Structure-guided design of a peripherally restricted chemogenetic system.

Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remotely controlling cellular signaling, neural activity, behavior, and physiology. Using a structure-guided approach, we provide a peripherally restricted Gi-DREADD, hydroxycarboxylic acid receptor DREADD (HCAD), whose native receptor is minimally expressed in the brain, and a chemical actuator that does not cross the blood-brain barrier (BBB). This was accomplished by combined mutagenesis, analoging via an ultra-large make-on-demand library, structural determination of the designed DREADD receptor via cryoelectron microscopy (cryo-EM), and validation of HCAD function.

Comprehensive mapping of sensory and sympathetic innervation of the developing kidney.

The kidneys act as finely tuned sensors to maintain physiological homeostasis. Both sympathetic and sensory nerves modulate kidney function through precise neural control. However, how the kidneys are innervated during development to support function remains elusive.

Upregulation of delta opioid receptor by meningeal interleukin-10 prevents relapsing pain.

Chronic pain often includes periods of transient amelioration and even remission that alternate with severe relapsing pain. While most research on chronic pain has focused on pain development and maintenance, there is a critical unmet need to better understand the mechanisms that underlie pain remission and relapse. We found that interleukin (IL)-10, a pain resolving cytokine, is produced by resident macrophages in the spinal meninges during remission from pain and signaled to IL-10 receptor-expressing sensory neurons.

Selective targeting of mu opioid receptors to primary cilia.

Opioid receptors are therapeutically important G protein-coupled receptors (GPCRs) with diverse neuromodulatory effects. The functional consequences of opioid receptor activation are known to depend on receptor location in the plasma membrane, but mechanisms mediating selective localization of receptors to any particular membrane domain remain elusive. Here, we demonstrate the targeting of the mu opioid receptor (MOR) to the primary cilium, a discrete microdomain of the somatic plasma membrane, both in vivo and in cultured cells.

Comprehensive mapping of sensory and sympathetic innervation of the developing kidney.

The kidney functions as a finely tuned sensor to balance body fluid composition and filter out waste through complex coordinated mechanisms. This versatility requires tight neural control, with innervating efferent nerves playing a crucial role in regulating blood flow, glomerular filtration rate, water and sodium reabsorption, and renin release. In turn sensory afferents provide feedback to the central nervous system for the modulation of cardiovascular function.

Interleukin-10 signaling in somatosensory neurons controls CCL2 release and inflammatory response.

Appropriate regulation of the inflammatory response is essential for survival. Interleukin-10 (IL-10), a well-known anti-inflammatory cytokine, plays a major role in controlling inflammation. In addition to immune cells, we previously demonstrated that the IL-10 receptor (IL-10R1) is expressed in dorsal root ganglion sensory neurons.

Validation of a neighborhood sentiment and safety index derived from existing data repositories.

Background: The communities we live in are central to our health. Neighborhood disadvantage is associated with worse physical and mental health and even early mortality, while resident sense of safety and positive neighborhood sentiment has been repeatedly linked to better physical and mental health outcomes. Therefore, understanding where negative neighborhood sentiment and safety are salient concerns can help inform public health interventions and as a result, improve health outcomes.

Prenatal exposure to PM and childhood cognition: Accounting for between-site heterogeneity in a pooled analysis of ECHO cohorts in the Northeastern United States.

Background: Emerging studies have investigated the adverse health effects of PM using data from multiple cohorts, and results often are not generalizable across cohorts. We aimed to assess associations between prenatal PM and childhood cognition in two U.S.

A numerical evaluation of a novel recovery fresh air heat pump concept for a generic electric bus.

Since the outbreak of the worldwide COVID-19 pandemic, public transportation networks have faced unprecedented challenges and have looked for practical solutions to address the rising safety concerns. It is deemed that in confined spaces, operating heating units (and cooling) in non-re-circulation mode ( all-fresh air mode) could reduce the airborne transmission of this infectious disease, by reducing the density of the pathogen and exposure time. However, this will expectedly increase the energy demand and reduce the driving range of electric buses.

Racial/ethnic and neighborhood disparities in metals exposure during pregnancy in the Northeastern United States.

Despite the unequal burden of environmental exposures borne by racially minoritized communities, these groups are often underrepresented in public health research. Here, we examined racial/ethnic disparities in exposure to metals among a multi-ethnic sample of pregnant women. The sample included women enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort (N = 382).

Sympathetic yet painful: Autonomic innervation drives cluster firing of somatosensory neurons.

In this issue of Neuron, Zheng et al. (2021) report synchronized cluster firing of dorsal root ganglion (DRG) neurons that correlates with spontaneous pain in the setting of nerve injury. The authors' findings further suggest that sympathetic sprouting in the DRG plays a key role in this phenomenon.

Endogenous and Exogenous Vanilloids Evoke Disparate TRPV1 Activation to Produce Distinct Neuronal Responses.

