Newly evolved genes in the human lineage are functional.

Genes restricted to a given species or lineage are mysterious. Many emerged de novo from ancestral noncoding genomic regions rather than from pre-existing genes. A new study by Vakirlis and colleagues shows that, in humans, many of these are associated with phenotypic effects, accelerating our understanding of their functional importance.

Native RNA sequencing in fission yeast reveals frequent alternative splicing isoforms.

The unicellular yeast Schizosaccharomyces pombe (fission yeast) retains many of the splicing features observed in humans and is thus an excellent model to study the basic mechanisms of splicing. Nearly half the genes contain introns, but the impact of alternative splicing in gene regulation and proteome diversification remains largely unexplored. Here we leverage Oxford Nanopore Technologies native RNA sequencing (dRNA), as well as ribosome profiling data, to uncover the full range of polyadenylated transcripts and translated open reading frames. We identify 332 alternative isoforms affecting the coding sequences of 262 different genes, 97 of which occur at frequencies higher than 20%, indicating that functional alternative splicing in S. pombe is more prevalent than previously suspected. Intron retention events make about 80% of the cases; these events may be involved in the regulation of gene expression and, in some cases, generate novel protein isoforms, as supported by ribosome profiling data in 18 of the intron retention isoforms. One example is the rpl22 gene, in which intron retention is associated with the translation of a protein of only 13 amino acids. We also find that lowly expressed transcripts tend to have longer poly(A) tails than highly expressed transcripts, highlighting an interdependence between poly(A) tail length and transcript expression level. Finally, we discover 214 novel transcripts that are not annotated, including 158 antisense transcripts, some of which also show translation evidence. The methodologies described in this work open new opportunities to study the regulation of splicing in a simple eukaryotic model.

Evolutionary Trajectories of New Duplicated and Putative De Novo Genes.

The formation of new genes during evolution is an important motor of functional innovation, but the rate at which new genes originate and the likelihood that they persist over longer evolutionary periods are still poorly understood questions. Two important mechanisms by which new genes arise are gene duplication and de novo formation from a previously noncoding sequence. Does the mechanism of formation influence the evolutionary trajectories of the genes? Proteins arisen by gene duplication retain the sequence and structural properties of the parental protein, and thus they may be relatively stable. Instead, de novo originated proteins are often species specific and thought to be more evolutionary labile. Despite these differences, here we show that both types of genes share a number of similarities, including low sequence constraints in their initial evolutionary phases, high turnover rates at the species level, and comparable persistence rates in deeper branchers, in both yeast and flies. In addition, we show that putative de novo proteins have an excess of substitutions between charged amino acids compared with the neutral expectation, which is reflected in the rapid loss of their initial highly basic character. The study supports high evolutionary dynamics of different kinds of new genes at the species level, in sharp contrast with the stability observed at later stages.

Single-pixel imaging through non-homogeneous turbid media with adaptive illumination.

The presence of scattering media limits the quality of images obtained by optical systems. Single-pixel imaging techniques based on structured illumination are highly tolerant to the presence of scattering between the object and the sensor, but very sensitive when the scattering medium is between the light source and the object. This makes it difficult to develop single-pixel imaging techniques for the case of objects immersed in scattering media. We present what we believe to be a new system for imaging objects through inhomogeneous scattering media in an epi-illumination configuration. It works in an adaptive way by combining diffuse optical imaging (DOI) and single pixel imaging (SPI) techniques in two stages. First, the turbid media is characterized by projecting light patterns with an LED array and applying DOI techniques. Second, the LED array is programmed to project light only through the less scattering areas of the media, while simultaneously using a digital micromirror device (DMD) to project light patterns onto the target using Hadamard basis coding functions. With this adaptive technique, we are able to obtain images of targets through two different scattering media with better quality than using conventional illumination. We also show that the system works with fluorescent targets.

High-fat and High-sucrose Diet-induced Hypothalamic Inflammation Shows Sex Specific Features in Mice.

