Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice.

Dysregulation of the c-Myc oncogene occurs in a wide variety of hematologic malignancies, and its overexpression has been linked with aggressive tumor progression. Here, we show that poly (ADP-ribose) polymerase 1 (PARP-1) and PARP-2 exert opposing influences on progression of c-Myc-driven B-cell lymphoma. PARP-1 and PARP-2 catalyze the synthesis and transfer of ADP-ribose units onto amino acid residues of acceptor proteins in response to DNA strand breaks, playing a central role in the response to DNA damage. Accordingly, PARP inhibitors have emerged as promising new cancer therapeutics. However, the inhibitors currently available for clinical use are not able to discriminate between individual PARP proteins. We found that genetic deletion of PARP-2 prevents c-Myc-driven B-cell lymphoma, whereas PARP-1 deficiency accelerates lymphomagenesis in the Eµ-Myc mouse model of aggressive B-cell lymphoma. Loss of PARP-2 aggravates replication stress in preleukemic Eµ-Myc B cells, resulting in accumulation of DNA damage and concomitant cell death that restricts the c-Myc-driven expansion of B cells, thereby providing protection against B-cell lymphoma. In contrast, PARP-1 deficiency induces a proinflammatory response and an increase in regulatory T cells, likely contributing to immune escape of B-cell lymphoma, resulting in an acceleration of lymphomagenesis. These findings pinpoint specific functions for PARP-1 and PARP-2 in c-Myc-driven lymphomagenesis with antagonistic consequences that may help inform the design of new PARP-centered therapeutic strategies, with selective PARP-2 inhibition potentially representing a new therapeutic approach for the treatment of c-Myc-driven tumors.

Plant-based diet adherence is associated with metabolic health status in adults living with and without obesity.

PURPOSE: Metabolic health phenotypes exist across the body mass index spectrum. Diet may be an important modifiable risk factor, yet limited research exists on dietary patterns in this context. We investigated associations between dietary patterns, reflecting dietary quality, healthfulness and inflammatory potential, and metabolic health phenotypes in adults living with and without obesity. METHODS: This cross-sectional study included 2,040 middle- to older-aged men and women randomly selected from a large primary care centre. The Dietary Approaches to Stop Hypertension score, Healthy Eating Index, Dietary Inflammatory Index, overall, healthful and unhealthful plant-based dietary indices and Nutri-Score were derived from validated food frequency questionnaires. Descriptive and logistic regression analyses were used to examine diet score relationships with metabolic health phenotypes (Metabolically Healthy/Unhealthy Obese (MHO/MUO) and Non-Obese (MHNO/MUNO)), defined using three separate metabolic health definitions, each capturing different aspects of metabolic health. RESULTS: In fully adjusted models, higher unhealthful plant-based dietary scores were associated with a lower likelihood of MHO (OR = 0.96, 95% CI: 0.93-1.00, p = 0.038) and MHNO (OR = 0.97, 95% CI: 0.95-0.99, p = 0.006). Higher Nutri-Score values were associated with an increased likelihood of MHNO (OR = 1.06, 95% CI: 1.01-1.13, p = 0.033). CONCLUSION: These findings provide evidence that more unhealthful plant-based diets may be linked with unfavourable metabolic health status, irrespective of BMI.

Cardiac index-guided therapy to maintain optimised postinduction cardiac index in high-risk patients having major open abdominal surgery: the multicentre randomised iPEGASUS trial.

BACKGROUND: It is unclear whether optimising intraoperative cardiac index can reduce postoperative complications. We tested the hypothesis that maintaining optimised postinduction cardiac index during and for the first 8 h after surgery reduces the incidence of a composite outcome of complications within 28 days after surgery compared with routine care in high-risk patients having elective major open abdominal surgery. METHODS: In three German and two Spanish centres, high-risk patients having elective major open abdominal surgery were randomised to cardiac index-guided therapy to maintain optimised postinduction cardiac index (cardiac index at which pulse pressure variation was <12%) during and for the first 8 h after surgery using intravenous fluids and dobutamine or to routine care. The primary outcome was the incidence of a composite outcome of moderate or severe complications within 28 days after surgery. RESULTS: We analysed 318 of 380 enrolled subjects. The composite primary outcome occurred in 84 of 152 subjects (55%) assigned to cardiac index-guided therapy and in 77 of 166 subjects (46%) assigned to routine care (odds ratio: 1.87, 95% confidence interval: 1.03-3.39, P=0.038). Per-protocol analyses confirmed the results of the primary outcome analysis. CONCLUSIONS: Maintaining optimised postinduction cardiac index during and for the first 8 h after surgery did not reduce, and possibly increased, the incidence of a composite outcome of complications within 28 days after surgery compared with routine care in high-risk patients having elective major open abdominal surgery. Clinicians should not strive to maintain optimised postinduction cardiac index during and after surgery in expectation of reducing complications. CLINICAL TRIAL REGISTRATION: NCT03021525.

Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing.

Common genetic contributions to autism spectrum disorder (ASD) reside in risk gene variants that individually have minimal effect sizes. As environmental factors that perturb neurodevelopment also underlie idiopathic ASD, it is crucial to identify altered regulators that can orchestrate multiple ASD risk genes during neurodevelopment. Cytoplasmic polyadenylation element binding proteins 1-4 (CPEB1-4) regulate the translation of specific mRNAs by modulating their poly(A)-tails and thereby participate in embryonic development and synaptic plasticity. Here we find that CPEB4 binds transcripts of most high-confidence ASD risk genes. The brains of individuals with idiopathic ASD show imbalances in CPEB4 transcript isoforms that result from decreased inclusion of a neuron-specific microexon. In addition, 9% of the transcriptome shows reduced poly(A)-tail length. Notably, this percentage is much higher for high-confidence ASD risk genes, correlating with reduced expression of the protein products of ASD risk genes. An equivalent imbalance in CPEB4 transcript isoforms in mice mimics the changes in mRNA polyadenylation and protein expression of ASD risk genes and induces ASD-like neuroanatomical, electrophysiological and behavioural phenotypes. Together, these data identify CPEB4 as a regulator of ASD risk genes.

Determinant factors for first-line treatment choice and effectiveness in pediatric eosinophilic esophagitis: an analysis of the EUREOS EoE CONNECT registry.

This study compared short-term effectiveness of proton pump inhibitors (PPI), swallowed topical corticosteroids (STC), and dietary therapies in reversing clinical and histological features in pediatric patients with eosinophilic esophagitits (EoE). Determinants for treatment choice and PPI therapy effectiveness were also assessed.  A cross-sectional study analysis of patients under 18 years old recruited onto the multicenter EoE CONNECT registry was performed. Clinico-histological response was defined as symptomatic improvement plus a peak eosinophil count below 15 per high-power field after treatment. Effectiveness of first-line options used in monotherapy was compared. Overall, 393 patients (64% adolescents) receiving PPI, STC, or dietary monotherapy to induce EoE remission were identified. PPI was the preferred option (71.5%), despite STC providing the highest clinico-histological response rates (66%) compared to PPI (44%) and diet (42%). Logistic regression identified fibrotic features and recruitment at Italian sites independently associated to first-line STC treatment; age under 12 associated to dietary therapy over other options. Analysis of 262 patients in whom PPI effectiveness was evaluated after median (IQR) 96 (70-145) days showed that this effectiveness was significantly associated with management at pediatric facilities and use of high PPI doses. Among PPI responders, decrease in rings and structures in endoscopy from baseline was documented, with EREFS fibrotic subscore for rings also decreasing among responders (0.27 ± 0.63 vs. 0.05 ± 0.22, p < 0.001). Conclusion: Initial therapy choice for EoE depends on endoscopic phenotype, patient's age, and patients' origin. High PPI doses and treatment in pediatric facilities significantly determined effectiveness, and reversed fibrotic endoscopic features among responders. What is Known: • Proton pump inhibitors are widely used to induce and maintain remission in EoE in real practice, despite other first-line alternative therapies possibly providing higher effectiveness. What is New: • Proton pump inhibitors represent up to two-thirds of first-line monotherapies used to induce EoE remission in pediatric and adolescent patients with EoE. The choice of STC as first-line treatment for EoE was significantly associated with fibrotic features at baseline endoscopy and recruitment in Italian centers; age less than 12 years was associated with dietary therapy. • PPI effectiveness was found to be determined by use of high doses, attendance at pediatric facilities, presenting inflammatory instead of fibrotic or mixed phenotypes, and younger age. Among responders, PPI therapy reversed both inflammatory and fibrotic features of EoE after short-term treatment.

