Human MHC Class II and Invariant Chain Knock-in Mice Mimic Rheumatoid Arthritis with Allele Restriction in Immune Response and Arthritis Association.

Transgenic mice expressing human major histocompatibility complex class II (MHCII) risk alleles are widely used in autoimmune disease research, but limitations arise due to non-physiologic expression. To address this, physiologically relevant mouse models are established via knock-in technology to explore the role of MHCII in diseases like rheumatoid arthritis. The gene sequences encoding the ectodomains are replaced with the human DRB1*04:01 and 04:02 alleles, DRA, and CD74 (invariant chain) in C57BL/6N mice. The collagen type II (Col2a1) gene is modified to mimic human COL2. Importantly, DRB1*04:01 knock-in mice display physiologic expression of human MHCII also on thymic epithelial cells, in contrast to DRB1*04:01 transgenic mice. Humanization of the invariant chain enhances MHCII expression on thymic epithelial cells, increases mature B cell numbers in spleen, and improves antigen presentation. To validate its functionality, the collagen-induced arthritis (CIA) model is used, where DRB1*04:01 expression led to a higher susceptibility to arthritis, as compared with mice expressing DRB1*04:02. In addition, the humanized T cell epitope on COL2 allows autoreactive T cell-mediated arthritis development. In conclusion, the humanized knock-in mouse faithfully expresses MHCII, confirming the DRB1*04:01 alleles role in rheumatoid arthritis and being also useful for studying MHCII-associated diseases.

Sexual behaviour of young rams is improved and less stressful after intranasal administration of oxytocin.

The aim of this study was to determine if intranasal administration of oxytocin modifies sexual behaviour and the stress response in young rams during sexual tests with ewes in oestrus. Ten rams were used in a cross-over design. At Day 0, the control group (CG, n = 5) received isotonic saline spray intranasally, and the treated group (OTG, n = 5) received oxytocin (24 IU) intranasally, 40 min before the sexual test. At Day 15, the groups were reversed. In each sexual test (20 min) with an oestrous-induced ewe, the sexual behaviour of the young rams was recorded. Serum cortisol concentrations were determined before and after the test. Less flehmen was observed in the OTG, but mounts with ejaculation were increased. The OTG presented lower serum cortisol concentration than the CG. In conclusion, intranasal administration of oxytocin modified the sexual behaviour of rams, evidenced by a decrease in flehmen behaviour and an increase in mounts with ejaculation, making sexual activity more efficacious. In addition, the treatment decreased the stress response of the rams in the sexual tests. Therefore, intranasal administration of oxytocin could be used to increase sexual activity in rams, and with less stress, providing better welfare conditions.

White-rot fungus Phlebia floridensis ITM 12: Laccase production, oxidoreductase profile, and hydrogen-peroxide independent activity.

Phlebia genus is a relevant group of fungi with a crucial role in numerous ecosystems. In tropical and subtropical areas this genus allows the efficient degradation of lignin and carbon recovery; however, the majority of these fungal species remain undiscovered. The main purpose of this work was to determine the enzymatic activity of extracellular proteins of a novel Phlebia floridensis strain isolated in Yucatan Peninsula, Mexico. The results that are reported here demonstrate that the soluble protein extract of P. floridensis can degrade a broad spectrum of recalcitrant compounds. This induced protein extract is able to modify not only phenolic and nonphenolic compounds, but also anthroquinone dyes, even without the addition of exogenous hydrogen peroxide. Using liquid chromatography-mass spectrometry (LC-MS), we were able to identify a novel chloroperoxidase in enzymatic extract. As far as we know, this is the first report about the presence of this type of enzyme in the Phlebia genus.

Us versus them: The role of national identity in the formation of false memories for fake news.

