Maintenance Of State Research Articles

Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR

Transitioning from pluripotency to differentiated cell fates is fundamental to both embryonic development and adult tissue homeostasis. Improving our understanding of this transition would facilitate our ability to manipulate pluripotent cells into tissues for therapeutic use. Here, we show that membrane voltage (Vm) regulates the exit from pluripotency and the onset of germ layer differentiation in the embryo, a process that affects both gastrulation and left-right patterning. By examining candidate genes of congenital heart disease and heterotaxy, we identify KCNH6, a member of the ether-a-go-go class of potassium channels that hyperpolarizes the Vm and thus limits the activation of voltage gated calcium channels, lowering intracellular calcium. In pluripotent embryonic cells, depletion of kcnh6 leads to membrane depolarization, elevation of intracellular calcium levels, and the maintenance of a pluripotent state at the expense of differentiation into ectodermal and myogenic lineages. Using high-resolution temporal transcriptome analysis, we identify the gene regulatory networks downstream of membrane depolarization and calcium signaling and discover that inhibition of the mTOR pathway transitions the pluripotent cell to a differentiated fate. By manipulating Vm using a suite of tools, we establish a bioelectric pathway that regulates pluripotency in vertebrates, including human embryonic stem cells.

Сellular composition and cytokine profile of synovial fluid in rheumatoid arthritis

Rheumatoid arthritis (RA) ranks first among chronic joint diseases. The disease often affects people at their working age, being accompanied by significant decrease in the life quality of patients and their early disability. Rheumatoid arthritis is an immunoinflammatory rheumatic disease. Therefore, the immune system provides evolving focus of primary damage, its persistence and periodic exacerbation. Elucidation of intercellular relationships mediated by cytokines at various stages of the chronic inflammatory process is required in order to develop immunotherapeutic approaches, aimed for both recovery from exacerbations and maintenance of remission state. Purpose of our study was to evaluate cellular composition and cytokine profile of synovial fluid in the patients with rheumatoid arthritis at acute phase and in remission state.We have studied the samples of synovial fluid taken in 60 patients with rheumatoid arthritis, with 30 subjects being at acute stage of the disease, and 30 patients in remission. Cellular composition and cytokine profile were assessed in the clinical samples. There were 21 women and 9 men at the acute stage (57.0±15.4 years old), with the disease duration of 8.55±6.9 years. The average age of 19 women and 11 men examined in remission state was 53.5±10.9 years, with comparable duration of illness (6.9±5.8 years). The leukocyte phenotyping was performed with a CytoFLEX flow cytometer (Beckman Coulter, USA). The cytokine contents were measured by enzyme immunoassay using a standard set of reagents from the “Proteinovy Contour” LLC (Russia). The results were registered by a Multiscan photometer (Labsystems, Finland).During the disease exacerbation, the leukocyte contents in synovial fluid increased 2.4-fold, as compared to the remission values. The cellular infiltrate was represented by neutrophils, whereas the contents of lymphocytes and monocytes did not change. Increased migration of neutrophils was accompanied by an 8-fold increase in TNFα levels, compared with remission state, and IL-1β levels were increased by 6.3 times. The absolute number of CD3+T lymphocytes, CD16+CD56+B cells, and CD3-CD19+NK during exacerbation was similar to the remission levels. However, the number of T cell subpopulations was changed, i.e., the number of CD4+ lymphocytes was decreased, and CD8+ cell counts were increased, like as numbers of Treg lymphocytes and NKT cells which showed a significant increase. A 4.3-fold increase in the IL-4 concentration during the RA exacerbation suggested the predominance of Th2 immune response. During remission, the concentrations of IL-6 and IFNγ in synovial fluid were increased, respectively, by 1.5 times and by 2.5 times, which is typical for activated Th1 response.