Fibrous Remodeling in Eosinophilic Esophagitis: Clinical Facts and Pathophysiological Uncertainties.

Eosinophilic esophagitis (EoE) is a chronic, progressive, type 2 inflammatory disease with increasing global prevalence. An eosinophil-predominant inflammation that permeates the epithelium and deeper esophageal layers characterizes the disease. Several cytokines, mainly derived from inflammatory T-helper 2 (Th2) cells and epithelial cells, are involved in perpetuating inflammatory responses by increasing surface permeability and promoting tissue remodeling characterized by epithelial-mesenchymal transition (EMT) and collagen deposition. This leads to esophageal strictures and narrow caliber esophagi, which are proportional a patient's age and untreated disease length. Pathophysiological mechanisms leading to EoE have been described in recent years, and transforming growth factor beta (TGF)-beta have been involved in fibrotic phenomena in EoE. However, evidence on the dependence of these phenomena on TGF-beta is scarce and contradictory. This review provides state-of-the art knowledge on intimate mechanisms of esophageal fibrosis in EoE and its clinical consequences.

Maternal and Paternal Dietary Quality and Dietary Inflammation Associations with Offspring DNA Methylation and Epigenetic Biomarkers of Aging in the Lifeways Cross-Generation Study.

BACKGROUND: Early-life nutritional exposures may contribute to offspring epigenetic modifications. However, few studies have evaluated parental dietary quality effects on offspring DNA methylation (DNAm). OBJECTIVES: We aim to fill this gap by elucidating the influence of maternal and paternal whole-diet quality and inflammatory potential on offspring DNAm in the Lifeways Cross-generation cohort. METHODS: Families (n = 1124) were recruited around 16 weeks of gestation in the Republic of Ireland between 2001 and 2003. Maternal dietary intake during the first trimester and paternal diet during the 12 previous months were assessed with an FFQ. Parental dietary inflammatory potential and quality were determined using the energy-adjusted Dietary Inflammatory Index (E-DII), the Healthy Eating Index-2015 (HEI-2015), and the maternal DASH score. DNAm in the saliva of 246 children at age nine was measured using the Illumina Infinium HumanMethylationEPIC array. DNAm-derived biomarkers of aging, the Pediatric-Buccal-Epigenetic clock and DNAm estimator of telomere length, were calculated. Parental diet associations with the DNAm concentrations of 850K Cytosine-phosphate-guanine sites (CpG sites) and with DNAm-derived biomarkers of aging were examined using an epigenome-wide association study and linear regressions, respectively. RESULTS: Maternal HEI-2015 scores were inversely associated with DNAm at CpG site (cg21840035) located near the PLEKHM1 gene, whose functions involve regulation of bone development (ß = -0.0036, per 1 point increase in the score; P = 5.6 × 10-8). Higher paternal HEI-2015 score was related to lower methylation at CpG site (cg22431767), located near cell signaling gene LUZP1 (ß = -0.0022, per 1 point increase in the score, P = 4.1 × 10-8). There were no associations with parental E-DII and DASH scores, and no evidence of major effects on biomarkers of aging. CONCLUSIONS: Parental dietary quality in the prenatal period, evaluated by the HEI-2015, may influence offspring DNAm during childhood. Further research to improve our understanding of parental nutritional programming is warranted.

Dinophysis acuminata or Dinophysis acuta: What Makes the Difference in Highly Stratified Fjords?

Dinophysis acuminata and D. acuta, which follows it seasonally, are the main producers of lipophilic toxins in temperate coastal waters, including Southern Chile. Strains of the two species differ in their toxin profiles and impacts on shellfish resources. D. acuta is considered the major cause of diarrhetic shellfish poisoning (DSP) outbreaks in Southern Chile, but there is uncertainty about the toxicity of D. acuminata, and little information on microscale oceanographic conditions promoting their blooms. During the austral summer of 2020, intensive sampling was carried out in two northern Patagonian fjords, Puyuhuapi (PUY) and Pitipalena (PIT), sharing D. acuminata dominance and D. acuta near detection levels. Dinophysistoxin 1 (DTX 1) and pectenotoxin 2 (PTX 2) were present in all net tow samples but OA was not detected. Although differing in hydrodynamics and sampling dates, D. acuminata shared behavioural traits in the two fjords: cell maxima (>103 cells L-1) in the interface (S ~ 21) between the estuarine freshwater (EFW)) and saline water (ESW) layers; and phased-cell division (µ = 0.3-0.4 d-1) peaking after dawn, and abundance of ciliate prey. Niche analysis (Outlying Mean Index, OMI) of D. acuta with a high marginality and much lower tolerance than D. acuminata indicated an unfavourable physical environment for D. acuta (bloom failure). Comparison of toxin profiles and Dinophysis niches in three contrasting years in PUY-2020 (D. acuminata bloom), 2018 (exceptional bloom of D. acuta), and 2019 (bloom co-occurrence of the two species)-shed light on the vertical gradients which promote each species. The presence of FW (S < 11) and thermal inversion may be used to provide short-term forecasts of no risk of D. acuta blooms and OA occurrence, but D. acuminata associated with DTX 1 pose a risk of DSP events in North Patagonian fjords.

