Identification of constrained sequence elements across 239 primate genomes.

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3-9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.

Proteome profiling of vascular sap regarding Eucalyptus grandis, Eucalyptus urophylla, and Eucalyptus camaldulensis.

The plant vascular system is a key element for long-distance communication. Understanding its composition may provide valuable information on how plants grow and develop themselves. In this study, a quantitative proteome dataset of the vascular sap proteome of three commercially important Eucalyptus species was shown. Protein extraction was carried out using a pressure bomb, whereas only in silico predicted extracellular proteins were considered as part of the sap proteome. A total of 132 different proteins were identified in all three Eucalyptus species and the most abundant proteome subset within all three species was comprised of proteins involved in the carbohydrate metabolic process, proteolysis, components of membrane, and defense response. The sap proteome of the species E. grandis and E. urophylla revealed the highest similarities. Functional classification indicated that the sap proteome of E. grandis and E. urophylla are mostly comprised of proteins involved in defense response and proteolysis; whereas no prominent functional class was observed for the E. camaldulensis species. Quantitative comparison highlighted characteristic sap proteins in each of the Eucalyptus species. The results that could be found in this study can be used as a reference for the proteome sap analysis of Eucalyptus plants grown under different conditions.

Breathing Air and Living Underwater: Molecular Evolution of Genes Related to Antioxidant Response in Cetaceans and Pinnipeds.

Cetaceans and pinnipeds are lineages of mammals that have independently returned to the aquatic environment, acquiring varying degrees of dependence on it while sharing adaptations for underwater living. Here, we focused on one critical adaptation from both groups, their ability to withstand the ischemia and reperfusion experienced during apnea diving, which can lead to the production of reactive oxygen species (ROS) and subsequent oxidative damage. Previous studies have shown that cetaceans and pinnipeds possess efficient antioxidant enzymes that protect against ROS. In this study, we investigated the molecular evolution of key antioxidant enzyme genes (CAT, GPX3, GSR, PRDX1, PRDX3, and SOD1) and the ROS-producing gene XDH, in cetaceans and pinnipeds lineages. We used the ratio of non-synonymous (dN) to synonymous (dS) substitutions as a measure to identify signatures of adaptive molecular evolution in these genes within and between the two lineages. Additionally, we performed protein modeling and variant impact analyzes to assess the functional consequences of observed mutations. Our findings revealed distinct selective regimes between aquatic and terrestrial mammals in five of the examined genes, including divergences within cetacean and pinniped lineages, between ancestral and recent lineages and between crowns groups. We identified specific sites under positive selection unique to Cetacea and Pinnipedia, with one site showing evidence of convergent evolution in species known for their long and deep-diving capacities. Notably, many sites under adaptive selection exhibited radical changes in amino acid properties, with some being damaging mutations in human variations, but with no apparent detrimental impacts on aquatic mammals. In conclusion, our study provides insights into the adaptive changes that have occurred in the antioxidant systems of aquatic mammals throughout their evolutionary history. We observed both distinctive features within each group of Cetacea and Pinnipedia and instances of convergence. These findings highlight the dynamic nature of the antioxidant system in response to challenges of the aquatic environment and provide a foundation for further investigations into the molecular mechanisms underlying these adaptations.

In vitro reminiscence: uterine programming in vivo affects respective luminal epithelial cells function in vitro†.

In cattle, the endometrium during diestrus and early pregnancy displays cellular responses that are consequences of prior, transient stimuli. Goal was to establish a model to study cellular memory in the endometrium. The hypothesis is that stimuli given to endometrium in vivo are retained as a cellular memory that remains after bovine uterine epithelial cells (BUECs) are isolated, cultured, and further stimulated in vitro. Objectives were to measure BUEC proliferation/migration and responsiveness to recombinant bovine Interferon-tau (rbIFNT) in vitro: among cows that showed estrus (experiment 1 [Exp1]), cows that became or not pregnant to artificial insemination (Exp2), cows that received or not supplemental progesterone (P4; Exp3) and cows that received or not a COX-1/2 inhibitor (Exp4). Only cows that displayed estrus were included in studies. For all experiments endometrial cytology was collected 4 days after estrus, BUECs were cultured, propagated, and submitted to rbIFNT treatment and an in vitro scratch assay. In Exp1, different cows spontaneously grouped according to proliferative/migratory capacity and responsiveness to rbIFNT of their respective BUECs. In Exp2, BUECs from pregnant cows showed greater rbIFNT responsiveness and cellular proliferation. In Exp3, BUECs from cows supplemented with P4 presented inhibited proliferation and increased expression of RSAD2. In Exp4, Flunixin Meglumine modified rbIFNT responsiveness of BUECs in an IFN-signaling pathway-specific manner. In conclusion, physiological and pharmacological stimuli received by the endometrium in vivo were retained as cellular memory in BUECs, persisted in culture, and changed BUEC proliferation/migration and responsiveness to rbIFNT, which are characteristics associated with fertility in cattle.

