Lack of mismatch repair enhances resistance to methylating agents for cells deficient in oxidative demethylation.

The human AlkB homologs, ALKBH2 and ALKBH3, respond to methylation damage to maintain genomic integrity and cellular viability. Both ALKBH2 and ALKBH3 are direct reversal repair (DRR) enzymes that remove 1meA and 3meC lesions commonly generated by alkylating chemotherapeutic agents. Thus, the existence of deficiencies in ALKBH proteins can be exploited in synergy with chemotherapy. In this study, we investigated possible interactions between ALKBH2 and ALKBH3 with other proteins that could alter damage response and discovered an interaction with the mismatch repair (MMR) system. To test whether the lack of active MMR impacts ALKBH2 and/or ALKBH3 response to methylating agents, we generated cells deficient in ALKBH2, ALKBH3, or both in addition to Mlh homolog 1 (MLH1), another MMR protein. We found that MLH1koALKBH3ko cells showed enhanced resistance towards SN1- and SN2-type methylating agents, whereas MLH1koALKBH2ko cells were only resistant to SN1-type methylating agents. Concomitant loss of ALKBH2 and ALKBH3 (ALKBH2ko3ko) rendered cells sensitive to SN1- and SN2-agents, but the additional loss of MLH1 enhanced resistance to both types of damage. We also showed that ALKBH2ko3ko cells have an ATR-dependent arrest at the G2/M checkpoint, increased apoptotic signalling, and replication fork stress in response to methylation. However, these responses were not observed with the loss of functional MLH1 in MLH1koALKBH2ko3ko cells. Finally, in MLH1koALKBH2ko3ko cells, we observed elevated mutant frequency in untreated and temozolomide treated cells. These results suggest that obtaining a more accurate prognosis of chemotherapeutic outcome requires information on the functionality of ALKBH2, ALKBH3, and MLH1.

Energy Expenditure Validation of an Exergame Platform: Ring Fit Adventure Use in Adults with Overweight and Obesity.

Objective: This study aims at comparing the energy expenditure (EE) and heart rate (HR) data from Ring Fit Adventure (RFA) with those from indirect calorimetry (COSMED) and a heart rate monitor (Polar FT7). A secondary goal is to evaluate self-reported enjoyment and perceived effort levels. Materials and Methods: Thirty participants (age = 21.8 ± 2.2; body mass index = 31.8 ± 4.4) were recruited for two laboratory visits. The first visit involved baseline measurements. In the second visit, participants performed a 55-minute ad libitum exercise session with the RFA in adventure mode with moderate difficulty. During this session, EE, HR, perceived effort, and enjoyment of physical activity were recorded. Results: Although no statistically significant overestimation of EE was found between the RFA and the metabolic cart, two-way analysis of variance results show a main effect of condition (RFA vs. Polar FT7) on HR (122.8 ± 20.1 bpm and 129.0 ± 18.6 bpm; P = 0.007; ᶯp2 = 0.235). Based on comprehensive statistical evaluations, including the mean absolute percent error, intraclass correlations, typical error of measurement, and limits of agreement, the data suggest that the RFA provides reliable estimates for EE and HR. Overall, participants enjoyed the game considerably (71.3 ± 5.9/80 arbitrary units), and their reported perceived exertion was low. Conclusion: This study underscores that the RFA values are relatively accurate and precise, and thus it can be safely suggested for individuals with overweight and obesity to adopt an active lifestyle.

Low-Density Lipoproteins Increase Proliferation, Invasion, and Chemoresistance via an Exosome Autocrine Mechanism in MDA-MB-231 Chemoresistant Cells.

