Comparative analysis of Krüppel-like factors expression in the retinas of zebrafish and mice during development and after injury.

The Krüppel-like factors (KLFs) have emerged as important transcriptional regulators of various cellular processes, including neural development. Some of them have been described as intrinsic factors involved in axon regeneration in the central nervous system (CNS) of vertebrates. Zebrafish are known for their ability to regenerate several tissues in adulthood, including the CNS, a capability lost during vertebrate evolution and absent in adult mammals. The role that KLFs could play in this differential ability remains unknown. Therefore, in this study, we analyzed the endogenous response of certain KLFs implicated in axon regeneration (KLFs 6, 7, 9, and 13) during retina development and after axon injury. The results showed that the expression of Klfs 6, 7, and 13 decreases in the developing retina of mice but not in zebrafish, while the mRNA levels of Klf9 strongly increase in both species. The response to injury was further analyzed using optic nerve crush (ONC) as a model of lesion. Our analysis during the acute phase (hours) demonstrated an induction of Klfs 6 and 7 expression exclusively in the zebrafish retina, while Klfs 9 and 13 mRNA levels increased in both species. Further analysis of the chronic response (days) showed that mRNA levels of Klf6 transiently increase in the retinas of both zebrafish and mice, whereas those of Klf7 decrease later after optic nerve injury. In addition, the analysis revealed that the expression of Klf9 decreases, while that of Klf13 increases in the retinas of zebrafish in response to optic nerve injury but remains unaltered in mice. Altogether, these findings support the hypothesis that KLFs may play a role in the differential axon regeneration abilities exhibited by fish and mice.

A summary of the main themes and findings presented at the ASM Intermountain Branch meeting (2024).

The annual meeting for the Intermountain Branch was held in April 2024 on the campus of Brigham Young University. There were 127 branch members from Utah, Idaho, and Nevada who attended the meeting and were composed of undergraduate students, graduate or medical students, and faculty. This report highlights the diversity of, and the emerging trends in, the research conducted by American Society for Microbiology members in the Intermountain Branch.

Differential peptide-dependent regulation of growth hormone (GH): A comparative analysis in pituitary cultures of reptiles, birds, and mammals.

Growth hormone (GH) is a pituitary protein that exerts pleiotropic roles in vertebrates. The mechanisms regulating GH synthesis and secretion are finely controlled by hypothalamic neuropeptides and other factors. These processes have been considerably studied in mammals but are still poorly understood in other groups. To better understand the pituitary GH regulation during vertebrate phylogeny, we compared the effects of incubating several peptides on cultures of ex-vivo pituitary fragments obtained from representative specimens of reptiles (iguana), birds (chicken) and mammals (rat). The peptides used were: growth hormone-releasing hormone (GHRH), thyrotropin-releasing hormone (TRH), pituitary adenylate cyclase-activating polypeptide (PACAP), ghrelin, gonadotropin-releasing hormone (GnRH), and somatostatin (SST). In rat pituitary cultures, GH secretion was stimulated by GHRH and TRH, while gh mRNA expression was increased by GHRH and PACAP. In the case of chicken pituitaries, GH release was promoted by GHRH, ghrelin, PACAP, and GnRH, although the latter two had a dual effect since at a shorter incubation time they decreased GH secretion; in turn, gh mRNA expression was significantly stimulated by TRH, PACAP, and GnRH. The most intense effects were observed in iguana pituitary cultures, where GH secretion was significantly augmented by GHRH, PACAP, TRH, ghrelin, and GnRH; while gh mRNA expression was stimulated by GHRH, TRH, and PACAP, but inhibited by ghrelin and SST. Also, in the three species, SST was able to block the GHRH-stimulated GH release. Furthermore, it was found that the expression of Pou1f1 mRNA was increased with greater potency by GHRH and PACAP in the iguana, than in chicken or rat pituitary cultures. Additionally, in-silico analysis of the gh gene promoter structures in the three species showed that the reptilian promoter has more Pit-1 consensus binding sites than their avian and mammalian counterparts. Taken together, results demonstrate that pituitary peptide-mediated GH regulatory mechanisms are differentially controlled along vertebrate evolution.

