Unbalanced Activity Research Articles

The relationship between cardiovagal baroreflex and cerebral autoregulation in postural orthostatic tachycardia disorder using advanced cross-correlation function

Postural orthostatic tachycardia syndrome (POTS) presents excessive orthostatic tachycardia and orthostatic intolerance. POTS is a common and therapeutically challenging condition affecting numerous people worldwide. As many disease entities can be confused with POTS, it becomes critical to identify this syndrome. Moreover, unbalanced autonomic nervous activity can induce cardiovascular diseases and influence the bio-feedback mechanism: Baroreflex (BR) and cerebral autoregulation (CA). BR and CA are important bio-mechanisms that maintain a stable circulatory system via the autonomic nervous system. Therefore, an impaired autonomic nervous system would lead to imbalanced BRS and CA. Consequently, we propose an advanced cross-correlation function (ACCF) time-domain approach to analyze baroreflex and cerebral autoregulation using physiological signals. This study assesses relation changes in BR and CA using ACCF in POTS for early clinical detection and diagnosis. The ACCF analysis results has thresholds that reveal that the BR of healthy and POTS groups present significantly different maximum CCF values (p < 0.05). The complete CCF index shows that the BR phase changes significantly into phase lag in the POTS group. Although CA analysis using the maximum CCF index was mildly weak, it did not differ in the POTS group. Thus, POTS only affects BR. An increasing sympathetic activity might induce an unbalanced baroreflex effect and increase cerebral vasomotor tone with CA. Maximum CCF value correlation coefficients between BR and CA indicated positive in POTS groups and negative in the healthy group. It could be speculated that the sympathetic nervous system compensates to improve BR function, which remains CA function. The advantage of this ACCF algorithm is that it helps observe BR and CA for early detection.

Epidermal Growth Factor Intralesional Delivery in Chronic Wounds: The Pioneer and Standalone Technique for Reversing Wound Chronicity and Promoting Sustainable Healing.

The early expectations about growth factors' (GFs') discovery as an undisputed therapeutic solution for chronic wounds progressively eclipsed when they failed to accelerate acute wound closure and restore the healing trajectory of stagnant ulcers. Critical knowledge about chronic wound biology and GF pharmacology was a conundrum at that time. Diabetes undermines keratinocytes' and fibroblasts' physiology, impairing skin healing abilities. Diabetic ulcers, as other chronic wounds, are characterized by hyperinflammation, unbalanced proteolytic activity, catabolism, and free radical cytotoxicity. This hostile scenario for the chemical stability, integrity, and functionality of GFs led to the conclusion that topical administration may jeopardize GFs' clinical effectiveness. Epidermal growth factor (EGF) has a proximal position in tissues homeostasis by activating survival and mitogenic pathways from embryonic life to adulthood. Seminal experiments disclosed unprecedented pharmacological bounties of parenterally administered EGF. Accordingly, the experience accumulated for more than 20 years of EGF intralesional infiltration of diabetic wound bottoms and edges has translated into sustained healing responses, such as low recurrences and amputation rates. This delivery route, in addition to being safe and tolerated, has shown to restore a variety of circulating biochemical markers ordinarily disturbed in diabetic conditions. EGF infiltration triggers a cascade of local fibroblast reactions, supporting its molecular integrity, prolonged mean residence time, and ultimately eliciting its receptor trafficking and nuclear translocation. The intralesional delivery route seems to warrant that EGF reaches wound fibroblasts' epigenetic core, mitigating the consequences of metabolic memory imprinting.

HUBUNGAN ASUPAN MAKAN, DURASI TIDUR DAN AKTIVITAS FISIK DENGAN STATUS GIZI KARYAWAN TOKO RITEL KOTA BATAM TAHUN 2023

Background: Nutritional status remains a global issue, including in Indonesia. Nutritional status is influenced by several factors, namely food intake, sleep duration, and unbalanced physical activity, which can lead to either excessive or insufficient nutritional status. This study aims to investigate the relationship between dietary intake, sleep duration, and physical activity with the nutritional status of retail store employees in Batam City in 2023. Methods: This research is a cross-sectional analytical study with accidental sampling technique involving 60 samples. Food intake is measured using a semi-qualitative Food Frequency Questionnaire (FFQ), sleep duration is measured using a questionnaire on average weekly sleep duration, physical activity is measured using the Global Physical Activity Questionnaire (GPAQ), and nutritional status is measured using the Body Mass Index (BMI) by measuring weight and height. Data analysis using correlation gamma test. Results: The correlation gamma test results indicate a significant relationship between food intake and nutritional status with a p-value of 0.000 (p ≤ 0.05)(r=0,919). However, the relationship between sleep duration and nutritional status resulted in a p-value of 0.137 (p &gt; 0.05)(r = -0,284), and the relationship between physical activity and nutritional status resulted in a p-value of 0.758 (p&gt;0.05)(r = -0,067). Conclusion: There is a significant relationship between food intake and the nutritional status of retail store employees in Batam City in 2023. However, there is no significant relationship between sleep duration, physical activity, and the nutritional status of retail store employees in Batam City in 2023. Keywords: Nutritional Status, Food Intake, Sleep Duration, Physical Activity

