Storage Pool Research Articles

Verification and Validation of Transient Body Force in GOTHIC for Spent Fuel Pool Response to Seismic Events and Other Applications

Post Fukushima the U.S. Nuclear Regulatory Commission issued an Order on Spent Fuel Instrumentation (EA-12-051) requiring all U.S. nuclear plants to install spent fuel pool (SFP) water level monitoring instrumentation and ensure the instrument would remain functional following a safe shutdown earthquake (SSE). The structural integrity analysis requires an assessment of the hydrodynamic loads and wave impact forces that the instrument is subjected to during an SSE. Modeling and simulation of the SFP response to an SSE can provide this type of information if the simulation tool is able to capture the important physical phenomena, such as seismic acceleration, surface wave formation, fluid velocities, and multidimensional effects. This paper describes the capabilities of GOTHICTM that can be used to simulate the sloshing surface waves and subsurface fluid motion of an SFP in response to an earthquake. GOTHIC is a versatile, general-purpose, thermal-hydraulic software package for multiphase flow that is a hybrid between traditional system thermal-hydraulic and computational fluid dynamics codes. It includes a transient, variable body force capability to simulate multi-axis acceleration, and is therefore applicable to seismic events; movement experienced on ships, airplanes, or spacecraft; and other events with system acceleration. Also, since the gravitational constant can be adjusted, GOTHIC can model systems placed outside the Earth’s atmosphere (e.g., spacecraft, space station, the Moon, or other extraterrestrial bodies). The variable body force capability makes GOTHIC well suited to model the hydrodynamic response of an SFP to a seismic event. This paper describes the governing equations that are solved by GOTHIC as they pertain to accelerating systems. A series of benchmarks covering a range of experiments for surface wave dynamics, acceleration-induced motion, and other important phenomena are presented to demonstrate the verification and validation of GOTHIC for these types of applications. Finally, results from a sample application of GOTHIC for SFP hydrodynamic response are presented that provide the necessary inputs for a structural integrity analysis.

An Analysis of Potentially Implementing Standardized Canisters in the U.S. Commercial Waste Management System

This analytical study focuses on loading standardized transportation, aging, and disposal canisters (STADs) at commercial reactor sites and subsequent transportation, e.g., to a consolidated interim storage facility (CISF). Specifically, the amount of spent nuclear fuel (SNF) available to load into STADs with varying deployment dates is explored, and the scenarios are compared with a scenario in which STADs are never loaded at reactor sites. Two key findings are that about half of the U.S. inventory of commercial SNF could be captured in STADs if they were fully deployed by 2035 and that the percentage of SNF available to load into STADs decreases as STAD deployment is delayed. In additional scenarios, the effects of shipping STADs directly from at-reactor spent fuel pools (SFPs) to a CISF are analyzed for a STAD full deployment year of 2035. A key finding from the analysis is that the dry storage of SNF in STADs at reactor sites can be minimized by direct shipment to a CISF from reactor site SFPs. However, minimizing dry storage at reactor sites means maximizing the receipt rate for STADs at a CISF, and there is likely a more optimal point between the two scenarios for an overall cost-effective operation of waste management systems.

Specifities of the storage pool and morphology of platelets in children with unspecified hemorrhagic syndrome

