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Microbes and Infection 2023Human Angiotensin-Converting Enzyme 2 (hACE2) is the major receptor enabling host cell invasion by SARS-CoV-2 via interaction with Spike. The murine ACE2 does not...
Human Angiotensin-Converting Enzyme 2 (hACE2) is the major receptor enabling host cell invasion by SARS-CoV-2 via interaction with Spike. The murine ACE2 does not interact efficiently with SARS-CoV-2 Spike and therefore the laboratory mouse strains are not permissive to SARS-CoV-2 replication. Here, we generated new hACE2 transgenic mice, which harbor the hACE2 gene under the human keratin 18 promoter, in "HHD-DR1" background. HHD-DR1 mice are fully devoid of murine Major Histocompatibility Complex (MHC) molecules of class-I and -II and express only MHC molecules from Human Leukocyte Antigen (HLA) HLA 02.01, DRA01.01, DRB1.01.01 alleles, widely expressed in human populations. We selected three transgenic strains, with various hACE2 mRNA expression levels and distinctive profiles of lung and/or brain permissiveness to SARS-CoV-2 replication. These new hACE2 transgenic strains display high permissiveness to the replication of SARS-CoV-2 Omicron sub-variants, while the previously available B6.K18-ACE2 mice have been reported to be poorly susceptible to infection with Omicron. As a first application, one of these MHC- and ACE2-humanized strains was successfully used to show the efficacy of a lentiviral-based COVID-19 vaccine.
Topics: Animals; Mice; Humans; Angiotensin-Converting Enzyme 2; SARS-CoV-2; COVID-19 Vaccines; Permissiveness; COVID-19; Major Histocompatibility Complex; Mice, Transgenic
PubMed: 37080384
DOI: 10.1016/j.micinf.2023.105142 -
Cell Reports Jan 2020Regulatory T cells (Tregs) express high levels of cell surface lymphotoxin alpha beta (LTα1β2) to activate the LT beta receptor (LTβR) on the lymphatic endothelial...
Regulatory T cells (Tregs) express high levels of cell surface lymphotoxin alpha beta (LTα1β2) to activate the LT beta receptor (LTβR) on the lymphatic endothelial cells (LECs), modulating LEC adhesion molecules, intercellular junctions, and chemokines. We demonstrate a role for Tregs through this pathway to condition the permissiveness of lymphatic endothelia for transendothelial migration (TEM), thus gating leukocyte traffic. Human Tregs share the same property with murine Tregs. Activation of TLR2 on Tregs during inflammation specifically augments LTα1β2-LTβR signaling, which further enhances the permissiveness of LECs to facilitate TEM. The conditioning of endothelia may promote the resolution of inflammation by directing leukocytes out of tissues to lymphatic vessels and draining lymph nodes (dLNs). Thus, Tregs interact with lymphatic endothelia under homeostasis and inflammation and dictate endothelial permissiveness and gating mechanisms for subsequent leukocyte migration through endothelial barriers.
Topics: Animals; CD4-Positive T-Lymphocytes; Cadherins; Cell Line; Cell Movement; Chemokine CCL21; Endothelium, Lymphatic; Humans; Inflammation; Interleukin-2; Islets of Langerhans; Lymph Nodes; Lymphotoxin beta Receptor; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; NF-kappa B; Protocadherins; Receptors, Interleukin-2; Signal Transduction; T-Lymphocytes, Regulatory; Toll-Like Receptor 2; Transendothelial and Transepithelial Migration; Vascular Cell Adhesion Molecule-1
PubMed: 31995749
DOI: 10.1016/j.celrep.2019.12.083 -
Cureus Jul 2021Trauma is one of the leading causes of death, with hemorrhage being one of the most preventable aspects. Aggressive fluid resuscitation protocols were implemented before... (Review)
Review
Trauma is one of the leading causes of death, with hemorrhage being one of the most preventable aspects. Aggressive fluid resuscitation protocols were implemented before their value was critically evaluated. Permissive hypotension limits blood loss while maintaining adequate perfusion and positively impacts outcomes in actively hemorrhaging trauma patients. Peer-reviewed articles pertaining to the use of hypotensive resuscitation were identified and selected from a search of the PubMed database. Based on this, seven primary research articles were selected for evaluation. The articles were grouped based on their approach to hypotensive resuscitation. We focused on the safety and viability of hypotensive resuscitation, compared it to normotensive resuscitation, and compared mortality rates. Our review shows that hypotensive resuscitation is safe and has a decreased mortality rate when compared to normotensive resuscitation in hemorrhagic shock patients. There is less blood loss, hemodilution, ischemia, and hypoxia in tissues. Additional research is required to determine the exact parameters that are most beneficial in different patient populations.