Transglutaminase2: An Enduring Enzyme in Diabetes and Age-Related Metabolic Diseases

Tissue transglutaminase2 (TG2) has emerged as a key enigmatic protein in the development of various metabolic and age-related diseases. It catalyzes covalent cross-linking of countless proteins and provides strength to the extracellular matrix and resistance to proteolytic degradation via different pathways, including NF-kβ, TGF-β and PI3K/Akt as the major signaling pathways. The etiology of diabetes and associated diseases has been found to be linked to unbalanced TG2 activity that may not only result in impaired or delayed wound healing in diabetics but also worsen degenerative and metabolic disease conditions. TG2 is usually overexpressed in diabetes, fibrosis, cancer, and neurodegenerative disorders. These TG2-linked diseases are usually associated with prolonged activation of inflammatory pathways. Therefore, reducing the inflammatory mechanisms and improving tissue remodeling appear to be the main treatment strategies to exterminate TG2-linked diseases. The present review aims to deliver a detailed overview of the existing understanding of TG2 in diabetes and associated diseases’ progression, as well as treatment strategies to regulate TG2 tightly and its potential clinical applications. Our research endorses the notion that TG2 can serve as an effective early-stage diagnostic biomarker for metabolic diseases and a therapeutic target for the development of potential drug.

Prefrontal Regulation of Safety Learning during Ethologically Relevant Thermal Threat.

Learning and adaptation during sources of threat and safety are critical mechanisms for survival. The prelimbic (PL) and infralimbic (IL) subregions of the medial prefrontal cortex (mPFC) have been broadly implicated in the processing of threat and safety. However, how these regions regulate threat and safety during naturalistic conditions involving thermal challenge still remains elusive. To examine this issue, we developed a novel paradigm in which adult mice learned that a particular zone that was identified with visuospatial cues was associated with either a noxious cold temperature ("threat zone") or a pleasant warm temperature ("safety zone"). This led to the rapid development of avoidance behavior when the zone was paired with cold threat or approach behavior when the zone was paired with warm safety. During a long-term test without further thermal reinforcement, mice continued to exhibit robust avoidance or approach to the zone of interest, indicating that enduring spatial-based memories were formed to represent the thermal threat and thermal safety zones. Optogenetic experiments revealed that neural activity in PL and IL was not essential for establishing the memory for the threat zone. However, PL and IL activity bidirectionally regulated memory formation for the safety zone. While IL activity promoted safety memory during normal conditions, PL activity suppressed safety memory especially after a stress pretreatment. Therefore, a working model is proposed in which balanced activity between PL and IL is favorable for safety memory formation, whereas unbalanced activity between these brain regions is detrimental for safety memory after stress.

Oncostatin M and STAT3 Signaling Pathways Support Human Trophoblast Differentiation by Inhibiting Inflammatory Stress in Response to IFNγ and GM-CSF.

Interleukin-6 (IL-6) superfamily cytokines play critical roles during human pregnancy by promoting trophoblast differentiation, invasion, and endocrine function, and maintaining embryo immunotolerance and protection. In contrast, the unbalanced activity of pro-inflammatory factors such as interferon gamma (IFNγ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) at the maternal-fetal interface have detrimental effects on trophoblast function and differentiation. This study demonstrates how the IL-6 cytokine family member oncostatin M (OSM) and STAT3 activation regulate trophoblast fusion and endocrine function in response to pro-inflammatory stress induced by IFNγ and GM-CSF. Using human cytotrophoblast-like BeWo (CT/BW) cells, differentiated in villous syncytiotrophoblast (VST/BW) cells, we show that beta-human chorionic gonadotrophin (βhCG) production and cell fusion process are affected in response to IFNγ or GM-CSF. However, those effects are abrogated with OSM by modulating the activation of IFNγ-STAT1 and GM-CSF-STAT5 signaling pathways. OSM stimulation enhances the expression of STAT3, the phosphorylation of STAT3 and SMAD2, and the induction of negative regulators of inflammation (e.g., IL-10 and TGFβ1) and cytokine signaling (e.g., SOCS1 and SOCS3). Using STAT3-deficient VST/BW cells, we show that STAT3 expression is required for OSM to regulate the effects of IFNγ in βhCG and E-cadherin expression. In contrast, OSM retains its modulatory effect on GM-CSF-STAT5 pathway activation even in STAT3-deficient VST/BW cells, suggesting that OSM uses STAT3-dependent and -independent mechanisms to modulate the activation of pro-inflammatory pathways IFNγ-STAT1 and GM-CSF-STAT5. Moreover, STAT3 deficiency in VST/BW cells leads to the production of both a large amount of βhCG and an enhanced expression of activated STAT5 induced by GM-CSF, independently of OSM, suggesting a key role for STAT3 in βhCG production and trophoblast differentiation through STAT5 modulation. In conclusion, our study describes for the first time the critical role played by OSM and STAT3 signaling pathways to preserve and regulate trophoblast biological functions during inflammatory stress.