ODP614 Two cases of Graves Disease Associated Hypokalemic Periodic Paralysis

Abstract Introduction Periodic paralysis (PP) is a rare neuromuscular disorder due to a defect in ion channels in muscle, characterized by episodes of painless muscle weakness or paralysis, which may be precipitated by heavy exercise or high-carbohydrate meals. Hypokalemic PP (HPP) is most common of the periodic paralyses, however is still very rare, with an estimated prevalence of 1 in 100,000. An acquired form of hypokalemic PP can be seen in thyrotoxicosis of any cause. We present 2 cases of HPP due to thyrotoxicosis. Case 1 27 year old Asian male presented to the ED due to sudden onset of acute weakness/near paralysis in lower extremities, with weakness of bilateral upper extremities. He was found to be hypokalemic with a potassium of 2.0 mmol/L (3.5-5.1). At the same time, he was also found to be hyperthyroid with a suppressed TSH of 0.03 uIU/Ml (0.35-5.5) and a free T4 2.2 ng/mL (0.5-1.3), Total T3 225 ng/Dl (70-204), Free T3 5.9 pg/mL (1.5-4.1). TSI antibodies elevated at 1.39 IU/L (<0.10). He was started on potassium supplements and methimazole. At a 3-month follow-up, patient reported no further episodes of weakness or paralysis. Case 2 23 year old White male presented to ED with severe muscle weakness and was found to have hypokalemia of 2 mmol/L (3.5-5.1). On further labs, TSH was undetectable at less than 0.01 uIU/mL (0.35-4.94), Free T4 2.81 ng/dL (0.61-1.82), Total T3 of 451 ng/dL(48-178), TSI antibodies were positive at 178%(</=122%). Nuclear uptake scan confirmed Graves’ disease with radioactive iodine uptake of 58.1% at 4 hours and 70% at 24 hours with homogenous uptake in the entire gland and no evidence of hot or cold nodules. He was started on methimazole and propranolol for tachycardia and palpitations and potassium supplements. Muscle weakness resolved on treatment methimazole. Discussion and conclusion We present two cases of HPP likely caused by Graves’ disease. Both patients presented with hypokalemia and further workup revealed underlying thyrotoxicosis. The exact mechanism behind HPP due to thyrotoxicosis is not well understood. It is proposed that excess thyroid hormone may predispose to paralytic episodes by increasing the susceptibility to the hypokalemic action of epinephrine or insulin. This condition has been most widely reported in Asian populations, in which the incidence is approximately 2% in contrast to non-asian population with incidence of 0.1 to 0.2%, and is more common in men. Treatment of thyrotoxicosis with restoration and maintenance of euthyroid state ceases attacks. To summarize, few case series report the association of HPP with Graves’ disease. These patients usually present acutely with severe muscle weakness or paralysis. In conclusion, in diagnosis of HPP, possibility of thyrotoxicosis should be considered, especially in the absence of family history of PP. Presentation: No date and time listed

Effects of a Cognitive Stimulation Program in Institutionalized Patients with Dementia.

Background: The advances achieved by the available research that focus on understanding memory operation and cognitive functions have helped the development of specific treatment approaches. These can help to maintain or improve the cognitive function and well-being of people with dementia. The use of cognitive stimulation in dementia has a long history. There are multiple studies that have demonstrated its benefits on the cognitive levels of patients with mild to moderate dementia. However, all of the studies on this type of non-pharmacological intervention conclude that there is a need for more clinical trials in order to give more solidity to the evidence already found. The objective of this pilot study was to assess the effects of an occupational therapy cognitive training program on the cognitive function of institutionalized older adults with dementia. Methods: The study was a pilot randomized clinical controlled trial. A total of 58 participants with major neurocognitive disorder or dementia were randomized to the occupational therapy cognitive training program group or to the conventional occupational therapy group twice a week for 5 weeks. The cognitive level was measured with the Global Deterioration Scale (GDS) and the Lobo’s Cognitive Mini Test (LCMT), which is the Mini-Mental Status Examination in Spanish. Measures were taken at baseline (week 0), after 5 weeks of treatment (week 5), and after 6 weeks of follow up (week 12). A value of p < 0.05 was considered as statistically significant. Results: There were no statistical differences between groups in the LCMT global scores at baseline or after the intervention at week 5. However, the analysis of the specific cognitive areas assessed in the Lobo’s Cognitive Mini Test indicated that that the intervention group significantly improved comprehension of verbal commands and praxis (p = 0.021). At the follow-up measure, the differences obtained in relation to verbal commands and praxis maintained the statistical differences significantly (p = 0.009). Conclusions: Occupational therapy based on cognitive training shows positive effects on the maintenance of the global cognitive state of institutionalized older adults with dementia and improves significantly the comprehension of verbal commands and praxis.