Dyslipidemias involving high concentrations of low-density lipoproteins (LDLs) increase the risk of developing triple-negative breast cancer (TNBC), wherein cholesterol metabolism and protein translation initiation mechanisms have been linked with chemoresistance. Doxorubicin (Dox) treatment, a member of the anthracycline family, represents a typical therapeutic strategy; however, chemoresistance remains a significant challenge. Exosomes (Exs) secreted by tumoral cells have been implicated in cell communication pathways and chemoresistance mechanisms; the content of exosomes is an outcome of cellular cholesterol metabolism. We previously induced Dox resistance in TNBC cell models, characterizing a variant denominated as variant B cells. Our results suggest that LDL internalization in parental and chemoresistant variant B cells is associated with increased cell proliferation, migration, invasion, and spheroid growth. We identified the role of eIF4F translation initiation factor and the down-regulation of tumor suppressor gene PDCD4, an inhibitor of eIF4A, in chemoresistant variant B cells. In addition, the exomes secreted by variant B cells were characterized by the protein content, electronic microscopy, and cell internalization assays. Critically, exosomes purified from LDL-treated variant B cell promoted cell proliferation, migration, and an increment in lactate concentration. Our results suggest that an autocrine phenomenon induced by exosomes in chemoresistant cells may induce modifications on signaling mechanisms of the p53/Mdm2 axis and activation of p70 ribosomal protein kinase S6. Moreover, the specific down-regulated profile of chaperones Hsp90 and Hsp70 secretion inside the exosomes of the chemoresistant variant could be associated with this phenomenon. Therefore, autocrine activation mediated by exosomes and the effect of LDL internalization may influence changes in exosome chaperone content and modulate proliferative signaling pathways, increasing the aggressiveness of MDA-MB-231 chemoresistant cells.

Asociación entre obesidad abdominal, consumo de alcohol y actividad física en universitarios panameños / Association between abdominal obesity, alcohol consumption and physical activity in Panamanian college students

Introducción. La obesidad abdominal es considerada un factor de riesgo de enfermedad cardiovascular y diabetes. El consumo excesivo episódico de alcohol y la inactividad física también son factores de riesgo comportamentales asociados a enfermedades no transmisibles. Objetivo: Analizar la asociación entre la obesidad abdominal, el consumo de alcohol y la inactividad física en universitarios panameños. Materiales y métodos: Estudio transversal analítico realizado en 374 estudiantes universitarios panameños en el periodo abril ­ diciembre de 2021. Se implementó el cuestionario para la vigilancia de factores de riesgo de enfermedades no transmisibles de la Organización Mundial de la Salud y se evaluó la circunferencia de cintura. La obesidad abdominal se estableció con una circunferencia de cintura ≥80 cm en mujeres y ≥90 cm en hombres. Se realizaron análisis descriptivos, bivariados y múltiples usando modelos de regresión logística para determinar la asociación entre las variables del estudio. Las pruebas U Mann-Whitney y Chi cuadrado fueron utilizadas para analizar diferencias por sexo. Resultados: Una tercera parte de los universitarios participantes presentaron obesidad abdominal. Las mujeres reportaron mayores niveles de inactividad física (<0,0001) y conducta sedentaria (p=0,0010) que los hombres. Después de ajustar por sexo, edad y nivel socioeconómico, la obesidad abdominal estuvo asociada con la inactividad física (OR: 1,762, IC 95%: 1,040 ­ 2,985, p=0,035) y el consumo excesivo episódico de alcohol (OR 1,114, IC: 1,015 ­ 1,223, p=0,023). Conclusiones: Los universitarios panameños que reportaron bajos niveles de actividad física y consumo excesivo episódico de alcohol tuvieron una mayor probabilidad de registrar obesidad abdominal(AU)