Genetic variations in immune mediators and prostate cancer risk: A field synopsis with Bayesian calculations.

OBJECTIVE: Our study aimed to revaluate the significant data from meta-analyses on genetic variations in immune mediators and the risk of prostate cancer (PCa) by Bayesian approaches. METHODS: We performed a search on the literature before September 5th, 2023, for meta-analytic studies on polymorphisms in immune mediator genes and the risk of PCa. Two Bayesian approaches were used to assess the level of noteworthiness in the meta-analytic data: the False-Positive Rate Probability (FPRP) and the Bayesian False Discovery Probability (BFDP) with a statistical power of 1.2 and 1.5 of Odds Ratio at a prior probability of 10-3 and 10-6. The quality evaluation of studies was performed with the Venice criteria. Gene-gene and protein-protein networks were designed for the genes and products enrolled in the results. RESULTS: As results, 18 meta-analyses on 17 polymorphisms in several immune mediator genes were included (IL1B rs16944/rs1143627, IL4 rs2243250/rs2227284/rs2070874, IL6 1800795/rs1800796/rs1800797, IL8 rs4073, IL10 rs1800896/rs1800871/rs1800872, IL18 rs1946518, COX2 rs2745557, TNFA rs361525 and PTGS2 rs20417/689470). The Bayesian calculations showed the rs1143627 and the rs1946518 polymorphisms in IL1B and IL18 genes, respectively, were noteworthy. The Venice criteria showed that only four studies received the highest level of evidence. The gene-gene and protein-protein networks reinforced the findings on IL1B and IL18 genes. CONCLUSION: In conclusion, this current Bayesian revaluation showed that the rs1143627 and the rs1946518 polymorphisms in the IL1B and IL18 genes, respectively, were noteworthy biomarker candidates for PCa risk.

Microglial phagolysosome dysfunction and altered neural communication amplify phenotypic severity in Prader-Willi Syndrome with larger deletion.

Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear. Our study employed postmortem hypothalamic tissues from PWS T1 and T2 individuals, conducting transcriptomic analyses and cell-specific protein profiling in white matter, neurons, and glial cells to unravel the cellular and molecular basis of phenotypic severity in PWS sub-genotypes. In PWS T1, key pathways for cell structure, integrity, and neuronal communication are notably diminished, while glymphatic system activity is heightened compared to PWS T2. The microglial defect in PWS T1 appears to stem from gene haploinsufficiency, as global and myeloid-specific Cyfip1 haploinsufficiency in murine models demonstrated. Our findings emphasize microglial phagolysosome dysfunction and altered neural communication as crucial contributors to the severity of PWS T1's phenotype.

Damaged bone microarchitecture by Trabecular Bone Score (TBS) and low appendicular muscle mass: main risk factors for vertebral and non-vertebral fractures in women with long-standing rheumatoid arthritis.