Despite modern possibilities of laboratory diagnosis of hemorrhagic syndrome, in some patients, the causes of bleeding remain unspecified. Among these reasons, mild defects in the platelet link of hemostasis can potentially be hidden. The aim of the work is to identify the features of the function of the platelet hemostasis in children with unspecified hemorrhagic syndrome. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. We examined 50 patients aged 2 to 17 years with various manifestations of bleeding and lack of laboratory data proving coagulopathy and/or thrombocytopenia; platelet cytofluorometry with activation was performed. The morphological characteristics of platelets in terms of size/granularity (FSC/SSC), the density of the CD62p receptor as a marker of a-granule secretion, and d-granules of platelets were assessed by the fluorescence of loaded mepacrine. Platelet activation was performed with a CRP + TRAP mixture. Comparison was carried out with the results of examination of 50 healthy children (control group - CG) aged 2 to 17 years. The severity of hemorrhagic syndrome was assessed using the standardized ISTH BAT score. The severity of hemorrhagic manifestations according to BAT ISTH score ranged from 2 to 6 points. As a result of the study, two groups of patients differing in the calculated parameter of the FSC/SSC ratio for non-activated platelets were identified. In the CG, the median FSC/SSC was 1.235 (from 1.1 to 1.4), in group 1 (n = 19), the median was 0.97 (from 0.9 to 1.05), and in group 2 (n = 31), the median was 1.24 (from 1.11 to 1.43). The number of platelets of the CG and the groups of patients did not differ significantly. A significant correlation between a decrease in the number of platelets and an increase in their size and granularity, while maintaining a high correlation between size and granularity was observed in groups of patients. In group 1, the overall granularity was increased regardless of the size and number of platelets, the volume of dense granules and membrane CD62p was increased, but the granular CD62p was decreased. The degranulation mechanism was not impaired in both groups of patients. Our results indicate convincingly the contribution of the storage pool and platelet morphology disorders to the development of hemorrhagic manifestations in children with unspecified hemorrhagic syndrome.

Dynamics of DHA and EPA supplementation: incorporation into equine plasma, synovial fluid, and surfactant glycerophosphocholines.

Horses with asthma or osteoarthritis frequently receive ω-3 fatty acid supplements. Docosahexaenoic (DHA; 22:6) and eicosapentaenoic (EPA; 20:5) acids are essential ω-3 fatty acid precursors of anti-inflammatory mediators and components of structural glycerophospholipids (GPL) that act as reservoirs of these fatty acids. Analysis of the incorporation of dietary DHA + EPA into GPL pools in different body compartments has not been undertaken in horses. We undertook a detailed study of dietary supplementation with DHA + EPA in horses and monitored incorporation into DHA- and EPA-containing glycerophosphocholines (GPC) 38:5, 38:6, 40:5, and 40:6 in plasma, synovial fluid (SF), and surfactant. Horses (n = 20) were randomly assigned to the supplement or control group and evaluated on days 0, 30, 60, and 90. GPC in plasma, SF, and surfactant were measured by high-resolution mass spectrometry with less than 3ppm mass error. Validation of DHA and EPA incorporation into these GPC was conducted utilizing MS2 of the [M + Cl]- adducts of GPC. Dietary supplementation resulted in augmented levels of GPC 38:5, 38:6, 40:5, and 40:6 in all compartments. Maximum incorporation into GPCs was delayed until 60days. Significant increases in the levels of GPC 38:5, 40:5, and 40:6, containing docosapentaenoic acid (DPA; 22:5), also was noted. DHA and EPA supplementation results in augmented storage pools of ω-3 essential fatty acids in SF and surfactant GPC. This has the potential to improve the ability of anti-inflammatory mechanisms to resolve inflammatory pathways in these critical compartments involved in arthritis and asthma.

Assessment of Criticality Safety for Spent Fuel Elements in Open Pool Type Storage

Storage of spent fuel elements needs a previous calculation to ensure verifying the criteria of storage from the nuclear criticality point of view. So, arrangement of spent fuel elements in the storage must result in a configuration that veri-fying an effective multiplication factor (k-eff) lower than 0.85. The spent fuel elements storage is an open pool con-nected with the main pool of the reactor via transfer channel to facilitate transporting the irradiated fuel elements under water surface to verify a high radiological safety. The fuel element is a plate type material testing reactor (MTR) with enrichment of 19.97%. The storage pool was designed to store around 800 spent fuel elements as a temporary stage before transporting to a permanent storage. Basket and pool models, loaded with fresh fuel elements, were applied using SCALE/KENO-VI sequence to determine the k-eff during normal storage condition as well as water-drop accident. TRITON and KENO-VI sequence was applied to determine the k-eff for the basket and pool, loaded with spent fuel elements, during the normal and the accidental conditions. All the spent fuel elements were irradiated in a core of 22 MW power to the maximum burn up of discharge. The k-eff values show a proper agreement with previous calculations developed with MCNP5 code.