People are prone to forming false memories for fictitious events described in fake news stories. In this preregistered study, we hypothesized that the formation of false memories may be promoted when the fake news includes stereotypes that reflect positively on one's own nationality or negatively on another nationality. We exposed German and Irish participants (N = 1,184) to fabricated news stories that were consistent with positive or negative stereotypes about Germany and Ireland. The predicted three-way interaction was not observed. Exploratory follow-up analyses revealed the expected pattern of results for German participants but not for Irish participants, who were more likely to remember positive stories and stories about Ireland. Individual differences in patriotism did not significantly affect false memory rates; however, higher levels of cognitive ability and analytical reasoning decreased false memories and increased participants' ability to distinguish between true and false news stories. These results demonstrate that stereotypical information pertaining to national identity can influence the formation of false memories for fake news, but variations in cultural context may affect how misinformation is received and processed. We conclude by urging researchers to consider the sociopolitical and media landscape when predicting the consequences of fake news exposure. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Increase in Incidence Rates and Risk Factors for Multidrug Resistant Bacteria in Septic Children: A Nationwide Spanish Cohort Study (2013-2019).

The emergence of multidrug-resistant (MDR) bacteria in children is a growing concern, particularly among septic patients, given the need for first-right dosing. Our aim was to determine the incidence rates and factors associated with MDR-sepsis in the pediatric intensive care unit (PICU), using data from the Spanish ENVIN-HELICS PICU registry between 2013 and 2019. The rate of MDR bacteria among septic children ranged between 5.8 and 16.2% throughout this study period, with a significant increase since 2015 (p = 0.013). MDR-gram-negative bacteria (92%), particularly EBL-Enterobacterales (63.7%), were the most frequent causative microorganisms of MDR-sepsis. During this study period, sixteen MDR-sepsis (32.6%) corresponded to intrahospital infections, and 33 (67.4%) had community-onset sepsis, accounting for 10.5% of the overall community-onset sepsis. Independent risk factors associated with MDR-sepsis were antibiotics 48 h prior to PICU admission (OR 2.38) and PICU onset of sepsis (OR 2.58) in >1 year-old children, and previous malnourishment (OR 4.99) in <1 year-old children. Conclusions: There was an alarming increase in MDR among septic children in Spain, mainly by gram-negative (ESBL-Enterobacterales), mostly coming from the community setting. Malnourished infants and children on antibiotics 48 h prior to PICU are at increased risk and therefore require closer surveillance.

Description of a Swine Infant Model of Volume-Controlled Hemorrhagic Shock.

Hemorrhagic shock is a leading cause of morbidity and mortality in pediatric patients. Interpretation of the clinical indicators validated in adults to guide resuscitation and comparison between different therapies is difficult in children due to the inherent heterogeneity of this population. As a result, compared to adults, appropriate management of pediatric hemorrhagic shock is still not well established. In addition, the scarcity of pediatric patients with hemorrhagic shock precludes the development of clinically relevant studies. For this reason, an experimental pediatric animal model is necessary to study the effects of hemorrhage in children as well as their response to different therapies. We present an infant animal model of volume-controlled hemorrhagic shock in anesthetized young pigs. Hemorrhage is induced by withdrawing a previously calculated blood volume, and the pig is subsequently monitored and resuscitated with different therapies. Here, we describe a precise and highly reproducible model of hemorrhagic shock in immature swine. The model yields hemodynamic data that characterizes compensatory mechanisms that are activated in response to severe hemorrhage.

Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice.

B cells undergo several rounds of selection to eliminate potentially pathogenic autoreactive clones, but in contrast to T cells, evidence of positive selection of autoreactive B cells remains moot. Using unique tetramers, we traced natural autoreactive B cells (C1-B) specific for a defined triple-helical epitope on collagen type-II (COL2), constituting a sizeable fraction of the physiological B cell repertoire in mice, rats, and humans. Adoptive transfer of C1-B suppressed arthritis independently of IL10, separating them from IL10-secreting regulatory B cells. Single-cell sequencing revealed an antigen processing and presentation signature, including induced expression of CD72 and CCR7 as surface markers. C1-B presented COL2 to T cells and induced the expansion of regulatory T cells in a contact-dependent manner. CD72 blockade impeded this effect suggesting a new downstream suppressor mechanism that regulates antigen-specific T cell tolerization. Thus, our results indicate that autoreactive antigen-specific naïve B cells tolerize infiltrating T cells against self-antigens to impede the development of tissue-specific autoimmune inflammation.

A cortico-amygdala neural substrate for endocannabinoid modulation of fear extinction.

