Nociceptors: the sensors of the pain pathway

Personalized medicine: from disease-centered to human-centered medicine Personalized medicine deals with individual diversities and the complexity of the human body. Current healthcare models are diseaseoriented and focus on pathogens and environmental or external factors [4]. Personalized medicine would enable the change from such disease-centered medicine to human-centered medicine. Pharmacogenomics arose in response to such recognition. Pharmacogenomics studies genetic variations among individuals to predict disease susceptibility and responses to therapeutic agents [5,6]. The investigation of genetic diversity may enable the identification of optimal drug targets for certain patient populations, and empower physicians to make the right decisions. By focusing on patients’ genetic or biomarker profiles, pharmacogenomics represents the evolution from treating the disease itself to treating the malfunction of an individual person, the ‘root’ of the disease [7]. With such practices, patients can be regrouped and drugs can be recategorized. For instance, similar diseases may require different treatments, while different diseases may be treated with the same or similar approaches. Because of the diversity of patients’ biological backgrounds, the same disease may be caused by genetic variation in different people, who will respond differently to the same drug. For example, polymorphisms in the ABCB1 gene contribute to cancer risk and different therapeutic responses [8]. Patients with certain genotypes, such as 1236C/C, showed poorer survival than patients with other genotypes. Such situations require individualized treatments for the same disease (cancer) to ensure the best possible results. On the other hand, Challenges & new concepts in biomedicine In this era of change, biomedicine is heading toward a revolutionary new path. This path is a transformation from reductionism toward a holistic paradigm, from ‘one-size-fits-all’ therapeutics towards personalized medicine. Such changes are necessary to meet the challenges in healthcare and the pharmaceutical industry, for example, the high costs in healthcare, low efficacy of drugs and increased incidents of adverse drug reactions (ADRs). ADRs are one of the leading causes of death and illness in the USA [1]. Although the research and development costs in the pharmaceutical industry are soaring, high-profile drug withdrawals are elevating, while the US FDA’s approval for new drugs is decreasing [2]. At the same time, the gap between biomedical science and clinical practice has made it hard to translate scientific advancements into improved healthcare. These challenges and difficulties are calling for the development of new strategies, new concepts, or even a new kind of medicine to meet these goals:

BackgroundWhen introduced to novel environments, the ability for a species to survive and rapidly proliferate corresponds with its adaptive potential. Of the many factors that can yield an environment inhospitable to foreign species, phenotypic response to variation in the thermal climate has been observed within a wide variety of species. Experimental evolution studies using bacteriophage model systems have been able to elucidate mutations, which may correspond with the ability of phage to survive modest increases/decreases in the temperature of their environment.ResultsPhage ΦX174 was subjected to both elevated (50°C) and extreme (70°C+) temperatures for anywhere from a few hours to days. While no decline in the phage's fitness was detected when it was exposed to 50°C for a few hours, more extreme temperatures significantly impaired the phage; isolates that survived these heat treatments included the acquisition of several mutations within structural genes. As was expected, long-term treatment of elevated and extreme temperatures, ranging from 50-75°C, reduced the survival rate even more. Isolates which survived the initial treatment at 70°C for 24 or 48 hours exhibited a significantly greater tolerance to subsequent heat treatments.ConclusionsUsing the model organism ΦX174, we have been able to study adaptive evolution on the molecular level under extreme thermal changes in the environment, which to-date had yet to be thoroughly examined. Under both acute and extended thermal selection, we were able to observe mutations that occurred in response to excessive external pressures independent of concurrently evolving hosts. Even though its host cannot tolerate extreme temperatures such as the ones tested here, this study confirms that ΦX174 is capable of survival.

The management of the pain state is of great therapeutic relevance to virtually every medical specialty. Failure to manage its expression has deleterious consequence to the well-being of the organism. An understanding of the complex biology of the mechanisms underlying the processing of nociceptive information provides an important pathway towards development of novel and robust therapeutics. Importantly, preclinical models have been of considerable use in determining the linkage between mechanism and the associated behaviorally defined pain state. This review seeks to provide an overview of current thinking targeting pain biology, the use of preclinical models and the development of novel pain therapeutics. Issues pertinent to the strengths and weaknesses of current development strategies for analgesics are considered.

