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Role of the Ca1.2 distal carboxy terminus in the regulation of L-type current
Arancibia F, De Giorgis D, Medina F, Hermosilla T, Simon F and Varela D
L-type calcium channels are essential for the excitation-contraction coupling in cardiac muscle. The Ca1.2 channel is the most predominant isoform in the ventricle which consists of a multi-subunit membrane complex that includes the Ca1.2 pore-forming subunit and auxiliary subunits like Caαδ and Caβ. The Ca1.2 channel's C-terminus undergoes proteolytic cleavage, and the distal C-terminal domain (DCD) associates with the channel core through two domains known as proximal and distal C-terminal regulatory domain (PCRD and DCRD, respectively). The interaction between the DCD and the remaining C-terminus reduces the channel activity and modifies voltage- and calcium-dependent inactivation mechanisms, leading to an autoinhibitory effect. In this study, we investigate how the interaction between DCRD and PCRD affects the inactivation processes and Ca1.2 activity. We expressed a 14-amino acid peptide miming the DCRD-PCRD interaction sequence in both heterologous systems and cardiomyocytes. Our results show that overexpression of this small peptide can displace the DCD and replicate the effects of the entire DCD on voltage-dependent inactivation and channel inhibition. However, the effect on calcium-dependent inactivation requires the full DCD and is prevented by overexpression of calmodulin. In conclusion, our results suggest that the interaction between DCRD and PCRD is sufficient to bring about the current inhibition and alter the voltage-dependent inactivation, possibly in an allosteric manner. Additionally, our data suggest that the DCD competitively modifies the calcium-dependent mechanism. The identified peptide sequence provides a valuable tool for further dissecting the molecular mechanisms that regulate L-type calcium channels' basal activity in cardiomyocytes.
Purinergic regulation of pulmonary vascular tone
Alveal M, Méndez A, García A and Henríquez M
Purinergic signaling is a crucial determinant in the regulation of pulmonary vascular physiology and presents a promising avenue for addressing lung diseases. This intricate signaling system encompasses two primary receptor classes: P1 and P2 receptors. P1 receptors selectively bind adenosine, while P2 receptors exhibit an affinity for ATP, ADP, UTP, and UDP. Functionally, P1 receptors are associated with vasodilation, while P2 receptors mediate vasoconstriction, particularly in basally relaxed vessels, through modulation of intracellular Ca levels. The P2X subtype receptors facilitate extracellular Ca influx, while the P2Y subtype receptors are linked to endoplasmic reticulum Ca release. Notably, the primary receptor responsible for ATP-induced vasoconstriction is P2X1, with α,β-meATP and UDP being identified as potent vasoconstrictor agonists. Interestingly, ATP has been shown to induce endothelium-dependent vasodilation in pre-constricted vessels, associated with nitric oxide (NO) release. In the context of P1 receptors, adenosine stimulation of pulmonary vessels has been unequivocally demonstrated to induce vasodilation, with a clear dependency on the A receptor, as evidenced in studies involving guinea pigs and rats. Importantly, evidence strongly suggests that this vasodilation occurs independently of endothelium-mediated mechanisms. Furthermore, studies have revealed variations in the expression of purinergic receptors across different vessel sizes, with reports indicating notably higher expression of P2Y, P2Y, and P2Y receptors in small pulmonary arteries. While the existing evidence in this area is still emerging, it underscores the urgent need for a comprehensive examination of the specific characteristics of purinergic signaling in the regulation of pulmonary vascular tone, particularly focusing on the disparities observed across different intrapulmonary vessel sizes. Consequently, this review aims to meticulously explore the current evidence regarding the role of purinergic signaling in pulmonary vascular tone regulation, with a specific emphasis on the variations observed in intrapulmonary vessel sizes. This endeavor is critical, as purinergic signaling holds substantial promise in the modulation of vascular tone and in the proactive prevention and treatment of pulmonary vascular diseases.