In toto imaging of early enteric nervous system development reveals that gut colonization is tied to proliferation downstream of Ret.

The enteric nervous system is a vast intrinsic network of neurons and glia within the gastrointestinal tract and is largely derived from enteric neural crest cells (ENCCs) that emigrate into the gut during vertebrate embryonic development. Study of ENCC migration dynamics and their genetic regulators provides great insights into fundamentals of collective cell migration and nervous system formation, and these are pertinent subjects for study due to their relevance to the human congenital disease Hirschsprung disease (HSCR). For the first time, we performed in toto gut imaging and single-cell generation tracing of ENCC migration in wild type and a novel ret heterozygous background zebrafish (retwmr1/+) to gain insight into ENCC dynamics in vivo. We observed that retwmr1/+ zebrafish produced fewer ENCCs localized along the gut, and these ENCCs failed to reach the hindgut, resulting in HSCR-like phenotypes. Specifically, we observed a proliferation-dependent migration mechanism, where cell divisions were associated with inter-cell distances and migration speed. Lastly, we detected a premature neuronal differentiation gene expression signature in retwmr1/+ ENCCs. These results suggest that Ret signaling may regulate maintenance of a stem state in ENCCs.

Nitric Oxide Metabolic Pathway in Drought-Stressed Nodules of Faba Bean (Vicia faba L.).

Drought is an environmental stress that strongly impacts plants. It affects all stages of growth and induces profound disturbances that influence all cellular functions. Legumes can establish a symbiosis with Rhizobium-type bacteria, whose function is to fix atmospheric nitrogen in organs called nodules and to meet plant nitrogen needs. Symbiotic nitrogen fixation (SNF) is particularly sensitive to drought. We raised the hypothesis that, in drought-stressed nodules, SNF inhibition is partly correlated to hypoxia resulting from nodule structure compaction and an increased O2 diffusion barrier, and that the nodule energy regeneration involves phytoglobin-nitric oxide (Pgb-NO) respiration. To test this hypothesis, we subjected faba bean (Vicia faba L.) plants nodulated with a Rhizobium laguerreae strain to either drought or osmotic stress. We monitored the N2-fixation activity, the energy state (ATP/ADP ratio), the expression of hypoxia marker genes (alcohol dehydrogenase and alanine aminotransferase), and the functioning of the Pgb-NO respiration in the nodules. The collected data confirmed our hypothesis and showed that (1) drought-stressed nodules were subject to more intense hypoxia than control nodules and (2) NO production increased and contributed via Pgb-NO respiration to the maintenance of the energy state of drought-stressed nodules.

Spinal GABAergic disinhibition allows microglial activation mediating the development of nociplastic pain in male mice

Previously we developed a murine model in which postinjury stimulation of an injured area triggers a transition to a nociplastic pain state manifesting as persistent mechanical hypersensitivity outside of the previously injured area. This hypersensitivity was maintained by sex-specific mechanisms; specifically, activated spinal microglia maintained the hypersensitivity only in males. Here we investigated whether spinal microglia drive the transition from acute injury-induced pain to nociplastic pain in males, and if so, how they are activated by normally innocuous stimulation after peripheral injury. Using intraplantar capsaicin injection as an acute peripheral injury and vibration of the injured paw as postinjury stimulation, we found that inhibition of spinal microglia prevents the vibration-induced transition to a nociplastic pain state. The transition was mediated by the ATP-P2X4 pathway, but not BDNF-TrkB signaling. Intrathecally injected GABA receptor agonists after intraplantar capsaicin injection prevented the vibration-induced transition to a nociplastic pain state. Conversely, in the absence of intraplantar capsaicin injection, intrathecally injected GABA receptor antagonists allowed the vibration stimulation of a normal paw to trigger the transition to a spinal microglia-mediated nociplastic pain state only in males. At the spinal level, TNF-α, IL-1β, and IL-6, but not prostaglandins, contributed to the maintenance of the nociplastic pain state in males. These results demonstrate that in males, the transition from acute injury-induced pain to nociplastic pain is driven by spinal microglia causing neuroinflammation and that peripheral injury-induced spinal GABAergic disinhibition is pivotal for normally innocuous stimulation to activate spinal microglia.