Fluorescence lifetime nanothermometer based on the equilibrium formation of anthracene AIE-excimers in living cells.

The effective measurement of temperature in living systems at the nano and microscopic scales continues to be a challenge to this day. Here, we study the use of 2-(anthracen-2-yl)-1,3-diisopropylguanidine, 1, as a nanothermometer based on fluorescence lifetime measurements and its bioimaging applications. In aqueous solution, 1 is shown in aggregated form and the equilibrium between the two main aggregate types (T-shaped and π-π) is highly sensitive to the temperature. The heating of the medium shifts the equilibrium toward the formation of highly emissive T-shaped aggregates. This species shows a high fluorescence emission and a long lifetime in comparison with the π-π aggregates and the freé monomer. A linear relationship between the fluorescence lifetime and the temperature both in aqueous solution and in a synthetic intracellular buffer was found. Fluorescence lifetime imaging microscopy (FLIM) also showed a linear relationship between lifetime and temperature with an excellent sensitivity in MCF7 breast cancer cells, which opens the door for its potential use as FLIM nanothermometer in the biomedical field.

Chromosome-specific induction of micronuclei and chromosomal aberrations by mitomycin C: Involvement of human chromosomes 9, 1 and 16.

Cytogenetic studies have shown that human chromosomes 1, 9, and 16, with a large heterochromatic region of highly methylated classical satellite DNA, are prone to induction of chromatid breaks and interchanges by mitomycin C (MMC). A couple of studies have indicated that material from chromosome 9, and possibly also from chromosomes 1 and 16, are preferentially micronucleated by MMC. Here, we further examined the chromosome-specific induction of micronuclei (MN; with and without cytochalasin B) and chromosomal aberrations (CAs) by MMC. Cultures of isolated human lymphocytes from two male donors were treated (at 48 h of culture, for 24 h) with MMC (500 ng/ml), and the induced MN were examined by a pancentromeric DNA probe and paint probe for chromosome 9, and by paint probes for chromosomes 1 and 16. MMC increased the total frequency of MN by 6-8-fold but the frequency of chromosome 9 -positive (9+) MN by 29-30-fold and the frequency of chromosome 1 -positive (1+) MN and chromosome 16 -positive (16+) MN by 12-16-fold and 10-17-fold, respectively. After treatment with MMC, 34-47 % of all MN were 9+, 17-20 % 1+, and 3-4 % 16+. The majority (94-96 %) of the 9+ MN contained no centromere and thus harboured acentric fragments. When MMC-induced CAs aberrations were characterized by using the pancentromeric DNA probe and probes for the classical satellite region and long- and short- arm telomeres of chromosome 9, a high proportion of chromosomal breaks (31 %) and interchanges (41 %) concerned chromosome 9. In 83 % of cases, the breakpoint in chromosome 9 was just below the region (9cen-q12) labelled by the classical satellite probe. Our results indicate that MMC specifically induces MN harbouring fragments of chromosome 9, 1, and 16. CAs of chromosome 9 are highly overrepresented in metaphases of MMC-treated lymphocytes. The preferential breakpoint is below the region 9q12.

Surrogate indices of insulin resistance using the Matsuda index as reference in adult men-a computational approach.