Preclinical and clinical studies implicate endocannabinoids (eCBs) in fear extinction, but the underlying neural circuit basis of these actions is unclear. Here, we employed in vivo optogenetics, eCB biosensor imaging, ex vivo electrophysiology, and CRISPR-Cas9 gene editing in mice to examine whether basolateral amygdala (BLA)-projecting medial prefrontal cortex (mPFC) neurons represent a neural substrate for the effects of eCBs on extinction. We found that photoexcitation of mPFC axons in BLA during extinction mobilizes BLA eCBs. eCB biosensor imaging showed that eCBs exhibit a dynamic stimulus-specific pattern of activity at mPFC→BLA neurons that tracks extinction learning. Furthermore, using CRISPR-Cas9-mediated gene editing, we demonstrated that extinction memory formation involves eCB activity at cannabinoid CB1 receptors expressed at vmPFC→BLA synapses. Our findings reveal the temporal characteristics and a neural circuit basis of eCBs' effects on fear extinction and inform efforts to target the eCB system as a therapeutic approach in extinction-deficient neuropsychiatric disorders.

Polyploid Giant Cancer Cells Are Frequently Found in the Urine of Prostate Cancer Patients.

Prostate cancer is the third cause of cancer-related deaths in men. Its early and reliable diagnosis is still a public health issue, generating many useless prostate biopsies. Prostate cancer cells detected in urine could be the target of a powerful test but they are considered too rare. By using an approach targeting rare cells, we have analyzed urine from 45 patients with prostate cancer and 43 healthy subjects under 50 y.o. We observed a relevant number of giant cells in patients with cancer. Giant cells, named Polyploid Giant Cancer Cells (PGCC), are thought to be involved in tumorigenesis and treatment resistance. We thus performed immune-morphological studies with cancer-related markers such as α-methylacyl-CoA racemase (AMACR), prostate-specific membrane antigen (PSMA), and telomerase reverse transcriptase (TERT) to understand if the giant cells we found are PGCC or other urinary cells. We found PGCC in the urine of 22 patients, including those with early-stage prostate cancer, and one healthy subject. Although these results are preliminary, they provide, for the first time, clinical evidence that prostate cancers release PGCC into the urine. They are expected to stimulate further studies aimed at understanding the role of urinary PGCC and their possible use as a diagnostic tool and therapeutic target.

Therapy targeting antigen-specific T cells by a peptide-based tolerizing vaccine against autoimmune arthritis.

A longstanding goal has been to find an antigen-specific preventive therapy, i.e., a vaccine, for autoimmune diseases. It has been difficult to find safe ways to steer the targeting of natural regulatory antigen. Here, we show that the administration of exogenous mouse major histocompatibility complex class II protein bounding a unique galactosylated collagen type II (COL2) peptide (Aq-galCOL2) directly interacts with the antigen-specific TCR through a positively charged tag. This leads to expanding a VISTA-positive nonconventional regulatory T cells, resulting in a potent dominant suppressive effect and protection against arthritis in mice. The therapeutic effect is dominant and tissue specific as the suppression can be transferred with regulatory T cells, which downregulate various autoimmune arthritis models including antibody-induced arthritis. Thus, the tolerogenic approach described here may be a promising dominant antigen-specific therapy for rheumatoid arthritis, and in principle, for autoimmune diseases in general.

Circulating cancer giant cells with unique characteristics frequently found in patients with myelodysplastic syndromes (MDS).

Myelodysplastic syndromes (MDS) are incurable diseases characterized by dysplastic hematopoietic cells, cytopenias in the blood and an inherent tendency for transformation to secondary acute myeloid leukemia (AML). Since most therapies fail to prevent rapid clonal evolution and disease resistance, new and non-invasive predictive markers are needed to monitor patients and adapt the therapeutic strategy. By using ISET, a very sensitive approach to isolate cells larger than mature leukocytes from peripheral blood samples, we looked for cellular markers in 99 patients (158 samples) with MDS and 66 healthy individuals (76 samples) used as controls. We found a total of 680 Giant Cells, defined as cells having a size of 40 microns or larger in 46 MDS patients (80 samples) and 28 Giant Cells in 11 healthy individuals (11 samples). In order to understand if we had enriched from peripheral blood atypical cells of the megakaryocyte line, we studied the Giant Cells using immunolabeling with megakaryocytes and tumor-specific markers. We report that the Giant Cells we found in the peripheral blood of MDS patients primarily express tumor markers. Our results show that Polyploid Giant Cancer Cells (PGCC), similar to those described in solid tumors, are found in the peripheral blood of patients with MDS and suggest the working hypothesis that they could play a role in hematological malignancies.

