Natural Killer Cells Degenerate Intact Sensory Afferents following Nerve Injury

Davies, Alexander J.,Kim, Hyoung Woo,Gonzalez-Cano, Rafael,Choi, Jahyang,Back, Seung Keun,Roh, Seung Eon,Johnson, Errin,Gabriac, Melanie,Kim, Mi-Sun,Lee, Jaehee,Lee, Jeong Eun,Kim, Yun Sook,Bae, Yong Cell Press 2019 Cell Vol. No.

<P><B>Summary</B></P> <P>Sensory axons degenerate following separation from their cell body, but partial injury to peripheral nerves may leave the integrity of damaged axons preserved. We show that an endogenous ligand for the natural killer (NK) cell receptor NKG2D, Retinoic Acid Early 1 (RAE1), is re-expressed in adult dorsal root ganglion neurons following peripheral nerve injury, triggering selective degeneration of injured axons. Infiltration of cytotoxic NK cells into the sciatic nerve by extravasation occurs within 3 days following crush injury. Using a combination of genetic cell ablation and cytokine-antibody complex stimulation, we show that NK cell function correlates with loss of sensation due to degeneration of injured afferents and reduced incidence of post-injury hypersensitivity. This neuro-immune mechanism of selective NK cell-mediated degeneration of damaged but intact sensory axons complements Wallerian degeneration and suggests the therapeutic potential of modulating NK cell function to resolve painful neuropathy through the clearance of partially damaged nerves.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Cytotoxic NK cells infiltrate the damaged peripheral nerve within days of injury </LI> <LI> Injured sensory axons express NKG2D ligand RAE1 to signal degeneration by NK cells </LI> <LI> Clearance of damaged axons reduces development of chronic pain after nerve injury </LI> <LI> NK cells complement Wallerian degeneration to aid functional regeneration of PNS </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>

State of Practice of Performance-Based Seismic Design in Indonesia

Sukamta, Davy,Alexander, Nick Council on Tall Building and Urban Habitat Korea 2012 International journal of high-rise buildings Vol.1 No.3

The current 2002 Indonesian Seismic Code consists of prescriptive criteria that are intended to result in buildings capable of providing certain levels of performance. However, the actual performance capability of buildings is not assessed as part of the code procedures. Several analysis procedures are allowed, and the state of practice is to use the RSA with six-zone seismic map developed for 475-year earthquake. This code is being revised and will adopt many of the ASCE7-10 provisions and 2475-year earthquake for MCE. The growth of tall buildings compels engineers to look for more optimal lateral system. The use of RC core wall as single system has been adopted by very few engineering firms, which is allowed in the current code but will no longer be the case if the new one is in effect. Other innovative structural system such as core wall and outrigger is not addressed in the proposed new code. Engineers must then resort to NLRHA. Currently, one 50-story building under construction using RC core wall and outrigger has been designed with RSA and employing capacity design principles, then evaluated using NLRHA per TBI Guidelines. Based on the evaluation, the performance of the 50-story building generally still meets the criteria of the TBI Guidelines. The result of the case study is presented in this paper.

Resignifying ‘responsibility’: India, exceptionalism and nuclear non-proliferation

Priya Chacko,Alexander E Davis 서울대학교행정대학원 2018 Asian Journal of Political Science Vol.26 No.3

Postcolonialscholarshiponnuclearweaponshasdemonstratedthat mainstream literature perpetuates a set of orientalist discourses about ‘Enlightenment’ and ‘civilization’ which legitimizes global hierarchies. What has been less studied is the role of non-Western countries in challenging or perpetuating these discourses. This article focuses on the discourse of ‘nuclear responsibility’ as it has been deployed by Indian official to challenge Western discourses of nuclear responsibility that are linked to the Nuclear NonProliferation Treaty (NPT). Using Judith Butler’s concept of resignification, we argue that India has sought to resignify the Western discourse of nuclear responsibility such that it is linked to nuclear disarmament and equality rather than nuclear nonproliferation and hierarchy. In its discourse on nuclear responsibility, India’s status as a responsible nuclear power is based, not on its compliance with international regimes or norms, but on its ‘civilizational exceptionalism’. We argue that resignification is a form of non-western agency but is highly circumscribed. Its success has been dependent upon the broader global political context and has been limited to moving India up the global nuclear hierarchy rather than challenging the hierarchy itself.

