Using a Patient Portal to Screen Patients for Symptoms After Starting New Medications.

OBJECTIVE: Conduct systematic proactive pharmacovigilance screening for symptoms patients experienced after starting new medications using an electronic patient portal. We aimed to design and test the feasibility of the system, measure patient response rates, provide any needed support for patients experiencing potentially drug-related problems, and describe types of symptoms and problems patients report. METHODS: We created an automated daily report of all new prescriptions, excluding likely non-new and various over-the-counter meds, and sent invitations via patient portal inviting patients to inquire if they had started the medication, and if "yes," inquire if they had they experienced any new symptoms that could be potential adverse drug effects. Reported symptoms were classified by clinical pharmacists using SOC MeDra taxonomy, and patients were offered follow-up and support as desired and needed. RESULTS: Of 11,724 included prescriptions for 9360 unique patients, 2758 (29.4%) patients responded. Of 2616 unique medication starts, patients reported at least 1 new symptom that represented a potential adverse drug reaction (ADR) in 678/2616 (25.9%). Nearly one-third of those experiencing new symptoms (30.3%) reported 2 or more new symptoms after initiating the drug. GI disorders accounted for 30% of the total reported ADRs. CONCLUSIONS: Systematic portal-based surveillance for potential adverse drug reactions was feasible, had higher response rates than other methods (such as automated interactive phone calling), and uncovered rates of potential ADRs (roughly 1 in 4 patients) consistent with other methods/studies.

Influence of Ingestion of Bicarbonate-Rich Water Combined with an Alkalizing or Acidizing Diet on Acid-Base Balance and Anaerobic Performance.

During high-intensity (HI) exercise, metabolic acidosis significantly impairs exercise performance. Increasing the body's buffering capacity through training and exogenous intake of alkalizing supplements may improve high-intensity performance. Manipulating water and diet intake may influence the acid-base balance. The aim of this study was to determine the effects of mineral water rich in bicarbonate ions (STY) or placebo water (PLA) on circulating biomarkers and anaerobic performance and to verify whether alkalizing (ALK) or acidizing (ACI) diet would modulate these effects. Twenty-four athletes, assigned either to ALK (n = 12) or ACI (n = 12) diet for four weeks, completed a 1-min rowing Wingate Test in a double-blind and randomized trial after one week of daily hydration (1.5 to 2L/d) with either STY or PLA. Blood samples were taken before and after each test, and urine samples were collected each week. Chronic consumption of bicarbonate-rich water significantly impacted resting urinary pH irrespective of alkalizing or acidizing dietary intake. STY induced a significant increase in blood pH, lactate, and HCO3 - ion concentration post-exercise compared to PLA. Similar changes were observed when STY was associated with the ALK diet. In contrast, STY combined with the ACI diet only significantly affected urine pH and peak blood lactate compared to PLA (p < 0.05). No effect of bicarbonate-rich water was reported on anaerobic performance (p > 0.05). Our results suggest that consumption of bicarbonate-rich water alters acid-base balance during a warm-up and after HI exercise, could potentiate beneficial effects of an alkalizing diet on the acid-base balance after HI exercise, and reduces the acid load induced by an acidifying diet.

The Effects of Different Dietary Patterns on Bone Health.

Bone metabolism is a process in which osteoclasts continuously clear old bone and osteoblasts form osteoid and mineralization within basic multicellular units, which are in a dynamic balance. The process of bone metabolism is affected by many factors, including diet. Reasonable dietary patterns play a vital role in the prevention and treatment of bone-related diseases. In recent years, dietary patterns have changed dramatically. With the continuous improvement in the quality of life, high amounts of sugar, fat and protein have become a part of people's daily diets. However, people have gradually realized the importance of a healthy diet, intermittent fasting, calorie restriction, a vegetarian diet, and moderate exercise. Although these dietary patterns have traditionally been considered healthy, their true impact on bone health are still unclear. Studies have found that caloric restriction and a vegetarian diet can reduce bone mass, the negative impact of a high-sugar and high-fat dietary (HSFD) pattern on bone health is far greater than the positive impact of the mechanical load, and the relationship between a high-protein diet (HPD) and bone health remains controversial. Calcium, vitamin D, and dairy products play an important role in preventing bone loss. In this article, we further explore the relationship between different dietary patterns and bone health, and provide a reference for how to choose the appropriate dietary pattern in the future and for how to prevent bone loss caused by long-term poor dietary patterns in children, adolescents, and the elderly. In addition, this review provides dietary references for the clinical treatment of bone-related diseases and suggests that health policy makers should consider dietary measures to prevent and treat bone loss.