Water is the single most abundant substance in cells and organisms and is an important molecule involved in several biochemical processes present in living cells. In humans 60-70% of body weight is water which equilibrates across the lipid bilayer in cell membranes. Forty years ago, a small number of scientists argued that specialized water-selective pores are necessary to explain the high water permeability of red blood cells and renal tubules. Therefore, the molecular identification of a 28 kDa integral membrane protein in these cells has characterized a new stream of research. Aquaporins (AQPs) are membrane proteins that transport water and, in some cases, also small solutes such as glycerol and urea. Each subtype has its own cellular distribution and distinct regulatory mechanisms of their expression. Their classical role in facilitating trans-epithelial fluid transport is well understood, as in the urinary concentrating mechanism and gland fluid secretion, while the molecular mechanisms to regulate water permeability in the nervous system are still unclear. Maintenance of the ionic and osmotic composition and volume of interstitial, glial and neuronal compartments within the nervous system is essential for normal function. Small changes in intracellular or extracellular ion or solute composition can dramatically modify bi-directional water pathway between the brain and blood vessels and alter cerebrospinal fluid formation, neural signal transduction and information processing. To date, only some AQP isoforms (AQP1, 3, 4, 5, 8, 9) have been reported in the central nervous system being identified in choroidal cells (AQP1), astrocytes (AQP1, 3, 4, 5, 8, 9), oligodendrocytes (AQP8), neurons (AQP1, 5, 8), tanycytes (AQP9) and ependymal cells (AQP1, 4, 9). In contrast to numerous studies of AQP localization and function in the central nervous system, little information is available on the expression and function of AQPs in peripheral nervous system. This issue includes six review articles in which the authors report and explore the recent findings about the involvement of AQPs both in peripheral and central nervous system. The paper by B. Buffoli summarizes the data about the structure, regulation and function of AQPs, giving more importance to their involvement in the nervous system and underlying the development of new methods for diagnosis and therapy diseases. The review of R. Albertini and R. Bianchi is focused on the different isoforms of AQP protein that have been identified in glial cells in central and peripheral nervous system and in reactive microglial. The chapter supports the idea that AQPs are involved in water homeostasis during different glial cell functions, such as differentiation, metabolism and excitability of neurons. F. Bonomini and R. Rezzani emphasize the role of some AQPs present in glial cells in the maintenance or/and in the regulatory mechanisms of blood brain barrier. On the basis of the role of AQPs in brain edema, a personal account of the role of AQPs is then presented by C. Loreto and E. Reggio, who summarized the implication of different isoforms of these proteins in relation with vascular diseases and nervous system. In the literature, there is a lot of evidence that indicates a correlation between the expression of AQPs and the development of neurodegenerative diseases in which preservation of brain homeostasis is at risk. The review of E. Foglio and L.F. Rodella was to consider this topic concentrating on some neurodegenerative diseases, such as Neuromyielitis Optica, Alzheimer’s Diseases, Parkinson’s Diseases, Amyotrophic lateral sclerosis, Transmissible Spongiform Encephalopathies. Recent evidence suggests a novel role of AQPs in pain transmission both in the central and peripheral nervous system. In this issue, E. Borsani reports the modulation of AQPs both in inflammatory and neuropathic pain considering different animal models and knock-out animals. In the future, the numerous ongoing studies will certainly reveal other multifunctional roles of these proteins in humans. These roles might be exploited clinically by the development of drugs to alter AQP expression or function that could serve in the treatment of different diseases associated to peripheral and central nervous system.

Biochemical and pharmacological assessment of MAP-kinase signaling along pain pathways in experimental rodent models: a potential tool for the discovery of novel antinociceptive therapeutics