Blood-Based Biomarkers for Eosinophilic Esophagitis and Concomitant Atopic Diseases: A Look into the Potential of Extracellular Vesicles.

Eosinophilic esophagitis (EoE) is a chronic, Th2-inflammatory disease of the esophagus that can severely affect food intake. Currently, diagnosis and assessing response to treatment of EoE is highly invasive and requires endoscopy with esophageal biopsies. Finding non-invasive and accurate biomarkers is important for improving patient well-being. Unfortunately, EoE is usually accompanied by other atopies, which make it difficult to identify specific biomarkers. Providing an update of circulating EoE biomarkers and concomitant atopies is therefore timely. This review summarizes the current knowledge in EoE blood biomarkers and two of its most common comorbidities, bronchial asthma (BA) and atopic dermatitis (AD), focusing on dysregulated proteins, metabolites, and RNAs. It also revises the current knowledge on extracellular vesicles (EVs) as non-invasive biomarkers for BA and AD, and concludes with the potential use of EVs as biomarkers in EoE.

Dietary score associations with markers of chronic low-grade inflammation: a cross-sectional comparative analysis of a middle- to older-aged population.

PURPOSE: To assess relationships between the Dietary Approaches to Stop Hypertension (DASH), Mediterranean Diet (MD), Dietary Inflammatory Index (DII®) and Energy-adjusted DII (E-DII™) scores and pro-inflammatory cytokines, adipocytokines, acute-phase response proteins, coagulation factors and white blood cells. METHODS: This was a cross-sectional study of 1862 men and women aged 46-73 years, randomly selected from a large primary care centre in Ireland. DASH, MD, DII and E-DII scores were derived from validated food frequency questionnaires. Correlation and multivariate-adjusted linear regression analyses with correction for multiple testing were performed to examine dietary score relationships with biomarker concentrations. RESULTS: In fully adjusted models, higher diet quality or a less pro-inflammatory diet was associated with lower concentrations of c-reactive protein, neutrophils (all dietary scores), complement component 3 [C3], interleukin 6 [IL-6], tumour necrosis factor-alpha [TNF-α], white blood cell count [WBC], the neutrophil-to-lymphocyte ratio [NLR] (DASH, DII and E-DII), monocytes (DASH and DII) and resistin (DII and E-DII). After accounting for multiple testing, relationships with C3 (DASH: ß = - 2.079, p = .011 and DII: ß = 2.521, p = .036), IL-6 (DASH: ß = - 0.063, p = .011), TNF-α (DASH: ß = - 0.027, p = .034), WBC (DASH: ß = - 0.028, p = .001 and DII: ß = 0.029, p = .02), neutrophils (DASH: ß = - 0.041, p = .001; DII: ß = 0.043, p = .007; E-DII: ß = 0.029, p = .009) and the NLR (DASH: ß = - 0.035, p = .011) persisted. CONCLUSIONS: Better diet quality, determined by the DASH score, may be more closely associated with inflammatory biomarkers related to health in middle- to older-aged adults than the MD, DII and E-DII scores.

Application of a new wax containing ethanol as a method to remove persimmon astringency during cold storage.

