ABSTRACT
The performance of molecular docking can be improved by comparing the shape similarity of the flexibly sampled poses against the target proteins' inverted binding cavities. The effectiveness of these pseudo-ligands or negative image-based models in docking rescoring is boosted further by performing enrichment-driven optimization. Here, we introduce a novel shape-focused pharmacophore modeling algorithm O-LAP that generates a new class of cavity-filling models by clumping together overlapping atomic content via pairwise distance graph clustering. Top-ranked poses of flexibly docked active ligands were used as the modeling input and multiple alternative clustering settings were benchmark-tested thoroughly with five demanding drug targets using random training/test divisions. In docking rescoring, the O-LAP modeling typically improved massively on the default docking enrichment; furthermore, the results indicate that the clustered models work well in rigid docking. The C+ +/Qt5-based algorithm O-LAP is released under the GNU General Public License v3.0 via GitHub ( https://github.com/jvlehtonen/overlap-toolkit ). SCIENTIFIC CONTRIBUTION: This study introduces O-LAP, a C++/Qt5-based graph clustering software for generating new type of shape-focused pharmacophore models. In the O-LAP modeling, the target protein cavity is filled with flexibly docked active ligands, the overlapping ligand atoms are clustered, and the shape/electrostatic potential of the resulting model is compared against the flexibly sampled molecular docking poses. The O-LAP modeling is shown to ensure high enrichment in both docking rescoring and rigid docking based on comprehensive benchmark-testing.
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Introducción: El desarrollo positivo es un estadio de ajuste psicosocial que acentúa las potencialidades y los recursos entre jóvenes y sus contextos próximos. En Australia, se desarrolló el primer modelo de desarrollo positivo para adultos emergentes, el cual consta de cinco componentes (competencia social, satisfacción con la vida, confianza y tolerancia con los otros, confianza hacia autoridades e instituciones, acción y compromiso cívico), pero no ha sido investigado en Chile. Objetivo: Analizar la evidencia disponible en la literatura científica sobre los cinco componentes del modelo de desarrollo positivo en adultos emergentes universitarios de Chile. Materiales y métodos: Revisión narrativa de la literatura publicada entre 2013 y 2023, en bases de datos Web of Science, Scopus, SciELO, Redalyc y Dialnet. Resultados: Se obtuvieron 83 artículos, de los cuales 53 cumplieron los requisitos de inclusión; en su mayor parte fueron estudios cuantitativos (81,13%) y en español (75,47%). Se evidenció una disparidad en la cantidad de estudios por temática; se encuentra mayor investigación en satisfacción con la vida y acción y compromiso cívico. Conclusiones: Existen brechas en la literatura científica chilena en el estudio del desarrollo positivo; además de que se discuten particularidades idiosincrásicas y desafíos asociados a la etapa de adultez emergente.
Introduction: Positive development is a stage of psychosocial adjustment that accentuates the potentials and resources of young people and their close contexts. The first positive development model for emerging adulthood was developed in Australia, which includes five components: social; life satisfaction; trust and tolerance of others; trust in the authorities and institutions; and action and civic engagement. However, this model has not been investigated in Chile. Objective: To analyze the evidence available in the scientific literature on the five components of the positive development model in emerging adults universities. Materials and methods: A narrative review of the literature published between 2013 and 2023 in the Web of Science, Scopus, SciELO, Redalyc, and Dialnet databases was conducted. Results: 83 articles were selected, of which 53 met the inclusion criteria; most of them were qualitative studies (81.13%) and in Spanish (75.47%). There is an evident disparity in terms of the number of studies and topics, e.g., there is more research on life satisfaction and civic action and commitment. Conclusions: There are gaps in the Chilean scientific literature in the study of positive development. In addition, idiosyncratic particularities and challenges associated with the stages of emerging adulthood are discussed.