Solder joints provide mechanical support, electrical and thermal interconnection between packaging levels in microelectronics assembly systems. Proper functioning of these interconnections and the reliability of the electronic packages depend largely on the mechanical properties of the solder joints. Lead free solders provide excellent thermomechanical properties and commonly used as interconnections in electronic packages. However, environmental conditions, such as, operating temperature, aging temperature, and aging time significantly affect these properties due to the microstructural evolution of the solder that occurs during aging. The most well-known and widely observed changes are coarsening of the Ag <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</sub> Sn and Cu <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">6</sub> Sn <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">5</sub> intermetallic compounds (IMCs)present in the eutectic regions between beta-Sn dendrites. In this work, we have investigated the variations in mechanical behavior of several SAC and SAC+X lead free solder alloys including SAC305 (96.5Sn-3.0Ag-0.5Cu)and SAC_Q subjected to high temperature aging. Specimens have been preconditioned at several extreme temperature aging conditions including T = 125 and 200°C. At each extreme temperature condition, several durations of aging were considered including 0, 1, 5 and 20 days. With each set of aging conditions, stress-strain tests were performed on the aged specimens. The evolution of the stress-strain behavior with aging temperature and time was determined. In addition, microstructural evolution of solder alloys during extreme high temperature aging has been explored, and aging induced coarsening of IMCs has been explored using Scanning Electron Microscopy (SEM)to validate our experimental results. Our experimental results show substantial degradations of the mechanical properties including initial modulus, yield stress, and ultimate tensile strength of lead-free solders with extreme temperature aging. The results suggested that there are large challenges to obtaining solder joint reliability when the joints are exposed to long-term high temperature aging. The addition of dopants (e.g. Bi)in the traditional SAC alloys significantly mitigated the high temperature aging induced degradations in both the microstructure and mechanical properties.

A scare in the OR highlights value of systems engineering.

Metabolic adaptations to complex perturbations, like the response to pharmacological treatments in multifactorial diseases such as cancer, can be described through measurements of part of the fluxes and concentrations at the systemic level and individual transporter and enzyme activities at the molecular level. In the framework of Metabolic Control Analysis (MCA), ensembles of linear constraints can be built integrating these measurements at both systemic and molecular levels, which are expressed as relative differences or changes produced in the metabolic adaptation. Here, combining MCA with Linear Programming, an efficient computational strategy is developed to infer additional non-measured changes at the molecular level that are required to satisfy these constraints. An application of this strategy is illustrated by using a set of fluxes, concentrations, and differentially expressed genes that characterize the response to cyclin-dependent kinases 4 and 6 inhibition in colon cancer cells. Decreases and increases in transporter and enzyme individual activities required to reprogram the measured changes in fluxes and concentrations are compared with down-regulated and up-regulated metabolic genes to unveil those that are key molecular drivers of the metabolic response.

Metabolic adaptations to complex perturbations, like the response to pharmacological treatments in multifactorial diseases such as cancer, can be described through measurements of part of the fluxes and concentrations at the systemic level and individual transporter and enzyme activities at the molecular level. In the framework of Metabolic Control Analysis (MCA), ensembles of linear constraints can be built integrating these measurements at both systemic and molecular levels, which are expressed as relative differences or changes produced in the metabolic adaptation. Here, combining MCA with Linear Programming, an efficient computational strategy is developed to infer additional non-measured changes at the molecular level that are required to satisfy these constraints. An application of this strategy is illustrated by using a set of fluxes, concentrations, and differentially expressed genes that characterize the response to cyclin-dependent kinases 4 and 6 inhibition in colon cancer cells. Decreases and increases in transporter and enzyme individual activities required to reprogram the measured changes in fluxes and concentrations are compared with down-regulated and up-regulated metabolic genes to unveil those that are key molecular drivers of the metabolic response.

Chronos Technology (Div. of FMI, Inc.) is presently involved in an SBIR phase II effort to produce and deliver a comprehensive, practical and commercially available solution for a novel extreme temperature (both cold & hot), and radiation tolerant, compact radio frequency clock source (RTXO). Offering compelling features such as surface mounting, scalable configuration and miniature footprint, this innovative technology directly targets a wide range of requirements. RTXO satisfies the critical requirements of NASA space programs such as Mars science laboratory (MSL), MER and future missions to Moon at both system and subsystem level with operating temperatures in the -180/spl deg/C to +120/spl deg/C. It also addresses the requirements of the extreme high temperature RTXO that could be utilized for the missions to Venus and other extreme environment space systems with highest operating temperature range to 460/spl deg/C. Furthermore, the RTXO enables and improves wide range of scientific, military & commercial space systems with its miniaturized footprint and rugged construction. As for non space systems, it delivers a higher level of performance at smaller size to critical down-hole, nuclear process monitoring and very demanding geothermal applications. We do expect that our solution will immediately and profoundly impact plans for the present and future space missions and other extreme environment applications. RTXO brings new paradigm to resolve space systems design risk in terms of higher reliability and performance at significantly reduced size, weight and manufacturing time which all point to lower cost. This effort will yield innovations ranging from unique extreme temperature and high-Q resonator material, a unique matching integrated resonator driver amplifier/buffer based on silicon carbide (SiC) and the smallest surface mount high reliability, space level, radiation tolerant clock source.

