based pressure ulcer Risk Assessment Framework. This was undertaken through the Pressure UlceR Programme Of reSEarch (RP-PG-0407-10056), funded by the National Institute for Health Research and incorporates five phases. This article reports phase two, a consensus study.DESIGN: Consensus study.METHOD: A modified nominal group technique based on the Research and Development/University of California at Los Angeles appropriateness method. This incorporated an expert group, review of the evidence and the views of a Patient and Public Involvement service user group. Data were collected December 2010-December 2011.FINDINGS: The risk factors and assessment items of the Minimum Data Set (including immobility, pressure ulcer and skin status, perfusion, diabetes, skin moisture, sensory perception and nutrition) were agreed. In addition, a draft Risk Assessment Framework incorporating all Minimum Data Set items was developed, comprising a two stage assessment process (screening and detailed full assessment) and decision pathways.CONCLUSION: The draft Risk Assessment Framework will undergo further design and pre-testing with clinical nurses to assess and improve its usability. It will then be evaluated in clinical practice to assess its validity and reliability. The Minimum Data Set could be used in future for large scale risk factor studies informing refinement of the Risk Assessment Framework

Brane Dynamics and 3D Seiberg Duality on the Domain Walls of 4D N=1 SYM

We study a three-dimensional U(k) Yang-Mills Chern-Simons theory with adjoint matter preserving two supersymmetries. According to Acharya and Vafa, this theory describes the low-energy worldvolume dynamics of BPS domain walls in four-dimensional N=1 SYM theory. We demonstrate how to obtain the same theory in a brane configuration of type IIB string theory that contains threebranes and fivebranes. A combination of string and field theory techniques allows us to re-formulate some of the well-known properties of N=1 SYM domain walls in a geometric language and to postulate a Seiberg-like duality for the Acharya-Vafa theory. In the process, we obtain new information about the dynamics of branes in setups that preserve two supersymmetries. Using similar methods we also study other N=1 CS theories with extra matter in the adjoint and fundamental representations of the gauge group.Comment: 25 pages, 5 figure

Friends, Strangers, and the Value of Ego Networks for Recommendation

Two main approaches to using social network information in recommendation have emerged: augmenting collaborative filtering with social data and algorithms that use only ego-centric data. We compare the two approaches using movie and music data from Facebook, and hashtag data from Twitter. We find that recommendation algorithms based only on friends perform no worse than those based on the full network, even though they require much less data and computational resources. Further, our evidence suggests that locality of preference, or the non-random distribution of item preferences in a social network, is a driving force behind the value of incorporating social network information into recommender algorithms. When locality is high, as in Twitter data, simple k-nn recommenders do better based only on friends than they do if they draw from the entire network. These results help us understand when, and why, social network information is likely to support recommendation systems, and show that systems that see ego-centric slices of a complete network (such as websites that use Facebook logins) or have computational limitations (such as mobile devices) may profitably use ego-centric recommendation algorithms.Comment: 5 pages, ICWSM 201