Penegakan Hukum Bagi Pelaku Tindak Pidana Kekerasan Seksual Terhadap Anak (Studi Kasus Putusan Nomor 482/Pid.Sus/2021/PN)

Introduction: sexual deviation where this leads to an unbalanced activity that poses a threat to certain individuals. Various kinds of sexual choices are being discussed in cases of violence, especially against children. Causing a deterrent effect is felt to be less able to have such a significant impact because the perpetrator of the psychological deviation is not only one child. The decision given by the court is very necessary to provide a deterrent effect to perpetrators of sexual violence against children, so that the incidence of sexual violence in Indonesia is decreasing.Purposes of the Research: The purpose of this study is to provide an overview of law enforcement in Indonesia against perpetrators of sexual violence against children, and to provide an overview of the role of law enforcement officers in taking action against perpetrators of sexual violence against children. Methods of the Research: The research method used in this paper consists of various methods and activities carried out in order to collect the data and materials needed to complete the preparation of the. The author uses a normative juridical research method.Result of the Research: The results of this study are that the District Court's decision only considers the elements that are fulfilled and the ability to equip criminal acts that elevate while in the High Court's decision it considers the consequences obtained by the victim's child and the victim's family where the victim's child and family enjoy shame, costs to care for, enlarge and educate the child to be born by the victim's child, besides the decision given by the high court 2 (two) years higher than the decision of the District Court aims to provide a deterrent effect and awareness of the actions committed by those who have destroyed the future victim's child.

The essential role of the ERK activation in large T antigen of BK polyomavirus regulated cell migration

Recent studies have suggested that BK polyomavirus (BKPyV) may be associated with the development of urothelial carcinoma. In Merkel cell carcinoma, TAg and tAg are the major viral proteins of Merkel cell polyomavirus with oncogenic potential. In this study, we aimed to distinguish the role of TAg and tAg in cell migration. Our result demonstrated that ERK was phosphorylated in human renal tubular cells expressing its TAg and tAg after BKPyV infection. Treatment with the ERK inhibitor U0126 suppressed BKPyV gene expression and reduced BKPyV replication. Both TAg and tAg induced cell migration via ERK-dependent signaling. Furthermore, the expression of TAg and tAg had a significant regulatory effect on focal adhesion molecules in renal proximal tubular cells, which strongly suggests that alterations in the focal adhesion complexes are critically involved in TAg and tAg-induced cell migration. Gelatin zymography profiling revealed that TAg regulates the expression and activity of MMP-2 and MMP-9, but not tAg. Interestingly, TAg regulates the expression and activity of MMP-9 through ERK signaling, whereas MMP-2 is regulated through an ERK-independent pathway. Unbalanced ERK pathway activity is frequently observed in many cancers, while MMP proteins are usually overexpressed in aggressive tumors. These findings support the view that BKPyV is an oncogenic virus.

Analyzing synergistic effects of tourist attractions on sustainable development of neighborhoods with emphasis on urban smart growth principles

ABSTRACT Despite the spatial effects of tourist attractions in promoting smart growth principles in tourist cities, it is necessary to pay attention to the spatial synergy between tourist attractions in order to control their destructive spatial effects and realize sustainable development (SD) in tourist cities. In this research, based on smart growth measures, the necessity of spatial synergy between tourist attractions in sustainable neighborhood development is explained using innovative spatial statistical analysis methods at the scale of 469 neighborhood units of Mashhad city. The findings of the research confirm significant synergistic effect of tourist attractions on urban smart growth indicators and composite indicator of smart growth of the surrounding neighborhood units. On the other hand, lack of spatial synergy between Mashhad’s main tourist attraction in the city center and other tourist attractions leads to unbalanced residential and activity development and unbalanced distribution of tourism services. This issue prevents integrated realization of smart growth and SD of all neighborhood units in Mashhad.