Hypothalamic inflammation underlies diet-induced obesity and diabetes in rodent models. While diet normalization largely allows for recovery from metabolic impairment, it remains unknown whether long-term hypothalamic inflammation induced by obesogenic diets is a reversible process. In this study, we aimed at determining sex specificity of hypothalamic neuroinflammation and gliosis in mice fed a fat- and sugar-rich diet, and their reversibility upon diet normalization. Mice were fed a 60%-fat diet complemented by a 20% sucrose drink (HFHSD) for 3 days or 24 weeks, followed by a third group that had their diet normalized for the last 8 weeks of the study (reverse diet group, RevD). We determined the expression of pro- and anti-inflammatory cytokines, and of the inflammatory cell markers IBA1, CD68, GFAP and EMR1 in the hypothalamus, and analyzed morphology of microglia (IBA-1+ cells) and astrocytes (GFAP+ cells) in the arcuate nucleus. After 3 days of HFHSD feeding, male mice showed over-expression of IL-13, IL-18, IFN-γ, CD68 and EMR1 and reduced expression of IL-10, while females showed increased IL-6 and IBA1 and reduced IL-13, compared to controls. After 24 weeks of HFHSD exposure, male mice showed a general depression in the expression of cytokines, with prominent reduction of TNF-α, IL-6 and IL-13, but increased TGF-ß, while female mice showed over-expression of IFN-γ and IL-18. Furthermore, both female and male mice showed some degree of gliosis after HFHSD feeding for 24 weeks. In mice of both sexes, diet normalization after prolonged HFHSD feeding resulted in partial neuroinflammation recovery in the hypothalamus, but gliosis was only recovered in females. In sum, HFHSD-fed mice display sex-specific inflammatory processes in the hypothalamus that are not fully reversible after diet normalization.

Chromosome ends and the theory of marginotomy: implications for reproduction.

Telomeres are the protective structures located at the ends of linear chromosomes. They were first described in the 1930s, but their biology remained unexplored until the early 70s, when Alexey M. Olovnikov, a theoretical biologist, suggested that telomeres cannot be fully copied during DNA replication. He proposed a theory that linked this phenomenon with the limit of cell proliferation capacity and the "duration of life" (theory of marginotomy), and suggested a potential of telomere lenghthening for the prevention of aging (anti-marginotomy). The impact of proliferative telomere shortening on life expectancy was later confirmed. In humans, telomere shortening is counteracted by telomerase, an enzyme that is undetectable in most adult somatic cells, but present in cancer cells and adult and embryonic stem and germ cells. Although telomere length dynamics are different in male and female gametes during gametogenesis, telomere lengths are reset at the blastocyst stage, setting the initial length of the species. The role of the telomere pathway in reproduction has been explored for years, mainly because of increased infertility resulting from delayed childbearing. Short telomere length in ovarian somatic cells is associated to decreased fertility and higher aneuploidy rates in embryos. Consequently, there is a growing interest in telomere lengthening strategies, aimed at improving fertility. It has also been observed that lifestyle factors can affect telomere length and improve fertility outcomes. In this review, we discuss the implications of telomere theory in fertility, especially in oocytes, spermatozoa, and embryos, as well as therapies to enhance reproductive success.

Racial and Ethnic Minorities Underrepresented in Pain Management Guidelines for Total Joint Arthroplasty: A Meta-analysis.