Hydromechanical method of aeration of open water bodies under conditions of urban development

Open water bodies in areas with dense urban development experience an increased anthropogenic impact and, therefore, need restoration work, reconstruction and maintenance of the normative sanitary state of water. Many of them are closed, without flow. The article discusses technical approaches for maintaining the oxygen regime of urban water bodies, which is the most important indicator that determines the normalization of biological processes occurring in the aquatic environment. At present the only way to maintain the necessary hydrobiological characteristics of water bodies in urbanized areas is to create special hydraulic systems for artificial jet aeration of water bodies and circulation currents in such objects.

EMPOWERING THE SUSTAINABILITY OF THE MALAY LANGUAGE AS A COMMUNICATION TRANSMISSION AND ELEMENT OF IDENTITY

The discussion in this paper refers to the effort to empower Malay language as a communication transmission bridge that is a significant element of Malaysian identity. The issues refined in this discussion refer to (i) The significance of the mother tongue as the language of knowledge in educational institutions, (ii) The balance between the use of Malay and English in HEIs, (iii) Efforts to uphold the Malay language as the national language, and (iv) The use national language in the public service sector. The application of a qualitative approach in this writing utilizes secondary sources such as research results in journals, scholarly writing, online news sources and public forums. The results of the study found that the government plays a critical role in the continued use and position of the Malay language by the people of this country and should be empowered by all parties. The rationale in the effort to dignify the Malay language is the maintenance of the nation state as enshrined in the national constitution which declares the Malay language as the official language of the country. The direction of this study is to pioneer the efforts of various parties in taking responsibility for preserving and empowering the mother tongue regardless of different backgrounds, religions and beliefs, in order to nourish the elements of identity, improve the quality and quality of the use of the national language, while maintaining the image of self-identity, race, and country. This is because in the face of global competition, the Malay language should be a bastion to defend the strength of the Malay nation's identity.

Retinoic acid and RARγ maintain satellite cell quiescence through regulation of translation initiation

In adult skeletal muscle, satellite cells are in a quiescent state, which is essential for the future activation of muscle homeostasis and regeneration. Multiple studies have investigated satellite cell proliferation and differentiation, but the molecular mechanisms that safeguard the quiescence of satellite cells remain largely unknown. In this study, we purposely activated dormant satellite cells by using various stimuli and captured the in vivo-preserved features from quiescence to activation transitions. We found that retinoic acid signaling was required for quiescence maintenance. Mechanistically, retinoic acid receptor gamma (RARγ) binds to and stimulates genes responsible for Akt dephosphorylation and subsequently inhibits overall protein translation initiation in satellite cells. Furthermore, the alleviation of retinoic acid signaling released the satellite cells from quiescence, but this restraint was lost in aged cells. Retinoic acid also preserves the quiescent state during satellite cell isolation, overcoming the cellular stress caused by the isolation process. We conclude that active retinoic acid signaling contributes to the maintenance of the quiescent state of satellite cells through regulation of the protein translation initiation process.