Single-cell deep phenotyping of cytokine release unmasks stimulation-specific biological signatures and distinct secretion dynamics

Cytokines are important mediators of the immune system, and their secretion level needs to be carefully regulated, as an unbalanced activity may lead to cytokine release syndromes. Dysregulation can be induced by various factors, including immunotherapies. Therefore, the need for risk assessment during drug development has led to the introduction of cytokine release assays (CRAs). However, the current CRAs offer little insight into the heterogeneous cellular dynamics. To overcome this limitation, we developed an advanced single-cell microfluidic-based cytokine secretion platform to quantify cytokine secretion on the single-cell level dynamically. Our approach identified different dynamics, quantities, and phenotypically distinct subpopulations for each measured cytokine upon stimulation. Most interestingly, early measurements after only 1h of stimulation revealed distinct stimulation-dependent secretion dynamics and cytokine signatures. With increased sensitivity and dynamic resolution, our platform provided insights into the secretion behavior of individual immune cells, adding crucial additional information about biological stimulation pathways to traditional CRAs.

Slow twitch paraspinal muscle dysregulation in adolescent idiopathic scoliosis exhibiting HIF-2α misexpression.

Adolescent idiopathic scoliosis (AIS) refers to a three-dimensional spinal deformity which has a typical onset during adolescence. In most cases, the cause of the deformity cannot be clearly identified. Unbalanced paraspinal muscle activity in AIS patients was reported and hypoxia was implicated to regulate myogenesis. This study aims to investigate the association between myogenesis/muscle toning and HIF-αs activity in the pathogenesis of AIS. HIF-αs expression was examined by enzyme-linked immunosorbent assay and western blot in paraspinal myoblasts isolated from 18 subjects who underwent deformity correction surgery. QPCR was conducted to measure the gene expression levels of perinatal muscle fiber markers MYH3, MYH8; slow twitch muscle fiber markers MHY7; fast twitch muscle fiber markers MYH4; and myogenic regulatory factors MYF5 and MYOG. Slow and fast twitch muscle fiber composition in concave/convex paraspinal musculature of AIS subjects was evaluated by immunostaining of myosin heavy chain type I (MyHC I) and myosin heavy chain type II (MyHC II). Reduced HIF-2α induction under hypoxia was found in paraspinal myoblast culture of 33% AIS subjects. We detected a suppression of perinatal and slow twitch muscle fiber associated genes, but not fast twitch muscle fiber-associated genes and myogenic regulatory factors in HIF-2α misexpressed AIS myoblasts. Distinct reduction of slow twitch muscle fiber was evidenced in convex paraspinal musculature, suggesting an asymmetric expression of slow twitch muscle fiber in HIF-2α misexpressed AIS patients. This study indicates an association of abnormal HIF-2α expression in paraspinal myoblasts and a disproportionate slow twitch muscle fiber content in the convexity of the curvature in a subset of AIS subjects, suggesting HIF-2α dysregulation as a possible risk factor for AIS. The role of HIF-2α in paraspinal muscle function during spinal growth and its relevance in AIS prognosis warrants further investigation.

Regulator of telomere elongation helicase 1 gene and its association with malignancy.

With the progression of next-generation sequencing technologies, researchers have identified numerous variants of the regulator of telomere elongation helicase 1 (RTEL1) gene that are associated with a broad spectrum of phenotypic manifestations, including malignancies. At the molecular level, RTEL1 is involved in the regulation of the repair, replication, and transcription of deoxyribonucleic acid (DNA) and the maintenance of telomere length. RTEL1 can act both as a promotor and inhibitor of tumorigenesis. Here, we review the potential mechanisms implicated in the malignant transformation of tissues under conditions of RTEL1 deficiency or its aberrant overexpression. A major hemostatic challenge during RTEL1 dysfunction could arise from its unbalanced activity for unwinding guanine-rich quadruplex DNA (G4-DNA) structures. In contrast, RTEL1 deficiency leads to alterations in telomeric and genome-wide DNA maintenance mechanisms, ribonucleoprotein metabolism, and the creation of an inflammatory and immune-deficient microenvironment, all promoting malignancy. Additionally, we hypothesize that functionally similar molecules could act to compensate for the deteriorated functions of RTEL1, thereby facilitating the survival of malignant cells. On the contrary, RTEL1 over-expression was directed toward G4-unwinding, by promoting replication fork progression and maintaining intact telomeres, may facilitate malignant transformation and proliferation of various pre-malignant cellular compartments. Therefore, restoring the equilibrium of RTEL1 functions could serve as a therapeutic approach for preventing and treating malignancies.