Perceived controllability of group membership does not moderate individuating information effects in implicit person perception.

Although the effects of counterstereotypic individuating information (i.e., information specific to individual members of stereotyped groups that disconfirms the group stereotype) on biases in explicit person perception are well-established, research shows mixed effects of such information on implicit person perception. The present research tested the overarching hypothesis that, when social group membership is perceived to be under an individual's control, diagnostic individuating information would have lesser effects on implicit person perception than it would when social group membership is perceived not to be under an individual's control. This hypothesis was tested in the domain of implicit attitudinal and stereotype-relevant judgments of individuals who belonged to existing social groups and individuals who belonged to novel social groups. We found that individuating information consistently shifted scores on implicit measures among targets belonging to existing social groups, but not in a theoretically predicted direction among targets belonging to novel social groups. Controllability of group membership did not moderate such effects. Results of implicit and explicit measures were mostly consistent when targets belonged to existing social groups, but mostly inconsistent when targets belonged to novel social groups.

Implications of Heat Stress-induced Metabolic Alterations for Endurance Training.

Inducing a heat-acclimated phenotype via repeated heat stress improves exercise capacity and reduces athletes̓ risk of hyperthermia and heat illness. Given the increased number of international sporting events hosted in countries with warmer climates, heat acclimation strategies are increasingly popular among endurance athletes to optimize performance in hot environments. At the tissue level, completing endurance exercise under heat stress may augment endurance training adaptation, including mitochondrial and cardiovascular remodeling due to increased perturbations to cellular homeostasis as a consequence of metabolic and cardiovascular load, and this may improve endurance training adaptation and subsequent performance. This review provides an up-to-date overview of the metabolic impact of heat stress during endurance exercise, including proposed underlying mechanisms of altered substrate utilization. Against this metabolic backdrop, the current literature highlighting the role of heat stress in augmenting training adaptation and subsequent endurance performance will be presented with practical implications and opportunities for future research.

Mechanical strain regulates osteogenesis via Antxr1/LncRNA H19/Wnt/ß-catenin axis.

Alleviating bone loss is an essential way to prevent osteoporotic fractures. Proper exercise improves bone density without the side effects of long-term medications, but the mechanism is unclear. Our study explored the role of Antxr1/LncRNA H19/Wnt/ß-catenin axis in the process of exercise-mediated alleviation of bone loss. Here we discovered that moderate-intensity treadmill exercise alleviates bone loss caused by ovariectomy and ameliorates bone strength accompanied by an increased lncRNA H19 expression. Concomitantly, Antxr1, a mechanosensitive protein was found downregulated by exercise but upregulated by ovariectomy. Interestingly, knockdown expression of Antxr1 increased lncRNA H19 expression and Wnt/ß-catenin signaling pathway in bone marrow mesenchymal stem cells, whereas overexpression of Antxr1 decreased lncRNA H19 expression and Wnt/ß-catenin signaling pathway. Hence, our study demonstrates the regulation of Antxr1/LncRNA H19/Wnt/ß-catenin axis in the process of mechanical strain-induced osteogenic differentiation, which provides further mechanistic insight into the role of mechanical regulation in bone metabolism.

An exercise physiologist's guide to metabolomics.