Introduction. Abdominal obesity is considered a risk factor for cardiovascular disease and diabetes. Episodic excessive consumption of alcohol and physical inactivity are behavioral risk factors associated with non-communicable diseases. Objective: To analyze the association between abdominal obesity, alcohol consumption and physical inactivity in Panamanian university students. Materials and methods: Analytical cross-sectional study conducted on 374 Panamanian university students in the period April ­ December 2021. The questionnaire for the surveillance of risk factors for non-communicable diseases of the World Health Organization was implemented and waist circumference was evaluated. Abdominal obesity was established with a waist circumference ≥80 cm in women and ≥90 cm in men. Descriptive, bivariate, and multiple analyzes were performed using logistic regression models to determine the association between the study variables. The Mann-Whitney U and Chi square tests were used to analyze differences by sex. Results: A third of the participating university students had abdominal obesity. Women reported higher levels of physical inactivity (<0,0001) and sedentary behavior (p=0,0010) than men. After adjusting for sex, age and socioeconomic status, abdominal obesity was associated with physical inactivity (OR: 1,762, 95% CI: 1,040 ­ 2,985, p=0,035) and episodic heavy alcohol consumption (OR 1,114, CI: 1,015 ­ 1,223, p=0,023). Conclusions: Students who reported low levels of physical inactivity and binge drinking were more likely to have abdominal obesity(AU)

Microwave Imaging System Based on Signal Analysis in a Planar Environment for Detection of Abdominal Aortic Aneurysms.

A proof-of-concept of a microwave imaging system for the fast detection of abdominal aortic aneurysms is shown. This experimental technology seeks to overcome the factors hampering the fast screening for these aneurysms with the usual equipment, such as high cost, long-time operation or hazardous exposure to chemical substances. The hardware system is composed of 16 twin antennas mastered by a microcontroller through a switching network, which connects the antennas to the measurement instrument for sequential measurement. The software system is run by a computer, mastering the whole system, automatizing the measurement process and running the signal processing and medical image generation algorithms. Two image generation algorithms are tested: Delay-and-Sum (DAS) and Improved Delay-and-Sum (IDAS). Own-modified versions of these algorithms adapted to the requirements of our system are proposed. The system is carefully calibrated and fine-tuned with known objects placed at known distances. An experimental proof-of-concept is shown with a human torso phantom, including an aorta phantom and an aneurysm phantom placed in different positions. The results show good imaging capabilities with the potential for detecting and locating possible abdominal aortic aneurysms and reporting acceptable errors.

Pancultural nostalgia in action: Prevalence, triggers, and psychological functions of nostalgia across cultures.

Nostalgia is a social, self-relevant, and bittersweet (although mostly positive) emotion that arises when reflecting on fond past memories and serves key psychological functions. The majority of evidence concerning the prevalence, triggers, and functions of nostalgia has been amassed in samples from a handful of largely Western cultures. If nostalgia is a fundamental psychological resource, it should perform similar functions across cultures, although its operational dynamics may be shaped by culture. This study (N = 2,606) examined dispositional nostalgia, self-reported triggers of nostalgia, and functions of experimentally induced nostalgia in young adults across 28 countries and a special administrative region of China (i.e., Hong Kong). Results indicated that nostalgia is frequently experienced across cultures, albeit better valued in more-developed countries (i.e., higher national wealth and life-expectancy). Nostalgia is triggered by psychological threats (especially in warmer countries), sensory stimuli (especially in more-developed countries), and social gatherings (especially in less-developed countries). The positive or negative affect prompted by experimentally induced nostalgia varied by country, but was mild overall. More importantly, recalling a nostalgic (vs. ordinary) memory increased social connectedness, self-continuity, and meaning in life across cultures. In less-developed countries, recalling an ordinary memory also conferred some of these functions, reducing the effect size of nostalgia. Finally, recalling a nostalgic (vs. ordinary) memory augmented state satisfaction with life in countries with lower quality of living (i.e., lower life-expectancy and life-satisfaction). Overall, findings confirm the relevance of nostalgia across a wide range of cultures and indicate cultural nuances in its functioning. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Mass Mortality of Sea Lions Caused by Highly Pathogenic Avian Influenza A(H5N1) Virus.

We report a massive mortality of 5,224 sea lions (Otaria flavescens) in Peru that seemed to be associated with highly pathogenic avian influenza A(H5N1) virus infection. The transmission pathway may have been through the close contact of sea lions with infected wild birds. We recommend evaluating potential virus transmission among sea lions.