BACKGROUND: Total joint arthroplasty aims to improve quality of life and functional outcomes for all patients, primarily by reducing their pain. This goal requires clinical practice guidelines (CPGs) that equitably represent and enroll patients from all racial/ethnic groups. To our knowledge, there has been no formal evaluation of the racial/ethnic composition of the patient population in the studies that informed the leading CPGs on the topic of pain management after arthroplasty surgery. QUESTIONS/PURPOSES: Using papers included in the 2021 Anesthesia and Analgesia in Total Joint Arthroplasty Clinical Practice Guidelines and comparing them with US National census data, we asked: (1) What is the representation of racial/ethnic groups in randomized controlled trials compared with their representation in the US national population? (2) Is there a relationship between the reporting of racial/ethnic groups and year of data collection/publication, location of study, funding source, or guideline section? METHODS: Participant demographic data (study year published, study type, guideline section, year of data collection, study site, study funding, study size, gender, age, and race/ethnicity) were collected from articles cited by this guideline. Studies were included if they were full text, were primary research articles conducted primarily within the United States, and if they reported racial and ethnic characteristics of the participants. The exclusion criteria included duplicate articles, articles that included the same participant population (only the latest dated article was included), and the following article types: systematic reviews, nonsystematic reviews, terminology reports, professional guidelines, expert opinions, population-based studies, surgical trials, retrospective cohort observational studies, prospective cohort observational studies, cost-effectiveness studies, and meta-analyses. Eighty-two percent (223 of 271) of articles met inclusion criteria. Our original literature search yielded 27 papers reporting the race/ethnicity of participants, including 24 US-based studies and three studies conducted in other countries; only US-based studies were utilized as the focus of this study. We defined race/ethnicity reporting as the listing of participants' race or ethnicity in the body, tables, figures, or supplemental data of a study. National census information from 2000 to 2019 was then used to generate a representation quotient (RQ), which compared the representation of racial/ethnic groups within study populations to their respective demographic representation in the national population. An RQ value greater than 1 indicates an overrepresented group and an RQ value less than 1 indicates an underrepresented group, relative to the US population. Primary outcome measures of RQ value versus time of publication for each racial/ethnic group were evaluated with linear regression analysis, and race reporting and manuscript parameters were analyzed with chi-square analyses. RESULTS: Two US-based studies reported race and ethnicity independently. Among the 24 US-based studies reporting race/ethnicity, the overall RQ was 0.70 for Black participants, 0.09 for Hispanic participants, 0.1 for American Indian/Alaska Natives, 0 for Native Hawaiian/Pacific Islanders, 0.08 for Asian participants, and 1.37 for White participants, meaning White participants were overrepresented by 37%, Black participants were underrepresented by 30%, Hispanic participants were underrepresented by 91%, Asian participants were underrepresented by 92%, American Indian/Alaska Natives were 90% underrepresented, and Native Hawaiian Pacific Islanders were virtually not represented compared with the US national population. On chi-square analysis, there were differences between race/ethnicity reporting among studies with academic, industry, and dual-supported funding sources (χ 2 = 7.449; p = 0.02). Differences were also found between race/ethnicity reporting among US-based and non-US-based studies (χ 2 = 36.506; p < 0.001), with 93% (25 of 27) of US-based studies reporting race as opposed to only 7% (2 of 27) of non-US-based studies. Finally, there was no relationship between race/ethnicity reporting and the year of data collection or guideline section referenced. CONCLUSION: The 2021 Anesthesia and Analgesia in Total Joint Arthroplasty Clinical Practice Guidelines provide evidence-based recommendations that reflect the current standards in orthopaedic surgery, but the studies upon which they are based overwhelmingly underenroll and underreport racial/ethnic minorities relative to their proportions in the US population. As these factors impact analgesic administration, their continued neglect may perpetuate inequities in outcomes after TJA. CLINICAL RELEVANCE: Our study demonstrates that all non-White racial/ethnic groups were underrepresented relative to their proportion of the US population in the 2021 Anesthesia and Analgesia in Total Joint Arthroplasty Clinical Practice Guidelines, underscoring a weakness in the orthopaedic surgery evidence base and questioning the overall external validity and generalizability of these combined CPGs. An effort should be made to equitably enroll and report outcomes for all racial/ethnic groups in any updated CPGs.

Upscaling the effect of traits in response to drought: The relative importance of safety-efficiency and acquisitive-conservation functional axes.

We tested the idea that functional trade-offs that underlie species tolerance to drought-driven shifts in community composition via their effects on demographic processes and subsequently on shifts in species' abundance. Using data from 298 tree species from tropical dry forests during the extreme ENSO-2015, we scaled-up the effects of trait trade-offs from individuals to communities. Conservative wood and leaf traits favoured slow tree growth, increased tree survival and positively impacted species abundance and dominance at the community-level. Safe hydraulic traits, on the other hand, were related to demography but did not affect species abundance and communities. The persistent effects of the conservative-acquisitive trade-off across organizational levels is promising for generalization and predictability of tree communities. However, the safety-efficient trade-off showed more intricate effects on performance. Our results demonstrated the complex pathways in which traits scale up to communities, highlighting the importance of considering a wide range of traits and performance processes.

Simple preparation of broadband UV filters based on TiO2 coated with aqueous extracts of native trees from the Chaco region of Argentina.