Introdução: O desenvolvimento positivo é uma fase de ajustamento psicossocial que acentua o potencial e os recursos dos jovens e dos seus contextos imediatos. Na Austrália, foi desenvolvido o primeiro modelo de desenvolvimento positivo para adultos emergentes, que consiste em cinco componentes (social, satisfação com a vida, confiança e tolerância com os outros, confiança nas autoridades e instituições, ação e envolvimento cívico), mas ainda não foi investigado no Chile. Objetivo: Analisar as evidências disponíveis na literatura científica sobre os cinco componentes do modelo de desenvolvimento positivo em adultos universitários emergentes no Chile. Materiais e métodos: Revisão narrativa da literatura publicada entre 2013 e 2023, nas bases de dados Web of Science, Scopus, SciELO, Redalyc e Dialnet. Resultados: foram obtidos 83 artigos, dos quais 53 atenderam aos requisitos de inclusão; A maioria deles eram estudos quantitativos (81,13%) e em espanhol (75,47%). Ficou evidente uma disparidade no número de estudos por tema; Há mais pesquisas sobre satisfação com a vida e ação e compromisso cívico. Conclusões: Existem lacunas na literatura científica chilena no estudo do desenvolvimento positivo; Além disso, são discutidas particularidades e desafios idiossincráticos associados à fase da idade adulta emergente.
Subject(s)
Humans , Male , Female , Young Adult , Young Adult , Psychology, Developmental , Universities , Growth and DevelopmentABSTRACT
Introduction: Daily solar ultraviolet (UV) radiation has an important impact on skin health. Understanding the initial events of the UV-induced response is critical to prevent deleterious conditions. However, studies in human volunteers have ethical, technical, and economic implications that make skin equivalents a valuable platform to investigate mechanisms related to UV exposure to the skin. In vitro human skin equivalents can recreate the structure and function of in vivo human skin and represent a valuable tool for academic and industrial applications. Previous studies have utilised non-pigmented full-thickness or pigmented epidermal skin equivalents to investigate skin responses to UV exposure. However, these do not recapitulate the dermal-epidermal crosstalk and the melanocyte role in photoprotection that occurs in vivo. In addition, the UV radiation used in these studies is generally not physiologically representative of real-world UV exposure. Methods: Well-characterised pigmented and non-pigmented skin equivalents that contain human dermal fibroblasts, endogenous secreted extracellular matrix proteins (ECM) and a well-differentiated and stratified epidermis have been developed. These constructs were exposed to UV radiation for ×5 consecutive days with a physiologically relevant UV dose and subsequently analysed using appropriate end-points to ascertain photodamage to the skin. Results: We have described that repeated irradiation of full-thickness human skin equivalents in a controlled laboratory environment can recreate UV-associated responses in vitro, mirroring those found in photoexposed native human skin: morphological damage, tanning, alterations in epidermal apoptosis, DNA lesions, proliferation, inflammatory response, and ECM-remodelling. Discussion: We have found a differential response when using the same UV doses in non-pigmented and pigmented full-thickness skin equivalents, emphasising the role of melanocytes in photoprotection.
ABSTRACT
The multifactorial basis of therapeutic response can obscure the relation between antimicrobial drug susceptibility and clinical outcome. To discern the relationship between parasite susceptibility to meglumine antimoniate (SbV) and therapeutic outcome of cutaneous leishmaniasis, risk factors for treatment failure were considered in evaluating this relationship in ninety-one cutaneous leishmaniasis patients and corresponding clinical strains of Leishmania (Viannia) panamensis. Parasite susceptibility to 32 µg SbV/mL (plasma Cmax) was evaluated in primary human macrophages, PBMCs, and U937 macrophages. Early parasitological response to treatment was determined in lesions of a subgroup of patients, and pathogenicity of Sb-resistant and sensitive clinical strains was compared in BALB/c mice. Parasite survival in cell models and patient lesions was determined by qRT-PCR of Leishmania 7SLRNA transcript. Parasite loads in BALB/c mice were quantified by limiting dilution analysis. The disparate Sb-susceptibility of parasite subpopulations distinguished by isoenzyme profiles (zymodemes) was manifest in all cell models. Notably, Sb-resistance defined by parasite survival, was most effectively discerned in U937 macrophages compared with primary human host cells, significantly higher among strains from patients who failed treatment than cured and, significantly associated with treatment failure. Each unit increase in transformed survival rate corresponded to a 10.6-fold rise in the odds of treatment failure. Furthermore, treatment failure was significantly associated with naturally Sb-resistant zymodeme 2.3 strains, which also produced larger lesions and parasite burdens in BALB/c mice than Sb-sensitive zymodeme 2.2 strains. The confounding effect of host risk factors for treatment failure in discerning this association was evidenced in comparing strains from patients with and without the defined risk factors for treatment failure. These results establish the association of natural resistance to meglumine antimoniate with treatment failure, the importance of host risk factors in evaluating drug susceptibility and treatment outcome, and the clinical and epidemiological relevance of natural Sb-resistance in L. (V.) panamensis subpopulations.