Proteus mirabilis biofilm expansion microscopy yields over 4-fold magnification for super-resolution of biofilm structure and subcellular DNA organization
Castagnini D, Palma K, Jara-Wilde J, Navarro N, González MJ, Toledo J, Canales-Huerta N, Scavone P and Härtel S
Bacterial biofilms form when bacteria attach to surfaces and generate an extracellular matrix that embeds and stabilizes a growing community. Detailed visualization and quantitative analysis of biofilm architecture by optical microscopy are limited by the law of diffraction. Expansion Microscopy (ExM) is a novel Super-Resolution technique where specimens are physically enlarged by a factor of ∼4, prior to observation by conventional fluorescence microscopy. ExM requires homogenization of rigid constituents of biological components by enzymatic digestion. We developed an ExM approach capable of expanding 48-h old Proteus mirabilis biofilms 4.3-fold (termed PmbExM), close to the theoretic maximum expansion factor without gross shape distortions. Our protocol, based on lytic and glycoside-hydrolase enzymatic treatments, degrades rigid components in bacteria and extracellular matrix. Our results prove PmbExM to be a versatile and easy-to-use Super-Resolution approach for enabling studies of P. mirabilis biofilm architecture, assembly, and even intracellular features, such as DNA organization.
Plasmodium falciparum alters the trophoblastic barrier and stroma villi organization of human placental villi explants
López-Guzmán C, García AM, Ramirez JD, Aliaga TT, Fernández-Moya A, Kemmerling U and Vásquez AM
The sequestration of Plasmodium falciparum infected erythrocytes in the placenta, and the resulting inflammatory response affects maternal and child health. Despite existing information, little is known about the direct impact of P. falciparum on the placental barrier formed by trophoblast and villous stroma. This study aimed to assess placental tissue damage caused by P. falciparum in human placental explants (HPEs).
Distinct positions of genetic and oral histories: Perspectives from India
Biddanda A, Bandyopadhyay E, de la Fuente Castro C, Witonsky D, Urban Aragon JA, Pasupuleti N, Moots HM, Fonseca R, Freilich S, Stanisavic J, Willis T, Menon A, Mustak MS, Kodira CD, Naren AP, Sikdar M, Rai N and Raghavan M
Over the past decade, genomic data has contributed to several insights on global human population histories. These studies have been met both with interest and critically, particularly by populations with oral histories that are records of their past and often reference their origins. While several studies have reported concordance between oral and genetic histories, there is potential for tension that may stem from genetic histories being prioritized or used to confirm community-based knowledge and ethnography, especially if they differ. To investigate the interplay between oral and genetic histories, we focused on the southwestern region of India and analyzed whole-genome sequence data from 156 individuals identifying as Bunt, Kodava, Nair, and Kapla. We supplemented limited anthropological records on these populations with oral history accounts from community members and historical literature, focusing on references to non-local origins such as the ancient Scythians in the case of Bunt, Kodava, and Nair, members of Alexander the Great's army for the Kodava, and an African-related source for Kapla. We found these populations to be genetically most similar to other Indian populations, with the Kapla more similar to South Indian tribal populations that maximize a genetic ancestry related to Ancient Ancestral South Indians. We did not find evidence of additional genetic sources in the study populations than those known to have contributed to many other present-day South Asian populations. Our results demonstrate that oral and genetic histories may not always provide consistent accounts of population origins and motivate further community-engaged, multi-disciplinary investigations of non-local origin stories in these communities.
Viral shedding and viraemia of Andes virus during acute hantavirus infection: a prospective study
Ferrés M, Martínez-Valdebenito C, Henriquez C, Marco C, Angulo J, Barrera A, Palma C, Barriga Pinto G, Cuiza A, Ferreira L, Rioseco ML, Calvo M, Fritz R, Bravo S, Bruhn A, Graf J, Llancaqueo A, Rivera G, Cerda C, Tischler N, Valdivieso F, Vial P, Mertz G, Vial C and Le Corre N
Andes virus (ANDV) is a zoonotic Orthohantavirus leading to hantavirus cardiopulmonary syndrome. Although most transmissions occur through environmental exposure to rodent faeces and urine, rare person-to-person transmission has been documented, mainly for close contacts. This study investigates the presence and infectivity of ANDV in body fluids from confirmed cases and the duration of viraemia.