The field of exercise physiology has undergone significant technological advancements since the pioneering works of exercise physiologists in the early to mid-20th century. Historically, the ability to detect metabolites in biofluids from exercising participants was limited to single-metabolite analyses. However, the rise of metabolomics, a discipline focused on the comprehensive analysis of metabolites within a biological system, has facilitated a more intricate understanding of metabolic pathways and networks in exercise. This review explores some of the pivotal technological and bioinformatic advancements that have propelled metabolomics to the forefront of exercise physiology research. Metabolomics offers a unique 'fingerprint' of cellular activity, offering a broader spectrum than traditional single-metabolite assays. Techniques, including mass spectrometry and nuclear magnetic resonance spectroscopy, have significantly improved the speed and sensitivity of metabolite analysis. Nonetheless, challenges persist, including study design and data interpretation issues. This review aims to serve as a guide for exercise physiologists to facilitate better research design, data analysis and interpretation within metabolomics. The potential of metabolomics in bridging the gap between genotype and phenotype is emphasised, underscoring the critical importance of careful study design and the selection of appropriate metabolomics techniques. Furthermore, the paper highlights the need to deeply understand the broader scientific context to discern meaningful metabolic changes. The emerging field of fluxomics, which seeks to quantify metabolic reaction rates, is also introduced as a promising avenue for future research.

Acquired Angioedema Associated with Lymphoproliferative Disorders.

Introduction: Acquired angioedema due to C1 esterase inhibitor deficiency (C1INH-AAE) is most associated with lymphoproliferative disorders (LPDs), particularly low-grade B-cell subtypes. The condition remains under-recognized with long diagnostic delays due to various challenges including a lack of awareness of the condition. Case Presentation: We discuss 4 cases of C1INH-AAE associated with low-grade B-cell LPDs, including various diagnostic and management challenges. As our cases illustrate, constitutional symptoms or overt manifestations of LPD at diagnosis are often absent. Hence, a comprehensive multimodal approach to screening for an underlying B-LPD is important when a diagnosis of acquired angioedema is made. Levels of complement C4, C1q, and C1INH are useful for diagnosing C1INH-AAE and for monitoring disease activity. Changes in these parameters may also indicate relapse of the underlying hematological malignancy. Treating the underlying disorder is important as this commonly leads to clinical improvement with decreased episodes of angioedema and normalization of complement studies. Conclusion: Awareness of C1INH-AAE can lead to an early diagnosis of hematological malignancies. The absence of constitutional symptoms emphasizes the need for a comprehensive multimodal approach to screening for LPD in C1INH-AAE. C4, C1INH level, and function are useful for monitoring disease activity.

Dragon blood resin ameliorates steroid-induced osteonecrosis of femoral head through osteoclastic pathways.

Objective: Dragon's Blood resin (DBR) is a traditional medicinal substance renowned for its diverse pharmacological effects, which consists of potent anti-inflammatory, antioxidant and angiogenic properties. This study aimed to elucidate its therapeutic mechanism in alleviating steroid-induced osteonecrosis of the femoral head (SIONFH). Methods: Techniques such as SPR and LC-MS were employed to identify and analyze the target proteins of DBR in bone marrow macrophages (BMMs). In vitro, BMMs were treated with RANKL and DBR, and TRAcP staining and actin belt staining were utilized to assess osteoclast activity. The inhibitory effects and underlying mechanisms of DBR on osteoclastogenesis and reactive oxygen species (ROS) generation were determined using real-time PCR, western blotting and immunofluorescence staining. An in vivo SIONFH rat model was set up to assess the curative impacts of DBR using micro-CT scanning and pathological staining. Results: Bioinformatic tools revealed a pivotal role of osteoclast differentiation in SIONFH. Proteomic analysis identified 164 proteins binding in BMMs. In vitro assessments demonstrated that DBR hindered osteoclastogenesis by modulating the expression of specific genes and proteins, along with antioxidant proteins including TRX1 and Glutathione Reductase. Notably, the resin effectively inhibited the expression of crucial proteins, such as the phosphorylation of JNK and the nuclear localization of p65 within the TRAF6/JNK and NFκB signaling pathways. In vivo experiments further confirmed that DBR mitigated the onset of SIONFH in rats by curbing osteoclast and ROS activities. Conclusion: These findings underscore the potential of Dragon's Blood as an effective administration for early-stage SIONFH, shedding light on its therapeutic influence on ROS-mediated osteoclastic signaling pathways.