Nowadays the treatment based on applying high CO2 concentrations to fruit is the main method used in astringent persimmon prior to being commercialized, but it can cause quality problems for fruit during cold storage. The aim of this study was to evaluate the effectiveness of a recently patented astringency removal method based on applying a new wax whose formulation includes ethanol before commercial packaging. During two seasons, three treatments were evaluated in cv. Rojo Brillante and Triumph: (1) CO2- standard treatment; (2) waxed and packed in plastic film according to the patented method; (3) packed in plastic film without any treatment. During a third season, the new method's effectiveness in removing astringency was evaluated under industrial conditions. After treatments fruit was stored at 0 °C for 15, 21 and 30 days before being transferred at 20 °C to simulate a 5-days shelf-life. All the fruit treated with the new wax completely lost astringency after 30 days at 0 °C, and commercial firmness was maintained. At the end of the storage, fruit quality was substantially higher in fruit submitted to the new treatment. CO2-treated fruit, manifested internal browning after 30 storage days and shelf-life, while this disorder was not detected in waxed fruit.

Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor-stroma crosstalk.

Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. A more comprehensive understanding of the complexity of PDA pathobiology, and especially of the role of the tumor microenvironment in disease progression, should pave the way for therapies to improve patient response rates. In this study, we identify galectin-1 (Gal1), a glycan-binding protein that is highly overexpressed in PDA stroma, as a major driver of pancreatic cancer progression. Genetic deletion of Gal1 in a Kras-driven mouse model of PDA (Ela-KrasG12Vp53-/- ) results in a significant increase in survival through mechanisms involving decreased stroma activation, attenuated vascularization, and enhanced T cell infiltration leading to diminished metastasis rates. In a human setting, human pancreatic stellate cells (HPSCs) promote cancer proliferation, migration, and invasion via Gal1-driven pathways. Moreover, in vivo orthotopic coinjection of pancreatic tumor cells with Gal1-depleted HPSCs leads to impaired tumor formation and metastasis in mice. Gene-expression analyses of pancreatic tumor cells exposed to Gal1 reveal modulation of multiple regulatory pathways involved in tumor progression. Thus, Gal1 hierarchically regulates different events implicated in PDA biology including tumor cell proliferation, invasion, angiogenesis, inflammation, and metastasis, highlighting the broad therapeutic potential of Gal1-specific inhibitors, either alone or in combination with other therapeutic modalities.

A novel translational control mechanism involving RNA structures within coding sequences.

The impact of RNA structures in coding sequences (CDS) within mRNAs is poorly understood. Here, we identify a novel and highly conserved mechanism of translational control involving RNA structures within coding sequences and the DEAD-box helicase Dhh1. Using yeast genetics and genome-wide ribosome profiling analyses, we show that this mechanism, initially derived from studies of the Brome Mosaic virus RNA genome, extends to yeast and human mRNAs highly enriched in membrane and secreted proteins. All Dhh1-dependent mRNAs, viral and cellular, share key common features. First, they contain long and highly structured CDSs, including a region located around nucleotide 70 after the translation initiation site; second, they are directly bound by Dhh1 with a specific binding distribution; and third, complementary experimental approaches suggest that they are activated by Dhh1 at the translation initiation step. Our results show that ribosome translocation is not the only unwinding force of CDS and uncover a novel layer of translational control that involves RNA helicases and RNA folding within CDS providing novel opportunities for regulation of membrane and secretome proteins.

Associations between a maternal healthy lifestyle score and adverse offspring birth outcomes and childhood obesity in the Lifeways Cross-Generation Cohort Study.

BACKGROUND/OBJECTIVES: Maternal adherence to healthy lifestyle behaviors during pregnancy has been associated with reduced risk of obesity in the offspring. Our objective is to examine associations between a composite healthy lifestyle score (HLS) in expectant mothers and adverse offspring birth outcomes and childhood obesity. SUBJECTS/METHODS: The Lifeways Study comprises 665 mother-child pairs. A composite HLS (scored 0-5) based on high dietary quality (top 40% of the Healthy Eating Index (HEI)-2015), moderate to vigorous physical activity (MVPA), healthy pre-pregnancy BMI (18.5-24.9 kg/m2), never smoker, and no/moderate alcohol intake was calculated. Birth outcomes were abstracted from hospital records. Offspring waist circumference (WC) and BMI was determined at age 5 and 9. Logistic regression tested HLS associations with offspring outcomes. RESULTS: Offspring birth weight, length, and head circumference were positively associated with the maternal HLS (p < 0.001), whereas child BMI and incidence of overweight/obesity at age 5 and 9 were negatively associated (p < 0.05). In multivariable models, a lower maternal HLS was associated with increased risk of low birth weight (LBW) (P trend = 0.04) and lower likelihood of macrosomia (P trend = 0.03). Examined individually, poor maternal dietary quality, smoking, and alcohol intake were associated with higher risk of LBW (p < 0.04). Likelihood of macrosomia and combined overweight/obesity at age 5 and 9 years were greater among mothers with a pre-pregnancy BMI in the range with obesity (p < 0.04). Smoking during pregnancy was also linked to greater risk of childhood overweight/obesity (OR:1.91, 95% CI:1.01-3.61, p = 0.04 at age 5 and OR: 2.14, 95% CI:1.01-4.11, p = 0.03 at age 9). CONCLUSIONS: Our findings suggest that maternal adherence to a healthy lifestyle during pregnancy, in particular having a good quality diet, not smoking, and no/low alcohol intake in combination with a healthy pre-pregnancy BMI, is associated with reduced risk of adverse offspring birth outcomes and childhood obesity.