Background: Overweight and obesity, high blood pressure, hyperglycemia, hyperlipidemia, and insulin resistance (IR) are strongly associated with non-communicable diseases (NCDs), including type 2 diabetes, cardiovascular disease, stroke, and cancer. Different surrogate indices of IR are derived and validated with the euglycemic-hyperinsulinemic clamp (EHC) test. Thus, using a computational approach to predict IR with Matsuda index as reference, this study aimed to determine the optimal cutoff value and diagnosis accuracy for surrogate indices in non-diabetic young adult men. Methods: A cross-sectional descriptive study was carried out with 93 young men (ages 18-31). Serum levels of glucose and insulin were analyzed in the fasting state and during an oral glucose tolerance test (OGTT). Additionally, clinical, biochemical, hormonal, and anthropometric characteristics and body composition (DEXA) were determined. The computational approach to evaluate the IR diagnostic accuracy and cutoff value using difference parameters was examined, as well as other statistical tools to make the output robust. Results: The highest sensitivity and specificity at the optimal cutoff value, respectively, were established for the Homeostasis model assessment of insulin resistance index (HOMA-IR) (0.91; 0.98; 3.40), the Quantitative insulin sensitivity check index (QUICKI) (0.98; 0.96; 0.33), the triglyceride-glucose (TyG)-waist circumference index (TyG-WC) (1.00; 1.00; 427.77), the TyG-body mass index (TyG-BMI) (1.00; 1.00; 132.44), TyG-waist-to-height ratio (TyG-WHtR) (0.98; 1.00; 2.48), waist-to-height ratio (WHtR) (1.00; 1.00; 0.53), waist circumference (WC) (1.00; 1.00; 92.63), body mass index (BMI) (1.00; 1.00; 28.69), total body fat percentage (TFM) (%) (1.00; 1.00; 31.07), android fat (AF) (%) (1.00; 0.98; 40.33), lipid accumulation product (LAP) (0.84; 1.00; 45.49), leptin (0.91; 1.00; 16.08), leptin/adiponectin ratio (LAR) (0.84; 1.00; 1.17), and fasting insulin (0.91; 0.98; 16.01). Conclusions: The computational approach was used to determine the diagnosis accuracy and the optimal cutoff value for IR to be used in preventive healthcare.

The 8:1:1 Supplementation of Branched-Chain Amino Acids in High-Intensity Training: A Case Study of the Protective Effect on Rhabdomyolysis.

INTRODUCTION: The increasing prevalence of high-intensity sports activities, notably the burgeoning popularity of CrossFit, underscores the contemporary significance of such physical pursuits. The discernible protective impact of branched-chain amino acids on muscle fatigue and injuries is emerging as a noteworthy area of investigation. Within the realm of sports, integrating BCAA supplementation into dietary practices holds promise for aiding athletes in their recovery, particularly in mitigating Delayed-Onset Muscle Soreness. METHODOLOGY: This study adopted an experimental pilot design with repeated measures, employing a controlled and randomized approach through double-blind procedures. The participant engaged in high-intensity activity, specifically the CrossFit Karen® test, which entailed executing 150 wall ball throws (9 kg) to a height of 3 m. The trial incorporated three randomized supplementation conditions: BCAAs in an 8:1:1 ratio or a 2:1:1 ratio or a placebo condition. The participant consumed 15 g daily for 7 days, commencing 72 h prior to the initial blood sample and the first Karen® test. RESULTS: In this study, BCAA supplementation at an 8:1:1 ratio demonstrated a discernible protective effect against muscular damage, as evidenced by creatine kinase values and ratings of perceived exertion.

Development of a Follow-Up Measure to Ensure Complete Screening for Colorectal Cancer.