Bimodal antibody-titer decline following BNT162b2 mRNA anti-SARS-CoV-2 vaccination in healthcare workers of the INT – IRCCS “Fondazione Pascale” Cancer Center (Naples, Italy)

BackgroundBoth SARS-CoV-2 mRNA-based vaccines [BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)] have shown high efficacy, with very modest side effects in limiting transmission of SARS-CoV-2 and in preventing the severe COVID-19 disease, characterized by a worrying high occupation of intensive care units (ICU), high frequency of intubation and ultimately high mortality rate. At the INT, in Naples, only the BNT162b2/Pfizer vaccine has been administered to cancer patients and healthcare professionals aged 16 and over. In the present study, the antibody response levels and their decline were monitored in an interval of 6–9 months after vaccine administration in the two different cohorts of workers of the INT – IRCCS "Fondazione Pascale" Cancer Center (Naples, Italy): the group of individuals previously infected with SARS-CoV-2 and vaccinated with a single dose; and that of individuals negative for previous exposure to SARS-CoV-2 vaccinated with two doses 21 days apart.MethodsSpecific anti-RBD (receptor-binding domain) titers against trimeric spike glycoprotein (S) of SARS-CoV-2 by Roche Elecsys Anti-SARS-CoV-2 S ECLIA immunoassay were determined in serum samples of 27 healthcare workers with a previously documented history of SARS-CoV-2 infection and 123 healthcare workers without, during antibody titers’ monitoring. Moreover, geometric mean titers (GMT) and relative fold changes (FC) were calculated.ResultsBimodal titer decline was observed in both previously infected and uninfected SARS-CoV-2 subjects. A first rapid decline was followed by a progressive slow decline in the 6/9 month-period before the further vaccine boost. The trend was explained by 2 different mathematical models, exponential and power function, the latter revealing as predictive of antibody titer decline either in infected or in not previously infected ones. The value of the prolonged lower vaccine titer was about 1 log below in the 6/9-month interval after the single dose for previously infected individuals with SARS-CoV-2 and the two doses for those not previously infected. The titer change, after the boost dose administration, on the other hand, was ≥ 1.5 FC higher than the titers at the 6/9-month time-points in both cohorts. A similar quantitative immune titer was observed in both cohorts 8 days after the last boost dose. The subsequent immunoresponse trend remains to be verified.DiscussionThe results show that a very rapid first decline, from the highest antibody peak, was followed by a very slow decline which ensured immune protection lasting more than 6 months. The apparent absence of adverse effects of the rapid decline on the vaccine's immune protective role has been related to a large majority of low avidity antibodies induced by current vaccines. High avidity antibodies with prolonged anti-transmission efficacy show a longer half-life and are lost over a longer interval period. The cellular immunity, capable of preventing severe clinical diseases, lasts much longer. The unbalanced dual activity (cellular vs humoral) while effective in limiting ICU pressure and overall mortality, does not protect against transmission of SARS-CoV-2, resulting in high circulation of the virus among unvaccinated subjects, including the younger population, and the continuous production of variants characterized by changes in transmissibility and pathogenicity. The high mutation rate, peculiar to the RNA virus, can however lead to a dual opposite results: selection of defective and less efficient viruses up to extinction; risk of more efficiently transmitted variants as the current omicron pandemic.ConclusionsIn conclusion the current bimodal antibody-titer decline, following BNT162b2 mRNA anti-SARS-CoV-2 vaccination, needs a further extended analysis to verify the protective borderline levels of immunity and the optimal administration schedule of vaccine boosters. Our current results can contribute to such goal, besides a direct comparison of other FDA-approved and candidate vaccines.