Mediating effect of social interaction anxiety between emotional intelligence and life satisfaction in physical education students: post-COVID-19 study.

The aim of this research is to analyze the effect of social interaction anxiety on satisfaction with life mediated by emotional intelligence. The research design was descriptive, cross-sectional, and non-randomized. In total, 1,164 Mexican physical education students participated (Mage = 21.21; SD = 3.26; 30.0% female; 69.6% male; 0.4% other). The scales used were the Social Interaction Anxiety Scale, Trait Meta-Mood Scale and Satisfaction with Life and a structural equation analysis with latent variables was conducted. The results highlight that it can be asserted that emotional clarity and repair had a mediating effect between social interaction anxiety and satisfaction with life, as they did decrease the negative effects of social interaction anxiety on satisfaction with life. In addition, social interaction anxiety had a direct and positive effect on emotional attention and a negative effect on emotional clarity and repair.

Predictive Effect of Grit Personality on Academic Engagement Among Undergraduate Physical Education Students: The Mediating Role of Resilience / Efecto predictivo de la personalidad valiente sobre el compromiso académico entre estudiantes universitarios de educación física: el papel mediador de la resiliencia

The primary objective of this study was to examine the mediating effect of resilience in the relationship between GRIT personality and academic engagement among undergraduate students majoring in physical education. A study was conducted using a non-experimental, cross-sectional, correlational-cause design. The study included a total of 1164 Mexican students, with an average age of 21.21 years (standard deviation = 3.26). The sample consisted of 30.0% female participants, 69.6% male participants, and 0.4% participants who identified as others. The researchers utilised the GRIT personality, resilience, and academic engagement scales in their study and performed a structural equation analysis incorporating latent variables. The findings derived from the structural equation model indicate a positive association between perseverance of effort and both behavioural and emotional academic engagement, while also revealing a negative correlation between perseverance of effort and behavioural disaffection. Moreover, the presence of resilience in students is associated with a notable increase in their behavioural and emotional involvement, while concurrently leading to a decrease in emotional disengagement. The phenomenon of interest consistency has been found to have predictive value for both emotional and behavioural disaffection.(AU)

Mediation of academic self-efficacy between emotional intelligence and academic engagement in physical education undergraduate students.

The aim of this study was to analyze academic self-efficacy as a mediator between emotional intelligence and academic engagement. A non-experimental, cross-sectional, correlational-causal study was designed in which 1,164 Mexican students participated (Mage = 21.21; SD = 3.26) (30.0% female; 69.6% male; 0.4% other). The scales of emotional intelligence, academic self-efficacy and academic engagement were used, and a structural equation analysis with latent variables was conducted. The results obtained demonstrate that emotional clarity and repair have a positive and direct effect on academic self-efficacy. In addition, emotional repair predicts behavioral and emotional engagement. It was also found that academic self-efficacy is an excellent mediator between emotional clarity and repair, and the dimensions of academic engagement, as it substantially improves behavioral and emotional engagement while decreasing behavioral and emotional disaffection.

Nutrient-dependent regulation of ß-cell proinsulin content.

Insulin is made from proinsulin, but the extent to which fasting/feeding controls the homeostatically regulated proinsulin pool in pancreatic ß-cells remains largely unknown. Here, we first examined ß-cell lines (INS1E and Min6, which proliferate slowly and are routinely fed fresh medium every 2-3 days) and found that the proinsulin pool size responds to each feeding within 1 to 2 h, affected both by the quantity of fresh nutrients and the frequency with which they are provided. We observed no effect of nutrient feeding on the overall rate of proinsulin turnover as quantified from cycloheximide-chase experiments. We show that nutrient feeding is primarily linked to rapid dephosphorylation of translation initiation factor eIF2α, presaging increased proinsulin levels (and thereafter, insulin levels), followed by its rephosphorylation during the ensuing hours that correspond to a fall in proinsulin levels. The decline of proinsulin levels is blunted by the integrated stress response inhibitor, ISRIB, or by inhibition of eIF2α rephosphorylation with a general control nonderepressible 2 (not PERK) kinase inhibitor. In addition, we demonstrate that amino acids contribute importantly to the proinsulin pool; mass spectrometry shows that ß-cells avidly consume extracellular glutamine, serine, and cysteine. Finally, we show that in both rodent and human pancreatic islets, fresh nutrient availability dynamically increases preproinsulin, which can be quantified without pulse-labeling. Thus, the proinsulin available for insulin biosynthesis is rhythmically controlled by fasting/feeding cycles.