Importance: The current quality performance measure for colorectal cancer (CRC) screening is limited to initial screening. Despite low rates, there is no measure for appropriate follow-up with colonoscopy after receipt of an abnormal result of a stool-based screening test (SBT) for CRC. A quality performance measure is needed. Objective: To develop and test a quality performance measure for follow-up colonoscopy within 6 months of an abnormal result of an SBT for CRC. Design, Setting, and Participants: This retrospective quality improvement study examined data from January 1, 2016, to December 31, 2020, with 2018 plus 6 months of follow-up as the primary measurement period to verify performance rates, specify a potential measure, and test for validity, reliability, and feasibility. The Optum Labs Data Warehouse (OLDW), a deidentified database of health care claims and clinical data, was accessed. The OLDW contains longitudinal health information on enrollees and patients, representing a diverse mixture of ages and geographic regions across the US. For the database study, adults from 38 health care organizations (HCOs) aged 50 to 75 years who completed an initial CRC SBT with an abnormal result were observed to determine follow-up colonoscopy rates within 6 months. Rates were stratified by race, ethnicity, sex, insurance, and test modality. Three HCOs participated in the feasibility field testing. Data were analyzed from June 1, 2022, to May 31, 2023. Main Outcome and Measures: The primary outcome consisted of follow-up colonoscopy rates following an abnormal SBT result for CRC. Reliability statistics were also calculated across HCOs, race, ethnicity, and measurement year. Results: Among 20 581 adults (48.6% men and 51.4% women; 307 [1.5%] Asian, 492 [7.2%] Black, 644 [3.1%] Hispanic, and 17 705 [86.0%] White; mean [SD] age, 63.6 [7.1] years) in 38 health systems, 47.9% had a follow-up colonoscopy following an abnormal SBT result for CRC within 6 months. There was significant variation between HCOs. Notably, significantly fewer Black patients (37.1% [95% CI, 34.6%-39.5%]) and patients with Medicare (49.2% [95% CI, 47.7%-50.6%]) or Medicaid (39.2% [95% CI, 36.3%-42.1%]) insurance received a follow-up colonoscopy. A quality performance measure that tracks rates of follow-up within 6 months of an abnormal SBT result was observed to be feasible, valid, and reliable, with a median reliability statistic between HCOs of 94.5% (range, 74.3%-99.7%). Conclusions and Relevance: The findings of this observational study of 20 581 adults suggest that a measure of follow-up colonoscopy within defined periods after an abnormal result of an SBT test for CRC is warranted based on low current performance rates and would be feasible to collect by health systems and produce valid, reliable results.

Efficacy of Continuous vs. Intermittent Administration of Cefepime in Adult ICU Patients with Gram-Negative Bacilli Bacteremia: A Randomized Double-Blind Clinical Study.

INTRODUCTION: The objective of this study was to compare the continuous infusion of cefepime with the intermittent infusion in patients with sepsis caused by Gram-negative bacilli (GNB). METHODS: Randomized 1:1 multicenter double-blinded placebo-controlled study with allocation concealment; multicenter study in the intensive care units of Colombia. Patients with sepsis, severe sepsis or septic shock, and GNB-suspected bacteremia. Cefepime was administered for 7 to 14 days over 30 m intermittently every 8 h over 24 h plus continuous saline solution (0.9%) (G1) or 3 g administered continuously plus saline solution every 8 h (0.9%) (G2). The percentage of clinical response at 3, 7, and 14 days, relapse at 28 days, and mortality at discharge were measured. RESULTS: The recruitment was stopped at the suggestion of the Institutional Review Board (IRB) following an FDA alert about cefepime. Thirty-two patients were randomized; 25 received the intervention, and GNB bacteremia was confirmed in 16 (9 G1 and 7 G2). Favorable clinical response in days 3, 7, and 14 was 88.8%, 88.8%, and 77.8% (G1) and was similar for G2 (85.7%). There were no relapses or deaths in G2, while in G1, one relapse and two deaths were observed. CONCLUSIONS: The results of this study support the use of cefepime for the treatment of Gram-negative infections in critically ill patients, but we could not demonstrate differences between continuous or intermittent administration because of the small sample size, given the early suspension of the study.

Oncostatin M and STAT3 Signaling Pathways Support Human Trophoblast Differentiation by Inhibiting Inflammatory Stress in Response to IFNγ and GM-CSF.

