Na+/Ca2+ exchanger isoform 1 takes part to the Ca2+-related prosurvival pathway of SOD1 in primary motor neurons exposed to beta-methylamino-l-alanine

Background The cycad neurotoxin beta-methylamino-l-alanine (L-BMAA), one of the environmental trigger factor for amyotrophic lateral sclerosis/Parkinson-dementia complex (ALS/PDC), may cause neurodegeneration by disrupting organellar Ca2+ homeostasis. Through the activation of Akt/ERK1/2 pathway, the Cu,Zn-superoxide dismutase (SOD1) and its non-metallated form, ApoSOD1, prevent endoplasmic reticulum (ER) stress-induced cell death in motor neurons exposed to L-BMAA. This occurs through the rapid increase of intracellular Ca2+ concentration ([Ca2+]i) in part flowing from the extracellular compartment and in part released from ER. However, the molecular components of this mechanism remain uncharacterized. Methods By an integrated approach consisting on the use of siRNA strategy, Western blotting, confocal double- labeling immunofluorescence, patch-clamp electrophysiology, and Fura 2-/SBFI-single-cell imaging, we explored in rat motor neuron-enriched cultures the involvement of the plasma membrane proteins Na+/Ca2+ exchanger (NCX) and purinergic P2X7 receptor as well as that of the intracellular cADP-ribose (cADPR) pathway, in the neuroprotective mechanism of SOD1. Results We showed that SOD1-induced [Ca2+]i rise was prevented neither by A430879, a P2X7 receptor specific antagonist or 8-bromo-cADPR, a cell permeant antagonist of cADP-ribose, but only by the pan inhibitor of NCX, CB-DMB. The same occurred for the ApoSOD1. Confocal double labeling immunofluorescence showed a huge expression of plasmalemmal NCX1 and intracellular NCX3 isoforms. Furthermore, we identified NCX1 reverse mode as the main mechanism responsible for the neuroprotective ER Ca2+ refilling elicited by SOD1 and ApoSOD1 through which they promoted translocation of active Akt in the nuclei of a subset of primary motor neurons. Finally, the activation of NCX1 by the specific agonist CN-PYB2 protected motor neurons from L-BMAA-induced cell death, mimicking the effect of SOD1. Conclusion Collectively, our data indicate that SOD1 and ApoSOD1 exert their neuroprotective effect by modulating ER Ca2+ content through the activation of NCX1 reverse mode and Akt nuclear translocation in a subset of primary motor neurons.

COVID-19—A Trigger Factor for Severe Immune-Mediated Thrombocytopenia in Active Rheumatoid Arthritis

Thrombocytopenia is defined as a platelet count below 150,000/mm3 for adults. There is still controversy about whether individuals with platelet counts of 100,000/mm3 to 150,000/mm3 should be classified as having genuine thrombocytopenia or borderline thrombocytopenia. Thrombocytopenia is considered mild when the platelet count is between 70,000 and 150,000/mm3 and severe if the count is less than 20,000/mm3. Thrombocytopenia in rheumatoid arthritis is a rare complication, with an incidence estimated between 3 and 10%. The main etiological aspects include drug-induced thrombocytopenia and immune thrombocytopenic purpura. The most common hematological abnormalities in SARS-CoV-2 infection are lymphopenia and thrombocytopenia. It has been observed that the severity of thrombocytopenia correlates with the severity of the infection, being a poor prognosis indicator and a risk factor for mortality. COVID-19 can stimulate the immune system to destroy platelets by increasing the production of autoantibodies and immune complexes. Autoimmunity induced by viral infections can be related to molecular mimicry, cryptic antigen expression and also spreading of the epitope. During the COVID-19 pandemic, it is of great importance to include the SARS-CoV-2 infection in differential diagnoses, due to the increased variability in forms of presentation of this pathology. In this review, our aim is to present one of the most recently discovered causes of thrombocytopenia, which is the SARS-CoV-2 infection and the therapeutic challenges it poses in association with an autoimmune disease such as rheumatoid arthritis.

Analisis Alih Fungsi Lahan Menggunakan Regresi Logistik Ordinal

The occurrence of landslides can not be separated from conditions that are prone to landslide movements such as steep slopes and high rainfall. The occurrence of landslides is also exacerbated by the indiscipline of the community in using land according to its function, which is called land conversion which can be a trigger factor for landslides. Conducting research on land use change is important to see the impact caused by human activities. The purpose of this study was to analyze the effect of land conversion on landslide hazard levels in Samigaluh District, Kulon Progo Regency. The method in this research was descriptive quantitative using primary data, namely field surveys and secondary data collection. The steps on this research were conducting field observations about the occurrence of land conversion and then retrieving level of landslide hazard at the observation point of land use change. Data analysis was performed using ordinal logistic regression. The result of the analysis showed that the p value (0.036) <0.05 which meant H0 was rejected. Thus, at the 95% confidence level it could be said that the variable of land use change affected the level of landslide hazard in Samigaluh District, Kulon Progo Regency. This output could be considered for the community to use the land according to its function. Key words: Land Function Change; Landslide; Ordinal

