Miracle-dz/UniFAR-FTUs huggingface dataset:
High-fat diet modifies cytokine gene expression and exacerbates the effects of acute pancreatitis in the liver of rats

Abstract Background: Obese patients have a higher risk of developing different metabolic syndromes (MeS), including acute pancreatitis (AP). Although obese individuals are more prone to MeS and more susceptible to local and systemic inflammation in response to AP, thus causing long-lasting hospitalization, higher morbidity and mortality, their underlying mechanisms remain unclear. This study aimed to investigate the relationship between obesity and the outcomes of AP in the rat model of AP. Methods: To assess the link between obesity and AP, 40 male albino rats were divided into two groups: control and those given a high-fat diet for 12 weeks. This was followed by the injection of a single dose of L-arginine (250 mg/100 gm) in half of each group to induce AP. Results: Data evaluation was done using 2-way ANOVA. Values were considered significant when p≤0.05. Markers of AP were evaluated in the serum and ascitic fluid. Moreover, the systemic inflammatory markers, such as IL-6, TNF-α, HMGB1 and TLR4, were quantified in the liver of all groups. Results showed that the OAP group had the highest levels of liver enzymes and amylase aside from several signs of liver damage, such as fat necrosis and steatosis. Conclusions: The inflammatory cytokine levels are synchronized, creating an early responsive stage and late inflammatory stage to realize the best defense mechanism. Results also indicate that obesity is a main determinant of the severity of AP at the late stage.
Shelterin promotes tethering of late replication origins to telomeres for replication‐timing control

DNA replication initiates at many discrete loci on eukaryotic chromosomes, and individual replication origins are regulated under a spatiotemporal program. However, the underlying mechanisms of this regulation remain largely unknown. In the fission yeast Schizosaccharomyces pombe, the telomere‐binding protein Taz1, ortholog of human TRF1/TRF2, regulates a subset of late replication origins by binding to the telomere‐like sequence near the origins. Here, we showed using a lacO/LacI‐GFP system that Taz1‐dependent late origins were predominantly localized at the nuclear periphery throughout interphase, and were localized adjacent to the telomeres in the G1/S phase. The peripheral localization that depended on the nuclear membrane protein Bqt4 was not necessary for telomeric association and replication‐timing control of the replication origins. Interestingly, the shelterin components Rap1 and Poz1 were required for replication‐timing control and telomeric association of Taz1‐dependent late origins, and this requirement was bypassed by a minishelterin Tpz1‐Taz1 fusion protein. Our results suggest that Taz1 suppresses replication initiation through shelterin‐mediated telomeric association of the origins at the onset of S phase.
Efficacy of Prosopilosidine from Prosopis glandulosa var. glandulosa against Cryptococcus neoformans Infection in a Murine Model

In this study, 2,3-dihydro-1H-indolizinium alkaloid-prosopilosidine (PPD), that was isolated from Prosopis glandulosa, was evaluated against C. neoformans in a murine model of cryptococcosis. In vitro and in vivo toxicity of indolizidines were also evaluated. Mice were infected via the tail vein with live C. neoformans. Twenty-four hours post-infection, the mice were treated with PPD once a day (i.p.) or twice a day (bid) orally, or with amphotericin B (Amp B) intraperitoneally (IP), or with fluconazole (Flu) orally for 5 days. The brains of all of the animals were aseptically removed and the numbers of live C. neoformans were recovered. In vitro toxicity of indolizidine alkaloids was determined in HepG2 cells. PPD showed to be potent in vivo activity against C. neoformans at a dose of 0.0625 mg/kg by eliminating ~76% of the organisms compared to ~83% with Amp B (1.5 mg/kg). In addition, PPD was found to be equally efficacious, but less toxic, at either 0.125 or 0.0625 mg/kg compared to Amp B (1.5 mg/kg) when it was administered bid (twice a day) by an i.p. route. When tested by an oral route, PPD (10 mg/kg) showed potent activity in this murine model of cryptococcosis with ~82% of organisms eliminated from the brain tissue, whereas Flu (15 mg/kg) reduced ~90% of the infection. In vitro results suggest that quaternary indolizidines were less toxic as compared to those of tertiary bases. PPD (20 mg/kg) did not cause any alteration in the plasma chemistry profiles. These results indicated that PPD was active in eliminating cryptococcal infection by oral and i.p. routes at lower doses compared to Amp B. or Flu.
Triglyceride‐rich very low‐density lipoproteins (VLDL) are independently associated with insulin secretion in a multiethnic cohort of adolescents