Interleukin-6 (IL-6) superfamily cytokines play critical roles during human pregnancy by promoting trophoblast differentiation, invasion, and endocrine function, and maintaining embryo immunotolerance and protection. In contrast, the unbalanced activity of pro-inflammatory factors such as interferon gamma (IFNγ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) at the maternal-fetal interface have detrimental effects on trophoblast function and differentiation. This study demonstrates how the IL-6 cytokine family member oncostatin M (OSM) and STAT3 activation regulate trophoblast fusion and endocrine function in response to pro-inflammatory stress induced by IFNγ and GM-CSF. Using human cytotrophoblast-like BeWo (CT/BW) cells, differentiated in villous syncytiotrophoblast (VST/BW) cells, we show that beta-human chorionic gonadotrophin (ßhCG) production and cell fusion process are affected in response to IFNγ or GM-CSF. However, those effects are abrogated with OSM by modulating the activation of IFNγ-STAT1 and GM-CSF-STAT5 signaling pathways. OSM stimulation enhances the expression of STAT3, the phosphorylation of STAT3 and SMAD2, and the induction of negative regulators of inflammation (e.g., IL-10 and TGFß1) and cytokine signaling (e.g., SOCS1 and SOCS3). Using STAT3-deficient VST/BW cells, we show that STAT3 expression is required for OSM to regulate the effects of IFNγ in ßhCG and E-cadherin expression. In contrast, OSM retains its modulatory effect on GM-CSF-STAT5 pathway activation even in STAT3-deficient VST/BW cells, suggesting that OSM uses STAT3-dependent and -independent mechanisms to modulate the activation of pro-inflammatory pathways IFNγ-STAT1 and GM-CSF-STAT5. Moreover, STAT3 deficiency in VST/BW cells leads to the production of both a large amount of ßhCG and an enhanced expression of activated STAT5 induced by GM-CSF, independently of OSM, suggesting a key role for STAT3 in ßhCG production and trophoblast differentiation through STAT5 modulation. In conclusion, our study describes for the first time the critical role played by OSM and STAT3 signaling pathways to preserve and regulate trophoblast biological functions during inflammatory stress.

Creation of a pandemic memory by tracing COVID-19 infections and immunity in Luxembourg (CON-VINCE).

BACKGROUND: During the COVID-19 pandemic swift implementation of research cohorts was key. While many studies focused exclusively on infected individuals, population based cohorts are essential for the follow-up of SARS-CoV-2 impact on public health. Here we present the CON-VINCE cohort, estimate the point and period prevalence of the SARS-CoV-2 infection, reflect on the spread within the Luxembourgish population, examine immune responses to SARS-CoV-2 infection and vaccination, and ascertain the impact of the pandemic on population psychological wellbeing at a nationwide level. METHODS: A representative sample of the adult Luxembourgish population was enrolled. The cohort was followed-up for twelve months. SARS-CoV-2 RT-qPCR and serology were conducted at each sampling visit. The surveys included detailed epidemiological, clinical, socio-economic, and psychological data. RESULTS: One thousand eight hundred sixty-five individuals were followed over seven visits (April 2020-June 2021) with the final weighted period prevalence of SARS-CoV-2 infection of 15%. The participants had similar risks of being infected regardless of their gender, age, employment status and education level. Vaccination increased the chances of IgG-S positivity in infected individuals. Depression, anxiety, loneliness and stress levels increased at a point of study when there were strict containment measures, returning to baseline afterwards. CONCLUSION: The data collected in CON-VINCE study allowed obtaining insights into the infection spread in Luxembourg, immunity build-up and the impact of the pandemic on psychological wellbeing of the population. Moreover, the study holds great translational potential, as samples stored at the biobank, together with self-reported questionnaire information, can be exploited in further research. TRIAL REGISTRATION: Trial registration number: NCT04379297, 10 April 2020.

Concordance between nice classification and histopathology in colonic polyps: a tertiary center experience.

Background: Narrow-Band imaging International Colorectal Endoscopic (NICE) could reduce histopathology study requirements in colorectal polyp evaluation. Local and regional studies are required to validate its utility. Objectives: To evaluate concordance between NICE classification and histopathology. Design: Prospective analytic study performed in the Hospital Universitario San Ignacio, Bogotá (Colombia) between 2021 and 2022. Methods: Concordance between NICE I, II and III classification and histopathology [Hyperplastic Polyp (HP), adenoma and deep submucosal invasive cancer (DSIC)] was evaluated using weighted kappa. Diagnostic performance was evaluated for NICE I-II versus NICE III for DSIC versus adenoma/HP. A subgroup analysis was performed for polyps ⩾10 mm and those located in the rectum, sigmoid, and left colon. Results: A total of 238 polyps from 135 patients were evaluated. Median age 67 years (IQR 58.5-74.5), 54.4% males. 23 (17.1%) had ⩾3 polyps. Of polyps, 52.1% were located on rectum, sigmoid and left colon. A total of 182 (76.5%) were <10 mm. NICE and histopathology evidenced a fair-moderate concordance (quadratic weighted kappa 0.36, linear weighted kappa 0.43). NICE classification (NICE I-II versus III) compared to histopathology (DSIC versus adenoma/HP) evidenced a sensitivity of 90.9% and specificity of 99.1%. For DSIC diagnosis specificity was ⩾95% on polyps ⩾10 mm and those left sided located. Conclusion: NICE and histopathology concordance is suboptimal. However, NICE III for DSIC diagnosis evidence good specificity. Therefore, NICE III polyps require a prompt histopathological evaluation and follow-up. Good operative characteristics stand in polyps ⩾10 mm and left sided located. NBI formal training is recommended in gastroenterology units in Latin America.