Divergent Regulation of OCT and MATE Drug Transporters by Cadmium Exposure

Coordinated transcellular transport by the uptake via organic cation transporters (OCTs) in concert with the efflux via multidrug and toxin extrusion proteins (MATEs) is an essential system for hepatic and renal drug disposition. Despite their clinical importance, the regulation of OCTs and MATEs remains poorly characterized. It has been reported that cadmium (Cd2+) increase the activities of OCTs while being a substrate of MATEs. Here, we found that human (h) OCT2 protein, as compared with hMATE1, was more active in trafficking between the plasma membrane and cytoplasmic storage pool. Cd2+ exposure could significantly enhance the translocation of hOCT2 and hOCT1, but not hMATE1, to the plasma membrane. We further identified that candesartan, a widely prescribed angiotensin II receptor blocker, behaved similarly toward OCT2 and MATE1 as Cd2+ did. Importantly, Cd2+ and candesartan treatments could lead to an enhanced accumulation of metformin, which is a well-characterized substrate of OCTs/MATEs, in mouse kidney and liver, respectively. Altogether, our studies have uncovered possible divergent regulation of OCTs and MATEs by certain xenobiotics, such as Cd2+ and candesartan due to the different cellular trafficking of these two families of transporter proteins, which might significantly affect drug disposition in the liver and kidney.

Heatwave frequency and seedling death alter stress-specific emissions of volatile organic compounds in Aleppo pine

Biogenic volatile organic compounds (BVOC) play important roles in plant stress responses and can serve as stress indicators. While the impacts of gradual environmental changes on BVOCs have been studied extensively, insights in emission responses to repeated stress and recovery are widely absent. Therefore, we studied the dynamics of shoot gas exchange and BVOC emissions in Pinus halepensis seedlings during an induced moderate drought, two four-day-long heatwaves, and the combination of drought and heatwaves. We found clear stress-specific responses of BVOC emissions. Reductions in acetone emissions with declining soil water content and transpiration stood out as a clear drought indicator. All other measured BVOC emissions responded exponentially to rising temperatures during heat stress (maximum of 43 °C), but monoterpenes and methyl salicylate showed a reduced temperature sensitivity during the second heatwave. We found that these decreases in monoterpene emissions between heatwaves were not reflected by similar declines in their internal storage pools. Because stress intensity was extremely severe, most of the seedlings in the heat-drought treatment died at the end of the second heatwave (dark respiration ceased). Interestingly, BVOC emissions (methanol, monoterpenes, methyl salicylate, and acetaldehyde) differed between dying and surviving seedlings, already well before indications of a reduced vitality became visible in gas exchange dynamics. In summary, we could clearly show that the dynamics of BVOC emissions are sensitive to stress type, stress frequency, and stress severity. Moreover, we found indications that stress-induced seedling mortality was preceded by altered methanol, monoterpene, and acetaldehyde emission dynamics.

Temperature conditions in the RBMK spent fuel pool in the event of disturbances in its cooling mode

The problems of reprocessing and long-term storage of spent nuclear fuel (SNF) at nuclear power plants with RBMK reactors have not been fully resolved so far. For this reason, nuclear power plants are forced to search for new options for the disposal of spent fuel, which can provide at least temporary SNF storage. One of the possible solutions to this problem is to switch to compacted SNF storage in reactor spent fuel pools (SFPs). As the number of spent fuel assemblies (SFAs) in SFPs increases, a greater amount of heat is released. In addition, no less important is the fact that a place for emergency FA discharging should be provided in SFPs. The paper presents the results of a numerical simulation of the temperature conditions in SFPs both for compacted SNF storage and for emergency FA discharging. Several types of disturbances in normal SFP cooling mode are considered, including partial loss of cooling water and exposure of SFAs. The simulation was performed using the ANSYS CFX software tool. Estimates were made of the time for heating water to the boiling point, as well as the time for heating the cladding of the fuel elements to a temperature of 650 °С. The most critical conditions are observed in the emergency FA discharging compartment. The results obtained make it possible to estimate the time that the personnel have to restore normal cooling mode of the spent fuel pool until the maximum temperature for water and spent fuel assemblies is reached.