L’Attachement dans les Troubles Dépressifs Persistants chez l’adulte : une revue de la littérature

Persistent depressive disorders (PDD) are frequent and disabling and their therapeutic management remains poorly defined. Attachment theory highlights the effect of insecure representations of relationships in the development and maintenance of PDD. The aim of this literature review is to identify the main findings regarding the place of attachment in persistent depressive disorders (PDD) to show the interest of this framework as an explanatory model of PDD and to determine the usefulness of taking attachment into consideration in the therapeutic intervention for the treatment of PDD. The current treatment of PDD faces a high rate of either failure or partial remission. Almost half of depressed patients do not achieve remission or develop chronic residual symptoms. Although there is a specific therapy built for PDD (CBASP), there is currently no psychotherapy that has been sufficiently scientifically verified to be recommended for PDD. Interpersonal difficulties seem to play a major role in the maintenance of a depressive state: the difficulty in establishing a therapeutic relationship would explain why patients with PDD often show a poor therapeutic response to traditional psychotherapies, including cognitive behavioural therapy (CBT). In addition, some characteristics that make treatment difficult may be a consequence of childhood maltreatment, in particular emotional abuse, and neglect, that are risk factors for early depression with a chronic course. Furthermore, insecure attachment is a major risk factor of severity or persistence of psychopathological disorders. Conversely, secure attachment reduces the risk of developing these symptoms. Empirical research has shown links between insecure attachment and specific psychological disorders. Insecure attachment is associated with internalizing disorders, including depression, in childhood and in adulthood. Insecure attachment is clearly associated with depressive symptoms. This relationship is mediated by several variables such as self-esteem, disrupted social and relational skills depressive cognitions and early maladaptive schemas. Taken together, these findings suggest that attachment is an important risk factor in the development of psychopathology, in particular depressive disorders. Therefore, Bosmans suggests that the integration of attachment into psychotherapies would enhance their effectiveness. Attachment should therefore be considered as an important target of clinical intervention to treat the symptoms of PDD and there seems to be a need to develop this therapeutic approach to determine the extent to which a treatment protocol can focus specifically on attachment for chronically depressed patients. Studies of attachment psychotherapies consider attachment style both as a predictor of treatment outcome and as an indicator of therapeutic orientation. The patient's attachment representations and behaviours can influence the therapeutic process and the relationship with the therapist, which means identifying them to use specific strategies: therapeutic techniques relevant to one attachment style may be problematic for another. These considerations show the need for research that considers the relationship between PDD symptoms and patients’ attachment styles at the beginning of therapy to verify which attachment patterns are related to this specific pathology and to determine the influence of patients’ attachment patterns on the therapeutic process. Finally, innovative therapies such as Integrated Attachment Therapy, that consider attachment as the foundation of the therapeutic process, are being developed and form a new care offer that seems promising for the treatment of PDD.

P326 DNA replication initiator proteins stabilize the kinetochore in the human fungal pathogen Cryptococcus neoformans

Poster session 3, September 23, 2022, 12:30 PM - 1:30 PMObjectivesDNA replication licensing ensures maintenance of the ploidy state by limiting DNA replication once per cell cycle. The mini-chromosome maintenance (MCM) complex is an evolutionarily conserved DNA helicase in eukaryotes that aids this process. Upon activation in the S phase by several protein kinases, the MCM complex unwinds the double-stranded DNA and moves away from DNA replication origins preventing re-initiation of replication in the remainder of the cell cycle. Deregulation of MCM function can lead to malignant transformation of proliferating cells as indicated by their upregulated expression in human cancer and pre-cancerous cells. MCMs, therefore, serve as important biomarkers and potential targets for anti-cancer drugs. This study aims to decipher the effect of deregulated expression of the MCM complex on the cell cycle events of the human fungal pathogen, Cryptococcus neoformans, which is more similar to metazoans than other budding yeast. Aneuploidy-mediated drug resistance is a common mechanism in many major human fungal pathogens including Cryptococcus and Candida.MethodsWe generated conditional mutants of individual subunits of the MCM complex in C. neoformans and assayed the impact of their altered expression on cell cycle events. We also tested the alternative role of MCM subunits in the assembly of the kinetochore, a vital component of the chromosome segregation machinery.ResultsOur screen with MCM conditional mutants identified two in vivo functional subcomplexes that comprise the MCM complex in C. neoformans. Although upregulated expression of either Mcm2 or Mcm3 does not affect cell cycle progression, overexpression of either Mcm6 or Mcm7 led to the accumulation of cells in the large bud stage with nuclear segregation defects. This work provides evidence for the first time for a mitotic role of pre-replication complex proteins, MCM 2-7 complex in Cryptococcus. Depletion of Mcm2 led to arrest of cells in the S and G2/M stages of the cell cycle with defects in nuclear segregation. Localization and expression of several kinetochore proteins upon depletion of Mcm2 established that Mcm2 is vital for kinetochore assembly/integrity. Although the centromeric histone H3 variant, CENP-A, remains largely clustered, the outer kinetochore did not mature indicating that Mcm2 alone or as part of the MCM complex plays a role in kinetochore assembly/integrity and thereby in chromosome segregation.ConclusionA conserved eukaryotic DNA helicase, MCM 2-7 complex, has an unexplored non-canonical role in kinetochore assembly/integrity and chromosome segregation.