We ascertained the fracture risk factors stratified by vertebral and non-vertebral sites in rheumatoid arthritis (RA) females. Bone/muscle features, but not disease activity, were the main markers for fractures in this long-standing RA population: low trabecular bone score (TBS) for vertebral fracture and decreased appendicular muscle mass for non-vertebral fracture. PURPOSE: To assess risk factors for fractures, including clinical, laboratory and dual energy X-ray absorptiometry (DXA) parameters (bone mass, trabecular bone score-TBS, muscle mass) in women with established rheumatoid arthritis (RA). METHODS: Three hundred females with RA (ACR, 2010) were studied. Clinical data were obtained by questionnaire and disease activity by composite indices (DAS28, CDAI, SDAI), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Bone mineral density (BMD), TBS, body composition and Vertebral Fracture Assessment (VFA) were performed by DXA. Logistic regression models were constructed to identify factors independently associated with vertebral (VF) and non-vertebral fractures (NVF), separately. RESULTS: Through rigorous eligibility criteria, a total of 265 women were yielded for final data analysis (median age, 55 [22-86] years; mean disease duration, 16.2 years). Prevalence of VF and NVF were 30.6% and 17.4%, respectively. In multivariate analyzes, TBS (OR = 1.6, 95%CI = 1.09-2.36, p = 0.017), CRP (OR = 1.54, 95%CI = 1.15-2.08, p = 0.004), and parathormone (OR = 1.24, 95%CI = 1.05-1.45, p = 0.009) were risk factors for VF, whereas low appendicular muscle mass (OR = 2.71; 95%CI = 1.01-7,28; p = 0.048), body mass index (BMI) (OR = 0.90, 95%CI = 0.82-0.99; p = 0.025), ESR (OR = 1.18, 95%CI = 1.01-1,38, p = 0,038) and hip BMD (OR = 1.82, 95%CI = 1.10-3.03, p = 0.02) were associated with NVF. CONCLUSION: In women with long-term RA, markers of fractures differed between distinct skeletal sites (vertebral and non-vertebral). The magnitude of association of bone/muscle parameters with fracture (TBS for VF and appendicular muscle mass for NVF) was greater than that of the association between RA activity and fracture. TBS seems to have greater discriminative power than BMD to identify subjects with VF in long-standing RA.

Application of nanoformulations as a strategy to optimize chemotherapeutic treatment of glioblastoma: a systematic review.

The aim of this review was to explore the advances of nanoformulations as a strategy to optimize glioblastoma treatment, specifically focusing on targeting and controlling drug delivery systems to the tumor. This review followed the PRISMA recommendations. The studies were selected through a literature search conducted in the electronic databases PubMed Central, Science Direct, Scopus and Web of Science, in April 2023, using the equation descriptors: (nanocapsule OR nanoformulation) AND (glioblastoma). Forty-seven investigations included were published between 2011 and 2023 to assess the application of different nanoformulations to optimize delivery of chemotherapies including temozolomide, carmustine, vincristine or cisplatin previously employed in brain tumor therapy, as well as investigating another 10 drugs. Data demonstrated the possible application of different matrices employed as nanocarriers and utilization of functionalizing agents to improve internalization of chemotherapeutics. Functionalization was developed with the application of peptides, micronutrients/vitamins, antibodies and siRNAs. Finally, this review demonstrated the practical and clinical application of nanocarriers to deliver multiple drugs in glioblastoma models. These nanomodels might ideally be developed using functionalizing ligand agents that preferably act synergistically with the drug these agents carry. The findings showed promising results, making nanoformulations one of the best prospects for innovation and improvement of glioblastoma treatment.

Pleonotoquinones, Cytotoxic Oxepinenaphthoquinones from Pleonotoma jasminifolia.

Two unusual naphthoquinones, named here as pleonotoquinones A (1) and B (2), were isolated along with two known anthraquinones (3 and 4) via chromatographic separations of an ethyl acetate extract of the roots of Pleonotoma jasminifolia. Compounds 1 and 2 are the first examples of quinones bearing a 2-methyloxepine moiety. The compounds were isolated with the aid of mass spectrometry and molecular networking, and their structures were resolved using 1D and 2D NMR and HRESIMS data. The isolated compounds were evaluated for their antiproliferative activity against human cancer cell lines, and compounds 1 and 2 displayed cytotoxicity against human colon cancer HCT116 cells (IC50 = 2.6 µM for compound 1 and IC50 = 4.3 µM for compound 2) and human liver cancer HepG2 cells (IC50 = 1.9 µM for compound 1 and IC50 = 6.4 µM for compound 2).

Learning curve and safety of the implementation of laparoscopic complete mesocolic excision with intracorporeal anastomosis for right-sided colon cancer: results from a propensity score-matched study.