Pathway Analysis of Behavioral Determinants in Preventing Genital Infections of Santri Putri Pondok Pesantren : Application of The Integrated Behavior Model

Female students who live in Islamic boarding schools are a population at risk for genital infections. The practice of personal/vaginal hygiene or menstrual hygiene is a form of maintaining reproductive health by preventing genital infections. Some bad behavior related to vaginal hygiene is a trigger factor for female genital infections. This study aimed to examine the factors behind the behavior of preventing genital infection in female students in the Islamic boarding school environment. This study was a quantitative study with a cross-sectional design. The population in this study was all female students. Determination of the sample in this study was carried out randomly with the number of subjects determined based on the rule-of-thumb sample size for path analysis, namely a minimum of 100 subjects, a minimum of 5 subjects per parameter, and a minimum of 10 subjects per variable. So that a sample of 150 female students was determined. The independent variable in this study was the behavior of preventing genital infection, while the dependent variables was: (1) behavioral intentions, (2) correct knowledge about behavior, (3) perception of the meaning of behavior, (4) environmental barriers, (5) experiential attitudes, (6) instrumental attitudes, (7) injunctive norms, (8) descriptive norms, (9) perceived behavioral control, (10) self-efficacy. This study indicated that infection prevention behavior can be determined by the behavior of female students prevention of genital infection is not influenced by the behavior of environmental barriers. Good knowledge and skills did not affect female students in taking measures to prevent genital infections; therefore, it was necessary to develop a more heterogeneous number of respondents and a questionnaire that can be understood by respondents so that an integrated behavioral model can become a reference to change behavior, and use methods that can improve their behavior.

Biological Efficacy Evaluation of a Non-Cross-Linked Hyaluronic Acid Dermal Filler for Biomedical Application in Inflammatory Scalp Conditions

(1) Background: The dysbiosis of some cutaneous commensal microorganisms is the trigger factor for the activation of the inflammatory cascade by keratinocytes in many skin disorders. Mesotherapy is an innovative technique for many scalp disorders, with the function of restoring the physiology of the skin. (2) Methods: the antimicrobial, antibiofilm and anti-inflammatory activity of the non-cross-linked HA formulation (Hydro Deluxe, Matex Lab S.p.a., Brindisi, Italy) was investigated against the most common microorganisms of the scalp (Staphyloccoccus epidermis, Staphyloccoccus aureus, Cutibacterium acnes and Malassezia furfur). Anti-inflammatory activity was evaluated on an internal 3D model of Reconstructed Human Epidermis (RHE) inserts infected with the strains as pro-inflammatory stimulus. (3) Results and Conclusions: the data collected showed a good antimicrobial and antibiofilm activity against all selected strains. The HA-based formulation did not show cytotoxicity on RHE, either alone or in presence of the infectious stimulus. The analysis of the expression of Interleukin (IL)-8 levels showed an excellent ability to reduce this pro-inflammatory marker. Overall, the efficacy assessment of the formulation supported its potential effectiveness in mesotherapy for the treatment of scalp disorders.

Common sequence motifs of nascent chains engage the ribosome surface and trigger factor

In the cell, the conformations of nascent polypeptide chains during translation are modulated by both the ribosome and its associated molecular chaperone, trigger factor. The specific interactions that underlie these modulations, however, are still not known in detail. Here, we combine protein engineering, in-cell and in vitro NMR spectroscopy, and molecular dynamics simulations to explore how proteins interact with the ribosome during their biosynthesis before folding occurs. Our observations of α-synuclein nascent chains in living Escherichia coli cells reveal that ribosome surface interactions dictate the dynamics of emerging disordered polypeptides in the crowded cytosol. We show that specific basic and aromatic motifs drive such interactions and directly compete with trigger factor binding while biasing the direction of the nascent chain during its exit out of the tunnel. These results reveal a structural basis for the functional role of the ribosome as a scaffold with holdase characteristics and explain how handover of the nascent chain to specific auxiliary proteins occurs among a host of other factors in the cytosol.

Tetramethylpyrazine Derivative T-006 Ameliorates the Amyloid-β Plagues of Transgenic Alzhermer's Mice by Modulation of TLR4-mediated MyD88/NF-κB Signaling