Abstract A037: TT-00420, a novel kinase inhibitor potentially benefiting c-Myc amplified/overexpressed osteosarcoma

Abstract Osteosarcoma (OS) is the most common bone tumor in pediatric patients, whose effective therapies are of great unmet medical needs, particularly for those of high-risk features. c-Myc, a well-known oncogene, is commonly amplified/overexpressed in OS patients, contributes to dismal prognosis and associates with lower 5-year overall survival rate, which is also confirmed by our retrospective analysis for the correlation between c-Myc gene amplification/overexpression and patient prognosis in our patient cohort. TT-00420, a clinical-stage small molecule targeting Aurora A/B, VEGFRs, FGFRs, JAKs and CSF1R, has demonstrated down-regulation on c-Myc expression in TNBC studies. Moreover, as reported, Aurora kinases and c-Myc regulate each other back and forth, triggering maintenance of the malignant state. In this study, we examined the efficacy of TT-00420 in c-Myc-amplified/overexpressed OS. In pre-clinical clonogenic assay, TT-00420 significantly inhibited the colony formation in c-Myc-overexpressed OS cell lines in a dose-dependent manner. In MNNG/HOS cell line, we demonstrated that TT-00420 dramatically suppressed Aurora kinase pathway and blunted c-Myc protein expression level, indicating TT-00420 might down-regulate c-Myc by Aurora kinases inhibition. In pre-clinical in-vivo efficacy studies, 143B cells were injected into the medullary cavity of the tibia to make the orthotopic OS xenograft model. With 15 mg/kg/day treatment of TT-00420, tumor growth was obviously inhibited as compared to vehicle group. Immunohistochemistry (IHC) analyses in tumors revealed that TT-00420-treated tumors exhibited increased apoptosis with upregulated expression of cleaved caspase 3 (CC3) and H2AX, and significantly decreased proliferations with raised expression of Ki67. Moreover, in a c-Myc-overexpressed OS patient-derived xenograft (PDX) model from a male pediatric patient, 15 mg/kg/day TT-00420 dramatically blunted the tumor growth with a TGI of 87.6%. In China, an investigator-initiated trial is currently ongoing to evaluate the safety and tolerability of TT-00420 in OS patients with c-Myc overexpression (ChiCTR2000036618). Taken together, TT-00420 depicted robust anti-tumor activity in c-Myc overexpressed OS both in vitro and in vivo with downregulation of c-Myc expression, indicating its potential as a novel monotherapy for OS patients with c-Myc overexpression. Future clinical trial result is of great expectation. Citation Format: Yingqi Hua, Xiaoyan Qiang, Kai Tian, Yafei Jiang, Frank Wu, Peng Peng. TT-00420, a novel kinase inhibitor potentially benefiting c-Myc amplified/overexpressed osteosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A037.