PubMed: 34430103
DOI: 10.7759/cureus.16487 -
Substance Use & Misuse 2022This study examined levels of substance-specific risk factors such as perception of harm from substance use among young adults in a range of cannabis-permissive...
PURPOSE
This study examined levels of substance-specific risk factors such as perception of harm from substance use among young adults in a range of cannabis-permissive environments. The main objective was to inform future preventive interventions aimed at reducing cannabis use in the context of increasingly permissive environments.
METHODS
Data came from the Community Youth Development Study (CYDS) collected in 2016 when participants were about 23 years old ( = 1,722 participants residing in 46 U.S. states). Young adults self-reported their perceptions about the harms related to cannabis, alcohol, and cigarette use; attitudes about and ease of access to cannabis and other substances; and perceived wrongfulness and social acceptability of cannabis, alcohol, and cigarette use and of selling of cannabis and other illegal drugs.
RESULTS
Young adults in more permissive cannabis contexts reported higher levels of all cannabis-specific risk factors (e.g., greater access to and more favorable attitudes about cannabis use), except for perception of harm from regular cannabis use. However, permissiveness of the cannabis environment was not associated with heightened levels of risk factors for other substance use (such as alcohol, cigarettes, and opioids).
CONCLUSIONS
Future preventive interventions for young adults living in more permissive cannabis contexts may need to focus on cannabis-specific risk factors in particular and go beyond considerations of harm from regular use. Future studies should replicate these findings with other samples.
Topics: Adolescent; Young Adult; Humans; Adult; Cannabis; Substance-Related Disorders; Illicit Drugs; Hallucinogens; Risk Factors; Ethanol
PubMed: 36151975
DOI: 10.1080/10826084.2022.2120363 -
Molecular Psychiatry Aug 2017Neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF) and other members of the neurotrophin family, are central mediators of the activity-dependent...
Neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF) and other members of the neurotrophin family, are central mediators of the activity-dependent plasticity through which environmental experiences, such as sensory information are translated into the structure and function of neuronal networks. Synthesis, release and action of BDNF is regulated by neuronal activity and BDNF in turn leads to trophic effects such as formation, stabilization and potentiation of synapses through its high-affinity TrkB receptors. Several clinically available drugs activate neurotrophin signaling and neuronal plasticity. In particular, antidepressant drugs rapidly activate TrkB signaling and gradually increase BDNF expression, and the behavioral effects of antidepressants are mediated by and dependent on BDNF signaling through TrkB at least in rodents. These findings indicate that antidepressants, widely used drugs, effectively act as TrkB activators. They further imply that neuronal plasticity is a central mechanism in the action of antidepressant drugs. Indeed, it was recently discovered that antidepressants reactivate a state of plasticity in the adult cerebral cortex that closely resembles the enhanced plasticity normally observed during postnatal critical periods. This state of induced plasticity, known as iPlasticity, allows environmental stimuli to beneficially reorganize networks abnormally wired during early life. iPlasticity has been observed in cortical as well as subcortical networks and is induced by several pharmacological and non-pharmacological treatments. iPlasticity is a new pharmacological principle where drug treatment and rehabilitation cooperate; the drug acts permissively to enhance plasticity and rehabilitation provides activity to guide the appropriate wiring of the plastic network. Optimization of iPlastic drug treatment with novel means of rehabilitation may help improve the efficacy of available drug treatments and expand the use of currently existing drugs into new indications.
Topics: Animals; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Cerebral Cortex; Depressive Disorder; Humans; Nerve Growth Factors; Neuronal Plasticity; Receptor, trkB; Signal Transduction
PubMed: 28397840
DOI: 10.1038/mp.2017.61 -
PloS One 2016Given the public health importance of improving dietary behavior in chronic disease prevention in low- and middle-income countries it is crucial to understand the...
OBJECTIVE
Given the public health importance of improving dietary behavior in chronic disease prevention in low- and middle-income countries it is crucial to understand the factors influencing dietary behavior in these settings. This study tested the validity of a conceptual framework linking individual and environmental factors to dietary behavior among Ecuadorian adolescents aged 10-16 years.