Galectins in the Tumor Microenvironment: Focus on Galectin-1.

In the last decades, the focus of cancer research has moved from epithelial cells to the tumor milieu, in an effort to better understand tumor development and progression, and with the important end goal of translating this knowledge into effective therapies. The galectin family of glycan-binding proteins displays important functions in cancer development and progression. Numerous groups have made outstanding contributions to deepen our knowledge about the role of galectins in the tumor-stroma crosstalk, defining them as key players in modulating interactions between tumor cells and the extracellular matrix, fibroblasts, endothelium, and the immune system. While several members of the family have been of particular interest until now, others are still considered as future exploding stars. This chapter provides an overview for galectin-1, the first identified and still one of the most well-studied galectins, and highlights the very important implications in its regulation of the tumor microenvironment in many different tumor types. Besides, a glimpse of the role of other galectins in the tumor milieu is also provided. Gaining a deeper understanding about the numerous roles of galectin-1 will not only help us to better understand other galectins but also is likely to result in the development of more effective cancer therapies.

Knockdown of α2,3-Sialyltransferases Impairs Pancreatic Cancer Cell Migration, Invasion and E-selectin-Dependent Adhesion.

Aberrant sialylation is frequently found in pancreatic ductal adenocarcinoma (PDA). α2,3-Sialyltransferases (α2,3-STs) ST3GAL3 and ST3GAL4 are overexpressed in PDA tissues and are responsible for increased biosynthesis of sialyl-Lewis (sLe) antigens, which play an important role in metastasis. This study addresses the effect of α2,3-STs knockdown on the migratory and invasive phenotype of PDA cells, and on E-selectin-dependent adhesion. Characterization of the cell sialome, the α2,3-STs and fucosyltransferases involved in the biosynthesis of sLe antigens, using a panel of human PDA cells showed differences in the levels of sialylated determinants and α2,3-STs expression, reflecting their phenotypic heterogeneity. Knockdown of ST3GAL3 and ST3GAL4 in BxPC-3 and Capan-1 cells, which expressed moderate to high levels of sLe antigens and α2,3-STs, led to a significant reduction in sLex and in most cases in sLea, with slight increases in the α2,6-sialic acid content. Moreover, ST3GAL3 and ST3GAL4 downregulation resulted in a significant decrease in cell migration and invasion. Binding and rolling to E-selectin, which represent key steps in metastasis, were also markedly impaired in the α2,3-STs knockdown cells. Our results indicate that inhibition of ST3GAL3 and ST3GAL4 may be a novel strategy to block PDA metastasis, which is one of the reasons for its dismal prognosis.

Flow Synthesis of Biologically-Relevant Compound Libraries.

Flow chemistry is one of the most prominent enabling technologies that has greatly shaped the way chemists' approach organic synthesis. Specifically, in drug discovery, the advantages of flow techniques over batch procedures allow the rapid and efficient assembly of compound libraries to be tested for biological properties. The aim of the present review is to comment on some representative examples from the last five years of literature that highlight how flow procedures are becoming of increasing importance for the synthesis of biologically-relevant molecules.

Physicochemical changes and chilling injury disorders in 'Tango' mandarins stored at low temperatures.