Abstract 3033: Glucose deprivation promotes lung adenocarcinoma de-differentiation due to unbalanced EZH2 activity

Abstract Lung cancer is the most frequent cancer-related cause of death, and adenocarcinoma (LUAD) is the most frequent type. Despite the recent success of immunotherapies, survival of lung cancer patients has not significantly improved in the last decades. New therapies are necessary. We have previously identified sodium-glucose transporter 2 (SGLT2) as the major responsible for glucose uptake in LUAD, and we have showed that treatment with SGLT2 inhibitors significantly delays LUAD development and prolongs survival in murine models. However, our data shows that SGLT2 inhibitors also induce de-differentiation of LUAD cells, leading to a more aggressive phenotype and increased resistance to cisplatin. Glucose deprivation causes reduced αKG levels, leading to reduced activity of αKG-dependent histone demethylases and consequent histone hypermethylation. Supplementation of αKG or inhibition of the histone methyltransferase EZH2 reverse this phenotype, suggesting that this de-differentiated phenotype depends on insufficiency of αKG-dependent histone demethylases and unbalanced EZH2 activity. Consistently, double treatment with an SGLT2 inhibitor and an EZH2 inhibitor significantly reduces the tumor burden in a genetically engineered murine model of LUAD. We further characterized the effect of low glucose-induced tumor de-differentiation, identifying stabilization of hypoxia inducible factor 1α (HIF1α) as a major pathway responsible for the acquisition of a more aggressive phenotype following glucose deprivation. Finally, we identified an HIF1α-dependent transcriptional signature with prognostic significance in human LUAD. Our studies further our knowledge of the relationship between glucose metabolism and cell differentiation in cancer, characterizing the epigenetic adaptation of cancer cells to nutrient deprivation and identifying novel targets to prevent the development of resistance to metabolic therapies. Citation Format: Pasquale Saggese, Aparamita Pandey, Eileen Fung, Giorgio Giurato, Alessandro Weisz, Steven M. Dubinett, Claudio Scafoglio. Glucose deprivation promotes lung adenocarcinoma de-differentiation due to unbalanced EZH2 activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3033.

Effects of Chronic Hypoxic Environment on Cognitive Function and Neuroimaging Measures in a High-Altitude Population.

ObjectiveThis study aimed to investigate the effects of long-term hypoxic environment exposure on cognitive ability and neuroimaging characteristics in a highland population in China.MethodsHealth system workers in Maduo County (4,300 m above sea level) and Minhe County (1,700 m above sea level) were selected as research participants and divided into a high-altitude (HA) group and low-altitude (LA) group, respectively. Cognitive ability was assessed using the Montreal Cognitive Assessment (MoCA), Verbal Fluency Test (VFT), Symbol Digit Modalities Test (SDMT), Trail Making Test A and B (TMT), Digit Span Test (DST), and Rey Auditory Verbal Learning Test (RAVLT). All participants underwent a magnetic resonance imaging (MRI) scan, resting state functional MRI scan, and diffusion tensor imaging to clarify changes in regional gray matter (GM) volume, anisotropy index (FA), local consistency (ReHo), and low-frequency oscillation amplitude (ALFF).ResultsThe HA group had significantly lower MoCA, DST, VFT, RAVLT, and TMT scores compared to the control group. No significant differences were found in SDMT score. Furthermore, compared to the LA group, the HA group had significantly lower GM density of the left olfactory cortex, right medial orbital superior frontal gyrus, bilateral insula, left globus pallidus, and temporal lobe (left superior temporal gyrus temporal pole, bilateral middle temporal gyrus temporal pole, and right middle temporal gyrus). In terms of FA, compared with the LA group, the HA group had lower values for the corpus callosum, corpus callosum knee, bilateral radiative corona, and left internal capsule. The HA group had lower ALFF values of the left cerebellum, left putamen, left orbital inferior frontal gyrus, and left precuneus, but higher ALFF values of the left fusiform gyrus, bilateral inferior temporal gyrus, left orbital superior frontal gyrus and medial superior frontal gyrus, compared to the LA group. There was no significant group difference in ReHo values.ConclusionOur findings suggest that a chronic hypoxic environment can induce extensive cognitive impairment. Decreased GM density in multiple brain regions, damaged nerve fibers, and unbalanced neuronal activity intensity in different brain regions may be the structural and functional basis of cognitive impairment due to hypoxia.

Glycogen Synthase Kinase 3: Ion Channels, Plasticity, and Diseases.

Glycogen synthase kinase 3β (GSK3) is a multifaceted serine/threonine (S/T) kinase expressed in all eukaryotic cells. GSK3β is highly enriched in neurons in the central nervous system where it acts as a central hub for intracellular signaling downstream of receptors critical for neuronal function. Unlike other kinases, GSK3β is constitutively active, and its modulation mainly involves inhibition via upstream regulatory pathways rather than increased activation. Through an intricate converging signaling system, a fine-tuned balance of active and inactive GSK3β acts as a central point for the phosphorylation of numerous primed and unprimed substrates. Although the full range of molecular targets is still unknown, recent results show that voltage-gated ion channels are among the downstream targets of GSK3β. Here, we discuss the direct and indirect mechanisms by which GSK3β phosphorylates voltage-gated Na+ channels (Nav1.2 and Nav1.6) and voltage-gated K+ channels (Kv4 and Kv7) and their physiological effects on intrinsic excitability, neuronal plasticity, and behavior. We also present evidence for how unbalanced GSK3β activity can lead to maladaptive plasticity that ultimately renders neuronal circuitry more vulnerable, increasing the risk for developing neuropsychiatric disorders. In conclusion, GSK3β-dependent modulation of voltage-gated ion channels may serve as an important pharmacological target for neurotherapeutic development.