CONTEXT: Digital therapeutics are growing as a solution to improve access and quality of care. Increasing evidence has shown the efficacy of digital therapeutics in managing pain for patients, but they are underutilized by primary care providers who see over half of the patients with chronic pain. Engaging providers to develop and use digital therapeutics with patients in chronic pain management has become necessary. OBJECTIVE: This study explored primary care providers’ challenges and strategies in chronic pain management to identify needs and practice gaps that inform development of digital therapeutics for chronic pain. STUDY DESIGN: Qualitative study, using a human-centered design approach. SETTING: Eleven providers from four primary care clinics in Washington and Colorado participated in semi-structured interviews between July and October 2021. POPULATION STUDIED: The sample (N=11) included seven primary care physicians, two behavioral health providers, one physician assistant and one nurse. Most providers worked in clinics affiliated with urban, academic health systems or in federally qualified health centers. OUTCOMES: Interviews focused on provider goals in chronic pain management, challenges and strategies used, and perceptions of digital therapeutics. RESULTS: Four themes related to provider needs emerged: patient-provider alliance, team-based care, tracking and monitoring, and social determinants of health. Providers desired resources to streamline pain education, counseling, and goal setting with patients. Greater accessibility to multidisciplinary care team consultations and non-pharmacological pain treatments would be beneficial to providers and patients. Infrastructure and systems are needed for providers to systematically track and monitor patients’ pain. Providers requested assistance with connecting underserved patients to wraparound social services and addressing healthcare access barriers. CONCLUSION: Digital therapeutics for chronic pain would benefit from incorporating multimodal features that strengthen patient-provider alliance, increase access to non-pharmacological treatment options, support population health tracking and management, and provide equitable solutions that require lower sophistication of device and Internet access. Leveraging digital therapeutics in healthcare settings requires meeting provider needs at individual care and system levels.

Primary afferent induced slow potentials in the spinal cord — Role of the NMDA receptor

The voltage dependent sodium channel Nav1.9, is expressed preferentially in peripheral sensory neurons and has been linked to human genetic pain disorders, which makes it target of interest for the development of new pain therapeutics. However, characterization of Nav1.9 pharmacology has been limited due in part to the historical difficulty of functionally expressing recombinant channels. Here we report the successful generation and characterization of human, mouse and rat Nav1.9 stably expressed in human HEK-293 cells. These cells exhibit slowly activating and inactivating inward sodium channel currents that have characteristics of native Nav1.9. Optimal functional expression was achieved by coexpression of Nav1.9 with β1/β2 subunits. While recombinantly expressed Nav1.9 was found to be sensitive to sodium channel inhibitors TC-N 1752 and tetracaine, potency was up to 100-fold less than reported for other Nav channel subtypes despite evidence to support an interaction with the canonical local anesthetic (LA) binding region on Domain 4 S6. Nav1.9 Domain 2 S6 pore domain contains a unique lysine residue (K799) which is predicted to be spatially near the local anesthetic interaction site. Mutation of this residue to the consensus asparagine (K799N) resulted in an increase in potency for tetracaine, but a decrease for TC-N 1752, suggesting that this residue can influence interaction of inhibitors with the Nav1.9 pore. In summary, we have shown that stable functional expression of Nav1.9 in the widely used HEK-293 cells is possible, which opens up opportunities to better understand channel properties and may potentially aid identification of novel Nav1.9 based pharmacotherapies.

From honeybee foraging to bird migration, the orientation of animals in their environments is vital for survival and provides opportunities for studying the neural mechanisms that underlie the perception and processing of sensory information. Temperature is a ubiquitous environmental variable that

Special issue editorial: Glial plasticity in health and disease.