Subject(s)
Antiprotozoal Agents , Drug Resistance , Leishmaniasis, Cutaneous , Macrophages , Meglumine Antimoniate , Meglumine , Mice, Inbred BALB C , Organometallic Compounds , Treatment Failure , Animals , Leishmaniasis, Cutaneous/drug therapy , Leishmaniasis, Cutaneous/parasitology , Meglumine Antimoniate/therapeutic use , Meglumine Antimoniate/pharmacology , Humans , Antiprotozoal Agents/therapeutic use , Antiprotozoal Agents/pharmacology , Female , Meglumine/therapeutic use , Meglumine/pharmacology , Organometallic Compounds/therapeutic use , Organometallic Compounds/pharmacology , Mice , Macrophages/parasitology , Macrophages/drug effects , Macrophages/immunology , Male , Leishmania guyanensis/drug effects , Adult , Middle Aged , Young Adult , Parasite Load , AdolescentABSTRACT
In Chile, since January 2023, a sudden and pronounced increase in strandings and mortality has been observed among South American (SA) sea lions (Otaria flavescens), prompting significant concern. Simultaneously, an outbreak of highly pathogenic avian influenza H5N1 (HPAIV H5N1) in avian species has emerged since December 2022. To investigate the cause of this unexpected mortality, we conducted a comprehensive epidemiological and pathologic study. One hundred sixty-nine SA sea lions were sampled to ascertain their HPAIV H5N1 status, and long-term stranding trends from 2009 to 2023 were analyzed. In addition, two animals were necropsied. Remarkably, a significant surge in SA sea lion strandings was observed initiating in January 2023 and peaking in June 2023, with a count of 4,545 stranded and deceased animals. Notably, this surge in mortality correlates geographically with HPAIV outbreaks affecting wild birds. Among 168 sampled SA sea lions, 34 (20%) tested positive for Influenza A virus, and 21 confirmed for HPAIV H5N1 2.3.4.4b clade in tracheal/rectal swab pools. Clinical and pathological evaluations of the two necropsied stranded sea lions revealed prevalent neurological and respiratory signs, including disorientation, tremors, ataxia, and paralysis, as well as acute dyspnea, tachypnea, profuse nasal secretion, and abdominal breathing. The lesions identified in necropsied animals aligned with observed clinical signs. Detection of the virus via immunohistochemistry (IHC) and real-time PCR in the brain and lungs affirmed the findings. The findings provide evidence between the mass mortality occurrences in SA sea lions and HPAIV, strongly indicating a causal relationship. Further studies are needed to better understand the pathogenesis and transmission.
Subject(s)
Influenza A Virus, H5N1 Subtype , Influenza in Birds , Sea Lions , Animals , Influenza in Birds/epidemiology , Chile/epidemiology , Disease Outbreaks/veterinary , Birds , PhylogenyABSTRACT
Introduction: Lung ultrasound (LUS) has proven to be a more sensitive tool than radiography (X-ray) to detect alveolar-interstitial involvement in COVID-19 pneumonia. However, its usefulness in the detection of possible pulmonary alterations after overcoming the acute phase of COVID-19 is unknown. In this study we proposed studying the utility of LUS in the medium- and long-term follow-up of a cohort of patients hospitalized with COVID-19 pneumonia. Materials and methods: This was a prospective, multicentre study that included patients, aged over 18 years, at 3 ± 1 and 12 ± 1 months after discharge after treatment for COVID-19 pneumonia. Demographic variables, the disease severity, and analytical, radiographic, and functional clinical details were collected. LUS was performed at each visit and 14 areas were evaluated and classified with a scoring system whose global sum was referred to as the "lung score." Two-dimensional shear wave elastography (2D-SWE) was performed in 2 anterior areas and in 2 posterior areas in a subgroup of patients. The results were compared with high-resolution computed tomography (CT) images reported by an expert radiologist. Results: A total of 233 patients were included, of whom 76 (32.6%) required Intensive Care Unit (ICU) admission; 58 (24.9%) of them were intubated and non-invasive respiratory support was also necessary in 58 cases (24.9%). Compared with the results from CT images, when performed in the medium term, LUS showed a sensitivity (S) of 89.7%, specificity (E) 50%, and an area under the curve (AUC) of 78.8%, while the diagnostic usefulness of X-ray showed an S of 78% and E of 47%. Most of the patients improved in the long-term evaluation, with LUS showing an efficacy with an S of 76% and E of 74%, while the X-ray presented an S of 71% and E of 50%. 2D-SWE data were available in 108 (61.7%) patients, in whom we found a non-significant tendency toward the presentation of a higher shear wave velocity among those who developed interstitial alterations, with a median kPa of 22.76 ± 15.49) versus 19.45 ± 11.39; p = 0.1). Conclusion: Lung ultrasound could be implemented as a first-line procedure in the evaluation of interstitial lung sequelae after COVID-19 pneumonia.