Characteristics of Spray Inflow and Quenching in Spent Fuel Pool under Loss of Cooling Accident

Characteristics of Spray Inflow and Quenching in Spent Fuel Pool under Loss of Cooling Accident

The holistic risk analysis of spent fuel pool considering the fuel route risk

The Fukushima nuclear disaster has raised the importance on the reliability and risk research of the spent fuel pool (SFP), including the risk of internal events, fire, external hazards and so on. From a safety point of view, the low decay heat of the spent fuel assemblies and large water inventory in the SFP has made the accident progress goes very slow, but a large number of fuel assemblies are stored inside the spent fuel pool and without containment above the SFP building, it still has an unignored risk to the safety of the nuclear power plant. In this paper, a standardized approach for performing a holistic and comprehensive evaluation approach of the SFP risk based on the probabilistic safety analysis (PSA) method has been developed, including the Level 1 SFP PSA and Level 2 SFP PSA and external hazard PSA. The research scope of SFP PSA covers internal events, internal flooding, internal fires, external hazards and new risk source-fuel route risk is also included. The research will provide the risk insight of Spent Fuel Pool operation, and can help to make recommendation for the prevention and mitigation of SFP accidents which will be applicable for the SFP configuration risk management.

Evaluation of the reactor building environmental conditions under a LOCA for the decommissioning Chinshan plant

Both units of the Chinshan plant have been approved for decommissioning. However, fuel assemblies cannot be discharged from the reactor core because the spent fuel pool (SFP) is almost full. Currently, the reactor remains open and connected to the SFP. This configuration would persist for years. Considering this, the nuclear regulatory authority requires the safety-grade instruments in the reactor building to remain operable under accident conditions. However, a loss of coolant accident in this configuration was not analyzed before. In this study, thermal analysis using GOTHIC is performed to evaluate the environmental conditions in the reactor building. The reactor, SFP, primary containment and reactor building are included. The results show that the reactor building temperature remains below 48.9 °C during 6 days following the accident. Thus, recovering any cooling function in 6 days following the accident is suggested. This ensures that the reactor building space is in a mild environment.

VVER-1000/V446 spent fuel pool risk assessment and support through portable mitigating equipment

The Spent Fuel Pool (SFP) accident at the Fukushima Daiichi unit 4 demonstrated the need for identifying and analyzing possible accident sequences and subsequent application of severe accident mitigating systems in LWR (Light Water Reactor) SFPs. In this study, Level 1 Probabilistic Safety Assessment (PSA) is applied to evaluate the Fuel Damage Frequency (FDF) in SFP of Bushehr Nuclear Power Plant unit-1 (BNPP-1). This paper specifically focuses on assessing the SFP risk using Portable Mitigating Equipment (PME) including a reliable robust Portable Diesel Generator (PDG), a Portable Diesel Pump (PDP), and an SFP-spray system proposed to maintain steady decay heat removal. PME is the recommended equipment proposed by IAEA -following the Fukushima disaster- to mitigate accident consequences. In this study, the fault/event trees have been applied to conduct PSA using the SAPHIRE code. The results indicate that the most dominant Initiating Events (IEs) in the reference plant are the Loss of Offsite Power (LOOP) and Loss of Service Water (LOSW), both simultaneously affecting the reactor core and the SFP. There is a significant decrease in calculated FDF – after implementing PDG and PDP- in respect of the reference plant from 3.086E to 6 to 2.166E−7 in the normal storage mode. Heavy load drop, which is a low probability/high consequence IE, becomes crucially important in cases where PME is employed as it directly leads to fuel damage. It is expected that the analyses set forth here would provide efficient guidelines and insights into the strengths and weaknesses inherent in the design and operation of SFP in VVER-1000/V-446 nuclear power plant.