METHODS
A cross-sectional survey was conducted in 784 school-going Ecuadorian adolescents in urban and rural Southern Ecuador. Participants provided data on socio-economic status, anthropometry, dietary behavior and its determining factors. The relationships between individual (perceived benefits and barriers, self-efficacy, habit strength, and a better understanding of healthy food) and environmental factors (physical environment: accessibility to healthy food; social environment: parental permissiveness and school support), and their association with key components of dietary behavior (fruit and vegetables, sugary drinks, breakfast, and unhealthy snack intake) were assessed using structural equation modeling.
RESULTS
The conceptual model performed well for each component of eating behavior, indicating acceptable goodness-of-fit for both the measurement and structural models. Models for vegetable intake and unhealthy snacking showed significant and direct effects of individual factors (perceived benefits). For breakfast and sugary drink consumption, there was a direct and positive association with socio-environmental factors (school support and parental permissiveness). Access to healthy food was associated indirectly with all eating behaviors (except for sugary drink intake) and this effect operated through socio-environmental (parental permissiveness and school support) and individual factors (perceived benefits).
CONCLUSION
Our study demonstrated that key components of adolescents' dietary behaviors are influenced by a complex interplay of individual and environmental factors. The findings indicate that the influence of these factors varied by type of dietary behavior.
Topics: Adolescent; Adolescent Behavior; Breakfast; Child; Cross-Sectional Studies; Diet; Dietary Sucrose; Ecuador; Feeding Behavior; Female; Food Preferences; Humans; Male; Psychological Theory; Snacks; Socioeconomic Factors
PubMed: 27447169
DOI: 10.1371/journal.pone.0157744 -
Archives of Sexual Behavior Feb 2022Pornography and attitude change studies most often adopt a sexual scripting (SS) perspective. The moral incongruence (MI) perspective on pornography has gained...
Pornography and attitude change studies most often adopt a sexual scripting (SS) perspective. The moral incongruence (MI) perspective on pornography has gained prominence in recent years, however, and may lead to differential predictions from the SS approach. Specifically, a detailed reading of MI and SS papers reveals the potential for discrepant predictions about the effect of pornography on sexual permissiveness, one of the most studied outcomes in pornography research. From an SS perspective, pornography use increases sexual permissiveness, but the preexisting traditional sexual scripts of the religious lessen the magnitude of this effect. Alternatively, the MI perspective implies the possibility that religious persons become more opposed to permissive sexuality as a result of their pornography use, as a way to mitigate the cognitive dissonance they feel for engaging in a sexual behavior proscribed by their faith tradition. The present study explored these divergent possibilities using nationally representative U.S. data. Across four meta-samples and four indicators of sexual permissiveness, religious nonviewers of pornography were the least sexually permissive, followed by religious viewers, nonreligious nonviewers, and nonreligious viewers. These results were robust over time and maintained after adjusting for demographics. For theorizing about pornography, religiosity, and sexual permissiveness, these results suggest that an SS approach may be preferable to an MI approach. The importance of continued research using both the SS and MI perspectives is discussed, however, emphasizing that the present study extrapolated a potential prediction from MI rather than a formal postulate put forth by the model's creators.
Topics: Attitude; Erotica; Humans; Morals; Religion; Sexual Behavior
PubMed: 34816358
DOI: 10.1007/s10508-021-02135-0 -
Social Psychiatry and Psychiatric... Jan 2022Adolescents' perceptions of parental norms may influence their substance use. The relationship between parental norms toward cigarette and alcohol use, and the use of...
PURPOSE
Adolescents' perceptions of parental norms may influence their substance use. The relationship between parental norms toward cigarette and alcohol use, and the use of illicit substances among their adolescent children is not sufficiently investigated. The purpose of this study was to analyze this relationship, including gender differences, using longitudinal data from a large population-based study.
METHODS
The present study analyzed longitudinal data from 3171 12- to 14-year-old students in 7 European countries allocated to the control arm of the European Drug Addiction Prevention trial. The impact of parental permissiveness toward cigarettes and alcohol use reported by the students at baseline on illicit drug use at 6-month follow-up was analyzed through multilevel logistic regression models, stratified by gender. Whether adolescents' own use of cigarette and alcohol mediated the association between parental norms and illicit drug use was tested through mediation models.
