Miracle-dz/UniFAR-FTUs huggingface dataset:
Control of inflammation by stromal Hedgehog pathway activation restrains colitis

Significance Inflammatory bowel disease (IBD) is a debilitating disorder with limited treatment options. Here, we report that manipulation of Hedgehog (Hh) pathway signaling affects disease severity in the well-established dextran sulfate mouse model of colitis. Genetic and pharmacologic manipulations that decrease Hh pathway signaling in the colon worsen colitis. Conversely, manipulations that increase Hh pathway signaling ameliorate colitis. We find that Hh pathway stimulation exerts its effects partially through increased expression of the antiinflammatory cytokine IL-10 in Hh pathway-responsive stromal cells and concomitant increases in CD4+Foxp3+ regulatory T cells in the colon. Our studies suggest that pharmacologic Hh pathway stimulation in colonic stromal cells may be a strategy to treat IBD. Inflammation disrupts tissue architecture and function, thereby contributing to the pathogenesis of diverse diseases; the signals that promote or restrict tissue inflammation thus represent potential targets for therapeutic intervention. Here, we report that genetic or pharmacologic Hedgehog pathway inhibition intensifies colon inflammation (colitis) in mice. Conversely, genetic augmentation of Hedgehog response and systemic small-molecule Hedgehog pathway activation potently ameliorate colitis and restrain initiation and progression of colitis-induced adenocarcinoma. Within the colon, the Hedgehog protein signal does not act directly on the epithelium itself, but on underlying stromal cells to induce expression of IL-10, an immune-modulatory cytokine long known to suppress inflammatory intestinal damage. IL-10 function is required for the full protective effect of small-molecule Hedgehog pathway activation in colitis; this pharmacologic augmentation of Hedgehog pathway activity and stromal IL-10 expression are associated with increased presence of CD4+Foxp3+ regulatory T cells. We thus identify stromal cells as cellular coordinators of colon inflammation and suggest their pharmacologic manipulation as a potential means to treat colitis.
Quality and efficiency of statin prescribing across countries with a special focus on South Africa; findings and future implications

Introduction: Statins are recommended first-line treatment for hyperlipidemia, with published studies suggesting limited differences between them. However, there are reports of under-dosing. South Africa has introduced measures to enhance generic utilization. Part one documents prescribed doses of statins in 2011. Part two determines the extent of generics versus originator and single-sourced statins in 2011 and their costs. Results: Underdosing of simvastatin in 2011 with average prescribed dose of 23.7 mg; however, not for atorvastatin (20.91 mg) or rosuvastatin (15.02 mg). High utilization of generics versus originators at 93–99% for atorvastatin and simvastatin, with limited utilization of single-sourced statins (22% of total statins – defined daily dose basis), mirroring Netherlands, Sweden and UK. Generics priced 33–51% below originator prices. Discussion: Opportunity to increase simvastatin dosing through education, prescribing targets and incentives. Opportunity to lower generic prices with generic simvastatin 96–98% below single-sourced prices in some European countries.
Effect of hypoenergetic feeding on muscle oxidative phosphorylation and mitochondrial complex I-IV activities in rats.