Topological insight of immune-vascular distribution in peri-implantitis lesions
Villalobos V, Silva I, Morales D, Canelo J, Garrido M, Carreño LJ, Cavalla F, Dutzan N and Caceres M
To characterize the distribution of macrophages, neutrophils, NK cells, and blood vessels in peri-implantitis compared to healthy aged gingiva samples.
The complex life of the HIV-1 full-length RNA
Soto-Rifo R
Alteration of Gut Microbiota Composition in the Progression of Liver Damage in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)
Zazueta A, Valenzuela-Pérez L, Ortiz-López N, Pinto-León A, Torres V, Guiñez D, Aliaga N, Merino P, Sandoval A, Covarrubias N, Pérez de Arce E, Cattaneo M, Urzúa A, Roblero JP, Poniachik J, Gotteland M, Magne F and Beltrán CJ
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex disorder whose prevalence is rapidly growing in South America. The disturbances in the microbiota-gut-liver axis impact the liver damaging processes toward fibrosis. Gut microbiota status is shaped by dietary and lifestyle factors, depending on geographic location. We aimed to identify microbial signatures in a group of Chilean MASLD patients. Forty subjects were recruited, including healthy controls (HCs), overweight/obese subjects (Ow/Ob), patients with MASLD without fibrosis (MASLD/F-), and MASLD with fibrosis (MASLD/F+). Both MASLD and fibrosis were detected through elastography and/or biopsy, and fecal microbiota were analyzed through deep sequencing. Despite no differences in α- and β-diversity among all groups, a higher abundance of and a lower presence of Defluviitaleaceae, Lachnospiraceae ND3007, and was found in MASLD/F- and MASLD/F+, compared to HC. Ruminococcaceae UCG-013 and were more abundant in MASLD/F+ than in Ow/Ob; both significantly differed between MASLD/F- and MASLD/F+, compared to HC. Significant positive correlations were observed between liver stiffness and , , , and abundance. Our results show that MASLD is associated with changes in bacterial taxa that are known to be involved in bile acid metabolism and SCFA production, with some of them being more specifically linked to fibrosis.
Detection of SARS-CoV-2 in Wastewater Associated with Scientific Stations in Antarctica and Possible Risk for Wildlife
González-Aravena M, Galbán-Malagón C, Castro-Nallar E, Barriga GP, Neira V, Krüger L, Adell AD and Olivares-Pacheco J
Before December 2020, Antarctica had remained free of COVID-19 cases. The main concern during the pandemic was the limited health facilities available at Antarctic stations to deal with the disease as well as the potential impact of SARS-CoV-2 on Antarctic wildlife through reverse zoonosis. In December 2020, 60 cases emerged in Chilean Antarctic stations, disrupting the summer campaign with ongoing isolation needs. The SARS-CoV-2 RNA was detected in the wastewater of several scientific stations. In Antarctica, treated wastewater is discharged directly into the seawater. No studies currently address the recovery of infectious virus particles from treated wastewater, but their presence raises the risk of infecting wildlife and initiating new replication cycles. This study highlights the initial virus detection in wastewater from Antarctic stations, identifying viral RNA via RT-qPCR targeting various genomic regions. The virus's RNA was found in effluent from two wastewater plants at Maxwell Bay and O'Higgins Station on King George Island and the Antarctic Peninsula, respectively. This study explores the potential for the reverse zoonotic transmission of SARS-CoV-2 from humans to Antarctic wildlife due to the direct release of viral particles into seawater. The implications of such transmission underscore the need for continued vigilance and research.