Metabolomic Profiling of End-Stage Heart Failure Secondary to Chronic Chagas Cardiomyopathy

Chronic Chagas cardiomyopathy (CCC) is the most frequent and severe clinical form of chronic Chagas disease, representing one of the leading causes of morbidity and mortality in Latin America, and a growing global public health problem. There is currently no approved treatment for CCC; however, omics technologies have enabled significant progress to be made in the search for new therapeutic targets. The metabolic alterations associated with pathogenic mechanisms of CCC and their relationship to cellular and immunopathogenic processes in cardiac tissue remain largely unknown. This exploratory study aimed to evaluate the potential underlying pathogenic mechanisms in the failing myocardium of patients with end-stage heart failure (ESHF) secondary to CCC by applying an untargeted metabolomic profiling approach. Cardiac tissue samples from the left ventricle of patients with ESHF of CCC etiology (n = 7) and healthy donors (n = 7) were analyzed using liquid chromatography-mass spectrometry. Metabolite profiles showed altered branched-chain amino acid and acylcarnitine levels, decreased fatty acid uptake and oxidation, increased activity of the pentose phosphate pathway, dysregulation of the TCA cycle, and alterations in critical cellular antioxidant systems. These findings suggest processes of energy deficit, alterations in substrate availability, and enhanced production of reactive oxygen species in the affected myocardium. This profile potentially contributes to the development and maintenance of a chronic inflammatory state that leads to progression and severity of CCC. Further studies involving larger sample sizes and comparisons with heart failure patients without CCC are needed to validate these results, opening an avenue to investigate new therapeutic approaches for the treatment and prevention of progression of this unique and severe cardiomyopathy.

Sensitization of Hypertension: The Impact of Earlier Life Challenges: Excellence Award for Hypertension Research 2021.

Hypertension affects over 1 billion individuals worldwide. Because the cause of hypertension is known only in a small fraction of patients, most individuals with high blood pressure are diagnosed as having essential hypertension. Elevated sympathetic nervous system activity has been identified in a large portion of hypertensive patients. However, the root cause for this sympathetic overdrive is unknown. A more complete understanding of the breadth of the functional capabilities of the sympathetic nervous system may lead to new insights into the cause of essential hypertension. By employing a unique experimental paradigm, we have recently discovered that the neural network controlling sympathetic drive is more reactive after rats are exposed to mild challenges (stressors) and that the hypertensive response can be sensitized (ie, hypertensive response sensitization [HTRS]). We have also found that the induction of HTRS involves plasticity in the neural network controlling sympathetic drive. The induction and maintenance of the latent HTRS state also require the functional integrity of the brain renin-angiotensin-aldosterone system and the presence of several central inflammatory factors. In this review, we will discuss the induction and expression of HTRS in adult animals and in the progeny of mothers with prenatal obesity/overnutrition or with maternal gestational hypertension. Also, interventions that reverse the effects of stressor-induced HTRS will be reviewed. Understanding the mechanisms underlying HTRS and identifying the beneficial effects of maternal or offspring early-life interventions that prevent or reverse the sensitized state can provide insights into therapeutic strategies for interrupting the vicious cycle of transgenerational hypertension.

Multiwalled Carbon Nanotubes Alter the PSII Photochemistry, Photosystem-Related Gene Expressions, and Chloroplastic Antioxidant System in Zea mays under Copper Toxicity.

A critical approach against copper (Cu) toxicity is the use of carbon nanomaterials (CNMs). However, the effect of CNMs on Cu toxicity-exposed chloroplasts is not clear. The photosynthetic, genetic, and biochemical effects of multiwalled carbon nanotubes (50-100-250 mg L-1 CNT) were investigated under Cu stress (50-100 μM CuSO4) in Zea mays chloroplasts. Fv/Fm and Fv/Fo were suppressed under stress. Stress altered the antioxidant system and the expression of psaA, psaB, psbA, and psbD. The chloroplastic activities of superoxide dismutase (SOD), ascorbate peroxidase (APX), glutathione S-transferase (GST), and glutathione peroxidase (GPX) increased under CNT + stress, and those of hydrogen peroxide (H2O2) and lipid peroxidation decreased. CNTs were promoted to the maintenance of the redox state by regulating enzyme/non-enzyme activity/contents involved in the AsA-GSH cycle. Furthermore, CNTs inverted the negative effects of Cu by upregulating the transcriptions of photosystem-related genes. However, the high CNT concentration had adverse effects on the antioxidant capacity. CNT has great potential to confer tolerance by reducing Cu-induced damage and protecting the biochemical reactions of photosynthesis.