BACKGROUND: Retrospective studies and randomized controlled trials support the safety of laparoscopic complete mesocolic excision (CME) for the treatment of right-sided colon cancer (RSCC). Few studies, however, examine the learning curve of this operation and its impact on safety during an implementation period. We aim to evaluate the learning curve and safety of the implementation of laparoscopic CME with intracorporeal anastomosis for RSCC. METHODS: Consecutive patients undergoing a laparoscopic right colectomy with intracorporeal anastomosis for RSCC between January 2016 and June 2023 were included. Clinical, perioperative, and histopathological variables were collected. Correlation and cumulative sum (CUSUM) analyses between the operating time and case number were performed. Breakpoints of the learning curve were estimated using the broken-line model. CME and conventional laparoscopic right colectomy outcomes were compared after propensity score matching (PSM). RESULTS: Two hundred and ninety patients underwent laparoscopic right colectomy during study period. One hundred and eight met inclusion criteria. After PSM, 56 non-CME and 28 CME patients were compared. CME group had a non-statistically significant tendency to a longer operating time (201 versus 195 min; p = 0.657) and a shorter hospital stay (3 versus 4 days; p = 0.279). No significant differences were found in total complication rates or their profile. Correlation analysis identified a significant trend toward operating time reduction with increasing case numbers (Pearson correlation coefficient = - 0.624; p = 0.001). According to the CUSUM analysis, an institutional learning curve was deemed completed after 13 cases and the broken-line model identified three phases: learning (1-6 cases), consolidation (7-13 cases), and mastery (after 13 cases). CONCLUSION: The learning curve of laparoscopic CME for RSCC can be achieved after 13 cases in centers with experience in advanced laparoscopic surgery and surgeons with familiarity with this technique. Its implementation within this setting seems to be as safe as performing a conventional right colectomy.

Does Trust Lead to the Adoption of a Productive Climate Attitude? Relationship Between Trust, Corruption, and Climate Attitude in Developing Regions.

This study examines the relationship between institutional trust from an individual and societal perspective and perceived corruption and climate attitudes of individuals in Latin America. To this end, multilevel modeling was used to test whether the attitudes of individuals from 285 regions of Latin America are influenced by these constructs. Based on the results, it was found that in contrast to studies in developed countries, where institutional trust is positively associated with pro-climate attitudes, in Latin America institutional trust acts as an inhibiting factor and is inversely related to climate attitudes. Furthermore, the perception of corruption in public institutions was also identified as a factor inhibiting collective action to combat climate change. Moderation analysis revealed that individuals' level of education significantly influences this relationship, with a notable difference in climate attitudes between individuals with low and high levels of trust, especially among those with less education. These findings highlight the importance of taking regional specificities into account when examining the relationship between institutional trust, perceptions of corruption, and climate attitudes, and underscore the need for public policies that promote transparency and accountability of institutions to foster effective collective action on climate change.

Clinical features and prognosis of malignant small bowel tumors: Experience from a university hospital in Chile.

BACKGROUND: Small bowel tumors (SBT) are infrequent and represent a small proportion of digestive neoplasms. There is scarce information about SBT in Latin America. AIM: To describe the epidemiology, clinical characteristics, diagnostic methods, and survival of malignant SBTs. METHODS: Retrospective observational study of adult patients with histopathological diagnosis of SBT between 2007 and 2021 in a university hospital in Chile. RESULTS: A total of 104 patients [51.9% men; mean age 57 years] with SBT. Histological type: neuroendocrine tumor (NET) (43.7%, n=38), gastrointestinal stromal tumors (GIST) (21.8%, n=19), lymphoma (17.2%, n=15) and adenocarcinoma (AC) (11.5%, n=10). GIST was more frequent in duodenum (50%; n=12) and NET in the ileum (65.8%; n=25). Metastasis was observed in 17 cases, most commonly from colon and melanoma. Nausea and vomiting were significantly more often observed in AC (p=0.035), as well as gastrointestinal bleeding in GIST (p=0.007). The most common diagnostic tools were CT and CT enteroclysis with an elevated diagnostic yield (86% and 94% respectively). The 5-year survival of GIST, NET, lymphoma and AC were 94.7% (95%CI: 68.1-99.2), 82.2% (95%CI: 57.6-93.3), 40.0% (95%CI: 16.5-82.8) and 25.9% (95%CI: 4.5-55.7%), respectively. NET (HR 6.1; 95%CI: 2.1-17.2) and GIST (HR 24.4; 95%CI: 3.0-19.8) were independently associated with higher survival compared to AC, adjusted for age and sex. CONCLUSIONS: Malignant SBT are rare conditions and NETs are the most common histological subtype. Clinical presentation at diagnosis, location or complications may suggest a more probable diagnosis. GIST and NET are associated with better survival compared to other malignant subtypes.