Abstract P1-07-07: Endoresist: Prognostic and predictive gene profiles in endocrine-resistant breast cancers

Abstract Background:. Up to 75% of breast cancer patients have tumors expressing the predictive biomarker estrogen receptor alpha (ER) and are consequently offered endocrine therapy. Approximately one third eventually relapse in their disease with the majority still expressing ER but resistant to one or several types of endocrine-based therapies. Molecular studies of ER-signaling suggest several potential factors influencing endocrine response such as ER structural and functional domains, posttranslational modifications and unbalanced receptor and co-regulator activity with alterations in downstream signaling pathways. However, the mechanism behind endocrine resistance is elusive and tumor cell expression of ER is the only clinically utilized biomarker for endocrine therapeutic response. This calls for a broader understanding of the resistance process in order to develop novel tools for therapy prediction and treatment alternatives. This study aims to improve our understanding of the underlying mechanism behind endocrine resistance and to identify biomarkers for an individualized approach to cancer therapy. Materials and methods:. A cohort comprising verified endocrine-resistant early breast cancer diagnosed in 2005-2006 and 2008-2014 at the Karolinska University Hospital, Stockholm, Sweden was retrospectively collected. Patients with ER+ and human epidermal growth factor receptor 2 (HER2)- primary breast cancer who had an ER+/HER2- relapse tumor during ongoing endocrine therapy (&amp;lt;5 years from diagnosis) were included as cases, with both primary tumors (n=68) and relapse tumors (n=67). A control cohort was selected consisting of patients with ER+/HER2- early breast cancer diagnosed in 2005, without relapse or disease progression at 10 years of follow-up (n=78), and matched to cases (2:1 ratio) by age and tumor stage. To determine the transcriptomic and genomic profiles, RNA and DNA were extracted from archived formalin-fixed paraffin-embedded tumor tissue. RNA samples were analyzed using Affymetrix DNA Microarray with Clariom D Chip and assessed through Transcriptome Array Console and R. DNA was analyzed through panel sequencing (GMCK gene panel consisting of 370 genes and a size of 2,4 Mb intended for genetic screening of solid tumors) with following assessments in R. Results:. The preliminary transcriptomic analysis showed several differentially expressed pathways and specific genes that differentiate both the primary tumors of cases that eventually relapse during endocrine therapy compared to controls, as well as between the cases’ relapses and their corresponding primary tumors. Intrinsic analyses show upregulation in tumor-driving pathways such as PI3K signaling pathway, androgen receptor and cell adhesion pathways in primary tumors of cases versus controls. This has further been investigated by gene analysis where genes such as PIK3CA, PTEN, CDK4/6 and ESR1 were upregulated between the groups. In the analysis of relapses compared to their primary tumors, pathways involving apoptosis and response to hypoxia were downregulated as well as specific genes such as IGF1R, whereas pathways including immune response were upregulated. Conclusion:. Our study suggests that endocrine resistant tumors are associated with distinct genomic and transcriptomic profiles that potentially could be utilized as predictive and prognostic markers for endocrine resistant breast cancer. These preliminary results can guide further investigations deciphering the mechanisms of endocrine resistance in breast cancer. This trial is a non-interventional study set up as a research collaboration between Karolinska Institutet and Novartis Sweden AB. Citation Format: Caroline Schagerholm, Stephanie Robertson, Barbro Holm, Karolina Lindberg, Emmanouil Sifakis, Linnea Hases, Cecilia Williams, Johan Hartman. Endoresist: Prognostic and predictive gene profiles in endocrine-resistant breast cancers [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-07-07.

Gut Microbiome and Neuroinflammation in Hypertension.