ABSTRACT
Histamine receptor 2 (HRH2) blockers are used to treat peptic ulcers and gastric reflux. Chlorquinaldol and chloroxine, which contain an 8-hydroxyquinoline (8HQ) core, have recently been identified as blocking HRH2. To gain insight into the mode of action of 8HQ-based blockers, here, we leverage an HRH2-based sensor in yeast to evaluate the role of key residues in the HRH2 active site on histamine and 8HQ-based blocker binding. We find that the HRH2 mutations D98A, F254A, Y182A, and Y250A render the receptor inactive in the presence of histamine, while HRH2:D186A and HRH2:T190A retain residual activity. Based on molecular docking studies, this outcome correlates with the ability of the pharmacologically relevant histamine tautomers to interact with D98 via the charged amine. Docking studies also suggest that, unlike established HRH2 blockers that interact with both ends of the HRH2 binding site, 8HQ-based blockers interact with only one end, either the end framed by D98/Y250 or T190/D186. Experimentally, we find that chlorquinaldol and chloroxine still inactivate HRH2:D186A by shifting their engagement from D98 to Y250 in the case of chlorquinaldol and D186 to Y182 in the case of chloroxine. Importantly, the tyrosine interactions are supported by the intramolecular hydrogen bonding of the 8HQ-based blockers. The insight gained in this work will aid in the development of improved HRH2 therapeutics. More generally, this work demonstrates that Gprotein-coupled receptor (GPCR)-based sensors in yeast can help elucidate the mode of action of novel ligands for GPCRs, a family of receptors that bind 30% of FDA therapeutics.
Subject(s)
Chlorquinaldol , Histamine , Receptors, Histamine H2/chemistry , Receptors, Histamine H2/genetics , Receptors, Histamine H2/metabolism , Molecular Docking Simulation , Oxyquinoline , Saccharomyces cerevisiae/metabolism , Receptors, Histamine/chemistry , Receptors, Histamine/metabolismABSTRACT
Human skin equivalents (HSEs) are a popular technology due to limitations in animal testing, particularly as they recapitulate aspects of structure and function of human skin. Many HSEs contain two basic cell types to model dermal and epidermal compartments, however this limits their application, particularly when investigating the effect of exogenous stressors on skin health. We describe the development of a novel platform technology that accurately replicates skin pigmentation in vitro. Through incorporation of melanocytes, specialized pigment producing cells, into the basal layer of the epidermis we are able to re-create skin pigmentation in vitro. We observe apical distribution of melanin within keratinocytes and formation of supranuclear caps (SPNCs), only when the epidermal compartment is co-cultured with a dermal compartment, leading to the conclusion that fibroblast support is essential for correct pigment organization. We also evaluate the commonly observed phenomenon that pigmentation darkens with time in vitro, which we further explore through mechanical exfoliation to remove a build-up of melanin deposits in the stratum corneum. Finally, we demonstrate the application of a pigmented HSE to investigate drug modulation of skin tone and protection from UV-induced damage, highlighting the importance of such a model in the wider context of skin biology.
ABSTRACT
Parkinson's disease (PD) is the most common α-synucleinopathy worldwide. The pathognomonic hallmark of PD is the misfolding and propagation of the α-synuclein (α-syn) protein, observed in post-mortem histopathology. It has been hypothesized that α-synucleinopathy triggers oxidative stress, mitochondrial dysfunction, neuroinflammation, and synaptic dysfunction, leading to neurodegeneration. To this date, there are no disease-modifying drugs that generate neuroprotection against these neuropathological events and especially against α-synucleinopathy. Growing evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists confer neuroprotective effects in PD, however, whether they also confer an anti-α-synucleinopathy effect is unknown. Here we analyze the reported therapeutic effects of PPARs, specifically the gamma isoform (PPARγ), in preclinical PD animal models and clinical trials for PD, and we suggest possible anti-α-synucleinopathy mechanisms acting downstream from these receptors. Elucidating the neuroprotective mechanisms of PPARs through preclinical models that mimic PD as closely as possible will facilitate the execution of better clinical trials for disease-modifying drugs in PD.