The native forest of northwestern Argentina, as part of the Chaco region, is a rich and unexploited source of phytochemical compounds for medicinal/cosmetic applications. In the present study, fruit, leaf, branch, and bark organs of the native trees Sarcomphalus mistol (Mistol, M) and Schinopsis lorentzii (Quebracho Colorado santiagueño, QC) were harvested, and aqueous plant extracts (PE) were prepared. The spectroscopic (UV-Vis absorbance, diffuse reflectance, ATR-FTIR) and antioxidant (TEAC, Folin-Ciocalteu) properties of PE were characterized and used as TiO2 coating material to obtain a series of TiO2@PE nanocomposites. These materials showed almost null photocatalytic activity compared to aqueous suspensions of bare TiO2, displaying yellowish to brownish coloration and high long-term stability in both freshwater and seawater model solutions. The loss of photocatalytic activity in TiO2@PE was associated with the combination of the internal filter effect and the antioxidant/radical capacity exerted by the phytochemicals of the PE coating, with higher broadband photoprotection for the nanocomposites prepared with QC extracts. Thus, this study shows the potential capacity of the forest resources of the Chaco region of Argentina for the development of new cosmetic and/or sun protection formulations.

ABCG2 transporter plays a key role in the biodistribution of melatonin and its main metabolites.

The ATP-binding cassette G2 (ABCG2) is an efflux transporter expressed in the apical membrane of cells from a large number of tissues, directly affecting bioavailability, tissue accumulation, and secretion into milk of both xenobiotics and endogenous compounds. The aim of this work was to characterize the role of ABCG2 in the systemic distribution and secretion into milk of melatonin and its main metabolites, 6-hydroxymelatonin, and 6-sulfatoxymelatonin. For this purpose, we first showed that these three molecules are transported by this transporter using in vitro transepithelial assays with MDCK-II polarized cells transduced with different species variants of ABCG2. Second, we tested the in vivo effect of murine Abcg2 in the systemic distribution of melatonin and its metabolites using wild-type and Abcg2-/- mice. Our results show that after oral administration of melatonin, the plasma concentration of melatonin metabolites in Abcg2-/-  mice was between 1.5 and 6-fold higher compared to the wild-type mice. We also evaluated in these animals differences in tissue accumulation of melatonin metabolites. The most relevant differences between both types of mice were found for small intestine and kidney (>sixfold increase for 6-sulfatoxymelatonin in Abcg2-/-  mice). Finally, melatonin secretion into milk was also affected by the murine Abcg2 transporter, with a twofold higher milk concentration in wild-type compared with Abcg2-/-  lactating female mice. In addition, melatonin metabolites showed a higher milk-to-plasma ratio in wild-type mice. Overall, our results show that the ABCG2 transporter plays a critical role in the biodistribution of melatonin and its main metabolites, thereby potentially affecting their biological and therapeutic activity.

Taurine and N-acetylcysteine treatments prevent memory impairment and metabolite profile alterations in the hippocampus of high-fat diet-fed female mice.

Background: Obesity constitutes a risk factor for cognitive impairment. In rodent models, long-term exposure to obesogenic diets leads to hippocampal taurine accumulation. Since taurine has putative cyto-protective effects, hippocampal taurine accumulation in obese and diabetic models might constitute a counteracting response to metabolic stress. Objective: We tested the hypothesis that treatment with taurine or with N-acetylcysteine (NAC), which provides cysteine for the synthesis of taurine and glutathione, prevent high-fat diet (HFD)-associated hippocampal alterations and memory impairment. Methods: Female mice were fed either a regular diet or HFD. Some mice had access to 3%(w/v) taurine or 3%(w/v) NAC in the drinking water. After 2 months, magnetic resonance spectroscopy (MRS) was used to measure metabolite profiles. Memory was assessed in novel object and novel location recognition tests. Results: HFD feeding caused memory impairment in both tests, and reduced concentration of lactate, phosphocreatine-to-creatine ratio, and the neuronal marker N-acetylaspartate in the hippocampus. Taurine and NAC prevented HFD-induced memory impairment and N-acetylaspartate reduction. NAC, but not taurine, prevented the reduction of lactate and phosphocreatine-to-creatine ratio. MRS revealed NAC/taurine-induced increase of hippocampal glutamate and GABA levels. Conclusion: NAC and taurine can prevent memory impairment, while only NAC prevents alterations of metabolite concentrations in HFD-exposed female mice.

Controlling Fusarium wilt of cape gooseberry by microbial consortia.