BACKGROUND Previous studies showed that malnutrition reduces the activity of complexes I, II, and III in the mitochondria of skeletal muscle. OBJECTIVE We hypothesized that malnutrition would influence oxidative phosphorylation and mitochondrial complex activity in the skeletal muscle of rats. DESIGN Thirty-two rats were assigned either to a control group with an ad libitum intake of 364 kJ/d or to a hypoenergetic group with an intake of 92 kJ/d. Eleven of these rats received the hypoenergetic diet for 10 d, 2 for 5 d, 2 for 6 d, 2 for 7 d, and 1 each for 8 and 11 d to achieve a distributed weight loss. Ten controls were fed for 10 d, 2 for 7 d, and 1 for 5 d, to match day 10, day 5, and the midpoint (day 7) of 6-8 d of hypoenergetic feeding. The 2 diets provided the same volume, electrolytes, vitamins, and trace elements but different amounts of energy. RESULTS A significant relation was observed between weight loss and the state 4 and 3 oxidation rates with pyruvate + malate and for state 3 glutamate + malate and succinate + rotenone but not with tetramethyl-p-phenylenediamine + ascorbate + antimycin A (TMPD). Similarly, a significant relation was observed between the degree of weight loss and complex I and III activities but not with complex II and IV activities. CONCLUSIONS The complex activities of the mitochondrial oxidative phosphorylation chain in muscle were depressed selectively with energy deprivation when compared with normally fed rats. These findings may partly explain the mechanism of reduced muscle energetics in energy malnutrition.
Plasma carotenoids, retinol, and tocopherols and the risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition study.

BACKGROUND Previous studies suggest that high plasma concentrations of carotenoids, retinol, or tocopherols may reduce the risk of prostate cancer. OBJECTIVE We aimed to examine the associations between plasma concentrations of 7 carotenoids, retinol, alpha-tocopherol, and gamma-tocopherol and prostate cancer risk. DESIGN A total of 137,001 men in 8 European countries participated. After a mean of 6 y, 966 incident cases of prostate cancer with plasma were available. A total of 1064 control subjects were selected and were matched for study center, age, and date of recruitment. The relative risk of prostate cancer was estimated by conditional logistic regression, which was adjusted for smoking status, alcohol intake, body mass index, marital status, physical activity, and education level. RESULTS Overall, none of the micronutrients examined were significantly associated with prostate cancer risk. For lycopene and the sum of carotenoids, there was evidence of heterogeneity between the associations with risks of localized and advanced disease. These carotenoids were not associated with the risk of localized disease but were inversely associated with the risk of advanced disease. The risk of advanced disease for men in the highest fifth of plasma concentrations compared with men in the lowest fifth was 0.40 (95% CI: 0.19, 0.88) for lycopene and 0.35 (95% CI: 0.17, 0.78) for the sum of carotenoids. CONCLUSIONS We observed no associations between plasma concentrations of carotenoids, retinol, or tocopherols and overall prostate cancer risk. The inverse associations of lycopene and the sum of carotenoids with the risk of advanced disease may involve a protective effect, an association of dietary choice with delayed detection of prostate cancer, reverse causality, or other factors.
Association of PTEN and Cyclin D1 expression with GH3 tumor cell proliferation and apoptosis in pituitary

Objective: To investigate the relationship between the expression of PTEN and Cyclin D1 in pituitary tumors and the proliferation and apoptosis of pituitary tumor cells. Methods: The pGPU6-GFP-Neo-PTEN/Cyclin D1 vector was constructed with pGPU6-GFP-Neo as the vector, and the low expression of PTEN and high expression of Cyclin D1 were established. MTT assay and soft agar colony formation assay were used to detect the growth curve change and clonogenic ability. Western blot was used to detect inhibition of PTEN and Cyclin D1 and its relationship with Cyclin D1, CDK4, CDK2 and Cyclin E expression. Results: Compared with the low PTEN expression group, the cell growth ability of the high PTEN expression group was significantly lower (p<0.05). The clonogenic ability significantly decreased with high expression of PTEN (p<0.01). The expression of Cyclin D1, CDK4, CDK2 and Cyclin E also significantly increased (p<0.01). Conclusion: PTEN and Cyclin D1 play important roles in the proliferation of pituitary tumor cells through up-regulation of cell cycle-associated protein Cyclin D1, CDK4, CDK2 and Cyclin E.
BAC library construction, screening and clone sequencing of lake whitefish (Coregonus clupeaformis, Salmonidae) towards the elucidation of adaptive species divergence