Subject(s)
Neuroprotective Agents , Parkinson Disease , Synucleinopathies , Animals , Parkinson Disease/metabolism , Peroxisome Proliferator-Activated Receptors , Neuroprotective Agents/therapeutic use , Neuroprotection , Disease Models, AnimalABSTRACT
Skin ageing is an intricate physiological process affected by intrinsic and extrinsic factors. There is a demand to understand how the skin changes with age and photoexposure in individuals with Fitzpatrick skin types I-III due to accelerated photoageing and the risk of cutaneous malignancies. To assess the structural impact of intrinsic and extrinsic ageing, we analysed 14 skin parameters from the photoprotected buttock and photoexposed dorsal forearm of young and ageing females with Fitzpatrick skin types II-III (n = 20) using histomorphic techniques. Whilst the minimum viable epidermis (Emin ) remained constant (Q > 0.05), the maximum viable epidermis (Emax ) was decreased by both age and photoexposure (Q ≤ 0.05), which suggests that differences in epidermal thickness are attributed to changes in the dermal-epidermal junction (DEJ). Changes in Emax were not affected by epidermal cell proliferation. For the first time, we investigated the basal keratinocyte morphology with age and photoexposure. Basal keratinocytes had an increased cell size, cellular height and a more columnar phenotype in photoexposed sites of young and ageing individuals (Q ≤ 0.05), however no significant differences were observed with age. Some of the most striking changes were observed in the DEJ, and a decrease in the interdigitation index was observed with both age and photoexposure (Q ≤ 0.001), accompanied by a decreased height of rête ridges and dermal papilla. Interestingly, young photoexposed skin was comparable to ageing skin across many parameters, and we hypothesise that this is due to accelerated photoageing. This study highlights the importance of skin care education and photoprotection from an early age.
Subject(s)
Skin Aging , Skin Diseases , Female , Humans , Skin/pathology , Epidermis/physiology , Skin Diseases/pathologyABSTRACT
"Bring Change 2 Mind" (BC2M) high school clubs may destigmatize mental illness among club members, but clubs' (1) reach and impact on non-club members at the same school, (2) connection to student help-seeking attitudes, and (3) mechanisms by which they destigmatize mental illness, are unknown. This community-partnered evaluation involved pre/post surveys of predominantly Latino (72%) students at three urban public schools and focus groups and interviews with a sample of club members (n = 26/65, 40%) and all club staff (n = 7, 100%). Multivariate regressions tested relationships between variables. In 84% of the student body responded in the Fall (n = 1,040) and Spring (n = 1,031). Non-club member engagement in BC2M (reach) increased from 25% (Fall) to 44% (Spring) (p < .01). Engagement with BC2M clubs was associated with decreased stigma among members (p < .05) but not non-members (p = .19). Decreased stigma was associated with help-seeking attitudes (p < .01). Possible BC2M mechanisms identified by students and staff include the following: (1) fostering a positive campus climate, (2) normalizing mental health discussions, (3) increasing peer support and help-seeking, and (4) increasing awareness of positive coping behaviors. While BC2M clubs likely reduce stigma for members, effects did not reach non-members, challenging the potential of BC2M clubs as a schoolwide strategy to destigmatize mental health services. Future projects could investigate how to reach non-BC2M members, complement BC2M with other school climate interventions to increase impact, and measure BC2M impact alongside other outcomes relevant to schools, such as academic achievement.