Выбор модели турбулентности для расчета профиля температуры у поверхности ТВС ВВЭР-1000 в бассейне выдержки АЭС

Выбор модели турбулентности для расчета профиля температуры у поверхности ТВС ВВЭР-1000 в бассейне выдержки АЭС

Activated factor X targeted stored in platelets as an effective gene therapy strategy for both hemophilia A and B.

BackgroundTreatment of hemophiliacs with inhibitors remains challenging, and new treatments are in urgent need. Coagulation factor X plays a critical role in the downstream of blood coagulation cascade, which could serve as a bypassing agent for hemophilia therapy. Base on platelet‐targeted gene therapy for hemophilia by our and other groups, we hypothesized that activated factor X (FXa) targeted stored in platelets might be effective in treating hemophilia A (HA) and B (HB) with or without inhibitors.MethodsTo achieve the storage of FXa in platelets, we constructed a FXa precursor and used the integrin αIIb promoter to control the targeted expression of FXa precursor in platelets. The expression cassette (2bFXa) was carried by lentivirus and introduced into mouse hematopoietic stem and progenitor cells (HSPCs), which were then transplanted into HA and HB mice. FXa expression and storage in platelets was examined in vitro and in vivo. We evaluated the therapeutic efficacy of platelet‐stored FXa by tail bleeding assays and the thrombelastography. In addition, thrombotic risk was assessed in the recipient mice and the lipopolysaccharide induced inflammation mice.ResultsBy transplanting 2bFXa lentivirus‐transduced HSPCs into HA and HB mice, FXa was observed stably stored in platelet α‐granules, the stored FXa is releasable and functional upon platelet activation. The platelet‐stored FXa can significantly ameliorate bleeding phenotype in HA and HB mice as well as the mice with inhibitors. Meanwhile, no FXa leakage in plasma and no signs of increased risk of hypercoagulability were found in transplantation recipients and lipopolysaccharide induced septicemia recipients.ConclusionsOur proof‐of‐principle data indicated that target expression of the FXa precursor to platelets can generate a storage pool of FXa in platelet α‐granules, the platelet‐stored FXa is effective in treating HA and HB with inhibitors, suggesting that this could be a novel choice for hemophilia patients with inhibitors.

Oral Squamous Cell Carcinoma Is Associated with a Low Thrombosis Risk Due to Storage Pool Deficiency in Platelets.

Venous thrombo-embolism (VTE) disease is the second most common cause of mortality in cancer patients, and evaluation and prevention of thrombosis risk is essential. VTE-associated risk varies according to the type of tumor disease. Oral cancer is the most frequent type of head and neck cancer, and it represents approximately 2.1% of all cancers worldwide. Most tumors are squamous cell carcinomas and are mainly due to tobacco and alcohol abuse. VTE risk associated with oral squamous cell carcinoma (OSCC) is low. However, many studies have shown that OSCC has the following biological features of cancers associated with a high thrombosis risk: modified thrombosis and fibrinolysis mechanisms; strong expression of procoagulant proteins; secretion of procoagulant microparticles; and production of procoagulant cytokines. Using an original mouse model of tongue squamous cell carcinoma, our study aimed to clarify this paradoxical situation. First, we showed that OSCC tumors have a pro-aggregatory phenotype and a high local thrombosis risk. Second, we found that tongue tumor mice do not have an elevated systemic thrombosis risk (the risk of an “at distance” thrombosis event such as lower extremity deep venous thrombosis or pulmonary embolism) and even show a reduction in risk. Third, we demonstrated that tongue tumor mice show a reduction in platelet reactivity, which explains the low systemic thrombosis risk. Finally, we found that tongue tumor mice present granule pool deficiency, thereby explaining the reduction in platelet reactivity and systemic thrombosis risk.