Hypertension is a worldwide problem with major impacts on health including morbidity and mortality, as well as consumption of health care resources. Nearly 50% of American adults have high blood pressure, and this rate is rising. Even with multiple antihypertensive drugs and aggressive lifestyle modifications, blood pressure is inadequately controlled in about 1 of 5 hypertensive individuals. This review highlights a hypothesis for hypertension that suggests alternative mechanisms for blood pressure elevation and maintenance. A better understanding of these mechanisms could open avenues for more successful treatments. The hypothesis accounts for recent understandings of the involvement of gut physiology, gut microbiota, and neuroinflammation in hypertension. It includes bidirectional communication between gut microbiota and gut epithelium in the gut-brain axis that is involved in regulation of autonomic nervous system activity and blood pressure control. Dysfunction of this gut-brain axis, including dysbiosis of gut microbiota, gut epithelial dysfunction, and deranged input to the brain, contributes to hypertension via inflammatory mediators, metabolites, bacteria in the circulation, afferent information alterations, etc resulting in neuroinflammation and unbalanced autonomic nervous system activity that elevates blood pressure. This in turn negatively affects gut function and its microbiota exacerbating the problem. We focus this review on the gut-brain axis hypothesis for hypertension and possible contribution to racial disparities in hypertension. A novel idea, that immunoglobulin A-coated bacteria originating in the gut with access to the brain could be involved in hypertension, is raised. Finally, minocycline, with its anti-inflammatory and antimicrobial properties, is evaluated as a potential antihypertensive drug acting on this axis.

Thyroid-Stimulating Hormone Favors Runx2-Mediated Matrix Mineralization in HOS and SaOS2 Cells: An In Vitro and In Silico Approach.

Osteoporosis is a skeletal disease that is both systemic and silent characterized by an unbalanced activity of bone remodeling leading to bone loss. Rising evidences demonstrate that thyroid stimulating hormone (TSH) has an important role in the regulation on the metabolism of bone. However, TSH regulation on human osteoblast essential transcriptional factors has not been identified. Current study examined the role of TSH on human osteoblastic Runx2 expression and their functional genes by in vitro and in slico analysis. Human osteoblast like (HOS and SaoS-2) cells were cultured with DMEM and treated with hTSH at the concentration of 0.01 ng/mL and 10 ng/mL. After treatment, osteoblastic Runx2 and IGF-1R beta expression were studied using RT-PCR and western blot analysis. TSH treatment induced osteoblastic essential transcriptional factor, Runx2 in HOS and SaOS2 cells on 48 h duration and elevated the expression of IGF-IR β gene and Protein in SaoS-2 cells. TSH also promotes Runx2 responsive genes such as ALP, Collagen and osteocalcin in SaOS2 cells on day 2 to day 14 of 10 ng/mL of treatment and favors’ matrix mineralization matrix in these cells. In addition, TSH facilitated human osteoblastic cells to mineralize their matrix confirmed by day 21 of alizarin red calcium staining. In silico study was performed to check CREB and ELK1 interaction with Runx2. Results of in silico analysis showed that TSH mediated signalling molecules such as CREB and ELK1 showed interaction with Runx2 which involve in osteobalstic gene expression and differentiation. Present findings confirm that TSH promotes Runx2 expression, osteoblastic responsive genes and bone matrix formation.

Glycerol suppresses glucose consumption in trypanosomes through metabolic contest.

Microorganisms must make the right choice for nutrient consumption to adapt to their changing environment. As a consequence, bacteria and yeasts have developed regulatory mechanisms involving nutrient sensing and signaling, known as "catabolite repression," allowing redirection of cell metabolism to maximize the consumption of an energy-efficient carbon source. Here, we report a new mechanism named "metabolic contest" for regulating the use of carbon sources without nutrient sensing and signaling. Trypanosoma brucei is a unicellular eukaryote transmitted by tsetse flies and causing human African trypanosomiasis, or sleeping sickness. We showed that, in contrast to most microorganisms, the insect stages of this parasite developed a preference for glycerol over glucose, with glucose consumption beginning after the depletion of glycerol present in the medium. This "metabolic contest" depends on the combination of 3 conditions: (i) the sequestration of both metabolic pathways in the same subcellular compartment, here in the peroxisomal-related organelles named glycosomes; (ii) the competition for the same substrate, here ATP, with the first enzymatic step of the glycerol and glucose metabolic pathways both being ATP-dependent (glycerol kinase and hexokinase, respectively); and (iii) an unbalanced activity between the competing enzymes, here the glycerol kinase activity being approximately 80-fold higher than the hexokinase activity. As predicted by our model, an approximately 50-fold down-regulation of the GK expression abolished the preference for glycerol over glucose, with glucose and glycerol being metabolized concomitantly. In theory, a metabolic contest could be found in any organism provided that the 3 conditions listed above are met.