Subject(s)
Mental Disorders , Mental Health Services , Humans , Adolescent , Mental Disorders/psychology , Schools , Mental Health , Adaptation, PsychologicalABSTRACT
Inflammaging is a theory of ageing which purports that low-level chronic inflammation leads to cellular dysfunction and premature ageing of surrounding tissue. Skin is susceptible to inflammaging because it is the first line of defence from the environment, particularly solar radiation. To better understand the impact of ageing and photoexposure on epidermal biology, we performed a system biology-based analysis of photoexposed face and arm, and photoprotected buttock sites, from women between the ages of 20s to 70s. Biopsies were analysed by histology, transcriptomics, and proteomics and skin surface biomarkers collected from tape strips. We identified morphological changes with age of epidermal thinning, rete ridge pathlength loss and stratum corneum thickening. The SASP biomarkers IL-8 and IL-1RA/IL1-α were consistently elevated in face across age and cis/trans-urocanic acid were elevated in arms and face with age. In older arms, the DNA damage response biomarker 53BP1 showed higher puncti numbers in basal layers and epigenetic ageing were accelerated. Genes associated with differentiation and senescence showed increasing expression in the 30s whereas genes associated with hypoxia and glycolysis increased in the 50's. Proteomics comparing 60's vs 20's confirmed elevated levels of differentiation and glycolytic-related proteins. Representative immunostaining for proteins of differentiation, senescence and oxygen sensing/hypoxia showed similar relationships. This system biology-based analysis provides a body of evidence that young photoexposed skin is undergoing inflammaging. We propose the presence of chronic inflammation in young skin contributes to an imbalance of epidermal homeostasis that leads to a prematurely aged appearance during later life.
Subject(s)
Epidermis , Skin , Humans , Female , Aged , Young Adult , Adult , Skin/metabolism , Homeostasis , Inflammation/metabolism , Hypoxia/metabolism , Cellular SenescenceABSTRACT
The α-synucleinopathies constitute a subset of neurodegenerative disorders, of which Parkinson's disease (PD) is the most common worldwide, characterized by the accumulation of misfolded α-synuclein in the cytoplasm of neurons, which spreads in a prion-like manner to anatomically interconnected brain areas. However, it is not clear how α-synucleinopathy triggers neurodegeneration. We recently developed a rat model through a single intranigral administration of the neurotoxic ß-sitosterol ß-D-glucoside (BSSG), which produces α-synucleinopathy. In this model, we aimed to evaluate the temporal pattern of levels in oxidative and nitrosative stress and mitochondrial complex I (CI) dysfunction and how these biochemical parameters are associated with neurodegeneration in different brain areas with α-synucleinopathy (Substantia nigra pars compacta, the striatum, in the hippocampus and the olfactory bulb, where α-syn aggregation spreads). Interestingly, an increase in oxidative stress and mitochondrial CI dysfunction accompanied neurodegeneration in those brain regions. Furthermore, in silico analysis suggests a high-affinity binding site for BSSG with peroxisome proliferator-activated receptors (PPAR) alpha (PPAR-α) and gamma (PPAR-γ). These findings will contribute to elucidating the pathophysiological mechanisms associated with α-synucleinopathies and lead to the identification of new early biomarkers and therapeutic targets.
Subject(s)
Brain , Electron Transport Complex I , Mitochondria , Oxidative Stress , Synucleinopathies , alpha-Synuclein , Animals , Brain/metabolism , Brain/physiopathology , Disease Models, Animal , Electron Transport Complex I/metabolism , Mitochondria/metabolism , Nitrosative Stress , Peroxisome Proliferator-Activated Receptors/metabolism , Rats , Synucleinopathies/metabolism , Synucleinopathies/physiopathology , alpha-Synuclein/chemistry , alpha-Synuclein/metabolismABSTRACT
Histamine receptor 2 (HRH2) activation in the stomach results in gastric acid secretion, and HRH2 blockers are used for the treatment of peptidic ulcers and acid reflux. Over-the-counter HRH2 blockers carry a five-membered aromatic heterocycle, with two of them additionally carrying a tertiary amine that decomposes to N-nitrosodimethylamine, a human carcinogen. To discover a novel HRH2 blocker scaffold to serve in the development of next-generation HRH2 blockers, we developed an HRH2-based sensor in yeast by linking human HRH2 activation to cell luminescence. We used the HRH2-based sensor to screen a 403-member anti-infection chemical library and identified three HRH2 blockers, chlorquinaldol, chloroxine, and broxyquinoline, all sharing an 8-hydroxyquinoline scaffold, which is not found among known HRH2 antagonists. Critically, we validate their HRH2-blocking ability in mammalian cells. Molecular docking suggests that the HRH2 blockers bind the histamine binding pocket and structure-activity data point toward these blockers acting as competitive antagonists. Chloroxine and broxyquinoline are antimicrobials that can be found in the gastrointestinal tract at concentrations that would block HRH2, thus likely modulating gastric acid secretion. Taken together, this work demonstrates the utility of GPCR-based sensors for rapid drug discovery applications, identifies a novel HRH2 blocker scaffold, and provides further evidence that antimicrobials not only target the human microbiota but also the human host.