RESULTS
Parental permissive norms toward cigarette smoking and alcohol use at baseline predicted adolescents' illicit drug use at follow-up. The association was stronger among boys than among girls and was mediated by adolescents' own cigarette and alcohol use.
CONCLUSION
Perceived parental permissiveness toward the use of legal drugs predicted adolescents' use of illicit drugs, especially among boys. Parents should be made aware of the importance of norm setting, and supported in conveying clear messages of disapproval of all substances.
Topics: Adolescent; Adolescent Behavior; Alcohol Drinking; Child; Cigarette Smoking; Cross-Sectional Studies; Female; Humans; Illicit Drugs; Longitudinal Studies; Male; Parents; Permissiveness; Substance-Related Disorders
PubMed: 34120221
DOI: 10.1007/s00127-021-02118-5 -
Biomedicine & Pharmacotherapy =... Dec 2016l-Thyroxine (T) is the principal replacement hormone for patients who have hypothyroidism. Some preclinical and clinical evidence supports the possibility that T can at... (Review)
Review
l-Thyroxine (T) is the principal replacement hormone for patients who have hypothyroidism. Some preclinical and clinical evidence supports the possibility that T can at least permissively affect certain features of established cancers and cancer-relevant angiogenesis. Thus, in the occasional patient with hypothyroidism and concomitant cancer, it appears reasonable to consider thyroid hormone replacement exclusively with 3,3',5-triiodo-l-thyronine (T). This use of T has been shown to be effective and safe in early experience with medical induction of euthyroid hypothyroxinemia in patients with advanced solid tumors.
Topics: Animals; Apoptosis; Hormone Replacement Therapy; Humans; Hypothyroidism; Neoplasms; Neovascularization, Pathologic; Patient Selection; Risk Assessment; Risk Factors; Thyroxine; Triiodothyronine
PubMed: 27697637
DOI: 10.1016/j.biopha.2016.09.053 -
Critical Care Explorations Oct 2023Mean arterial hypotension between 55 and 65 mm Hg could be tolerated safely in the absence of tissue hypoperfusion, but the consequences on fluid balance and kidney...
OBJECTIVES
Mean arterial hypotension between 55 and 65 mm Hg could be tolerated safely in the absence of tissue hypoperfusion, but the consequences on fluid balance and kidney function remain unknown.
DESIGN
During a 1-year period, we retrospectively collected data of consecutive septic patients admitted for sepsis with a mean arterial pressure (MAP) less than 65 mm Hg despite fluid resuscitation.
SETTING
Medical 18-bed ICU in a tertiary teaching hospital.
PATIENTS
Septic patients with a MAP less than 65 mm Hg despite initial resuscitation.
INTERVENTIONS
In our ICU, MAP between 55 and 65 mm Hg was tolerated in the absence of peripheral hypoperfusion (permissive hypotension) or corrected using norepinephrine (septic shock group) when peripheral tissue hypoperfusion was present.
MEASUREMENTS AND MAIN RESULTS
Ninety-four consecutive septic patients were included, 15 in the permissive hypotension group and 79 in the septic shock group. Median age was 66 years (57-77 yr) and 42% were women. The main sources of infection were respiratory (45%) and abdominal (18%). Severity was more important in septic shock group with higher Sequential Organ Failure Assessment score (7 [5-10] vs. 4 [1-6]; < 0.0001), more frequent organ support therapy and ultimately higher mortality (38 vs. 0%; < 0.01). The total volume of crystalloids infused before ICU admission was not different between groups (1930 ± 250 vs. 1850 ± 150 mL; = 0.40). Within the 6 first hours of ICU stay, patients in the permissive hypotension group received less fluids (530 ± 170 vs. 1100 ± 110 mL; = 0.03) and had higher urinary output (1.4 mL [0.88-2.34 mL] vs. 0.47 mL/kg/hr [0.08-1.25 mL/kg/hr]; < 0.001). In addition, kidney injury evaluated using KDIGO score was lower in the permissive hypotension group at 48 hours (0 hr [0-1 hr] vs. 1 hr [0-2 hr]; < 0.05).
CONCLUSIONS
In septic patients without clinical peripheral hypoperfusion, mean arterial hypotension between 55 and 65 mm Hg could be tolerated safely without vasopressor infusion and was not associated with excessive fluid administration or kidney damage.
PubMed: 37868030
DOI: 10.1097/CCE.0000000000000991