Genomic DNA sequences and other genomic resources are essential towards the elucidation of the genomic bases of adaptive divergence and reproductive isolation. Here, we describe the construction, characterization and screening of a nonarrayed BAC library for lake whitefish (Coregonus clupeaformis). We then show how the combined use of BAC library screening and next‐generation sequencing can lead to efficient full‐length assembly of candidate genes. The lake whitefish BAC library consists of 181 050 clones derived from a single heterozygous fish. The mean insert size is 92 Kb, representing 5.2 haploid genome equivalents. Ten BAC clones were isolated following a quantitative real‐time PCR screening approach that targeted five previously identified candidate genes. Sequencing of these clones on a 454 GS FLX system yielded 178 000 reads with a mean length of 358 bp, for a total of 63.8 Mb. De novo assembly and annotation then allowed retrieval of contigs corresponding to each candidate gene, which also contained up‐ and/or downstream noncoding sequences. These results suggest that the lake whitefish BAC library combined with next‐generation sequencing technologies will be key resources to achieve a better understanding of both adaptive divergence and reproductive isolation in lake whitefish species pairs as well as salmonid evolution in general.
Temporal Yield Variability under Conventional and Alternative Management Systems

Year to year variation in yield is an inherent risk associated with crop production and many growers rely on intensive mechanical or chemical inputs to preserve crop yield in the face of fluctuating environmental conditions. However, as interest grows in alternative crop management systems which depend less on external inputs, determining the degree to which management systems can impact the temporal yield variability will help the development of sustainable agroecosystems. This study assessed average crop yields and temporal yield variability over a 12-yr period in four agricultural management systems that are part of a long-term cropping systems experiment at the W.K. Kellogg Biological Station (KBS) Long Term Ecological Research (LTER) site in southwestern Michigan. The four systems follow a corn (Zea mays L.), soybean [Glycine max (L.) Merr. ], and winter wheat (Triticum aestivum L.) 3-yr rotation under conventional (CT), no-till (NT), low-input (LI), or organic (ORG) management, and each crop phase was present in the rotation four times from 1993 to 2004. Yields were measured each year and crop yield variability was estimated using the coefficient of variation calculated separately for each crop phase. Averaged over the study period, yields in the CT and NT systems were similar across all crop phases of the rotation and of higher magnitude than the LI system only in the winter wheat phase of the rotation. Compared to the other three management systems, yields in the ORG system were lower in the corn and winter wheat phases of the rotation. Yields in the soybean phase were similar across the four management systems. Temporal yield variability differed among management systems and rotation phases and was highest in the ORG system during the soybean (CV = 48%) and winter wheat (CV = 33%) phases of the rotation. Compared to the CT system, yield variability was 40% lower in the LI (corn phase), 33% lower in the NT (soybean phase) and similar in the NT (corn and winter wheat phases) systems. Results of this study suggest that yield and temporal yield variability under alternative management systems such as no-till and low-input can be comparable to that in conventional systems. However, temporal yield variability can be as high or higher in organic cropping systems without external inputs of manure or compost.
Maternal vitamin D intake during pregnancy and early childhood wheezing.

BACKGROUND Maternal intake of vitamin D in pregnancy is a potentially modifiable but understudied risk factor for the development of asthma in children. OBJECTIVE We investigated whether maternal vitamin D intake in pregnancy is associated with decreased risks of wheezing symptoms in young children. DESIGN Subjects were from a birth cohort recruited in utero with the primary objective of identifying associations between maternal diet during pregnancy and asthma and allergies in children. A random sample of 2000 healthy pregnant women was recruited while attending antenatal clinics at the Aberdeen Maternity Hospital, Scotland, at approximately 12 wk gestation. Maternal vitamin D intake was ascertained from a food-frequency questionnaire completed at 32 wk of gestation. The main outcome measures were wheezing symptoms, spirometry, bronchodilator response, atopic sensitization, and exhaled nitric oxide at 5 y. RESULTS Respiratory details through 5 y and maternal food-frequency-questionnaire data were available for 1212 children. In models adjusted for potential confounders, including the children's vitamin D intake, a comparison of the highest and lowest quintiles of maternal total vitamin D intake conferred lower risks for ever wheeze [odds ratio (OR): 0.48; 95% CI: 0.25, 0.91], wheeze in the previous year (OR: 0.35; 95% CI: 0.15, 0.83), and persistent wheeze (OR: 0.33; 95% CI: 0.11, 0.98) in 5-y-old children. In addition, lower maternal total vitamin D intakes in pregnancy were also associated with decreased bronchodilator response (P = 0.04). No associations were observed between maternal vitamin D intakes and spirometry or exhaled nitric oxide concentrations. CONCLUSION Increasing maternal vitamin D intakes during pregnancy may decrease the risk of wheeze symptoms in early childhood.
Introducing Mobile Money in Rural Mozambique: Evidence from a Field Experiment