Metabolic elasticity: A new measure of age.

Promoting healthy aging is contingent on understanding the underlying mechanisms for the age-associated decline in metabolic physiology. Through developing a novel concept of "metabolic elasticity" to evaluate metabolic adaptability in response to cyclical changes in energy balance, Zhou et al. present an impactful gauge of metabolic health that is particularly relevant to aging.

Environmental heat stress offsets adaptation associated with carbohydrate periodization in trained male triathletes.

PURPOSE: Carbohydrate (CHO) intake periodization via the sleep low train low (SL-TL) diet-exercise model increases fat oxidation during exercise and may enhance endurance-training adaptation and performance. Conversely, training under environmental heat stress increases CHO oxidation, but the potential of combined SL-TL and heat stress to enhance metabolic and performance outcomes is unknown. METHODS: Twenty-three endurance-trained males were randomly assigned to either control (n = 7, CON), SL-TL (n = 8, SLTemp ) or SL-TL + heat stress (n = 8, SLHeat ) groups and prescribed identical 2-week cycling training interventions. CON and SLTemp completed all sessions at 20°C, but SLHeat at 35°C. All groups consumed matched CHO intake (6 g·kg-1 ·day-1 ) but timed differently to promote low CHO availability overnight and during morning exercise in both SL groups. Submaximal substrate utilization was assessed (at 20°C), and 30-min performance tests (at 20 and 35°C) were performed Pre-, Post-, and 1-week post-intervention (Post+1). RESULTS: SLTemp improved fat oxidation rates at 60% MAP (~66% VO2peak ) at Post+1 compared with CON (p < 0.01). Compared with SLTemp , fat oxidation rates were significantly lower in SLHeat at Post (p = 0.02) and Post+1 (p < 0.05). Compared with CON, performance was improved at Post in SLTemp in temperate conditions. Performance was not different between any groups or time points in hot conditions. CONCLUSION: SL-TL enhanced metabolic adaptation and performance compared with CON and combined SL-TL and heat stress. Additional environmental heat stress may impair positive adaptations associated with SL-TL.

The therapeutic effect and mechanism of parthenolide in skeletal disease, cancers, and cytokine storm.

Parthenolide (PTL or PAR) was first isolated from Magnolia grandiflora and identified as a small molecule cancer inhibitor. PTL has the chemical structure of C15H20O3 with characteristics of sesquiterpene lactones and exhibits the biological property of inhibiting DNA biosynthesis of cancer cells. In this review, we summarise the recent research progress of medicinal PTL, including the therapeutic effects on skeletal diseases, cancers, and inflammation-induced cytokine storm. Mechanistic investigations reveal that PTL predominantly inhibits NF-κB activation and other signalling pathways, such as reactive oxygen species. As an inhibitor of NF-κB, PTL appears to inhibit several cytokines, including RANKL, TNF-α, IL-1ß, together with LPS induced activation of NF-κB and NF-κB -mediated specific gene expression such as IL-1ß, TNF-α, COX-2, iNOS, IL-8, MCP-1, RANTES, ICAM-1, VCAM-1. It is also proposed that PTL could inhibit cytokine storms or hypercytokinemia triggered by COVID-19 via blocking the activation of NF-κB signalling. Understanding the pharmacologic properties of PTL will assist us in developing its therapeutic application for medical conditions, including arthritis, osteolysis, periodontal disease, cancers, and COVID-19-related disease.

Enhancing the metabolic benefits of exercise: Is timing the key?