Analysis of Academic Psychological Variables, Physical Education, and Physical Activity Levels of Mexican Students.

Physical inactivity is a current worldwide, and especially Mexican adolescents. Therefore, this study has the following objectives: (i) to analyze the PA-LT pattern of Mexican adolescents; (ii) to analyze whether there are differences in emotional intelligence, basic psychological needs, academic motivation, self-esteem, and academic satisfaction according to the PA-LT pattern; (iii) to analyze the relationship between emotional intelligence, basic psychological needs, academic motivation, self-esteem, and academic satisfaction. A total of 748 secondary school students participated, of which 374 were girls (Mean age = 13.99; SD = 0.30) and 374 boys (Mean age = 14.02; SD = 0.33). The questionnaire comprised the following scales: IE, NPB-ESC, EMA, EA, and SIE. The main results obtained show that none of the girls stick to any active physical activity pattern during their spare time. In addition, physically active boys obtained better scores in emotional clarity, emotional repair, perception of academic competence, perception of social relationships, extrinsic motivation, intrinsic motivation, self-esteem, and satisfaction with school.

Alcohol self-administration and nicotine withdrawal alter biomarkers of stress and inflammation and prefrontal cortex changes in Gß subunits.

Background: Although alcohol and nicotine are often used together, the biological consequences of these substances are not well understood. Identifying shared targets will inform cessation pharmacotherapies and provide a deeper understanding of how co-use of alcohol and nicotine impacts health, including biomarkers of stress and inflammation.Objective: We examined the effects of nicotine exposure and withdrawal on alcohol self-administration (SA), stress and inflammatory biomarkers, and a G-protein coupled receptor subunit (Gß) in brain areas associated with drug use.Methods: Male rats were trained to SA alcohol and then received a nicotine pump (n = 7-8 per group). We assessed alcohol intake for 12 days during nicotine exposure and then following pump removal to elicit withdrawal. After the behavioral studies, we assessed plasma leptin, corticosterone, and interleukin-1ß (IL-1ß), and Gß protein expression in the amygdala, nucleus accumbens (NAc), and prefrontal cortex (PFC).Results: Nicotine exposure or withdrawal did not alter alcohol intake (p > .05). Alcohol and nicotine withdrawal elevated corticosterone levels (p = .015) and decreased Gß levels in the PFC (p = .004). In the absence of nicotine, alcohol SA suppressed IL-1ß levels (p = .039). Chronic exposure to nicotine or withdrawal during alcohol SA did not alter leptin levels or Gß expression in the amygdala or NAc (p's > .05).Conclusions: The combination of alcohol SA and nicotine withdrawal produced a persistent increase in stress biomarkers and a suppression in Gß expression in the PFC, providing an important first step toward understanding the common biological mechanisms of alcohol/nicotine misuse.

Stem-Cell-Derived ß-Like Cells with a Functional PTPN2 Knockout Display Increased Immunogenicity.