Excess insulin secretion and hyperinsulinaemia contribute to the progression of type 2 diabetes. However, the mechanisms leading to insulin hypersecretion remain largely unknown. Based on our preliminary data, we examined whether triglycerides and very low‐density lipoprotein (VLDL) are independently associated with insulin secretion, and whether ethnicity/race modulates these associations. Fasting triglycerides and VLDL were measured in a multiethnic cohort of 630 non‐diabetic adolescents. Insulin secretion, β‐cell function parameters, insulin sensitivity and insulin clearance were estimated through a 3‐h oral glucose tolerance test. Metabolic assessments were repeated after 2 years in 239 subjects. Triglycerides and triglyceride‐rich VLDL (large and medium size fractions) were associated with both basal and glucose‐stimulated insulin secretion, after adjustment for age, sex, ethnicity, BMI z‐score, plasma glucose, and insulin sensitivity. Ethnicity per se had an impact on lipid profile and β‐cell function, but did not modulate the effect of triglycerides/VLDL on insulin secretion. At follow‐up, changes in triglyceride levels were proportional to changes in insulin secretion. These findings support the hypothesis that hypertriglyceridaemia is an important stimulus for β‐cell insulin release in young people under both fasting and fed conditions.
The Nitrogen Heterocycle Content of Meteorites and Their Significance for the Origin of Life

Carbonaceous chondrites are very primitive meteorites that are rich in carbon. They contain many soluble organic compounds, including nitrogen heterocycles. These play a crucial role in present-day living organisms as they are components of the genetic material and of the co-factors of enzymes. This review outlines the nitrogen heterocycle content of carbonaceous meteorites. The potential mechanisms of formation of these molecules are also described. Measurements of the compound-specific carbon and hydrogen isotopic compositions are mentioned as a way of establishing the origin of the nitrogen heterocycles detected in meteorites.
Maternal Support as a Predictor of Children’s Sexualized Behaviors Following Childhood Sexual Abuse

Although previous studies have concluded that maternal support following children’s sexual abuse disclosures is an important predictor of children’s symptoms, the empirical data to support this is limited. Much of the small prior literature has used measures of maternal support without adequately reported psychometric properties, which may obscure the true relationship between support and children’s sexual behaviors. Further, it is unclear whether maternal support is related to children’s sexual acting out in the context of known predictors of sexual behaviors. The purposes of the current study were to (1) examine the relationships between support and children’s sexual behaviors and (2) determine whether support is related to sexual behaviors after controlling for known predictors among 161 treatment-seeking children (6–12 years old; M = 8.70, SD = 2.69) and their nonoffending mothers. In the bivariate analyses, emotional support was negatively related to children’s sexual behaviors, whereas maternal blame/doubt was positively correlated with sexual behaviors. Nonetheless, after controlling for other predictors, emotional support predicted developmentally related sexual behaviors but not sexual abuse–specific sexual behaviors. Levels of emotional support and blame/doubt predicted children’s total sexual behaviors, after accounting for identified predictors, suggesting that support may play a small role in understanding children’s sexual behaviors.
CYP3A4*22 Impairs the Elimination of Ticagrelor, But Has No Significant Effect on the Bioactivation of Clopidogrel or Prasugrel

CYP3A enzymes participate in the elimination of ticagrelor and the bioactivation of clopidogrel and prasugrel. We studied the effects of functional CYP3A genetic variants (CYP3A4*22; rs35599367 and CYP3A5*3; rs776746) on the pharmacokinetics and pharmacodynamics of ticagrelor, clopidogrel, and prasugrel. Six healthy volunteers with the CYP3A4*1/*22 and CYP3A5*3/*3 genotype (CYP3A4*22 carriers), eight with the CYP3A4*1/*1 and CYP3A5*1/*3 genotype (CYP3A5 expressors), and 11–13 with the CYP3A4*1/*1 and CYP3A5*3/*3 genotypes (controls) ingested single doses of ticagrelor, clopidogrel, and prasugrel on separate occasions. Ticagrelor area under the plasma concentration‐time curve (AUC) was 89% (P = 0.004) higher in CYP3A4*22 carriers than in controls. CYP3A4*22 carriers also showed more pronounced platelet inhibition at 24 hours after ticagrelor ingestion than the controls (43% vs. 21%; P = 0.029). The CYP3A5 genotype did not affect ticagrelor pharmacokinetics. Neither CYP3A5 nor CYP3A4 genotypes significantly affected prasugrel or clopidogrel. In conclusion, the CYP3A4*22 allele markedly impairs ticagrelor elimination enhancing its antiplatelet effect.
Targeting mitochondria by anthelmintic drug atovaquone sensitizes renal cell carcinoma to chemotherapy and immunotherapy