Physical activity represents a potent, non-pharmacological intervention delaying the onset of over 40 chronic metabolic and cardiovascular diseases, including type 2 diabetes, coronary heart disease, and reducing all-cause mortality. Acute exercise improves glucose homeostasis, with regular participation in physical activity promoting long-term improvements in insulin sensitivity spanning healthy and disease population groups. At the skeletal muscle level, exercise promotes significant cellular reprogramming of metabolic pathways through the activation of mechano- and metabolic sensors, which coordinate downstream activation of transcription factors, augmenting target gene transcription associated with substrate metabolism and mitochondrial biogenesis. It is well established that frequency, intensity, duration, and modality of exercise play a critical role in the type and magnitude of adaptation; albeit, exercise is increasingly considered a vital lifestyle factor with a critical role in the entrainment of the biological clock. Recent research efforts revealed the time-of-day-dependent impact of exercise on metabolism, adaptation, performance, and subsequent health outcomes. The synchrony between external environmental and behavioural cues with internal molecular circadian clock activity is a crucial regulator of circadian homeostasis in physiology and metabolism, defining distinct metabolic and physiological responses to exercise unique to the time of day. Optimising exercise outcomes following when to exercise would be essential to establishing personalised exercise medicine depending on exercise objectives linked to disease states. We aim to provide an overview of the bimodal impact of exercise timing, i.e. the role of exercise as a time-giver (zeitgeber) to improve circadian clock alignment and the underpinning clock control of metabolism and the temporal impact of exercise timing on the metabolic and functional outcomes associated with exercise. We will propose research opportunities that may further our understanding of the metabolic rewiring induced by specific exercise timing.

Cerebrovascular Manifestations of SARS-CoV-2: A Comprehensive Review.

Purpose of review: The risks of cerebrovascular manifestations due to SARS-CoV-2 infection are significantly increased within the first 6 months of the infection. Our work aims to give an update on current clinical aspects of diagnosis and treatment of cerebrovascular manifestations during acute and long-term SARS-CoV-2 infection. Recent findings: The incidence of acute ischemic stroke and haemorrhagic stroke during acute SARS-CoV-2 patients is estimated at 0.9 to 4.6% and 0.5-0.9%, respectively, and were associated with increased mortality. The majority presented with hemiparesis, dysarthria, sensory deficits, and a NIHSS score within 5-15. In addition, beyond the first 30 days of infection people with COVID-19 exhibited increased risk of stroke. During acute phase, age, hypertension, diabetes, and medical history of vascular disease were increased in patients with COVID-19 with new onset of cerebrovascular manifestations, while during long-COVID-19, the risk of cerebrovascular manifestations were found increased regardless of these factors. The management of patients with large-vessel ischemic stroke fulfilling the intravenous thrombolysis criteria are successfully treated according to the guidelines, while hyperosmolar therapy is typically administered in 4- to 6-h intervals. In addition, prophylaxis of anticoagulation therapy is associated with a better prognosis and low mortality during acute and post hospital discharge of patients with COVID-19. Summary: In this work, we provide a comprehensive review of the current literature on acute and post-acute COVID-19 cerebrovascular sequelae, symptomatology, and its pathophysiology mechanisms. Moreover, we discuss therapeutic strategies for these patients during acute and long-term care and point populations at risk. Our findings suggest that older patients with risk factors such as hypertension, diabetes, and medical history of vascular disease are more likely to develop cerebrovascular complications.

Acute heat stress amplifies exercise-induced metabolomic perturbations and reveals variation in circulating amino acids in endurance-trained males.