Concordance between colonoscopy polyp evaluation with NBI optical technology and histopathology evaluation Most colorectal cancer are developed from polyps. A proper polyp evaluation is required to orientate which polyp could be a potential neoplasia. However, a definitive diagnosis is made according to histopathology evaluation. On the other hand, Narrow-Band imaging International Colorectal Endoscopic (NICE) classification based on colonoscopy could predict neoplastic polyps and drive therapeutic decisions. Our tertiary center study in Colombia evidence that NICE classification predicts adequately neoplastic polyps but is suboptimal to categorize low risk polyps. Therefore, histopathology polyp evaluation should be still recommended and NBI formal training is recommended in gastroenterology units in Latin -America.

Predictive models for health outcomes due to SARS-CoV-2, including the effect of vaccination: a systematic review.

BACKGROUND: The interaction between modelers and policymakers is becoming more common due to the increase in computing speed seen in recent decades. The recent pandemic caused by the SARS-CoV-2 virus was no exception. Thus, this study aims to identify and assess epidemiological mathematical models of SARS-CoV-2 applied to real-world data, including immunization for coronavirus 2019 (COVID-19). METHODOLOGY: PubMed, JSTOR, medRxiv, LILACS, EconLit, and other databases were searched for studies employing epidemiological mathematical models of SARS-CoV-2 applied to real-world data. We summarized the information qualitatively, and each article included was assessed for bias risk using the Joanna Briggs Institute (JBI) and PROBAST checklist tool. The PROSPERO registration number is CRD42022344542. FINDINGS: In total, 5646 articles were retrieved, of which 411 were included. Most of the information was published in 2021. The countries with the highest number of studies were the United States, Canada, China, and the United Kingdom; no studies were found in low-income countries. The SEIR model (susceptible, exposed, infectious, and recovered) was the most frequently used approach, followed by agent-based modeling. Moreover, the most commonly used software were R, Matlab, and Python, with the most recurring health outcomes being death and recovery. According to the JBI assessment, 61.4% of articles were considered to have a low risk of bias. INTERPRETATION: The utilization of mathematical models increased following the onset of the SARS-CoV-2 pandemic. Stakeholders have begun to incorporate these analytical tools more extensively into public policy, enabling the construction of various scenarios for public health. This contribution adds value to informed decision-making. Therefore, understanding their advancements, strengths, and limitations is essential.

Evaluation of heteroscorpionate ligands as scaffolds for the generation of Ruthenium(II) metallodrugs in breast cancer therapy.

The modular synthesis of the heteroscorpionate core is explored as a tool for the rapid development of ruthenium-based therapeutic agents. Starting with a series of structurally diverse alcohol-NN ligands, a family of heteroscorpionate-based ruthenium derivatives was synthesized, characterized, and evaluated as an alternative to platinum therapy for breast cancer therapy. In vitro, the antitumoral activity of the novel derivatives was assessed in a series of breast cancer cell lines using UNICAM-1 and cisplatin as metallodrug control. Through this approach, a bimetallic heteroscorpionate-based metallodrug (RUSCO-2) was identified as the lead compound of the series with an IC50 value range as low as 3-5 µM. Notably, RUSCO-2 was found to be highly cytotoxic in TNBC cell lines, suggesting a mode of action independent of the receptor status of the cells. As a proof of concept and taking advantage of the luminescent properties of one of the complexes obtained, uptake was monitored in human breast cancer MCF7 cell lines by fluorescence lifetime imaging microscopy (FLIM) to reveal that the compound is evenly distributed in the cytoplasm and that the incorporation of the heteroscorpionate ligand protects it from aqueous processes, conversion in another entity, or the loss of the chloride group. Finally, ROS studies were conducted, lipophilicity was estimated, the chloride/water exchange was studied, and stability studies in simulated biological media were carried out to propose structure-activity relationships.