Field Hip Stability Isometric Test (F-HipSIT): Reliability of Assessing the Hip Posterolateral Muscle Strength in Sports Settings.

CONTEXT: The Hip Stability Isometric Test (HipSIT) is commonly employed in clinical settings for evaluating the hip posterolateral muscle strength. In this study, we introduced the "Field Hip Stability Isometric Test" (F-HipSIT) and assessed the intrarater and interrater reliability of this strength assessment specifically designed for sports settings. DESIGN: Reliability study. METHODS: Two independent raters (A and B) went to athletes' training facilities to conduct 2 sessions of F-HipSIT spaced at least 1 week apart. The average peak force value from 3 valid attempts of each leg was recorded and normalized by the participant's body mass for statistical analysis. RESULTS: Thirty male and 30 female amateur athletes took part in this study. Rater A obtained similar values in the first (0.39 [0.05] and 0.44 [0.07] kg·f/kg) and second (0.39 [0.06] and 0.45 [0.07] kg·f/kg) testing days for men and women, respectively. Rater B also found similar values in the first (0.35 [0.06] and 0.42 [0.08] kg·f/kg) and second (0.36 [0.06] and 0.45 [0.08] kg·f/kg) testing days for men and women, respectively. Excellent intrarater intraclass correlation coefficient (ICC) values were found for men (ICC = .922) and women (ICC = .930), with coefficient of variation of 6% to 8% and minimal detectable change of 0.06 to 0.10 kg·f/kg. The F-HipSIT presented good interrater reliability for men (ICC = .857) and women (ICC = .868), with coefficient of variation of 5% and minimal detectable change of 0.05 to 0.06 kg·f/kg. CONCLUSION: The F-HipSIT intrarater and interrater reliability among male and female recreational athletes supports this field test as a quick and convenient screening tool to monitor hip posterolateral muscle strength in sports settings.

[Reduction in Helicobacter pylori infection among patients referred for upper gastrointestinal endoscopy in Santiago, Chile, between 2010-2020]. / Reducción de la infección por Helicobacter pylori en pacientes derivados a endoscopia digestiva alta en Santiago de Chile entre 2010-2020.

Latin America presents a high prevalence of Helicobacter pylori(Hp) infection. Between1996-2003, the prevalence in Santiago, Chile, was 70%; recent studies indicate a decreasein this infection. Updating the frequency of Hp is crucial due to its associated health impact. OBJECTIVE: Our objective was to describe the trend in Hp infection in patients undergoingambulatory esophagogastroduodenoscopy (EGD) in a Chilean population. MATERIALS AND METHODS: A retrospective observational study was conducted on patients over 18 years old who attended a first EGD with a rapid urease test between 2010-2020. Time trendswere described through time series analysis. A Poisson model was constructed to estimatethe risk of infection, adjusted for age and gender. RESULTS: 11,355 patients were included[66.9% females; mean age 52 years; Hp 41.6%]. Male gender presented a higher frequencyof Hp infection [RR 1.13; (95% CI: 1.08-1.18)].Hp frequency infection decreased significantlyfrom 45.1% in 2010 to 29% in 2020, with a 36% lower probability of Hp infection in 2020 compared to 2010 [RR 0.64;(95% CI: 0.55-0.74)]. A progressive decline in Hp infectiontrend was projected, reaching values close to 25% by year 2025. CONCLUSION: A significantreduction in Hpinfection was observed between 2010-2020. This decrease could be explained by the implementation of public health policies in the last decade associated with socio-sanitary changes.

Molecular Footprints on Osmoregulation-Related Genes Associated with Freshwater Colonization by Cetaceans and Sirenians.