NEW FINDINGS: What is the central question of this study? Whole-body substrate utilisation is altered during exercise in hot environments, characterised by increased glycolytic metabolism: does heat stress alter the serum metabolome in response to high intensity exercise? What are the main finding and its importance? Alongside increases in glycolytic metabolite abundance, circulating amino acid concentrations are reduced following exercise under heat stress. Prior research has overlooked the impact of heat stress on protein metabolism during exercise, raising important practical implications for protein intake recommendations in the heat. ABSTRACT: Using untargeted metabolomics, we aimed to characterise the systemic impact of environmental heat stress during exercise. Twenty-three trained male triathletes ( V ̇ O 2 peak ${\dot V_{{{\rm{O}}_2}{\rm{peak}}}}$  = 64.8 ± 9.2 ml kg min-1 ) completed a 30-min exercise test in hot (35°C) and temperate (21°C) conditions. Venous blood samples were collected immediately pre- and post-exercise, and the serum fraction was assessed via untargeted 1 H-NMR metabolomics. Data were analysed via uni- and multivariate analyses to identify differences between conditions. Mean power output was higher in temperate (231 ± 36 W) versus hot (223 ± 31 W) conditions (P < 0.001). Mean heart rate (temperate, 162 ± 10 beats min-1 , hot, 167 ± 9 beats min-1 , P < 0.001), peak core temperature (Trec ), core temperature change (ΔTrec ) (P < 0.001) and peak rating of perceived exertion (P = 0.005) were higher in hot versus temperate conditions. Change in metabolite abundance following exercise revealed distinct clustering following multivariate analysis. Six metabolites increased (2-hydroxyvaleric acid, acetate, alanine, glucarate, glucose, lactate) in hot relative to temperate (P < 0.05) conditions. Leucine and lysine decreased in both conditions but to a greater extent in temperate conditions (P < 0.05). Citrate (P = 0.04) was greater in temperate conditions whilst creatinine decreased in hot conditions only (P > 0.05). Environmental heat stress increased glycolytic metabolite abundance and led to distinct alterations in the circulating amino acid availability, including increased alanine, glutamine, leucine and isoleucine. The data highlight the need for additional exercise nutrition and metabolism research, specifically focusing on protein requirements for exercise under heat stress.

Effects of follicle-stimulating hormone on fat metabolism and cognitive impairment in women during menopause.

Lipid metabolism disorder is a common pathological manifestation of menopausal women, and is also an important risk factor for many diseases at this stage of life. Epidemiological studies have shown that high levels of follicle-stimulating hormone (FSH) in menopausal women are closely associated with changes in body composition, central obesity, and cognitive decline. Exogenous FSH causes growth and proliferation of adipose, whereas blockage of the FSH signaling pathway leads to decline in adipose. Mechanistically, FSH, FSH receptor (FSHR), G protein coupling, gene mutation and other pathways are involved in adipogenesis and cognitive impairment. Here, we review the critical role and potential interactions of FSH in adipogenesis and cognitive impairment in menopausal women. Further understanding of the exact mechanisms of FSH aggravating obesity and cognitive impairment may provide a new perspective for promoting healthy aging in menopausal women.

Galanin family peptides: Molecular structure, expression and roles in the neuroendocrine axis and in the spinal cord.

Galanin is a neurohormone as well as a neurotransmitter and plays versatile physiological roles for the neuroendocrine axis, such as regulating food intake, insulin level and somatostatin release. It is expressed in the central nervous system, including hypothalamus, pituitary, and the spinal cord, and colocalises with other neuronal peptides within neurons. Structural analyses reveal that the human galanin precursor is 104 amino acid (aa) residues in length, consisting of a mature galanin peptide (aa 33-62), and galanin message-associated peptide (GMAP; aa 63-104) at the C-terminus. GMAP appears to exhibit distinctive biological effects on anti-fungal activity and the spinal flexor reflex. Galanin-like peptide (GALP) has a similar structure to galanin and acts as a hypothalamic neuropeptide to mediate metabolism and reproduction, food intake, and body weight. Alarin, a differentially spliced variant of GALP, is specifically involved in vasoactive effect in the skin and ganglionic differentiation in neuroblastic tumors. Dysregulation of galanin, GALP and alarin has been implicated in various neuroendocrine conditions such as nociception, Alzheimer's disease, seizures, eating disorders, alcoholism, diabetes, and spinal cord conditions. Further delineation of the common and distinctive effects and mechanisms of various types of galanin family proteins could facilitate the design of therapeutic approaches for neuroendocrine diseases and spinal cord injury.

