Toward Understanding COVID-19 Recovery: National Institutes of Health Workshop on Postacute COVID-19.

Over the past year, the SARS-CoV-2 pandemic has swept the globe, resulting in an enormous worldwide burden of infection and mortality. However, the additional toll resulting from long-term consequences of the pandemic has yet to be tallied. Heterogeneous disease manifestations and syndromes are now recognized among some persons after their initial recovery from SARS-CoV-2 infection, representing in the broadest sense a failure to return to a baseline state of health after acute SARS-CoV-2 infection. On 3 to 4 December 2020, the National Institute of Allergy and Infectious Diseases, in collaboration with other Institutes and Centers of the National Institutes of Health, convened a virtual workshop to summarize existing knowledge on postacute COVID-19 and to identify key knowledge gaps regarding this condition.

Unraveling the Mysteries of Acute Flaccid Myelitis: Scientific Opportunities and Priorities for Future Research.

Since 2014, cases of acute flaccid myelitis (AFM) have been reported in the United States in increasing numbers biennially, occurring in the late summer and early fall. Although there is unlikely to be a single causative agent of this syndrome, non-polio enteroviruses, including enterovirus D-68 (EV-D68), have had epidemiological and laboratory associations with AFM. Much remains to be known about AFM and AFM-associated enteroviruses, including disease pathogenesis and the best strategies for development of therapeutics or preventive modalities including vaccines. To catalyze research that addresses these scientific and clinical gaps, the National Institute of Allergy and Infectious Diseases convened a workshop entitled "AFM Preparedness: Addressing EV-D68 and Other AFM-Associated Enteroviruses" on 19-20 February 2020.

Modulation of presynaptic activity by phosphorylation in cultured rat spinal dorsal horn neurons.

UNLABELLED: Phosphorylation, in particular by protein kinase C (PKC), modulates spinal sensory transmission and nociceptive behaviors. Whereas PKC's postsynaptic actions are well established, its presynaptic effects in spinal sensory neurons are mostly inferred from postsynaptic recordings. Here we first show that the amphipathic styryl dye FM 1-43 can be used to image presynaptic activity in cultured spinal dorsal horn cultures and then test whether PKC modulates presynaptic activity in cultured spinal dorsal horn neurons. Pretreatment with the broad-spectrum kinase inhibitor staurosporine (2 micromol/L) inhibited dye release. Bisindolylmaleimide I, a PKC inhibitor, potentiated dye release at low doses (200 nmol/L and 1 micromol/L), while inhibiting it at a higher dose (5 micromol/L). Activating PKC with phorbol dibutyrate (0.5 micromol/L) induced an increase in exocytosis, which is partially blocked by bisindolylmaleimide I. These results indicate that styryl dyes can be used to observe presynaptic regulation of spinal dorsal horn neurons, and that PKC acts presynaptically to modulate spinal sensory transmission. PERSPECTIVE: With dye imaging technique, we demonstrate here that PKC presynaptically regulates sensory transmission in spinal dorsal horn neurons. In combination with conventional whole-cell patch-clamp recording technique, the present study provides a new methodology for studying spinal sensory transmission and modulation and facilitates our understanding of pain mechanism.

Endogenous facilitation: from molecular mechanisms to persistent pain.

It is well documented that sensory transmission, including pain, is subject to endogenous inhibitory modulatory influences at dorsal horn of the spinal cord. Recent results, from behavioral to molecular studies, demonstrate that endogenous modulatory systems are bi-phasic, including inhibitory as well as new facilitatory systems. In this review, we propose the existence of endogenous facilitatory systems in the brain, and review evidence supporting the hypothesis. We believe that understanding molecular and cellular mechanisms of endogenous facilitatory systems hold the hope for better future treatment of patients with chronic pain.

Inducible protein knockout reveals temporal requirement of CaMKII reactivation for memory consolidation in the brain.

By integrating convergent protein engineering and rational inhibitor design, we have developed an in vivo conditional protein knockout andor manipulation technology. This method is based on the creation of a specific interaction interface between a modified protein domain and sensitized inhibitors. By introducing this system into genetically modified mice, we can readily manipulate the activity of a targeted protein, such as alpha-Ca(2+)calmodulin-dependent protein kinase II (alphaCAMKII), on the time scale of minutes in specific brain subregions of freely behaving mice. With this inducible and region-specific protein knockout technique, we analyzed the temporal stages of memory consolidation process and revealed the first postlearning week as the critical time window during which a precise level of CaMKII reactivation is essential for the consolidation of long-term memories in the brain.

Calcium calmodulin-dependent protein kinase IV is required for fear memory.

The ability to remember potential dangers in an environment is necessary to the survival of animals and humans. The cyclic AMP responsive element binding protein (CREB) is a key transcription factor in synaptic plasticity and memory consolidation. We have found that in CaMKIV(-/-) mice--which are deficient in a component of the calcium calmodulin-dependent protein kinase (CaMK) pathway, a major pathway of CREB activation--fear memory, but not persistent pain, was significantly reduced. CREB activation by fear conditioning and synaptic potentiation in the amygdala and cortical areas was reduced or blocked. We propose that cognitive memory related to a noxious shock can be disassociated from behavioral responses to tissue injury and inflammation.

Genetic analysis of pain mechanisms.

Pain is the major reason for visits to the doctor. It is a complex sensation, with both a sensory and an emotional component. Its detailed regulation at all levels of the central nervous system, from the periphery to the cortex, has hindered our understanding of the neurobiological basis of pain. Furthermore, injury can produce long-lasting changes in pain pathways and chronic pain. The recent use of genetically modified organisms has significantly advanced our comprehension of the molecular and cellular mechanisms underlying pain. In this article we present the current state of knowledge regarding pain transmission, modulation, and plasticity, and some of the contributions made by studies of genetically altered mice. The cellular mechanisms explaining observed phenotypes, the involvement of supraspinal areas, and the plasticity underlying chronic pain are the three areas just beginning to be explored.