Uncontrollable combustion characteristics of energy storage oil pool: Modelling of mass loss rate and flame merging time of annular pools

Hydrocarbon energy storage has a wide range of applications in modern production and life. Regarded as an important form of energy dissipation, combustion plays an important role in energy storage failure. Energy burning rate and flame shape are the key factors of the combustion system. The classic theories of uncontrollable combustion characteristics for energy storage oil pool will be unable to apply to the cases with annular oil pool burning calculation directly, which never been revealed before. The study of oil energy storage burning rate and flame shape characteristics is of great significance to predict and control the energy storage pool transfer between the fuel surface and the unburned area during the combustion process. Experiments were carried out using an annular pool with an outer diameter that used heptane as fuel. Based on dimensionless theoretical derivation, a non-dimensional correlation is proposed the flame merging time. The received energy heat feedback at the center of pool can explain the change of energy mass loss rate, and a dimensional analysis model with Spalding number was developed to interpret the energy mass loss rate in the energy storage annular pool. Experiments show that the characteristic diameter can be well correlated non-dimensionally with all flame height, indicating that the proposed correlation is applicable not only for annular pools but also for solid burners. The study on these issues have the benefit the current utilization and management of the energy storage oil pool.

Root carbon and nutrient homeostasis determines downy oak sapling survival and recovery from drought.

The role of carbon (C) and nutrient uptake, allocation, storage and especially their interactions in survival and recovery of trees under increased frequencies and intensities of drought events is not well understood. A full factorial experiment with four soil water content regimes ranging from extreme drought to well-watered conditions and two fertilization levels was carried out. We aimed to investigate whether nutrient addition mitigates drought effects on downy oak (Quercus pubescens Willd.) and whether storage pools of non-structural carbohydrates (NSC) are modified to enhance survival after 2.5 years of drought and recovery after drought relief. Physiological traits, such as photosynthesis, predawn leaf water potential as well as tissue biomass together with pools and dynamics of NSC and nutrients at the whole-tree level were investigated. Our results showed that fertilization played a minor role in saplings’ physiological processes to cope with drought and drought relief, but reduced sapling mortality during extreme drought. Irrespective of nutrient supply, Q. pubescens showed increased soluble sugar concentration in all tissues with increasing drought intensity, mostly because of starch degradation. After 28 days of drought relief, tissue sugar concentrations decreased, reaching comparable values to those of well-watered plants. Only during the recovery process from extreme drought, root NSC concentration strongly declined, leading to an almost complete NSC depletion after 28 days of rewetting, simultaneously with new leaves flushing. These findings suggest that extreme drought can lead to root C exhaustion. After drought relief, the repair and regrowth of organs can even exacerbate the root C depletion. We concluded that under future climate conditions with repeated drought events, the insufficient and lagged C replenishment in roots might eventually lead to C starvation and further mortality.

Calcium ions trigger the exposure of phosphatidylserine on the surface of necrotic cells.

Intracellular Ca2+ level is under strict regulation through calcium channels and storage pools including the endoplasmic reticulum (ER). Mutations in certain ion channel subunits, which cause mis-regulated Ca2+ influx, induce the excitotoxic necrosis of neurons. In the nematode Caenorhabditis elegans, dominant mutations in the DEG/ENaC sodium channel subunit MEC-4 induce six mechanosensory (touch) neurons to undergo excitotoxic necrosis. These necrotic neurons are subsequently engulfed and digested by neighboring hypodermal cells. We previously reported that necrotic touch neurons actively expose phosphatidylserine (PS), an “eat-me” signal, to attract engulfing cells. However, the upstream signal that triggers PS externalization remained elusive. Here we report that a robust and transient increase of cytoplasmic Ca2+ level occurs prior to the exposure of PS on necrotic touch neurons. Inhibiting the release of Ca2+ from the ER, either pharmacologically or genetically, specifically impairs PS exposure on necrotic but not apoptotic cells. On the contrary, inhibiting the reuptake of cytoplasmic Ca2+ into the ER induces ectopic necrosis and PS exposure. Remarkably, PS exposure occurs independently of other necrosis events. Furthermore, unlike in mutants of DEG/ENaC channels, in dominant mutants of deg-3 and trp-4, which encode Ca2+ channels, PS exposure on necrotic neurons does not rely on the ER Ca2+ pool. Our findings indicate that high levels of cytoplasmic Ca2+ are necessary and sufficient for PS exposure. They further reveal two Ca2+-dependent, necrosis-specific pathways that promote PS exposure, a “two-step” pathway initiated by a modest influx of Ca2+ and further boosted by the release of Ca2+ from the ER, and another, ER-independent, pathway. Moreover, we found that ANOH-1, the worm homolog of mammalian phospholipid scramblase TMEM16F, is necessary for efficient PS exposure in thapsgargin-treated worms and trp-4 mutants, like in mec-4 mutants. We propose that both the ER-mediated and ER-independent Ca2+ pathways promote PS externalization through activating ANOH-1.