Mitochondrial Ca Uniporter-Dependent Energetic Dysfunction Drives Hypertrophy in Heart Failure
Alves-Figueiredo H, Silva-Platas C, Estrada M, Oropeza-Almazán Y, Ramos-González M, Bernal-Ramírez J, Vázquez-Garza E, Tellez A, Salazar-Ramírez F, Méndez-Fernández A, Galaz JL, Lobos P, Youker K, Lozano O, Torre-Amione G and García-Rivas G
The role of the mitochondrial calcium uniporter (MCU) in energy dysfunction and hypertrophy in heart failure (HF) remains unknown. In angiotensin II (ANGII)-induced hypertrophic cardiac cells we have shown that hypertrophic cells overexpress MCU and present bioenergetic dysfunction. However, by silencing MCU, cell hypertrophy and mitochondrial dysfunction are prevented by blocking mitochondrial calcium overload, increase mitochondrial reactive oxygen species, and activation of nuclear factor kappa B-dependent hypertrophic and proinflammatory signaling. Moreover, we identified a calcium/calmodulin-independent protein kinase II/cyclic adenosine monophosphate response element-binding protein signaling modulating MCU upregulation by ANGII. Additionally, we found upregulation of MCU in ANGII-induced left ventricular HF in mice, and in the LV of HF patients, which was correlated with pathological remodeling. Following left ventricular assist device implantation, MCU expression decreased, suggesting tissue plasticity to modulate MCU expression.
Fluorescently labelled vedolizumab to visualise drug distribution and mucosal target cells in inflammatory bowel disease
Gabriëls RY, van der Waaij AM, Linssen MD, Dobosz M, Volkmer P, Jalal S, Robinson D, Hermoso MA, Lub-de Hooge MN, Festen EAM, Kats-Ugurlu G, Dijkstra G and Nagengast WB
Improving patient selection and development of biological therapies such as vedolizumab in IBD requires a thorough understanding of the mechanism of action and target binding, thereby providing individualised treatment strategies. We aimed to visualise the macroscopic and microscopic distribution of intravenous injected fluorescently labelled vedolizumab, vedo-800CW, and identify its target cells using fluorescence molecular imaging (FMI).
Co-Culture of . and . Synergistically Elevates IL-6 Expression via TLR4 Signaling in Oral Keratinocytes
Yáñez L, Soto C, Tapia H, Pacheco M, Tapia J, Osses G, Salinas D, Rojas-Celis V, Hoare A, Quest AFG, Díaz-Elizondo J, Pérez-Donoso JM and Bravo D
Periodontitis, characterized by persistent inflammation in the periodontium, is intricately connected to systemic diseases, including oral cancer. Bacteria, such as and , play a pivotal role in periodontitis development because they contribute to dysbiosis and tissue destruction. Thus, comprehending the interplay between these bacteria and their impacts on inflammation holds significant relevance in clinical understanding and treatment advancement. In the present work, we explored, for the first time, their impacts on the expressions of pro-inflammatory mediators after infecting oral keratinocytes (OKs) with a co-culture of pre-incubated and . Our results show that the co-culture increases IL-1β, IL-8, and TNF-α expressions, synergistically augments IL-6, and translocates NF-kB to the cell nucleus. These changes in pro-inflammatory mediators-associated with chronic inflammation and cancer-correlate with an increase in cell migration following infection with the co-cultured bacteria or alone. This effect depends on TLR4 because TLR4 knockdown notably impacts IL-6 expression and cell migration. Our study unveils, for the first time, crucial insights into the outcomes of their co-culture on virulence, unraveling the role of bacterial interactions in polymicrobial diseases and potential links to oral cancer.