Type 1 diabetes is a polygenic disease that results in an autoimmune response directed against insulin-producing beta cells. PTPN2 is a known high-risk type 1 diabetes associated gene expressed in both immune- and pancreatic beta cells, but how genes affect the development of autoimmune diabetes is largely unknown. We employed CRISPR/Cas9 technology to generate a functional knockout of PTPN2 in human pluripotent stem cells (hPSC) followed by differentiating stem-cell-derived beta-like cells (sBC) and detailed phenotypical analyses. The differentiation efficiency of PTPN2 knockout (PTPN2 KO) sBC is comparable to wild-type (WT) control sBC. Global transcriptomics and protein assays revealed the increased expression of HLA Class I molecules in PTPN2 KO sBC at a steady state and upon exposure to proinflammatory culture conditions, indicating a potential for the increased immune recognition of human beta cells upon differential PTPN2 expression. sBC co-culture with autoreactive preproinsulin-reactive T cell transductants confirmed increased immune stimulations by PTPN2 KO sBC compared to WT sBC. Taken together, our results suggest that the dysregulation of PTPN2 expression in human beta cell may prime autoimmune T cell reactivity and thereby contribute to the development of type 1 diabetes.

Human stem cell derived beta-like cells engineered to present PD-L1 improve transplant survival in NOD mice carrying human HLA class I.

There is a critical need for therapeutic approaches that combine renewable sources of replacement beta cells with localized immunomodulation to counter recurrence of autoimmunity in type 1 diabetes (T1D). However, there are few examples of animal models to study such approaches that incorporate spontaneous autoimmunity directed against human beta cells rather than allogenic rejection. Here, we address this critical limitation by demonstrating rejection and survival of transplanted human stem cell-derived beta-like cells clusters (sBCs) in a fully immune competent mouse model with matching human HLA class I and spontaneous diabetes development. We engineered localized immune tolerance toward transplanted sBCs via inducible cell surface overexpression of PD-L1 (iP-sBCs) with and without deletion of all HLA class I surface molecules via beta-2 microglobulin knockout (iP-BKO sBCs). NOD.HLA-A2.1 mice, which lack classical murine MHC I and instead express human HLA-A*02:01, underwent transplantation of 1,000 human HLA-A*02:01 sBCs under the kidney capsule and were separated into HLA-A2 positive iP-sBC and HLA-class I negative iP-BKO sBC groups, each with +/- doxycycline (DOX) induced PD-L1 expression. IVIS imaging showed significantly improved graft survival in mice transplanted with PD-L1 expressing iP-sBC at day 3 post transplantation compared to controls. However, luciferase signal dropped below in vivo detection limits by day 14 for all groups in this aggressive immune competent diabetes model. Nonetheless, histological examination revealed significant numbers of surviving insulin+/PD-L1+ sBCs cells for DOX-treated mice at day 16 post-transplant despite extensive infiltration with high numbers of CD3+ and CD45+ immune cells. These results show that T cells rapidly infiltrate and attack sBC grafts in this model but that significant numbers of PD-L1 expressing sBCs manage to survive in this harsh immunological environment. This investigation represents one of the first in vivo studies recapitulating key aspects of human autoimmune diabetes to test immune tolerance approaches with renewable sources of beta cells.

High-throughput identification of RNA localization elements in neuronal cells.

Hundreds of RNAs are enriched in the projections of neuronal cells. For the vast majority of them, though, the sequence elements that regulate their localization are unknown. To identify RNA elements capable of directing transcripts to neurites, we deployed a massively parallel reporter assay that tested the localization regulatory ability of thousands of sequence fragments drawn from endogenous mouse 3' UTRs. We identified peaks of regulatory activity within several 3' UTRs and found that sequences derived from these peaks were both necessary and sufficient for RNA localization to neurites in mouse and human neuronal cells. The localization elements were enriched in adenosine and guanosine residues. They were at least tens to hundreds of nucleotides long as shortening of two identified elements led to significantly reduced activity. Using RNA affinity purification and mass spectrometry, we found that the RNA-binding protein Unk was associated with the localization elements. Depletion of Unk in cells reduced the ability of the elements to drive RNAs to neurites, indicating a functional requirement for Unk in their trafficking. These results provide a framework for the unbiased, high-throughput identification of RNA elements and mechanisms that govern transcript localization in neurons.