The genetic basis underlying adaptive physiological mechanisms has been extensively explored in mammals after colonizing the seas. However, independent lineages of aquatic mammals exhibit complex patterns of secondary colonization in freshwater environments. This change in habitat represents new osmotic challenges, and additional changes in key systems, such as the osmoregulatory system, are expected. Here, we studied the selective regime on coding and regulatory regions of 20 genes related to the osmoregulation system in strict aquatic mammals from independent evolutionary lineages, cetaceans, and sirenians, with representatives in marine and freshwater aquatic environments. We identified positive selection signals in genes encoding the protein vasopressin (AVP) in mammalian lineages with secondary colonization in the fluvial environment and in aquaporins for lineages inhabiting the marine and fluvial environments. A greater number of sites with positive selection signals were found for the dolphin species compared to the Amazonian manatee. Only the AQP5 and AVP genes showed selection signals in more than one independent lineage of these mammals. Furthermore, the vasopressin gene tree indicates greater similarity in river dolphin sequences despite the independence of their lineages based on the species tree. Patterns of distribution and enrichment of Transcription Factors in the promoter regions of target genes were analyzed and appear to be phylogenetically conserved among sister species. We found accelerated evolution signs in genes ACE, AQP1, AQP5, AQP7, AVP, NPP4, and NPR1 for the fluvial mammals. Together, these results allow a greater understanding of the molecular bases of the evolution of genes responsible for osmotic control in aquatic mammals.

Hormonal profile prior to luteolysis modulates the uterine luminal transcriptome in the subsequent cycle in beef cross-bred cows†.

Sex steroid concentrations modulate endometrial function and fertility in cattle. Our objective was to compare the post-estrus luminal transcriptome of cows that were exposed to contrasting concentrations of progesterone (P4) before luteolysis that displayed estrus and ovulated spontaneously. Cross-bred beef cows received either (1) a new CIDR and GnRH (day -9; high progesterone treatment; HP4; n = 16) or (2) a previously used CIDR, PGF2α, and GnRH (low progesterone treatment; LP4; n = 24). All cows received PGF2α at CIDR removal (day -2). Ovarian ultrasonography and blood collections were performed on days -9, -2, -0.5, and 0 (day of observed estrus), and days 4, 7, and 14 for measurement of ovarian structures, P4, and estradiol (E2). Luminal epithelial cells were collected using a cytology brush on days 4, 7, and 14 for RNAseq. On day -2, CL area and concentrations of P4 were greater, while on day -0.5, concentrations of E2 were decreased in HP4. Ovarian structures and hormonal concentrations were similar on days 4, 7, or 14 (P > 0.05). There were enriched pathways in HP4 related to activation and signaling of the innate immune system at day 4, downregulation in the network involved in the extracellular matrix remodeling at day 7, and exacerbated inflammatory response as well as differentiation and activation of macrophages at day 14 (Benjamini-Hochberg P-value ≤ 0.05). In conclusion, manipulation of pre-luteolysis sex steroid concentrations altered the post-estrus luminal transcriptome even though all cows showed estrus and ovulated spontaneously.

Pre-estrus progesterone does not affect post-estrus luminal metabolome in cross-bred beef cows.

In brief: The concentration of progesterone through the estrous cycle modulates uterine function to affect the luminal metabolome. This paper reports that the dynamic changes in the bovine uterine luminal metabolome during diestrus are independent of the concentration of progesterone in the previous cycle. Abstract: In cattle, the concentration of sex steroids modulates uterine function, which is reflected in the composition of the luminal metabolome. Ultimately, the uterine luminal metabolome influences embryonic growth and development. Our objectives were (i) to compare the luminal metabolome 4, 7, and 14 days after estrus of cows that were exposed to greater (HP4; n = 16) vs lower (LP4; n = 24) concentrations of progesterone before displaying estrus and ovulating spontaneously and (ii) to identify changes in the luminal concentration of metabolites across these time points. Luminal epithelial cells and fluid were collected using a cytology brush, and gene expression and metabolite concentrations were assessed by RNAseq and targeted mass spectrometry, respectively. Metabolome profile was similar between treatments within each of days 4, 7, and 14 (false discovery rate (FDR): ≥ 0.1). Concentrations of 53 metabolites changed, independent of treatment, across the diestrus. Metabolites were mostly lipids (40 out 53) and the greatest concentrations were at day 14 (FDR: ≤ 0.1). On day 7, the concentration of putrescine and the gene expression of ODC1, PAOX, SLC3A2, and SAT1 increased (P ≤ 0.05). On day 14, the concentration of 3 ceramides, 4 glucosylceramides, and 12 sphingomyelins and the expression of SGMS2 were increased, in addition to the concentration of choline and 20 phosphatidylcholines. Collectively, the post-estrus concentration of luminal metabolites changed dynamically, independent of the concentration of sex steroids on the previous cycle, and the greatest magnitude changes were on day 14 when lipid metabolism was the most enriched pathway.