Obesogenic Diet in Mice Leads to Inflammation and Oxidative Stress in the Mother in Association with Sex-Specific Changes in Fetal Development, Inflammatory Markers and Placental Transcriptome
Candia AA, Lean SC, Zhang CXW, McKeating DR, Cochrane A, Gulacsi E, Herrera EA, Krause BJ and Sferruzzi-Perri AN
Obesity during pregnancy is related to adverse maternal and neonatal outcomes. Factors involved in these outcomes may include increased maternal insulin resistance, inflammation, oxidative stress, and nutrient mishandling. The placenta is the primary determinant of fetal outcomes, and its function can be impacted by maternal obesity. The aim of this study on mice was to determine the effect of obesity on maternal lipid handling, inflammatory and redox state, and placental oxidative stress, inflammatory signaling, and gene expression relative to female and male fetal growth.
Long-Term Survival and Immune Response Dynamics in Melanoma Patients Undergoing TAPCells-Based Vaccination Therapy
Tittarelli A, Pereda C, Gleisner MA, López MN, Flores I, Tempio F, Lladser A, Achour A, González FE, Durán-Aniotz C, Miranda JP, Larrondo M and Salazar-Onfray F
Cancer vaccines present a promising avenue for treating immune checkpoint blockers (ICBs)-refractory patients, fostering immune responses to modulate the tumor microenvironment. We revisit a phase I/II trial using Tumor Antigen-Presenting Cells (TAPCells) (NCT06152367), an autologous antigen-presenting cell vaccine loaded with heat-shocked allogeneic melanoma cell lysates. Initial findings showcased TAPCells inducing lysate-specific delayed-type hypersensitivity (DTH) reactions, correlating with prolonged survival. Here, we extend our analysis over 15 years, categorizing patients into short-term (<36 months) and long-term (≥36 months) survivors, exploring novel associations between clinical outcomes and demographic, genetic, and immunologic parameters. Notably, DTH patients exhibit a 53.1% three-year survival compared to 16.1% in DTH patients. Extended remissions are observed in long-term survivors, particularly DTH/M1c patients. Younger age, stage III disease, and moderate immune events also benefit short-term survivors. Immunomarkers like increased C-type lectin domain family 2 member D on CD4 T cells and elevated interleukin-17A were detected in long-term survivors. In contrast, toll-like receptor-4 D229G polymorphism and reduced CD32 on B cells are associated with reduced survival. TAPCells achieved stable long remissions in 35.2% of patients, especially M1c/DTH cases. Conclusions: Our study underscores the potential of vaccine-induced immune responses in melanoma, emphasizing the identification of emerging biological markers and clinical parameters for predicting long-term remission.
Supra-Threshold LS CE-Chirp Auditory Brainstem Response in the Elderly
Maass JC, Leiva A, Torrente M, Vergara R, Belkhiria C, Delgado C and Delano PH
Aging deteriorates peripheral and central auditory structures and functions. In elders, for an accurate audiological evaluation, it is important to explore beyond the cochlear receptor. Audiograms provide an estimation of hearing thresholds, while the amplitudes and latencies of supra-threshold auditory brainstem response (ABR) can offer noninvasive measures of the auditory pathways functioning. Regarding ABR, in young populations, level-specific chirp (LS CE-chirp) stimulus has been proposed as an alternative synchronizing method to obtain larger ABR responses than those evoked by clicks. However, the supra-threshold characteristics of chirp evoked ABR, and their association to hearing thresholds is relatively unknown in the elderly. The aim of this study was to evaluate supra-threshold LS CE-chirp ABRs in an aged population by comparing their features with click ABRs, and evaluating their relationship with audiometric hearing thresholds.