Assessment of cerebrospinal fluid analysis and short-term survival outcomes in South American camelids: A retrospective study of 54 cases (2005-2021).

BACKGROUND: Cerebrospinal fluid (CSF) is commonly analyzed in South American camelids with suspected neurologic disease because of ease of collection and characteristic findings associated with certain diseases. OBJECTIVES: To assess CSF findings associated with short-term survival or non-survival in South American camelids in which neurologic disease was a differential diagnosis based on history and physical examination. ANIMALS: Twenty-one llamas and 33 alpacas that underwent CSF analysis at the University of Missouri Veterinary Health Center. METHODS: Retrospective study. Medical records of camelids that underwent CSF analysis between January 2005 and September 2021 were studied. Short-term survival was defined as survival to discharge from the Veterinary Health Center. A Fisher's exact test was used to compare species, CSF results, and survival. RESULTS: Odds of survival were 3.9 times higher in camelids with a total nucleated cell count (TNCC) <3 cells/µL (P = .04). No significant association was found between survival and total protein concentration (TPC; P = .15) or percentage of eosinophils (P = 1.0). No significant correlation was found between species and increased TNCC (P = .63), TPC (P = .55), or percentage of eosinophils (P = .30). Among camelids diagnosed with Paralephostrongylus tenuis infestation, odds of survival were 4.95 times higher in alpacas (P = .05). CONCLUSIONS: Cerebrospinal fluid TNCC ≥3 cells/µL is associated with decreased odds of short-term survival in South American camelids.

The versatile roles of odontogenic ameloblast-associated protein in odontogenesis, junctional epithelium regeneration and periodontal disease.

Junctional epithelium (JE) is a vital epithelial component which forms an attachment to the tooth surface at the gingival sulcus by the adhesion of protein complexes from its basal layer. Disruption of the JE is associated with the development of gingivitis, periodontal disease, and alveolar bone loss. Odontogenic ameloblast-associated (ODAM) is comprised of a signal peptide and an ODAM protein with 12 putative glycosylation sites. It is expressed during odontogenesis by maturation stage ameloblasts and is incorporated into the enamel matrix during the formation of outer and surface layer enamel. ODAM, as a secreted protein which is accumulated at the interface between basal lamina and enamel, mediates the adhesion of the JE to the tooth surface; and is involved with extracellular signalling of WNT and ARHGEF5-RhoA, as well as intracellular signalling of BMP-2-BMPR-IB-ODAM. ODAM is also found to be highly expressed in salivary glands and appears to have implications for the regulation of formation, repair, and regeneration of the JE. Bioinformatics and research data have identified the anti-cancer properties of ODAM, indicating its potential both as a prognostic biomarker and therapeutic target. Understanding the biology of ODAM will help to design therapeutic strategies for periodontal and dental disorders.

AAA + ATPase Thorase inhibits mTOR signaling through the disassembly of the mTOR complex 1.

The mechanistic target of rapamycin (mTOR) signals through the mTOR complex 1 (mTORC1) and the mTOR complex 2 to maintain cellular and organismal homeostasis. Failure to finely tune mTOR activity results in metabolic dysregulation and disease. While there is substantial understanding of the molecular events leading mTORC1 activation at the lysosome, remarkably little is known about what terminates mTORC1 signaling. Here, we show that the AAA + ATPase Thorase directly binds mTOR, thereby orchestrating the disassembly and inactivation of mTORC1. Thorase disrupts the association of mTOR to Raptor at the mitochondria-lysosome interface and this action is sensitive to amino acids. Lack of Thorase causes accumulation of mTOR-Raptor complexes and altered mTORC1 disassembly/re-assembly dynamics upon changes in amino acid availability. The resulting excessive mTORC1 can be counteracted with rapamycin in vitro and in vivo. Collectively, we reveal Thorase as a key component of the mTOR pathway that disassembles and thus inhibits mTORC1.