Discovery of dual PKS involved in sclerotiorin biosynthesis in Penicillium meliponae using genome mining and gene knockout.

Fungi of the genus Penicillium section Sclerotiora have as their main characteristic the presence of orange-pigmented mycelium, which is associated with sclerotiorin, a chlorinated secondary metabolite of the azaphilone subclass of polyketides. Sclerotiorin presents anti-diabetes, antioxidant, anti-inflammatory, anti-Alzheimer, antiviral, and antimicrobial activities, which has always attracted the attention of researchers worldwide. During our ongoing search for azaphilone-producing Amazonian fungi, the strain of Penicillium MMSRG-058 was isolated as an endophyte from the roots of Duguetia stelechantha and showed great capacity for producing sclerotiorin-like metabolites. Using multilocus phylogeny, this strain was identified as Penicillium meliponae. Moreover, based on the genome mining of this strain through the reverse approach, a cluster of putative biosynthetic genes (BGC) responsible for the biosynthesis of sclerotiorin-like metabolites (scl cluster) was identified. The knockout of the sclA (highly reducing PKS) and sclI (non-reducing PKS) genes resulted in mutants with loss of mycelial pigmentation and terminated the biosynthesis of sclerotiorin-like metabolites: geumsanol B, chlorogeumsanol B, 7-deacetylisochromophilone VI, isochromophilone VI, ochrephilone, isorotiorin, and sclerotiorin. Based on these results, a biosynthetic pathway was proposed considering the homology of BGC scl genes with the azaphilone BGCs that have already been functionally characterized.

Awareness of Disease and Its Domains in Young-onset and Late-onset Dementia: The Role of Executive Function.

INTRODUCTION: Executive function (EF) involves a general cognitive process linked to strategic organization and control of complex goal-oriented tasks. In young-onset dementia (YOD), especially Alzheimer's disease, the symptoms that stand out in the initial stage are deficits in attention, visual-spatial function, praxis, and language. The present study aims to investigate what components of EF differ in young and late-onset dementia (LOD) and its impact on awareness and its domains. METHODS: Using a cross-sectional design, we included 44 people with YOD and 70 with LOD. We assessed awareness and its domains, cognition, dementia severity, EF, functionality, and neuropsychiatric symptoms. RESULTS: The YOD group was more impaired in general cognition ( P =0.017) and had a worse performance in Wechsler Digit Span Backward (DSB) ( P =0.007) and Phonemic fluency task (FAS) ( P =0.046) tests. In the LOD group, deficits in EF had a greater impact on awareness and on most domains (awareness total score, cognitive functioning and health condition, functional activity impairments and social function). CONCLUSIONS: Our study findings support the heterogeneity of awareness, not only with regard to the difference between the domains and the measures of EF, but also to the groups studied.

Buthionine sulfoximine and chemoresistance in cancer treatments: a systematic review with meta-analysis of preclinical studies.

Buthionine sulfoximine (BSO) is a synthetic amino acid that blocks the biosynthesis of reduced glutathione (GSH), an endogenous antioxidant cellular component present in tumor cells. GSH levels have been associated with tumor cell resistance to chemotherapeutic drugs and platinum compounds. Consequently, by depleting GSH, BSO enhances the cytotoxicity of chemotherapeutic agents in drug-resistant tumors. Therefore, the aim of this study was to conduct a systematic review with meta-analysis of preclinical studies utilizing BSO in cancer treatments. The systematic search was carried out using the following databases: PubMed, Web of Science, Scopus, and EMBASE up until March 20, 2023, in order to collect preclinical studies that evaluated BSO, alone or in association, as a strategy for antineoplastic therapy. One hundred nine investigations were found to assess the cytotoxic potential of BSO alone or in combination with other compounds. Twenty-one of these met the criteria for performing the meta-analysis. The evidence gathered indicated that BSO alone exhibits cytotoxic activity. However, this compound is generally used in combination with other antineoplastic strategies, mainly chemotherapy ones, to improve cytotoxicity to carcinogenic cells and treatment efficacy. Finally, this review provides important considerations regarding BSO use in cancer treatment conditions, which might optimize future studies as a potential adjuvant antineoplastic therapeutic tool.