The use of microbial consortia has become a promising alternative for the management of various diseases. In this study, 18 artificial consortia were designed, consisting of five bacteria, five fungi, and a mixture of five fungi and five bacteria; from a collection of microorganisms isolated from the rhizosphere of cape gooseberry plants grown in two soils potentially suppressive against Fusarium oxysporum. When evaluated under greenhouse conditions for their biocontrol activity on cape gooseberry plants, one consortium was selected for their high efficacy (over 90%) in the control of vascular wilt caused by F. oxysporum f. sp. physali. This was constituted by 10 microorganisms, the bacteria Paenibacillus peoriae, Bacillus subtilis, Lysinibacillus sp., B. simplex, and Pseudomonas chlororaphis; and the fungi Beauveria bassiana, Scopulariopsis brevicaulis, Trichoderma gamsii, T. ghanense, and T. lignicola. On the other hand, four of the consortia evaluated in the presence of the pathogen mitigated the deleterious effect produced by the pathogen on plant growth, expressing higher dry weights, both in the aerial and root parts. This work represents the first report on using these mixtures of microorganisms to control vascular wilt produced by F. oxysporum. However, further studies are needed to determine their activity in cape gooseberry fields.

Heterologous microProtein expression identifies LITTLE NINJA, a dominant regulator of jasmonic acid signaling.

MicroProteins are small, often single-domain proteins that are sequence-related to larger, often multidomain proteins. Here, we used a combination of comparative genomics and heterologous synthetic misexpression to isolate functional cereal microProtein regulators. Our approach identified LITTLE NINJA (LNJ), a microProtein that acts as a modulator of jasmonic acid (JA) signaling. Ectopic expression of LNJ in Arabidopsis resulted in stunted plants that resembled the decuple JAZ (jazD) mutant. In fact, comparing the transcriptomes of transgenic LNJ overexpressor plants and jazD revealed a large overlap of deregulated genes, suggesting that ectopic LNJ expression altered JA signaling. Transgenic Brachypodium plants with elevated LNJ expression levels showed deregulation of JA signaling as well and displayed reduced growth and enhanced production of side shoots (tiller). This tillering effect was transferable between grass species, and overexpression of LNJ in barley and rice caused similar traits. We used a clustered regularly interspaced short palindromic repeats (CRISPR) approach and created a LNJ-like protein in Arabidopsis by deleting parts of the coding sentence of the AFP2 gene that encodes a NINJA-domain protein. These afp2-crispr mutants were also stunted in size and resembled jazD Thus, similar genome-engineering approaches can be exploited as a future tool to create LNJ proteins and produce cereals with altered architectures.

Predictors of Preexposure Prophylaxis Eligibility among Pregnant People with Opioid Use Disorder.

OBJECTIVE: We seek to evaluate risk factors for eligibility for preexposure prophylaxis (PrEP) among pregnant people with opioid use disorder (OUD). STUDY DESIGN: This is a single-site retrospective cohort study of pregnant people admitted for management of OUD at an urban, tertiary care center from 2013 to 2022. PrEP eligibility was defined based on (1) modified American College of Obstetricians and Gynecologists' (ACOG) 2014 criteria: diagnosis of a sexually transmitted infection (STI), engagement in transactional sex work, intravenous drug use (IVDU), or incarceration and (2) modified 2021 Centers for Disease Control (CDC) criteria: diagnosis of bacterial STI (e.g., gonorrhea or syphilis) or transactional sex work. Risk factors associated with PrEP eligibility were evaluated using chi- square or Fischer's exact tests for categorical variables and t-tests or Wilcoxon rank-sum tests for continuous variables. Multivariable regression was used to control for confounding covariates, defined as p < 0.10 on bivariate analysis. p < 0.05 was used to indicate statistical significance. RESULTS: A total of 132 individuals met inclusion criteria, of whom 101 (76.5%) were deemed eligible for PrEP by meeting one or more modified 2014 ACOG criteria: 42 (31.8%) were incarcerated or had one or more STIs, while 30 (22.7%) endorsed engaging in transactional sex work and 68 (58.6%) endorsed IVDU. Using modified 2021 CDC criteria, 37 (28%) met PrEP eligibility, with 12 (9.1%) diagnosed specifically with a bacterial STI and 30 (22.7%) engaging in transactional sex work. Only comorbid psychiatric illness was associated with an increased risk for PrEP eligibility based on 2014 criteria, which persisted after controlling for maternal race/ethnicity (aRR 1.52, 95% confidence interval [CI] 1.24-1.86), and 2021 criteria, which persisted after controlling for nulliparity (aRR 2.12, 95% CI 1.30-3.57). CONCLUSION: A significant number of pregnant people with OUD meet one or more criteria for PrEP, with comorbid psychiatric conditions increasing the risk of meeting criteria. KEY POINTS: · Comorbid psychiatric illness is significantly associated with high risk of PrEP eligibility.. · A large proportion of pregnant individuals with active OUD meet criteria for PrEP prescribing.. · Risk-based screening algorithms for PrEP eligibility have limitations..