BackgroundMicroglial activation mediated neuroinflammation was considered as a vital trigger factor in the pathogenesis of Alzheimer’s disease (AD). T-006, a new tetramethylpyrazine derivative, has been recently found to alleviate cognitive deficits via inhibition of Tau expression and phosphorylation in AD transgenic mouse models. Here, we hypothesized that T-006 may ameliorate AD-like pathology by suppressing the neuroinflammation. MethodsAPP/PS1 transgenic AD mouse model was used here to evaluate the anti-inflammatory effect of T-006 and its underlying mechanisms, as well as its potential protective effects against lipopolysaccharide (LPS)-activated microglial-induced neurotoxicity.ResultsOur results indicated that T-006 significantly decreased the levels of total amyloid β peptide (Aβ) and glial fibrillary acidic protein (GFAP) as well as the ionized calcium binding adaptor molecule-1 (Ibα-1) expression in the APP/PS1 mice. Moreover, T-006 dramatically suppressed abnormal elevation of inflammatory mediators and reduced the levels of Toll-like receptor 4 (TLR4), myeloid differential protein-88 (MyD88) and NF-κB signaling related proteins in lipopolysaccharide (LPS)-induced BV2 microglial cells. We also found that TAK242, a TLR4 inhibitor could abolish the down-regulation of T-006 on LPS-induced proinflammatory mediators and reversed the downstream proteins expression containing MyD88 and NF-κB signaling. Importantly, T-006 prevented against neuroinflammation induced neurotoxicity by mitigating reactive oxygen species (ROS) overproduction and mitochondrial membrane potential (MMP) dissipation. Conclusions T-006 exerts neuroprotective effect in treating AD by suppressing the neuroinflammation through modulation of TLR4-mediated MyD88/NF-κB signaling pathways.

Identification and validation of objective triggers for initiation of resuscitation management of acutely ill non-trauma patients: the INITIATE IRON MAN study

Background While there are clear national resuscitation room admission guidelines for major trauma patients, there are no comparable alarm criteria for critically ill nontrauma (CINT) patients in the emergency department (ED). The aim of this study was to define and validate specific trigger factor cut-offs for identification of CINT patients in need of a structured resuscitation management protocol. Methods All CINT patients at a German university hospital ED for whom structured resuscitation management would have been deemed desirable were prospectively enrolled over a 6-week period (derivation cohort, n = 108). The performance of different thresholds and/or combinations of trigger factors immediately available during triage were compared with the National Early Warning Score (NEWS) and Quick Sequential Organ Failure Assessment (qSOFA) score. Identified combinations were then tested in a retrospective sample of consecutive nontrauma patients presenting at the ED during a 4-week period (n = 996), and two large external datasets of CINT patients treated in two German university hospital EDs (validation cohorts 1 [n = 357] and 2 [n = 187]). Results The any-of-the-following trigger factor iteration with the best performance in the derivation cohort included: systolic blood pressure < 90 mmHg, oxygen saturation < 90%, and Glasgow Coma Scale score < 15 points. This set of triggers identified > 80% of patients in the derivation cohort and performed better than NEWS and qSOFA scores in the internal validation cohort (sensitivity = 98.5%, specificity = 98.6%). When applied to the external validation cohorts, need for advanced resuscitation measures and hospital mortality (6.7 vs. 28.6%, p < 0.0001 and 2.7 vs. 20.0%, p < 0.012) were significantly lower in trigger factor-negative patients. Conclusion Our simple, any-of-the-following decision rule can serve as an objective trigger for initiating resuscitation room management of CINT patients in the ED.

Molecular Effects of Elongation Factor Ts and Trigger Factor on the Unfolding and Aggregation of Elongation Factor Tu Induced by the Prokaryotic Molecular Chaperone Hsp33

Hsp33, a prokaryotic redox-regulated holding chaperone, has been recently identified to be able to exhibit an unfoldase and aggregase activity against elongation factor Tu (EF-Tu) in its reduced state. In this study, we investigated the effect of elongation factor Ts (EF-Ts) and trigger factor (TF) on Hsp33-mediated EF-Tu unfolding and aggregation using gel filtration, light scattering, circular dichroism, and isothermal titration calorimetry. We found that EF-Tu unfolding and subsequent aggregation induced by Hsp33 were evident even in its complex state with EF-Ts, which enhanced EF-Tu stability. In addition, although TF alone had no substantial effect on the stability of EF-Tu, it markedly amplified the Hsp33-mediated EF-Tu unfolding and aggregation. Collectively, the present results constitute the first example of synergistic unfoldase/aggregase activity of molecular chaperones and suggest that the stability of EF-Tu is modulated by a sophisticated network of molecular chaperones to regulate protein biosynthesis in cells under stress conditions.

SARS-CoV-2 and Atherosclerosis: Should COVID-19 Be Recognized as a New Predisposing Cardiovascular Risk Factor?

At the beginning of the COVID-19 pandemic, the lung was recognized as the main target organ; now, new evidence suggests that SARS-CoV-2 infection leads to vascular disease. In a previous review, we supposed a bidirectional link between endothelial dysfunction and COVID-19, identifying atherosclerosis as having a crucial role in its pathogenesis. Atherosclerosis with an existing endothelial dysfunction may worsen COVID-19 manifestations, leading to adverse outcomes, as largely reported. However, COVID-19 may be the trigger factor in the progression of the atherosclerotic process up to making it clinically manifest. The thrombotic complications can involve not only the atherosclerotic plaque, but also the durability of the surgical device implanted to treat a pre-existing coronary artery disease as recently reported. The burden of the disease makes necessary a long-term stratification of patients, revising drastically targeted therapy among others.