The limitations of access to finance in Africa, together with the recent boom in cell phone use in that continent, created high expectations regarding the introduction of mobile money in many African countries. The success story of M-PESA in Kenya raised the bar further. We designed and conducted a field experiment to assess the impact of randomized mobile money dissemination in rural Mozambique. For this purpose we benefit from the fact that mobile money was only recently launched in the country, allowing for the identification of a pure control group. This paper reports on the first results of this ongoing project after the first wave of dissemination efforts in rural locations, which included the recruitment and training of mobile money agents, community meetings and theaters, as well as individual rural campaigning. Administrative and behavioral data both show clear adherence to the services in the treatment group. Financial literacy and trust outcomes are also positively affected by the treatment. We present behavioral evidence that the marginal willingness to remit was increased by the availability of mobile money. Finally, we observe a tendency for mobile money to substitute traditional alternatives for both savings and remittances. JEL codes: O12, O33, G20, R23
PD‐L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy

Pancreatic ductal adenocarcinoma (PDAC) is considered a non‐immunogenic tumor, and immune checkpoint inhibitor monotherapy lacks efficacy in this disease. Radiotherapy (RT) can stimulate the immune system. Here, we show that treatment of KPC and Pan02 murine PDAC cells with RT and gemcitabine upregulated PD‐L1 expression in a JAK/Stat1‐dependent manner. In vitro, PD‐L1 inhibition did not alter radio‐ and chemosensitivity. In vivo, addition of anti‐PD‐L1 to high (12, 5 × 3, 20 Gy) but not low (6, 5 × 2 Gy) RT doses significantly improved tumor response in KPC and Pan02 allografts. Radiosensitization after PD‐L1 blockade was associated with reduced CD11b+Gr1+ myeloid cell infiltration and enhanced CD45+CD8+ T‐cell infiltration with concomitant upregulation of T‐cell activation markers including CD69, CD44, and FasL, and increased CD8:Treg ratio. Depletion of CD8+ T cells abrogated radiosensitization by anti‐PD‐L1. Blockade of PD‐L1 further augmented the effect of high RT doses (12 Gy) in preventing development of liver metastases. Exploring multiple mathematical models reveals a mechanism able to explain the observed synergy between RT and anti‐PD‐L1 therapy. Our findings provide a rationale for testing the use of immune checkpoint inhibitors with RT in PDAC.
Scale decisions can reverse conclusions on community assembly processes.