Translation of Small Open Reading Frames: Roles in Regulation and Evolutionary Innovation.

The translatome can be defined as the sum of the RNA sequences that are translated into proteins in the cell by the ribosomal machinery. Until recently, it was generally assumed that the translatome was essentially restricted to evolutionary conserved proteins encoded by the set of annotated protein-coding genes. However, it has become increasingly clear that it also includes small regulatory open reading frames (ORFs), functional micropeptides, de novo proteins, and the pervasive translation of likely nonfunctional proteins. Many of these ORFs have been discovered thanks to the development of ribosome profiling, a technique to sequence ribosome-protected RNA fragments. To fully capture the diversity of translated ORFs, we propose a comprehensive classification that includes the new types of translated ORFs in addition to standard proteins.

Non-muscle-invasive micropapillary bladder cancer has a distinct lncRNA profile associated with unfavorable prognosis.

BACKGROUND: Molecular subtyping of bladder cancer has revealed luminal tumors generally have a more favourable prognosis. However, some aggressive forms of variant histology, including micropapillary, are often classified luminal. In previous work, we found long non-coding RNA (lncRNA) expression profiles could identify a subgroup of luminal bladder tumors with less aggressive biology and better outcomes. OBJECTIVE: In the present study, we aimed to investigate whether lncRNA expression profiles could identify high-grade T1 micropapillary bladder cancer with differential outcome. DESIGN, SETTING, AND PARTICIPANTS: LncRNAs were quantified from RNA-seq data from a HGT1 bladder cancer cohort that was enriched for primary micropapillary cases (15/84). Unsupervised consensus clustering of variant lncRNAs identified a three-cluster solution, which was further characterised using a panel of micropapillary-associated biomarkers, molecular subtypes, gene signatures, and survival analysis. A single-sample genomic signature was trained using lasso-penalized logistic regression to classify micropapillary-like gene-expression, as characterised by lncRNA clustering. The genomic classifier (GC) was tested on luminal tumors derived from the TCGA cohort (N = 202). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patient and tumor characteristics were compared between subgroups by using X2 tests and two-sided Wilcoxon rank-sum tests. Primary endpoints were overall, progression-free and high-grade recurrence-free survival, calculated as the date of high-grade T1 disease at TURBT till date of death from any cause, progression, or recurrence, respectively. Survival rates were estimated using weighted Kaplan-Meier (KM) curves. RESULTS AND LIMITATIONS: Primary micropapillary HGT1 showed decreased FGFR3, SHH, and p53 pathway activity relative to tumors with conventional urothelial carcinoma. Many bladder cancer-associated lncRNAs were downregulated in micropapillary tumors, including UCA1, LINC00152, and MALAT1. Unsupervised consensus clustering resulted in a lncRNA cluster 1 (LC1) with worse prognosis that was enriched for primary micropapillary histology and the Luminal Unstable (LumU) molecular subtype. Interestingly, LC1 appeared to better identify aggressive HGT1 disease, compared to stratifying outcomes using primary histologic characteristics. A signature trained to identify LC1 cases showed good performance in the testing cohort, identifying seven cases with significantly worse survival (p < 0.001). Limitations include the retrospective nature of the study and the lack of a validation cohort. CONCLUSIONS: Using the lncRNA transcriptome we identified a subgroup of aggressive HGT1 bladder cancer that was enriched with micropapillary histology. These data suggest that lncRNAs can facilitate the identification of aggressive micropapillary-like tumors, potentially improving patient management.

Secretion into Milk of the Main Metabolites of the Anthelmintic Albendazole Is Mediated by the ABCG2/BCRP Transporter.