Targeting mitochondria respiration is an effective therapeutic strategy in renal cell carcinoma (RCC). Atovaquone is a FDA‐approved antibiotic but is also known as a mitochondrial inhibitor. We found that atovaquone inhibited proliferation and induced apoptosis of RCC cells. Mechanistically, atovaquone inhibits mitochondrial respiration in a concentration‐dependent and time‐dependent manner, via targeting mitochondrial respiratory complex III. Although increased glycolysis was observed in atovaquone‐treated cells, atovaquone decreased ATP levels. As a consequence of mitochondrial respiration inhibition, reactive oxygen species levels were increased by atovaquone. The complete rescue of atovaquone's effects by an antioxidant suggests the important role of oxidative stress in the action of atovaquone in RCC. Importantly, atovaquone enhanced the in vitro and in vivo efficacy of 5‐fluorouracil (5‐FU) and interferon‐α (IFN‐α). Our preclinical findings suggest that atovaquone is a useful addition for RCC treatment. Our work also further demonstrates that RCC is more dependent on mitochondrial respiration than glycolysis.
Long‐term histological changes in the macaque primary visual cortex and the lateral geniculate nucleus after monocular deprivation produced by early restricted retinal lesions and diffuser induced form deprivation

Ocular dominance (OD) plasticity has been extensively studied in various mammalian species. While robust OD shifts are typically observed after monocular eyelid suture, relatively poor OD plasticity is observed for early eye removal or after tetrodotoxin (TTX) injections in mice. Hence, abnormal binocular signal interactions in the visual cortex may play a critical role in eliciting OD plasticity. Here, we examined the histochemical changes in the lateral geniculate nucleus (LGN) and the striate cortex (V1) in macaque monkeys that experienced two different monocular sensory deprivations in the same eye beginning at 3 weeks of age: restricted laser lesions in macular or peripheral retina and form deprivation induced by wearing a diffuser lens during the critical period. The monkeys were subsequently reared for 5 years under a normal visual environment. In the LGN, atrophy of neurons and a dramatic increase of GFAP expression were observed in the lesion projection zones (LPZs). In V1, although no obvious shift of the LPZ border was found, the ocular dominance columns (ODCs) for the lesioned eye shrunk and those for the intact eye expanded over the entirety of V1. This ODC size change was larger in the area outside the LPZ and in the region inside the LPZ near the border compared to that in the LPZ center. These developmental changes may reflect abnormal binocular interactions in V1 during early infancy. Our observations provide insights into the nature of degenerative and plastic changes in the LGN and V1 following early chronic monocular sensory deprivations.
Targeting of the Cholecystokinin-2 Receptor with the Minigastrin Analog 177Lu-DOTA-PP-F11N: Does the Use of Protease Inhibitors Further Improve In Vivo Distribution?