Land abandonment as driver of woody vegetation dynamics in Tamaulipan thornscrub at Northeastern Mexico.

Background: Vegetation structure is defined as the temporal and spatial distribution of plant species in a particular site. Vegetation structure includes vertical and horizontal distribution and has been widely used as an indicator of successional changes. Ecological succession plays an essential role in the determination of the mechanisms that structure plant communities under anthropogenic disturbances. After an anthropogenic disturbance, such as grazing, forests follow changes in the original composition and vegetation structure, which eventually could restore some of their attributes to become mature forests again. To know how the time of abandonment affects woody plant communities, we ask the following questions: (1) How does the species richness, diversity, and vertical structure (A index) change concerning the time of abandonment? (2) Are species similarities among woody vegetation communities determined by land abandonment? (3) Which woody species have the highest ecological importance in each successional stage? Methods: We explored how successional stages after land abandonment mediated the species richness, species diversity (alpha and beta), and ecological importance value index on four areas of Tamaulipan thornscrub. We selected four areas that differed in time of abandonment: 10, 20, 30, and >30 years. The first three areas were used for cattle grazing, whereas the >30-year area was selected as a control since it does not have a record of disturbance by cattle grazing or agriculture. During the summer of 2012, we randomly established four square plots (40 m × 40 m) in each area, separated at least 200 m from each other. In each plot, we recorded all woody individuals per species with a basal diameter ≥1 cm at 10 cm above ground level. We estimated species richness indices, species diversity (alpha and beta), and ecological importance value index. Results: We recorded 27 woody species belonging to 23 genera and 15 families. Fabaceae accounted for 40% of the species. Acacia farnesiana was the most important and abundant species in the first three successional stages. We suggested that older successional stages of Tamaulipan thornscrub promote woody plant communities, characterized by a higher complex structure than younger communities. We observed the highest species similarity between the sites with a closer time of abandonment, while the lowest similarity was shown between the sites with extreme time of abandonment. We conclude that Tamaulipan thornscrub shows a similar trend of ecological succession to other dry forests and the time of abandonment has a high mediation on plant dynamics in the Tamaulipan thornscrub. Also, we stand out the importance of secondary forests for Tamaulipan thornscrub woody plant communities. Finally, we recommended future studies include aspects of regeneration speed, the proximity of mature vegetation, and the interactions of plants with their seed dispersers.

Juvenile Exposure to BPA Alters the Estrous Cycle and Differentially Increases Anxiety-like Behavior and Brain Gene Expression in Adult Male and Female Rats.

Perinatal exposure to bisphenol A (BPA) in murine models has been reported to affect social behavior and increase anxiety. However, there is little information about the effects of BPA exposure during puberty, a period in which sex hormones influence the maturation and differentiation of the brain. In this work, we evaluated the effect of BPA administration during the juvenile stage (PND 21-50) on anxiety in male and female rats. Newly weaned Wistar rats were treated with BPA (0, 50, or 500 µg/kg/day) for 30 days. To compare the intra- and inter-sex behavioral profiles, rats were evaluated using four different anxiety models: the Open field test (OFT), the Elevated plus maze (EPM), the Light-dark box test (LDBT), and the Defensive burying test (DBT). Males exhibited a clear-cut anxious profile at both doses in all four tests, while no clear behavioral effect of BPA exposure was observed in female rats. The latter showed an altered estrous cycle that initiated earlier in life and had a shorter duration, with the estrous phase predominating. Moreover, the expression of ESR1, ESR2, GABRA1, GRIN1, GR, MR, and AR genes increased in the hippocampus and hypothalamus of male rats treated with 50 µg/kg, but not in females. Our results indicate that BPA consistently induces a higher anxiety profile in male than in female rats, as evidenced predominantly by an increase in passive-coping behaviors and changes in brain gene expression, highlighting the importance of sex in peripubertal behavioral toxicology studies.