TRPV1 in GABAergic Interneurons Mediates Neuropathic Mechanical Allodynia and Disinhibition of the Nociceptive Circuitry in the Spinal Cord

Kim, Y.,Back, S.,Davies, Alexander J.,Jeong, H.,Jo, H.,Chung, G.,Na, H.,Bae, Y.,Kim, S.,Kim, J.,Jung, S.,Oh, S. Cell Press 2012 Neuron Vol.74 No.4

Neuropathic pain and allodynia may arise from sensitization of central circuits. We report a mechanism of disinhibition-based central sensitization resulting from long-term depression (LTD) of GABAergic interneurons as a consequence of TRPV1 activation in the spinal cord. Intrathecal administration of TRPV1 agonists led to mechanical allodynia that was not dependent on peripheral TRPV1 neurons. TRPV1 was functionally expressed in GABAergic spinal interneurons and activation of spinal TRPV1 resulted in LTD of excitatory inputs and a reduction of inhibitory signaling to spinothalamic tract (STT) projection neurons. Mechanical hypersensitivity after peripheral nerve injury was attenuated in TRPV1<SUP>-/-</SUP> mice but not in mice lacking TRPV1-expressing peripheral neurons. Mechanical pain was reversed by a spinally applied TRPV1 antagonist while avoiding the hyperthermic side effect of systemic treatment. Our results demonstrate that spinal TRPV1 plays a critical role as a synaptic regulator and suggest the utility of central nervous system-specific TRPV1 antagonists for treating neuropathic pain.

Contemporary treatment with radiosurgery for spine metastasis and spinal cord compression in 2015

Samuel Ryu,Hannah Yoon,Alexander Stessin,PhD,Fred Gutman,Arthur Rosiello,Raphael Davis 대한방사선종양학회 2015 Radiation Oncology Journal Vol.33 No.1

With the progress of image-guided localization, body immobilization system, and computerized delivery of intensity-modulated radiation delivery, it became possible to perform spine radiosurgery. The next question is how to translate the high technology treatment to the clinical application. Clinical trials have been performed to demonstrate the feasibility of spine radiosurgery and efficacy of the treatment in the setting of spine metastasis, leading to the randomized trials by a cooperative group. Radiosurgery has also demonstrated its efficacy to decompress the spinal cord compression in selected group of patients. The experience indicates that spine radiosurgery has a potential to change the clinical practice in the management of spine metastasis and spinal cord compression.

Acute inflammation reveals GABAA receptor‐mediated nociception in mouse dorsal root ganglion neurons via PGE ₂ receptor 4 signaling

Jang, In Jeong,Davies, Alexander J.,Akimoto, Nozomi,Back, Seung Keun,Lee, Pa Reum,Na, Heung Sik,Furue, Hidemasa,Jung, Sung Jun,Kim, Yong Ho,Oh, Seog Bae John Wiley and Sons Inc. 2017 Physiological reports Vol.5 No.8