Patients with metastatic medullary thyroid cancer (MTC) have limited systemic treatment options. The use of radiolabeled gastrin analogs targeting the cholecystokinin-2 receptor (CCK2R) is an attractive approach. However, their therapeutic efficacy is presumably decreased by their enzymatic degradation in vivo. We aimed to investigate whether the chemically stabilized analog 177Lu-DOTA-PP-F11N (177Lu-DOTA-(dGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) performs better than reference analogs with varying in vivo stability, namely 177Lu-DOTA-MG11 (177Lu-DOTA-dGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) and 177Lu-DOTA-PP-F11 (177Lu-DOTA-(dGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2), and whether the use of protease inhibitors further improves CCKR2 targeting. First human data on 177Lu-DOTA-PP-F11N are also reported. Methods: In vitro stability of all analogs was assessed against a panel of extra- and intracellular endoproteases, whereas their in vitro evaluation was performed using the human MTC MZ-CRC-1 and the transfected A431-CCK2R(+) cell lines. Biodistribution without and with the protease inhibitors phosphoramidon and thiorphan was assessed 4 h after injection in MZ-CRC-1 and A431-CCK2R(+) dual xenografts. Autoradiography of 177Lu-DOTA-PP-F11N (without and with phosphoramidon) and NanoSPECT/CT were performed. SPECT/CT images of 177Lu-DOTA-PP-F11N in a metastatic MTC patient were also acquired. Results: natLu-DOTA-PP-F11N is less of a substrate for neprilysins than the other analogs, whereas intracellular cysteine proteases, such as cathepsin-L, might be involved in the degradation of gastrin analogs. The uptake of all radiotracers was higher in MZ-CRC-1 tumors than in A431-CCK2R(+), apparently because of the higher number of binding sites on MZ-CRC-1 cells. 177Lu-DOTA-PP-F11N had the same biodistribution as 177Lu-DOTA-PP-F11; however, uptake in the MZ-CRC-1 tumors was almost double (20.7 ± 1.71 vs. 11.2 ± 2.94 %IA [percentage injected activity]/g, P = 0.0002). Coadministration of phosphoramidon or thiorphan increases 177Lu-DOTA-MG11 uptake significantly in the CCK2R(+) tumors and stomach. Less profound was the effect on 177Lu-DOTA-PP-F11, whereas no influence or even reduction was observed for 177Lu-DOTA-PP-F11N (20.7 ± 1.71 vs. 15.6 ± 3.80 [with phosphoramidon] %IA/g, P < 0.05 in MZ-CRC-1 tumors). The first clinical data show high 177Lu-DOTA-PP-F11N accumulation in tumors, stomach, kidneys, and colon. Conclusion: The performance of 177Lu-DOTA-PP-F11N without protease inhibitors is as good as the performance of 177Lu-DOTA-MG11 in the presence of inhibitors. The human application of single compounds without unessential additives is preferable. Preliminary clinical data spotlight the stomach as a potential dose-limiting organ besides the kidneys.
Association of Second Allogeneic Hematopoietic Cell Transplant vs Donor Lymphocyte Infusion With Overall Survival in Patients With Acute Myeloid Leukemia Relapse

Importance The optimal treatment approach to patients with acute myeloid leukemia (AML) who relapse after an allogeneic hematopoietic cell transplant (allo-HCT) remains elusive. No randomized clinical trial comparing survival outcomes of a second allo-HCT (allo-HCT2) vs donor lymphocyte infusion (DLI) has been conducted to date. Objective To compare overall survival (OS) after an allo-HCT2 or DLI in relapsed AML after a first allo-HCT. Design, Setting, and Participants A retrospective registry study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation involving 418 adults who received an allo-HCT2 (n = 137) or DLI (n = 281) for postallograft-relapsed AML. Analysis was assessed on the principle of intent-to-first received intervention. The data were collected from November 21, 2015, to May 15, 2017, and analysis was performed June 1, 2017. Main Outcomes and Measures Number of patients with relapsed AML who are alive after 2 years and 5 years from receiving an allo-HCT2 or DLI. Results Of the 418 patients, 228 (54.5%) were men; mean age was 46.2 years (interquartile range, 36.5-56.9 years). There was no apparent difference in OS whether an allo-HCT2 or DLI was prescribed (2-year OS with allo-HCT2, 26%; 5-year OS with allo-HCT2, 19%; 2-year OS with DLI, 25%; 5-year OS with DLI, 15%; P = .86). Overall survival was better if either of these procedures was offered when the patient was in complete remission (hazard ratio, 0.55; 95% CI, 0.41-0.74; P < .001). Conversely, OS was low for patients relapsing within less than 6 months after an allo-HCT1, regardless of the treatment prescribed (5-year OS: allo-HCT2, 9%; 95% CI, 1%-17% vs DLI, 4%; 95% CI, 1%-8%; P = .86). Conclusion and Relevance Heterogeneity of the patient-, disease-, and treatment-related characteristics limit the ability to recommend one approach over another. Findings of this study highlight that best outcomes seem to be achieved in patients relapsing 6 or more months from an allo-HCT1 or those in complete remission at the time of either allo-HCT2 or DLI.
Expansion of hedgehog disrupts mesenchymal identity and induces emphysema phenotype