Impact of Lifestyle Modification on Quality of Life in Patients with Metabolic Syndrome: Findings from the CHANGE Program Intervention Study in Prince Edward Island, Canada.

Purpose: To assess the modification in quality of life (QoL) of patients with metabolic syndrome (MetS) after participating in Canadian Health Advanced by Nutrition and Graded Exercise (CHANGE) program and identify predictors of this modification in QoL among participants. Methods: A convenience sample of 100 patients with MetS completed the 12-month CHANGE program (diet and exercise regular counseling). 36-Item Short Form Health Survey (SF-36), International Physical Activity Questionnaire (IPAC), Physician Assessment and Clinical Education (PACE), and the Mediterranean Diet Score (MDS) questionnaires were employed to assess participants' QoL, physical activity (PA), sedentary behaviors, and quality of diet, respectively. In addition, physical fitness tests (6-Minute Walk Test, One-Leg Stance Test, and Grip Strength Test) were used. Medical history, blood tests, and anthropometric [height, weight, and waist circumference (WC)] and blood pressure measurements were performed by a nurse. Linear regression analysis was performed to identify predictors of QoL. Results: Participants' mean age was 58.3 ± 11.0, and 75.4% were females. After the CHANGE program, participants demonstrated significant reduction in the number of MetS criteria and significant improvement of physical and mental components of QoL. Moreover, there was significant increase in participants' PA, MDS, and physical fitness mean scores with corresponding significant reduction in sedentary behavior time, blood pressure, and WC measures. Linear regression analysis revealed that age, WC, screen time, PA, and physical fitness were significant predictors of QoL. Conclusion: The 12-month group-based diet and exercise counseling led to clinically significant improvement in MetS criteria and in important measures of health and fitness among participants, which improved their QoL. Age, fitness measures, and daily screen time were associated with QoL.

Spanish Translation, Transcultural Adaptation, Validation and Clinical Applicability of Female Genital-Self Image Scale (FGSIS).

BACKGROUND: As female genital cosmetic surgeries have significantly increased, appropriate tools to evaluate self-esteem about women's own genitalia are necessary. AIM: to translate, culturally adapt to Spanish women and to evaluate the psychometric properties of the Female Genital Self-Image Scale (FGSIS). METHODS: FGSIS was forward and backward translated, culturally adapted into Spanish and its content evaluated through Delphi consensus. One item from the original scale was discarded after expert panel evaluation, developing the final Spanish scale (FGSIS-S) consisting of 6 items. Its psychometric properties were evaluated among 202 women attending gynecological consults through an online survey. The survey included socio-demographic data and FGSIS-S. MAIN OUTCOME MEASURE: Socio-demographic items, psychometric characteristics of the FGSIS-S (construct evaluation, internal consistency and test-retest reliability) were assessed. RESULTS: FGSIS-S proved to relate appropriately with the proposed construct (sum-content validity index 0.9, and significant inverse correlation with women concerned about their genital appearance or considering cosmetic surgery) with a 1-factor solution on exploratory factor analysis. The test proved good internal consistency (McDonald's omega 0.86) and test-retest reliability (intraclass correlation 0.86, P < .001). In 41.1% of cases, women referred concern about their genital's self-image and in 12.4% had considered undergoing cosmetic surgery. CLINICAL TRANSLATION: The validated version of FGSIS-S can help both professionals and patients, and its implementation can be easily made in gynecological consults. STRENGTHS AND LIMITATIONS: The main limitation is a self-selection bias in women attending gynecological consults, who may be more worried about their gynecological/sexual health. The sample is also a relatively homogeneous Caucasian population, with medium-high educational level, coming from gynecological consults. Strengths include the large sample size and the demographic survey that permitted evaluating the performance of FGSIS-S in the context of concern about genitals or consideration of cosmetic surgery. CONCLUSION: FGSIS-S is an adequate scale to measure women's genital image self-perception in Spanish-speaking population of Spain. Bartolomé A, Villalaín C, Bermejo R, et al. Spanish Translation, Transcultural Adaptation, Validation and Clinical Applicability of Female Genital-Self Image Scale (FGSIS). Sex Med 2022;10:100558.

Enfermedad de células falciformes en cuidados intensivos pediátricos / Sickle cell disease in pediatric intensive care

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