Valp1, a Newly Identified Temperate Phage Facilitating Coexistence of Lysogenic and Non-Lysogenic Populations of
Arce M, Venegas G, Paez K, Latz S, Navarrete P, Caruffo M, Feijoo C, García K and Bastías R
is a pathogen for several fish and shellfish species. Its ecology is influenced by diverse factors, including bacteriophages. Here, we identify and characterize a new temperate bacteriophage (Valp1) of . Valp1 is a myovirus with a 60 nm head and a 90 nm contractile tail. Its double-stranded DNA genome of 42,988 bp contains 68 genes, including a protelomerase gene, typical of telomeric phages. Valp1 inhibits the growth of the virulent strain of PF4, while the derived lysogenic strain P1.1 presents a slight reduction in its growth but is not affected by the presence of Valp1. Both strains present similar virulence in a larval zebrafish () model, and only slight differences have been observed in their biochemical profile. Co-culture assays reveal that PF4 and P1.1 can coexist for 10 h in the presence of naturally induced Valp1, with the proportion of PF4 ranging between 28% and 1.6%. By the end of the assay, the phage reached a concentration of ~10 PFU/mL, and all the non-lysogenic PF4 strains were resistant to Valp1. This equilibrium was maintained even after five successive subcultures, suggesting the existence of a coexistence mechanism between the lysogenic and non-lysogenic populations of in conjunction with the phage Valp1.
A novel "microbiota-host interaction model" to study the real-time effects of fermentation of non-digestible carbohydrate (NDCs) on gut barrier function
Chen X, Moreno LL, Tang X, Gasaly N, Schols HA and de Vos P
In this study, an co-culture model using an electric cell-substrate impedance sensing system (ECIS) for testing the impact of real-time fermentation of non-digestible carbohydrates (NDCs) by the intestinal microbiota on gut barrier function was established. We applied as a model intestinal bacterium and alginate-pectin as immobilization polymers as well as a source of NDCs to determine the impact of pectin fermentation on the barrier function of T84 gut epithelial cells. In the first design, was encapsulated in an alginate capsule followed by embedding in an agar layer to mimic a firm mucus layer that might be present in the colon. In this experimental design, the presence of the agar layer interfered with the transepithelial electrical resistance (TEER) measurement of T84 cells. Subsequently, we removed the agar layer and used encapsulated bacteria in an alginate gel and found that the TEER measurement was adequate. The encapsulation of the does avoid direct contact with cells. Also, the encapsulation system allows higher amounts of packing densities of in a limited space which can limit the oxygen concentration within the capsule and therefore create anaerobic conditions. To test this design, T84 cells were co-incubated with alginate-capsules supplemented with graded loads of fermentable pectin (0, 4, and 8 mg/ml per capsule) to investigate the effect of pectin fermentation on gut barrier function. We observed that as the pectin content in the capsules increased, pectin showed a gradually stronger protective effect on the TEER of the gut epithelium. This could partly be explained by enhanced SCFA production as both lactate and acetate were enhanced in containing alginate capsules with 8 mg/ml pectin. Overall, this newly designed co-culture model allows for studying the impact of bacteria-derived fermentation products but also for studying the direct effects of NDCs on gut barrier function in a relatively high-throughput way.
Corrigendum: The role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD
Astorga J, Gasaly N, Dubois-Camacho K, De la Fuente M, Landskron G, Faber KN, Urra FA and Hermoso MA
[This corrects the article DOI: 10.3389/fimmu.2022.1028953.].
Natural killer T cells in allergic asthma: implications for the development of novel immunotherapeutical strategies
Gutiérrez-Vera C, García-Betancourt R, Palacios PA, Müller M, Montero DA, Verdugo C, Ortiz F, Simon F, Kalergis AM, González PA, Saavedra-Avila NA, Porcelli SA and Carreño LJ
Allergic asthma has emerged as a prevalent allergic disease worldwide, affecting most prominently both young individuals and lower-income populations in developing and developed countries. To devise effective and curative immunotherapy, it is crucial to comprehend the intricate nature of this condition, characterized by an immune response imbalance that favors a proinflammatory profile orchestrated by diverse subsets of immune cells. Although the involvement of Natural Killer T (NKT) cells in asthma pathology is frequently implied, their specific contributions to disease onset and progression remain incompletely understood. Given their remarkable ability to modulate the immune response through the rapid secretion of various cytokines, NKT cells represent a promising target for the development of effective immunotherapy against allergic asthma. This review provides a comprehensive summary of the current understanding of NKT cells in the context of allergic asthma, along with novel therapeutic approaches that leverage the functional response of these cells.