BACKGROUND: The susceptibility to chilling injury and quality changes of 'Tango' mandarins stored at different temperatures was evaluated in fruit grown at two locations in Andalusia (Spain) and grafted on Carrizo Citrange or FA5 rootstock. The peel disorders were also characterized by a microstructural study. RESULTS: Fruit developed chilling injuries, manifested as pitting lesions affecting the equatorial area of the fruit stored at 1 °C or 5 °C; fruit growing on FA5 rootstock showed a slightly lower incidence. The microstructural study revealed that only the upper layers of flavedo were affected in the damaged fruit, the epidermal and hypodermal tissues being dramatically collapsed. Although the fruit was prone to accumulate ethanol, especially after the shelf life that followed the different periods of cold storage, the ethanol did not compromise the overall flavor. CONCLUSIONS: Storage of 'Tango' fruit was limited by chilling injuries when stored at 1 °C or 5 °C for more than 20 days. Moreover, at these temperatures, the fruit was prone to accumulate ethanol and develop off flavors. At 9° C, the fruit could be stored for 30 days without compromising external or internal quality. Growing location and rootstock influenced some quality attributes at harvest but not during storage. © 2020 Society of Chemical Industry.

Maternal Dietary Glycemic and Insulinemic Indexes Are Not Associated with Birth Outcomes or Childhood Adiposity at 5 Years of Age in an Irish Cohort Study.

BACKGROUND: High maternal dietary glycemic index (GI) and glycemic load (GL) may be associated with adverse offspring birth and postnatal adiposity outcomes through metabolic programming, but the evidence thus far, mainly from studies conducted in high-risk pregnant populations, has been inconclusive. No study has examined the influence of maternal insulin demand [measured by food insulinemic index (II) and insulinemic load (IL)] on offspring outcomes. OBJECTIVES: We investigated associations between maternal GI, GL, II, and IL and offspring birth outcomes and postnatal adiposity in a general pregnant population. METHODS: The study was based on data from 842 mother-child pairs from the Lifeways prospective cohort study in Ireland. Through the use of standard methodology, maternal GI, GL, II, and IL were derived from dietary information obtained via a validated food-frequency questionnaire in early pregnancy (12-16 wk). Birth outcomes were abstracted from hospital records. At 5-y follow-up, children's body mass index (BMI) and waist circumference were measured. Associations were assessed through the use of multivariable-adjusted regression analysis. RESULTS: Mothers had a mean ± SD age of 30.3 ± 5.7 y and a mean BMI (kg/m2) of 23.9 ± 4.2. The mean ± SD for dietary glycemic and insulinemic indexes were: GI = 58.9 ± 4.4; GL = 152 ± 49; II = 57.4 ± 14.5; IL = 673 ± 267. After adjustment for confounders, no consistent associations were observed between maternal GI, GL, II, and IL and birth outcomes including birth weight, macrosomia, gestational age, and postterm births. Similarly, no association was observed with BMI and waist circumference z scores and childhood obesity (general and central) at 5-y follow-up. There was no evidence of a nonlinear relation between the studied indexes and outcomes. CONCLUSIONS: We observed no clear relation between maternal GI, GL, II, and IL and offspring birth outcomes and childhood obesity in a general pregnant population.

Systematic review of drug bioavailability following gastrointestinal surgery.

PURPOSE: Inter- and intraindividual pharmacokinetics variability in humans affects the way in which drugs act on the body. Gastrointestinal surgery has an impact on this variability and significantly alters the kinetics of drugs in post-surgical patients. The way in which pharmacokinetic profiles are modified depends on the type of operative procedure performed. The extent to which the absorption of different groups of drugs is affected varies according to the site and length of intestinal resections. METHODS: A literature search was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. Three databases were searched: MEDLINE, Embase, and the Cochrane Library. For each drug, potential changes in absorption were described, including recommendations extracted from the results of the studies and collected according to authors' criteria as practical conclusions, and grades of recommendation were determined by levels of evidence using the Oxford Centre for Evidence-Based Medicine scale. RESULTS: Sixty-eight articles were collected during the selection process after the bibliographic search. The main outcomes for 60 drugs from the various studies were classified according to each type of surgery. CONCLUSIONS: Modifications in the digestive tract secondary to gastrointestinal surgery may compromise the bioavailability of drugs. Decreased absorption surface, gastric emptying speed, and gastric pH alteration are factors to be taken into account in the management of pharmacological treatment after surgery. Evidence supported by data in clinical practice is scarce, but after studying the pharmacokinetic profile of some molecules, it is possible to offer recommendations for its adaptation to the patient's clinical situation.