Albendazole (ABZ) is an anthelmintic with a broad-spectrum activity, widely used in human and veterinary medicine. ABZ is metabolized in all mammalian species to albendazole sulfoxide (ABZSO), albendazole sulfone (ABZSO2) and albendazole 2-aminosulphone (ABZSO2-NH2). ABZSO and ABZSO2 are the main metabolites detected in plasma and all three are detected in milk. The ATP-binding cassette transporter G2 (ABCG2) is an efflux transporter that is involved in the active secretion of several compounds into milk. Previous studies have reported that ABZSO was in vitro transported by ABCG2. The aim of this work is to correlate the in vitro interaction between ABCG2 and the other ABZ metabolites with their secretion into milk by this transporter. Using in vitro transepithelial assays with cells transduced with murine Abcg2 and human ABCG2, we show that ABZSO2 and ABZSO2-NH2 are in vitro substrates of both. In vivo assays carried out with wild-type and Abcg2-/- lactating female mice demonstrated that secretion into milk of these ABZ metabolites was mediated by Abcg2. Milk concentrations and milk-to-plasma ratio were higher in wild-type compared to Abcg2-/- mice for all the metabolites tested. We conclude that ABZ metabolites are undoubtedly in vitro substrates of ABCG2 and actively secreted into milk by ABCG2.

Improving cardiorespiratory fitness protects against inflammation in children: the IDEFICS study.

BACKGROUND: Muscular and cardiorespiratory fitness (MF and CRF) have been related to inflammation. Thus, the aim of this study was to assess the relationship between fitness and high-sensitivity C-reactive protein (hs-CRP) in European children both in the cross-sectional and longitudinal analysis. METHODS: Three hundred and fifty-seven children (46.2% males) aged 2-9 years with hs-CRP measured, data from MF and CRF, diet quality, objectively measured physical activity (PA) and screen time at baseline and follow-up after 2 years were included. Body mass index z-score (zBMI), waist circumference (WC) and fat mass index (FMI) were assessed. MF and CRF were also dichotomized as follows: low-medium quartiles (Q1-Q3) and highest quartile (Q4). RESULTS: At follow-up, children with the highest CRF (Q4) showed a lower probability of having high hs-CRP. In the longitudinal analysis, children who improved their CRF over time showed a significantly lower probability (p < 0.05) of being in the highest hs-CRP category at follow-up, independently of the body composition index considered: odds ratio (OR) = 0.22 for zBMI, OR = 0.17 for WC, and OR = 0.21 for FMI. CONCLUSIONS: Improving CRF during childhood reduces the odds of an inflammatory profile, independently of body composition and lifestyle behaviours. These highlight the importance of enhancing fitness, especially CRF, to avoid an inflammatory state in children. IMPACT: Improvements in the cardiorespiratory profile during childhood could reverse an unfavourable inflammatory status. There is a longitudinal and inverse association between CRF and inflammation in children. This is the first longitudinal study assessing the relationship between fitness and inflammation during childhood that takes also into account the lifestyle behaviours. Results from the present study suggest a protective role of fitness already in childhood. Efforts to improve fitness in children should be aimed at as inflammation could trigger future cardiovascular disease.

Noncovalent Assembly and Catalytic Activity of Hybrid Materials Based on Pd Complexes Adsorbed on Multiwalled Carbon Nanotubes, Graphene, and Graphene Nanoplatelets.

Green catalysts with excellent performance in Cu-free Sonogashira coupling reactions can be prepared by the supramolecular decoration of graphene surfaces with Pd(II) complexes. Here we report the synthesis, characterization, and catalytic properties of new catalysts obtained by the surface decoration of multiwalled carbon nanotubes (MWCNTs), graphene (G), and graphene nanoplatelets (GNPTs) with Pd(II) complexes of tetraaza-macrocyclic ligands bearing one or two anchor functionalities. The decoration of these carbon surfaces takes place under environmentally friendly conditions (water, room temperature, aerobic) in two steps: (i) π-π stacking attachment of the ligand via electron-poor anchor group 6-amino-3,4-dihydro-3-methyl-5-nitroso-4-oxo-pyrimidine and (ii) Pd(II) coordination from PdCl42-. Ligands are more efficiently adsorbed on the flat surfaces of G and GNPTs than on the curved surfaces of MWCNTs. All catalysts work very efficiently under mild conditions (50 °C, aerobic, 7 h), giving a similar high yield (90% or greater) in the coupling of iodobenzene with phenylacetylene to form diphenylacetylene in one catalytic cycle, but catalysts based on G and GNPTs (especially on GNPTs) provide greater catalytic efficiency in reuse (four cycles). The study also revealed that the active centers of the ligand-Pd type decorating the support surfaces are much more efficient than the Pd(0) and PdCl42- centers sharing the same surfaces. All of the results allow a better understanding of the structural factors to be controlled in order to obtain an optimal efficiency from similar catalysts based on graphene supports.