Deregulation of ABCG1 early in life contributes to prostate carcinogenesis in maternally malnourished offspring rats.

AIMS: The developmental Origins of Health and Disease (DOHaD) concept has provided the framework to assess how early life experiences can shape health and disease throughout the life course. Using a model of maternal exposure to a low protein diet (LPD; 6% protein) during the gestational and lactational periods, we demonstrated changes in the ventral prostate (VP) transcriptomic landscape in young rats exposed to maternal malnutrition. Male offspring Sprague Dawley rats were submitted to maternal malnutrition during gestation and lactation, and they were weighed, and distance anogenital was measured, followed were euthanized by an overdose of anesthesia at 21 postnatal days. Next, the blood and the ventral prostate (VP) were collected and processed by morphological analysis, biochemical and molecular analyses. RNA-seq analysis identified 411 differentially expressed genes (DEGs) in the VP of maternally malnourished offspring compared to the control group. The molecular pathways enriched by these DEGs are related to cellular development, differentiation, and tissue morphogenesis, all of them involved in both normal prostate development and carcinogenesis. Abcg1 was commonly deregulated in young and old maternally malnourished offspring rats, as well in rodent models of prostate cancer (PCa) and in PCa patients. Our results described ABCG1 as a potential DOHaD gene associated with perturbation of prostate developmental biology with long-lasting effects on carcinogenesis in old offspring rats. A better understanding of these mechanisms may help with the discussion of preventive strategies against early life origins of non-communicable chronic diseases.

Characterizing the Relationship between HIV Peer Support Groups and Internalized Stigma Among People Living with HIV in Nigeria.

HIV-related stigma remains a significant barrier to implementing effective HIV treatment and prevention strategies in Nigeria. Despite the high uptake of peer support groups among people living with HIV (PLHIV) in Nigeria, the potential role of such peer support on the burden of internalized stigma remains understudied. To address this gap, we conducted a secondary analysis of the PLHIV Stigma Index 2.0, a socio-behavioral survey implemented by PLHIV led-organizations to assess the relationship between group membership and internalized stigma. Internalized stigma was measured using the Internalized AIDS-related Stigma Scale. Multinomial logistic regression was used to measure the association between self-reported engagement in peer support groups and internalized stigma adjusting for age, education, duration since HIV diagnosis, employment, disclosure status, and sex-work engagement. Of the 1,244 respondents in this study, 75.1% were engaged in HIV peer support groups. Over half (55.5%) and about one-fourth (27.3%) demonstrated low/moderate and high levels of internalized stigma, respectively. PLHIV engaged in HIV peer support groups were less likely to report both low/moderate (versus no) (adjusted odds ratio (aOR): 0.47 [95% CI: 0.27 to 0.81]; p = 0.006) and high (versus no) (aOR: 0.30 [95% CI: 0.17 to 0.53]; p < 0.001) levels of internalized stigma compared to those not engaged. In this study, the burden of internalized stigma is high among PLHIV in Nigeria. However, engagement in peer support groups appears to mitigate these stigmas. Stigma mitigation strategies to increase peer support may represent a critical tool in decreasing sustained HIV treatment gaps among PLHIV in Nigeria.

Influence of the time of day in the effect of caffeine on maximal fat oxidation during exercise in women: a randomized, crossover, double-blind, and placebo-controlled study.