Inflammatory Biomarkers in Postural Orthostatic Tachycardia Syndrome with Elevated G-Protein-Coupled Receptor Autoantibodies.

A growing body of evidence suggests that postural orthostatic tachycardia syndrome (POTS) may be an autoimmune disorder. We have reported in a previous manuscript that 89% of POTS patients (n = 55) had elevations in G-protein-coupled adrenergic A1 receptor autoantibodies and 53% had elevations in muscarinic acetylcholine M4 receptor autoantibodies, as assessed by ELISA. Patients with autoimmune disorders have been reported with a variety of elevated cytokines and cytokines (such as rheumatoid arthritis); thus, we evaluated a limited number of cytokines/chemokines in POTS patients with elevated adrenergic and muscarinic receptor autoantibodies. We utilized the plasma of 34 patients from a previous study; all of the patients (100%) had autoantibodies against the A1 adrenergic receptor and 55.9% (19/34) had autoantibodies against the M4 muscarinic acetylcholine receptor. In particular, the plasma cytokine/chemokine levels were measured as biomarkers of inflammation by Quantibody® technology (Raybiotech, Peachtree Corners, GA, USA). We also evaluated the platelet dense granule numbers, as these patients frequently complain of symptoms related to platelet dysfunction. Patients were predominantly young females who displayed a multitude of co-morbidities but generally reported viral-like symptoms preceding episodes of syncope. Eighty five percent (29/34) had platelet storage pool deficiency. Patients had elevations in five of ten cytokine/chemokines biomarkers (IL1β, IL21, TNFα, INFγ, and CD30), whereas two biomarkers had decreased levels (CD40L and RANTES). Our observations demonstrate that POTS patients known to have autoantibodies against the G-protein-coupled adrenergic A1 receptor have abnormal plasma concentrations of inflammatory cytokines.

A zinc transporter, transmembrane protein 163, is critical for the biogenesis of platelet dense granules

Lysosome-related organelles (LROs) are a category of secretory organelles enriched with ions such as calcium, which are maintained by ion transporters or channels. Homeostasis of these ions is important for LRO biogenesis and secretion. Hermansky-Pudlak syndrome (HPS) is a recessive disorder with defects in multiple LROs, typically platelet dense granules (DGs) and melanosomes. However, the underlying mechanism of DG deficiency is largely unknown. Using quantitative proteomics, we identified a previously unreported platelet zinc transporter, transmembrane protein 163 (TMEM163), which was significantly reduced in BLOC-1 (Dtnbp1sdy and Pldnpa)–, BLOC-2 (Hps6ru)–, or AP-3 (Ap3b1pe)–deficient mice and HPS patients (HPS2, HPS3, HPS5, HPS6, or HPS9). We observed similar platelet DG defects and higher intracellular zinc accumulation in platelets of mice deficient in either TMEM163 or dysbindin (a BLOC-1 subunit). In addition, we discovered that BLOC-1 was required for the trafficking of TMEM163 to perinuclear DG and late endosome marker–positive compartments (likely DG precursors) in MEG-01 cells. Our results suggest that TMEM163 is critical for DG biogenesis and that BLOC-1 is required for the trafficking of TMEM163 to putative DG precursors. These new findings suggest that loss of TMEM163 function results in disruption of intracellular zinc homeostasis and provide insights into the pathogenesis of HPS or platelet storage pool deficiency.