<P><B>Abstract</B></P><P>Gamma‐aminobutyric acid (GABA) depolarizes dorsal root ganglia (DRG) primary afferent neurons through activation of Cl<SUP>−</SUP> permeable GABAA receptors but the physiologic role of GABAA receptors in the peripheral terminals of DRG neurons remains unclear. In this study, we investigated the role of peripheral GABAA receptors in nociception using a mouse model of acute inflammation. In vivo, peripheral administration of the selective GABAA receptor agonist muscimol evoked spontaneous licking behavior, as well as spinal wide dynamic range (WDR) neuron firing, after pre‐conditioning with formalin but had no effect in saline‐treated mice. GABAA receptor‐mediated pain behavior after acute formalin treatment was abolished by the GABAA receptor blocker picrotoxin and cyclooxygenase inhibitor indomethacin. In addition, treatment with prostaglandin E2 (PGE<SUB>2</SUB>) was sufficient to reveal muscimol‐induced licking behavior. In vitro, GABA induced sub‐threshold depolarization in DRG neurons through GABAA receptor activation. Both formalin and PGE<SUB>2</SUB> potentiated GABA‐induced Ca<SUP>2+</SUP> transients and membrane depolarization in capsaicin‐sensitive nociceptive DRG neurons; these effects were blocked by the prostaglandin E2 receptor 4 (EP4) antagonist AH23848 (10 <I>μ</I>mol/L). Furthermore, potentiation of GABA responses by PGE<SUB>2</SUB> was prevented by the selective Na<SUB>v</SUB>1.8 antagonist A887826 (100 nmol/L). Although the function of the Na<SUP>+</SUP>‐K<SUP>+</SUP>‐2Cl<SUP>‐</SUP> co‐transporter NKCC1 was required to maintain the Cl<SUP>‐</SUP> ion gradient in isolated DRG neurons, NKCC1 was not required for GABAA receptor‐mediated nociceptive behavior after acute inflammation. Taken together, these results demonstrate that GABAA receptors may contribute to the excitation of peripheral sensory neurons in inflammation through a combined effect involving PGE<SUB>2</SUB>‐EP4 signaling and Na<SUP>+</SUP> channel sensitization.</P>

Contemporary treatment with radiosurgery for spine metastasis and spinal cord compression in 2015

Ryu, Samuel,Yoon, Hannah,Stessin, Alexander,Gutman, Fred,Rosiello, Arthur,Davis, Raphael The Korean Society for Radiation Oncology 2015 Radiation Oncology Journal Vol.33 No.1

With the progress of image-guided localization, body immobilization system, and computerized delivery of intensity-modulated radiation delivery, it became possible to perform spine radiosurgery. The next question is how to translate the high technology treatment to the clinical application. Clinical trials have been performed to demonstrate the feasibility of spine radiosurgery and efficacy of the treatment in the setting of spine metastasis, leading to the randomized trials by a cooperative group. Radiosurgery has also demonstrated its efficacy to decompress the spinal cord compression in selected group of patients. The experience indicates that spine radiosurgery has a potential to change the clinical practice in the management of spine metastasis and spinal cord compression.

Stabilization of Polymer-Hydrogel Capsules via Thiol–Disulfide Exchange

Chong, Siow-Feng,Chandrawati, Rona,Stä,dler, Brigitte,Park, Jeongju,Cho, Jinhan,Wang, Yajun,Jia, Zhongfan,Bulmus, Volga,Davis, Thomas P.,Zelikin, Alexander N.,Caruso, Frank WILEY-VCH Verlag 2009 Small Vol.5 No.22

<P>Polymer hydrogels are used in diverse biomedical applications including drug delivery and tissue engineering. Among different chemical linkages, the natural and reversible thiol–disulfide interconversion is extensively explored to stabilize hydrogels. The creation of macro-, micro-, and nanoscale disulfide-stabilized hydrogels commonly relies on the use of oxidizing agents that may have a detrimental effect on encapsulated cargo. Herein an oxidization-free approach to create disulfide-stabilized polymer hydrogels via a thiol–disulfide exchange reaction is reported. In particular, thiolated poly(methacrylic acid) is used and the conditions of polymer crosslinking in solution and on colloidal porous and solid microparticles are established. In the latter case, removal of the core particles yields stable, hollow, disulfide-crosslinked hydrogel capsules. Further, a procedure is developed to achieve efficient disulfide crosslinking of multilayered polymer films to obtain stable, liposome-loaded polymer-hydrogel capsules that contain functional enzymatic cargo within the liposomal subcompartments. This approach is envisaged to facilitate the development of biomedical applications of hydrogels, specifically those including fragile cargo.</P> <B>Graphic Abstract</B> <P>Polymer-hydrogel capsules are stabilized via disulfide linkages whereby crosslinking relies on the thiol–disulfide exchange without the use of oxidizing agents (see image). The method permits the formation of hollow capsules as well as functional capsosomes, hydrogel capsules subcompartmentalized with enzyme-loaded liposomes, without the loss of activity of liposome-encapsulated enzymes. <img src='wiley_img/16136810-2009-5-22-SMLL200900906-content.gif' alt='wiley_img/16136810-2009-5-22-SMLL200900906-content'> </P>