PURPOSE: Caffeine is a stimulant with well-recognized performance and metabolic benefits, however, there is a lack of studies investigating the time-of-day influence in the properties of caffeine to enhance fat oxidation in women. Thus, the aim of the present study was to evaluate the influence of the time of the day on the effect of caffeine on the maximal rate of fat oxidation during aerobic exercise in trained women. METHODS: Fourteen female athletes (25.5 ± 7.1 years) took part in a randomized, crossover, double-blind study. All participants undertook four different experimental trials combining the ingestion of 3 mg/kg caffeine and a placebo either in the morning (8.00-10.00 h) and in the evening (17.00-19.00 h) realizing an incremental test on a cycle ergometer with 3 min stages at workloads from 30 to 70% of maximal oxygen uptake (VO2max). Substrate oxidation rates were measured by indirect calorimetry. In each trial, the maximum rate of fat oxidation (MFO) and the intensity that elicited MFO (Fatmax) were measured. RESULTS: In comparison to placebo, MFO was significantly higher with caffeine both in the morning (0.24 ± 0.13 vs 0.30 ± 0.14 g/min; p < 0.001; ES = 0.79) and in the evening (0.21 ± 0.08 vs 0.28 ± 0.10 g/min; p = 0.002; ES = 0.72). No time-of-day effect on the capacity of caffeine to increase MFO was found (all p = 0.336) CONCLUSION: The intake of 3 mg/kg of caffeine increased the use of fat as a fuel during exercise independently of the time-of-day in trained women. TRIAL REGISTRATION: The study was registered in ClinicalTrials.gov with the following ID: NCT05880186 by 15 May 2023.

Integrated Genomic Analysis of Primary Prostate Tumor Foci and Corresponding Lymph Node Metastases Identifies Mutations and Pathways Associated with Metastasis.

Prostate cancer is a highly heterogeneous disease and mortality is mainly due to metastases but the initial steps of metastasis have not been well characterized. We have performed integrative whole exome sequencing and transcriptome analysis of primary prostate tumor foci and corresponding lymph node metastases (LNM) from 43 patients enrolled in clinical trial. We present evidence that, while there are some cases of clonally independent primary tumor foci, 87% of primary tumor foci and metastases are descended from a common ancestor. We demonstrate that genes related to oxidative phosphorylation are upregulated in LNM and in African-American patients relative to White patients. We further show that mutations in TP53, FLT4, EYA1, NCOR2, CSMD3, and PCDH15 are enriched in prostate cancer metastases. These findings were validated in a meta-analysis of 3929 primary tumors and 2721 metastases and reveal a pattern of molecular alterations underlying the pathology of metastatic prostate cancer. We show that LNM contain multiple subclones that are already present in primary tumor foci. We observed enrichment of mutations in several genes including understudied genes such as EYA1, CSMD3, FLT4, NCOR2, and PCDH15 and found that mutations in EYA1 and CSMD3 are associated with a poor outcome in prostate cancer.

Host Transcriptional Regulatory Genes and Microbiome Networks Crosstalk through Immune Receptors Establishing Normal and Tumor Multiomics Metafirm of the Oral-Gut-Lung Axis.

The microbiome has shown a correlation with the diet and lifestyle of each population in health and disease, the ability to communicate at the cellular level with the host through innate and adaptative immune receptors, and therefore an important role in modulating inflammatory process related to the establishment and progression of cancer. The oral cavity is one of the most important interaction windows between the human body and the environment, allowing the entry of an important number of microorganisms and their passage across the gastrointestinal tract and lungs. In this review, the contribution of the microbiome network to the establishment of systemic diseases like cancer is analyzed through their synergistic interactions and bidirectional crosstalk in the oral-gut-lung axis as well as its communication with the host cells. Moreover, the impact of the characteristic microbiota of each population in the formation of the multiomics molecular metafirm of the oral-gut-lung axis is also analyzed through state-of-the-art sequencing techniques, which allow a global study of the molecular processes involved of the flow of the microbiota environmental signals through cancer-related cells and its relationship with the establishment of the transcription factor network responsible for the control of regulatory processes involved with tumorigenesis.