Freedom As and Against Democracy

Freedom As and Against Democracy

Decoherence and maintenance of an entangled state in three-spin system coupled to ferromagnetic electrodes

We study the model of three-spin system by using Born-Markov master equation for density matrix. Three-spin system consists of a spin-1/2 quantum dot and two spin-1 magnetic particles arranged in triangular geometry and a quantum dot is also tunnel-coupled to ferromagnetic electrodes, respectively. In this case, we are interested in decoherence of entangled state of the system. Decoherence occurs due to tunneling of electrons through coupling to ferromagnetic electrodes. Therefore, an entangled state undergoes decoherence dependent on the spin polarization as well as magnetization orientations of electrodes. We have established master-equation formalism for the density matrix of three-spin system and calculated spin-spin correlation function between two magnetic particles corresponding to entangled state. The results show that with the increase of spin polarization, spin-spin correlation function for parallel configuration of electrodes’ magnetizations decays more rapidly, while spin-spin correlation function for antiparallel configuration decays more slowly.

Improvement of Oral Absorption of Poorly Water-Soluble Drugs by Solid Dispersions with Amphiphilic Phospholipid Polymer

Solid dispersions are one of methods for solubilizing water-insoluble drugs. To enhance the bioavailability, maintenance of the supersaturated state and absorption of the dissolved drug in the gastrointestinal tract are important. We designed and synthesized amphiphilic 2-methacryloyloxyethyl phosphorylcholine (MPC) copolymers as carriers for solid dispersions and evaluated the dissolution behavior in test solutions with different pH and additives. Solid dispersion of troglitazone with amphiphilic MPC copolymers having both aromatic rings and urethane bonds in the side chains showed rapid dissolution and excellent supersaturation maintenance. It was indicated that the balance between the interactions with drug molecules and the water affinity of the polymer should be considered when carriers for solid dispersions are designed. In addition, cell membrane permeability of the solid dispersion with the amphiphilic MPC copolymer was evaluated by the Dissolution / Permeation system, which consists of two liquid chambers and a monolayer of epithelial cells that mimics the intestinal dissolution and permeation process. Further, blood concentration of the drug when solid dispersions were orally administered in mice was also evaluated. The cell membrane permeability and oral absorbability were significantly improved, compared to the solid dispersions with poly(N-vinylpyrrolidone) and suspension or solution of crystalline troglitazone.

The effects of continuous exposure to low-dose chlorine dioxide gas on the characteristics of induced pluripotent stem cells.

BackgroundRecently, various regenerative therapies have been developed based on induced pluripotent stem (iPS) cells. However, hygienic control strategies have not been established at the manufacturing facilities. We aimed to evaluate the safety and effects of continuous exposure to low-dose chlorine dioxide (ClO2) gas on cell fates, and to determine the optimum dose for safe usage of this disinfectant.MethodsWe cultured an iPS cell line in the absence or presence of various doses of ClO2 gas. We evaluated cell proliferation, cell death, the maintenance of undifferentiated state, and cell senescence.ResultsWe found that iPS cell proliferation was not affected by 0.05 or 0.1 ppmv ClO2 gas in the atmosphere. Although 0.1 ppmv ClO2 slightly affected apoptosis, it was not a significant effect. Moreover, neither at 0.05 nor 0.1 ppmv ClO2 gas significantly affected the characteristics of iPS cells.Discussion and conclusionContinuous exposure to 0.05 or 0.1 ppmv ClO2 gas did not affect the fate of iPS cells. These results may contribute to the development of new strategies for hygiene control in cell processing facilities.