How effects on health equity are assessed in systematic reviews of interventions.

BACKGROUND: Enhancing health equity is endorsed in the Sustainable Development Goals. The failure of systematic reviews to consider potential differences in effects across equity factors is cited by decision-makers as a limitation to their ability to inform policy and program decisions.  OBJECTIVES: To explore what methods systematic reviewers use to consider health equity in systematic reviews of effectiveness. SEARCH METHODS: We searched the following databases up to 26 February 2021: MEDLINE, PsycINFO, the Cochrane Methodology Register, CINAHL, Education Resources Information Center, Education Abstracts, Criminal Justice Abstracts, Hein Index to Foreign Legal Periodicals, PAIS International, Social Services Abstracts, Sociological Abstracts, Digital Dissertations and the Health Technology Assessment Database. We searched SCOPUS to identify articles that cited any of the included studies on 10 June 10 2021. We contacted authors and searched the reference lists of included studies to identify additional potentially relevant studies. SELECTION CRITERIA: We included empirical studies of cohorts of systematic reviews that assessed methods for measuring effects on health inequalities. We define health inequalities as unfair and avoidable differences across socially stratifying factors that limit opportunities for health. We operationalised this by assessing studies which evaluated differences in health across any component of the PROGRESS-Plus acronym, which stands for Place of residence, Race/ethnicity/culture/language, Occupation, Gender or sex, Religion, Education, Socioeconomic status, Social capital. "Plus" stands for other factors associated with discrimination, exclusion, marginalisation or vulnerability such as personal characteristics (e.g. age, disability), relationships that limit opportunities for health (e.g. children in a household with parents who smoke) or environmental situations which provide limited control of opportunities for health (e.g. school food environment). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data using a pre-tested form. Risk of bias was appraised for included studies according to the potential for bias in selection and detection of systematic reviews.  MAIN RESULTS: In total, 48,814 studies were identified and the titles and abstracts were screened in duplicate. In this updated review, we identified an additional 124 methodological studies published in the 10 years since the first version of this review, which included 34 studies. Thus, 158 methodological studies met our criteria for inclusion. The methods used by these studies focused on evidence relevant to populations experiencing health inequity (108 out of 158 studies), assess subgroup analysis across PROGRESS-Plus (26 out of 158 studies), assess analysis of a gradient in effect across PROGRESS-Plus (2 out of 158 studies) or use a combination of subgroup analysis and focused approaches (20 out of 158 studies). The most common PROGRESS-Plus factors assessed were age (43 studies), socioeconomic status in 35 studies, low- and middle-income countries in 24 studies, gender or sex in 22 studies, race or ethnicity in 17 studies, and four studies assessed multiple factors across which health inequity may exist. Only 16 studies provided a definition of health inequity. Five methodological approaches to consider health equity in systematic reviews of effectiveness were identified: 1) descriptive assessment of reporting and analysis in systematic reviews (140 of 158 studies used a type of descriptive method); 2) descriptive assessment of reporting and analysis in original trials (50 studies); 3) analytic approaches which assessed differential effects across one or more PROGRESS-Plus factors (16 studies); 4) applicability assessment (25 studies) and 5) stakeholder engagement (28 studies), which is a new finding in this update and examines the appraisal of whether relevant stakeholders with lived experience of health inequity were included in the design of systematic reviews or design and delivery of interventions. Reporting for both approaches (analytic and applicability) lacked transparency and was insufficiently detailed to enable the assessment of credibility. AUTHORS' CONCLUSIONS: There is a need for improvement in conceptual clarity about the definition of health equity, describing sufficient detail about analytic approaches (including subgroup analyses) and transparent reporting of judgments required for applicability assessments in order to consider health equity in systematic reviews of effectiveness.