GWAS have repeatedly mapped susceptibility loci for emphysema to genes that modify hedgehog signaling, but the functional relevance of hedgehog signaling to this morbid disease remains unclear. In the current study, we identified a broad population of mesenchymal cells in the adult murine lung receptive to hedgehog signaling, characterized by higher activation of hedgehog surrounding the proximal airway relative to the distal alveoli. Single-cell RNA-sequencing showed that the hedgehog-receptive mesenchyme is composed of mostly fibroblasts with distinct proximal and distal subsets with discrete identities. Ectopic hedgehog activation in the distal fibroblasts promoted expression of proximal fibroblast markers and loss of distal alveoli and airspace enlargement of over 20% compared with controls. We found that hedgehog suppressed mesenchymal-derived mitogens enriched in distal fibroblasts that regulate alveolar stem cell regeneration and airspace size. Finally, single-cell analysis of the human lung mesenchyme showed that segregated proximal-distal identity with preferential hedgehog activation in the proximal fibroblasts was conserved between mice and humans. In conclusion, we showed that differential hedgehog activation segregates mesenchymal identities of distinct fibroblast subsets and that disruption of fibroblast identity can alter the alveolar stem cell niche, leading to emphysematous changes in the murine lung.
Selection of treatment modalities for hepatocellular carcinoma at stages T1 and T2: A preliminary analysis based on the Surveillance, Epidemiology, and End Results registry database.

PURPOSE To explore the selection of treatment modalities for hepatocellular carcinoma (HCC) at stages T1 and/or T2 and to compare the survival of patients treated with surgery alone vs radiation therapy (RT) alone. METHODS Surveillance, Epidemiology, and End Results (SEER) database was used to identify the patients diagnosed with HCC between 2004 and 2013. The tumor-nodemetastasis (TNM) stage was established according to the American Joint Committee on Cancer (AJCC) Staging. After age, sex, TNM stage, and tumor extension were matched, the survival was further compared between patients undergoing surgery alone vs RT alone. RESULTS Of 11967 patients at stages T1 (n=7829) and T2 (n=4138), 10449 (87.31%) underwent surgery alone, 1241 (10.37%) RT alone, and 277 (2.32%) surgery combined with RT. Compared with those treated with RT alone and in combination with surgery, patients treated with surgery alone were younger, with smaller tumor size, higher proportion of females, single lesion, and AJCC stage I/II, and lower proportion of regional and distant lymph nodes, bone, brain, and lung invasion. Among them, 758 pairs (surgery alone and RT alone) at stage T1 and 430 pairs (surgery alone and RT alone) at stage T2 were matched. Regardless of stage T1 or T2, patients undergoing surgery alone had a significantly better cumulative survival than those undergoing RT alone (p<0.001). CONCLUSION The treatment selection of HCC was dependent on the age, sex, tumor size, number of lesions, and extrahepatic invasion. Surgery alone should be the preferred treatment modality of HCC at stages T1 and T2.
Mood impedes monitoring of emotional false memories: evidence for the associative theories

ABSTRACT In the present experiment, we investigated whether warnings provided at the time of retrieval would reduce emotional false memories in the Deese-Roediger-McDermott (DRM) paradigm. The provision of retrieval warnings allowed us to test specific predictions based on the associative theories (e.g., Activation-Monitoring Theory; AMT) and Fuzzy-Trace Theory (FTT) that have been used to account for false memories in the DRM paradigm. Participants were randomly assigned to either a no-warning group or a retrieval-warning group. In each group, mood-induction procedures were used to elicit a positive, negative, or neutral mood and participants were then presented with word lists comprised of positive, negative, or neutral words. Retrieval warnings reduced false recognition, regardless of the valence of the to-be-remembered information or participants’ mood. Consistent with the associative theories’ predictions, within the warning condition, positive moods yielded greater false recognition for positive critical lures, and negative moods yielded greater false recognition for negative critical lures, compared to neutral moods. These findings have important practical implications for our understanding of the effect of mood on memory.
Locus of control as a modifiable risk factor for cognitive function in midlife

Few modifiable risk factors for cognitive decline have been identified. Despite an external locus of control (LoC) being adversely associated with many psychological and physical health outcomes, few studies have examined whether it is related to cognitive function in adulthood. In 1178 women from the Avon Longitudinal Study of Parents and Children, we examined whether LoC, and change in LoC over time, is associated with cognitive function in midlife. LoC was prospectively measured at mean ages 30 and 48 years using the validated Nowicki-Strickland scale. Cognitive function was examined at mean age 51 years. At both time points, greater externality was associated with lower cognitive function. For example, the group of women classified as being external at mean age 48 years had, on average, a 0.18 lower cognitive function score (95% CI: (0.11 to 0.25) than the group classified as being internal (p<0.001). Participants who changed from external to internal over time, on average, had better cognitive function than those who remained external or changed to become external. In summary, an external LoC may be detrimental to cognitive function. Thus, interventions to increase internality may help to minimise the adverse consequences on cognitive health later in life.