Subject(s)
Phagocytosis , Receptors, Histamine , Animals , Humans , Mammals , Molecular Docking Simulation , OxyquinolineABSTRACT
Background: Increased intracranial pressure (ICP) and hypotension have long been shown to lead to worse outcomes in the severe traumatic brain injury (TBI) population. Adequate sedation is a fundamental principle in TBI care, and ketamine is an attractive option for sedation since it does not commonly cause systemic hypotension, whereas most other sedative medications do. We evaluated the effects of ketamine boluses on both ICP and cerebral perfusion pressure (CPP) in patients with severe TBI and refractory ICP. Methods: We conducted a retrospective review of all patients admitted to the neurointensive care unit at a single tertiary referral center who had a severe traumatic brain injury with indwelling intracranial pressure monitors. We identified those patients with refractory intracranial pressure who received boluses of ketamine. We defined refractory as any sustained ICP greater than 20 mmHg after the patient was adequately sedated, serum Na was at goal, and CO2 was maintained between 35 and 40 mmHg. The primary outcome was a reduction in ICP with a subsequent increase in CPP. Results: The patient cohort consisted of 44 patients with a median age of 30 years and a median presenting Glasgow Coma Scale (GCS) of 5. The median reduction in ICP after administration of a ketamine bolus was -3.5 mmHg (IQR -9 to +1), and the postketamine ICP was significantly different from baseline (p < 0.001). Ketamine boluses led to an increase in CPP by 2 mmHg (IQR -5 to +12), which was also significantly different from baseline (p < 0.001). Conclusion: In this single-institution study of patients with severe traumatic brain injury, ketamine boluses were associated with a reduction in ICP and an increase in CPP. This was a retrospective review of 43 patients and is therefore limited in nature, but further randomized controlled trials should be performed to confirm the findings.
ABSTRACT
BACKGROUND: Cryptococcus neoformans is an opportunistic fungal pathogen that can cause meningitis in immunocompromised individuals. The objective of this work was to study the relationship between the phenotypes and genotypes of isolates of clinical origin from different cities in Colombia. METHODS: Genome classification of 29 clinical isolates of C. neoformans var. grubii was performed using multilocus sequence typing (MLST), and genomic sequencing was used to genotype protein-coding genes. Pathogenicity was assessed in a larval model, and melanin production and capsule size were evaluated in vitro and in vivo. RESULTS: Eleven MLST sequence types (STs) were found, the most frequent being ST69 (n = 9), ST2, ST93, and ST377 (each with n = 4). In the 29 isolates, different levels of pigmentation, capsule size and pathogenicity were observed. Isolates classified as highly pathogenic showed a tendency to exhibit larger increases in capsule size. In the analysis of polymorphisms, 48 non-synonymous variants located in the predicted functional domains of 39 genes were found to be associated with capsule size change, melanin, or pathogenicity. CONCLUSIONS: No clear patterns were found in the analysis of the phenotype and genotype of Cryptococcus. However, the data suggest that the increase in capsule size is a key variable for the differentiation of pathogenic isolates, regardless of the method used for its induction.
ABSTRACT
Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a potentially lethal clinical entity that belongs to the group of antibody-mediated encephalitis against synaptic proteins. It shows IgG antibodies against the NR1 subunit of the NMDA receptor (NMDA-R), which have been associated with psychiatric and neurological symptoms that develop in stages in the course of the disease. The predominance of neuropsychiatric symptoms in the early stages of the disease results in an increased number of patients that search for psychiatric evaluation as their first contact with the health system. For this reason, it is vital for physicians to recognize this entity as an important differential diagnosis in their clinical practice because, despite the severity of this condition, more than 75 % of patients achieve a substantial recovery with appropriate and timely treatment. We present a review of the literature on this disease, with special emphasis on the neuropsychiatric aspects.