AIM Phylogenetic diversity patterns are increasingly being used to better understand the role of ecological and evolutionary processes in community assembly. Here, we quantify how these patterns are influenced by scale choices in terms of spatial and environmental extent and organismic scales. LOCATION European Alps. METHODS We applied 42 sampling strategies differing in their combination of focal scales. For each resulting sub-dataset, we estimated the phylogenetic diversity of the species pools, phylogenetic α-diversities of local communities, and statistics commonly used together with null models in order to infer non-random diversity patterns (i.e. phylogenetic clustering versus over-dispersion). Finally, we studied the effects of scale choices on these measures using regression analyses. RESULTS Scale choices were decisive for revealing signals in diversity patterns. Notably, changes in focal scales sometimes reversed a pattern of over-dispersion into clustering. Organismic scale had a stronger effect than spatial and environmental extent. However, we did not find general rules for the direction of change from over-dispersion to clustering with changing scales. Importantly, these scale issues had only a weak influence when focusing on regional diversity patterns that change along abiotic gradients. MAIN CONCLUSIONS Our results call for caution when combining phylogenetic data with distributional data to study how and why communities differ from random expectations of phylogenetic relatedness. These analyses seem to be robust when the focus is on relating community diversity patterns to variation in habitat conditions, such as abiotic gradients. However, if the focus is on identifying relevant assembly rules for local communities, the uncertainty arising from a certain scale choice can be immense. In the latter case, it becomes necessary to test whether emerging patterns are robust to alternative scale choices.
Bioassay-directed isolation of quaternary benzylisoquinolines from Berberis integerrima with bactericidal activity against Brucella abortus

Berberis integerrima Bonge. (Syn: Berberis densiflora Boiss. & Buhse) is a shrub widely distributed in Middle East and central part of Asia. An ethnobotanical study revealed that indigenous and tribal people in Iran use B. integerrima root decoction for treatment of brucellosis. Therefore, the aim of this study was bioassay directed isolation of antibacterial compounds from this plant based on their in vitro bactericidal activity against Brucella abortus. Briefly, the ethanol extract of B. integerrima was fractioned and subjected to preliminary antibacterial screening tests against Brucella. The more active fraction (Fr.3) was subjected to purification by repeated chromatography systems. Quaternary benzylisoquinoline alkaloids including columbamine, palmatine, berberine, and jatrorhizine were four main components identified in the selected active fraction. Except for berberine which is reported before, palmatine, columbamine and jatrorhizine are isolated for the first time from this plant. Anti-brucellosis properties of isolated compounds 1-4 were studied against B. abortus under different test conditions. In minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) results, jatrorhizine (4) showed more antibacterial activity with MIC and MBC of 0.78 and 1.56 μg/mL, respectively. In both agar well diffusion and disk diffusion ANOVA results showed that there were statistically significant differences between compounds 1-4 versus placebo in all of the tested concentration (P <0.001). In conclusion, all of four alkaloids showed potent antibacterial activity against B. abortus but jatrorhizine and columbamine with free hydroxyl group on C-3 or C-2 showed more activity than palmatine and berberine without any free hydroxyl group on their structures. The antibacterial effects of columbamine (15 μg/mL) and jatrorhizine (15 μg/mL) were comparative to streptomycin (10 μg/mL) as standard drug which candidate them for more pharmacological researches to find new antibacterial agents against brucellosis.
SEXUAL SELECTION AFFECTS THE EVOLUTION OF LIFESPAN AND AGEING IN THE DECORATED CRICKET GRYLLODES SIGILLATUS

Recent work suggests that sexual selection can influence the evolution of ageing and lifespan by shaping the optimal timing and relative costliness of reproductive effort in the sexes. We used inbred lines of the decorated cricket, Gryllodes sigillatus, to estimate the genetic (co)variance between age‐dependent reproductive effort, lifespan, and ageing within and between the sexes. Sexual selection theory predicts that males should die sooner and age more rapidly than females. However, a reversal of this pattern may be favored if reproductive effort increases with age in males but not in females. We found that male calling effort increased with age, whereas female fecundity decreased, and that males lived longer and aged more slowly than females. These divergent life‐history strategies were underpinned by a positive genetic correlation between early‐life reproductive effort and ageing rate in both sexes, although this relationship was stronger in females. Despite these sex differences in life‐history schedules, age‐dependent reproductive effort, lifespan, and ageing exhibited strong positive intersexual genetic correlations. This should, in theory, constrain the independent evolution of these traits in the sexes and may promote intralocus sexual conflict. Our study highlights the importance of sexual selection to the evolution of sex differences in ageing and lifespan in G. sigillatus.