Neuronal signals are processed along the nociceptive pathway to convey discriminative information, which would manifest in the produced pain sensation. The transient receptor potential vanilloid 1 (TRPV1), an important signaling complex in nociceptors termini, is activated by different noxious stimuli that underlie distinct pain sensations. For example, while endovanilloids are associated with inflammatory pain and hypersensitivity through TRPV1 activation, the exovanilloid toxin, capsaicin, evokes an acute pain by activating this channel.

Production and Purification of Recombinant Toxins.

Recombinant expression of toxins enables us to produce adequate quantities of these proteins which can be used to perform experiments at molecular, cellular, and behavioral levels. Furthermore, toxins can be edited by using simple molecular biology methods when producing them recombinantly. Thus, in many cases establishing a protocol for the recombinant expression of a toxin of interest is crucial in exploring the structure and function of the toxin and its effectors.

The Role of Toxins in the Pursuit for Novel Analgesics.

Chronic pain is a major medical issue which reduces the quality of life of millions and inflicts a significant burden on health authorities worldwide. Currently, management of chronic pain includes first-line pharmacological therapies that are inadequately effective, as in just a portion of patients pain relief is obtained. Furthermore, most analgesics in use produce severe or intolerable adverse effects that impose dose restrictions and reduce compliance.

TRPV1 pore turret dictates distinct DkTx and capsaicin gating.

Many neurotoxins inflict pain by targeting receptors expressed on nociceptors, such as the polymodal cationic channel TRPV1. The tarantula double-knot toxin (DkTx) is a peptide with an atypical bivalent structure, providing it with the unique capability to lock TRPV1 in its open state and evoke an irreversible channel activation. Here, we describe a distinct gating mechanism of DkTx-evoked TRPV1 activation.

Animal Toxins Providing Insights into TRPV1 Activation Mechanism.

Beyond providing evolutionary advantages, venoms offer unique research tools, as they were developed to target functionally important proteins and pathways. As a key pain receptor in the nociceptive pathway, transient receptor potential vanilloid 1 (TRPV1) of the TRP superfamily has been shown to be a target for several toxins, as a way of producing pain to deter predators. Importantly, TRPV1 is involved in thermoregulation, inflammation, and acute nociception.

Modulation of Renal GLUT2 by the Cannabinoid-1 Receptor: Implications for the Treatment of Diabetic Nephropathy.

Altered glucose reabsorption the facilitative glucose transporter 2 (GLUT2) during diabetes may lead to renal proximal tubule cell (RPTC) injury, inflammation, and interstitial fibrosis. These pathologies are also triggered by activating the cannabinoid-1 receptor (CBR), which contributes to the development of diabetic nephropathy (DN). However, the link between CBR and GLUT2 remains to be determined.

Controllable Ion Channel Expression through Inducible Transient Transfection.

Transfection, the delivery of foreign nucleic acids into a cell, is a powerful tool in protein research. Through this method, ion channels can be investigated through electrophysiological analysis, biochemical characterization, mutational studies, and their effects on cellular processes. Transient transfections offer a simple protocol in which the protein becomes available for analysis within a few hours to days.

Protein toxins of the Echis coloratus viper venom directly activate TRPV1.

Background: Peptide and protein toxins are essential tools to dissect and probe the biology of their target receptors. Venoms target vital physiological processes to evoke pain. Snake venoms contain various factors with the ability to evoke, enhance and sustain pain sensation.

Activation of transient receptor potential vanilloid 1 by lipoxygenase metabolites depends on PKC phosphorylation.

Peripheral neuronal activation by inflammatory mediators is a multifaceted physiological response that involves a multitude of regulated cellular functions. One key pathway that has been shown to be involved in inflammatory pain is Gq/GPCR, whose activation by inflammatory mediators is followed by the regulated response of the cation channel transient receptor potential vanilloid 1 (TRPV1). However, the mechanism that underlies TRPV1 activation downstream of the Gq/GPCR pathway has yet to be fully defined.

A singular case of intravesical bleeding angiomyolipoma in a bladder diverticulum.

Neoplasms arising from intravesical diverticula are rare and considered by urologists as an important surgical challenge. A hamartomatous lesion noted in a bladder diverticulum has never been reported. To our knowledge, we report the first angiomyolipoma, a subtype of mesenchymal hamartoma uncommonly located extrarenally, seen in a bladder dome diverticulum.

Combination of CFD and DOE to analyze and improve the mass flow rate in urinary catheters.

The urinary catheter is a thin plastic tube that has been designed to empty the bladder artificially, effortlessly, and with minimum discomfort. The current CH14 male catheter design was examined with a view to optimizing the mass flow rate. The literature imposed constraints to the analysis of the urinary catheter to ensure that a compromise between optimal flow, patient comfort, and everyday practicality from manufacture to use was achieved in the new design.

[Effect of nutritional status on absorption kinetics of vitamin E in mucoviscidosis].

Exocrine pancreatic insufficiency with varying severity must be anticipated in 85-95% of CF patients. It leads to fat maldigestion and malabsorption of the liposoluble vitamins - A, D, E, K - and fecal loss of fat. In general, supplementation with fat-soluble vitamins is recommended in CF patients.