La encefalitis por anticuerpos contra el receptor anti-N-metil-D-aspartato (NMDA) es una entidad clínica potencialmente letal perteneciente al grupo de las encefalitis mediadas por anticuerpos contra proteínas sinápticas. En esta se demuestran anticuerpos IgG contra el receptor de NMDA (NMDAr), asociados con síntomas psiquiátricos y neurológicos que se desarrollan por estadios en el curso de la enfermedad. El predominio de síntomas neuropsiquiátricos en las etapas tempranas provoca que un elevado porcentaje de pacientes busquen evaluación psiquiátrica como un primer contacto con el sistema de salud. Por esta razón, es vital que los médicos reconozcan esta entidad como un diagnóstico diferencial importante en la práctica clínica, puesto que, a pesar de la gravedad de esta condición, más de 75 % de los pacientes logra una recuperación sustancial con un tratamiento adecuado y oportuno. Presentamos una revisión de la literatura sobre esta enfermedad, con especial énfasis en los aspectos neuropsiquiátricos.
Subject(s)
Anti-N-Methyl-D-Aspartate Receptor Encephalitis , Anti-N-Methyl-D-Aspartate Receptor Encephalitis/diagnosis , Anti-N-Methyl-D-Aspartate Receptor Encephalitis/psychology , Autoantibodies , Diagnosis, Differential , Humans , Immunoglobulins , Receptors, N-Methyl-D-AspartateABSTRACT
The current pandemic caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a public health emergency. To date, March 1, 2021, coronavirus disease 2019 (COVID-19) has caused about 114 million accumulated cases and 2.53 million deaths worldwide. Previous pieces of evidence suggest that SARS-CoV-2 may affect the central nervous system (CNS) and cause neurological symptoms in COVID-19 patients. It is also known that angiotensin-converting enzyme-2 (ACE2), the primary receptor for SARS-CoV-2 infection, is expressed in different brain areas and cell types. Thus, it is hypothesized that infection by this virus could generate or exacerbate neuropathological alterations. However, the molecular mechanisms that link COVID-19 disease and nerve damage are unclear. In this review, we describe the routes of SARS-CoV-2 invasion into the central nervous system. We also analyze the neuropathologic mechanisms underlying this viral infection, and their potential relationship with the neurological manifestations described in patients with COVID-19, and the appearance or exacerbation of some neurodegenerative diseases.
ABSTRACT
Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Histopathologically, AD presents with two hallmarks: neurofibrillary tangles (NFTs), and aggregates of amyloid ß peptide (Aß) both in the brain parenchyma as neuritic plaques, and around blood vessels as cerebral amyloid angiopathy (CAA). According to the vascular hypothesis of AD, vascular risk factors can result in dysregulation of the neurovascular unit (NVU) and hypoxia. Hypoxia may reduce Aß clearance from the brain and increase its production, leading to both parenchymal and vascular accumulation of Aß. An increase in Aß amplifies neuronal dysfunction, NFT formation, and accelerates neurodegeneration, resulting in dementia. In recent decades, therapeutic approaches have attempted to decrease the levels of abnormal Aß or tau levels in the AD brain. However, several of these approaches have either been associated with an inappropriate immune response triggering inflammation, or have failed to improve cognition. Here, we review the pathogenesis and potential therapeutic targets associated with dysfunction of the NVU in AD.
Subject(s)
Alzheimer Disease/physiopathology , Brain/blood supply , Brain/physiopathology , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Amyloid/metabolism , Animals , Blood-Brain Barrier/pathology , Blood-Brain Barrier/physiopathology , Brain/pathology , Humans , Molecular Targeted TherapyABSTRACT
The objective of the study was to evaluate the capacity of GERH®-derived local resistance maps (LRMs) to predict antibiotic susceptibility profiles and recommend the appropriate empirical treatment for ICU patients with nosocomial infection. Data gathered between 2007 and 2016 were retrospectively studied to compare susceptibility information from antibiograms of microorganisms isolated in blood cultures, lower respiratory tract samples, and urine samples from all ICU patients meeting clinical criteria for infection with the susceptibility mapped by LRMs for these bacterial species. Susceptibility described by LRMs was concordant with in vitro study results in 73.9% of cases. The LRM-predicted outcome agreed with the antibiogram result in >90% of cases infected with the bacteria for which GERH® offers data on susceptibility to daptomycin, vancomycin, teicoplanin, linezolid, and rifampicin. Full adherence to LRM recommendations would have improved the percentage adequacy of empirical prescriptions by 2.2% for lower respiratory tract infections (p = 0.018), 3.1% for bacteremia (p = 0.07), and 5.3% for urinary tract infections (p = 0.142). LRMs may moderately improve the adequacy of empirical antibiotic therapy, especially for lower respiratory tract infections. LRMs recommend appropriate prescriptions in approximately 50% of cases but are less useful in patients with bacteremia or urinary tract infection.