Miracle-dz/UniFAR-FTUs huggingface dataset:
A Systems Biology Approach Identifies Hidden Regulatory Connections Between the Circadian and Cell-Cycle Checkpoints

Circadian rhythms form a self-sustaining, endogenous, time-keeping system that allows organisms to anticipate daily environmental changes. The core of the clock network consists of interlocking transcriptional-translational feedback loops that ensures that metabolic, behavioral, and physiological processes run on a 24 h timescale. The hierarchical nature of the clock manifests itself in multiple points of control on the daily cell division cycle, which relies on synthesis, degradation, and post-translational modification for progression. This relationship is particularly important for understanding the role of clock components in sensing stress conditions and triggering checkpoint signals that stop cell cycle progression. A case in point is the interplay among the circadian factor PERIOD2 (PER2), the tumor suppressor p53, and the oncogenic mouse double minute-2 homolog protein (MDM2), which is the p53’s negative regulator. Under unstressed conditions, PER2 and p53 form a stable complex in the cytosol and, along with MDM2, a trimeric complex in the nucleus. Association of PER2 to the C-terminus end of p53 prevents MDM2-mediated ubiquitylation and degradation of p53 as well as p53’s transcriptional activation. Remarkably, when not bound to p53, PER2 acts as substrate for the E3-ligase activity of MDM2; thus, PER2 is degraded in a phosphorylation-independent fashion. Unexpectedly, the phase relationship between PER2 and p53 are opposite; however, a systematic modeling approach, inferred from the oscillatory time course data of PER2 and p53, aided in identifying additional regulatory scenarios that explained, a priori, seemingly conflicting experimental data. Therefore, we advocate for a combined experimental/mathematical approach to elucidating multilevel regulatory cellular processes.
Computational Modeling on Aquaporin-3 as Skin Cancer Target: A Virtual Screening Study

Aquaporin-3 (AQP3) is one of the aquaglyceroporins, which is expressed in the basolateral layer of the skin membrane. Studies have reported that human skin squamous cell carcinoma overexpresses AQP3 and inhibition of its function may alleviate skin tumorigenesis. In the present study, we have applied a virtual screening method that encompasses filters for physicochemical properties and molecular docking to select potential hit compounds that bind to the Aquaporin-3 protein. Based on molecular docking results, the top 20 hit compounds were analyzed for stability in the binding pocket using unconstrained molecular dynamics simulations and further evaluated for binding free energy. Furthermore, examined the ligand-unbinding pathway of the inhibitor from its bound form to explore possible routes for inhibitor approach to the ligand-binding site. With a good docking score, stability in the binding pocket, and free energy of binding, these hit compounds can be developed as Aquaporin-3 inhibitors in the near future.
ANXA6 Contributes to Radioresistance by Promoting Autophagy via Inhibiting the PI3K/AKT/mTOR Signaling Pathway in Nasopharyngeal Carcinoma

Radiotherapy is a conventional and effective treatment method for nasopharyngeal carcinoma (NPC), although it can fail, mainly because radioresistance results in residual or recurrent tumors. However, the mechanisms and predictive markers of NPC radioresistance are still obscure. In this study, we identified Annexin A6 (ANXA6) as a candidate radioresistance marker by using Tandem Mass Tag quantitative proteomic analysis of NPC cells and gene chip analysis of NPC clinical samples with different radiosensitivities. It was observed that a high expression level of ANXA6 was positively correlated with radioresistance of NPC and that inhibition of ANXA6 by siRNA increased the radiosensitivity. The incidence of autophagy was enhanced in the established radioresistant NPC cells in comparison with their parent cells, and silencing autophagy with LC3 siRNA (siLC3) sensitized NPC cells to irradiation. Furthermore, ANXA6 siRNA (siANXA6) suppressed cellular autophagy by activating the PI3K/AKT/mTOR pathway, ultimately leading to radiosensitization. The combination of siANXA6 and CAL101 (an inhibitor of PI3K, p-AKT, and mTOR, concurrently) significantly reversed the above siANAX6-reduced autophagy. Suppression of PI3K/AKT/mTOR by CAL101 also increased the expression of ANXA6 in a negative feedback process. In conclusion, this study revealed for the first time that ANXA6 could promote autophagy by inhibiting the PI3K/AKT/mTOR pathway and that it thus contributes to radioresistance of NPC. The significance of this is that ANXA6 could be applied as a new predictive biomarker of NPC prognosis after radiotherapy.
Trypanosoma brucei and Trypanosoma cruzi DNA Mismatch Repair Proteins Act Differently in the Response to DNA Damage Caused by Oxidative Stress

MSH2, associated with MSH3 or MSH6, is a central component of the eukaryotic DNA Mismatch Repair (MMR) pathway responsible for the recognition and correction of base mismatches that occur during DNA replication and recombination. Previous studies have shown that MSH2 plays an additional DNA repair role in response to oxidative damage in Trypanosoma cruzi and Trypanosoma brucei. By performing co-immunoprecipitation followed by mass spectrometry with parasites expressing tagged proteins, we confirmed that the parasites' MSH2 forms complexes with MSH3 and MSH6. To investigate the involvement of these two other MMR components in the oxidative stress response, we generated knockout mutants of MSH6 and MSH3 in T. brucei bloodstream forms and MSH6 mutants in T. cruzi epimastigotes. Differently from the phenotype observed with T. cruzi MSH2 knockout epimastigotes, loss of one or two alleles of T. cruzi msh6 resulted in increased susceptibility to H2O2 exposure, besides impaired MMR. In contrast, T. brucei msh6 or msh3 null mutants displayed increased tolerance to MNNG treatment, indicating that MMR is affected, but no difference in the response to H2O2 treatment when compared to wild type cells. Taken together, our results suggest that, while T. cruzi MSH6 and MSH2 are involved with the oxidative stress response in addition to their role as components of the MMR, the DNA repair pathway that deals with oxidative stress damage operates differently in T. brucei.
Myricetin Possesses Anthelmintic Activity and Attenuates Hepatic Fibrosis via Modulating TGFβ1 and Akt Signaling and Shifting Th1/Th2 Balance in Schistosoma japonicum-Infected Mice

Schistosomiasis is a zoonotic and debilitating parasitic disease caused by Schistosoma japonicum. Praziquantel remains the choice for treating schistosomiasis, but its efficacy could be hampered by emergence of resistance. In this study, using large-scale drug screening, we selected out myricetin, a natural flavonol compound, having a good anti-schistosome effect. We found that myricetin exhibited dose and time-dependent insecticidal effect on S. japonicum in vitro, with an LC50 of 600 μM for 24 h, and inhibited female spawning. The drug mainly destroyed the body structure of the worms and induced apoptosis of the worm cells, which in turn led to death. In addition, oral administration of myricetin in mice infected with S. japonicum showed a deworming effect in vivo, as evidenced by a significant reduction in the liver egg load. H&E staining, quantitative RT-PCR, and Western blotting assays showed that myricetin significantly alleviated liver fibrosis in mice infected with S. japonicum. Myricetin also effectively inhibited the expression of TGFβ1, Smad2, phospho-Smad2, Smad3, phospho-Smad3, ERK, phospho-ERK, Akt, and phospho-Akt in the liver of infected mice, suggesting that myricetin attenuated liver fibrosis in mice via modulating TGFβ1 and Akt signaling. Flow cytometric analysis of Th subtypes (Th1/Th2/Th17/Treg) in the mouse spleen further revealed that myricetin significantly increased the percentage Th1 cells in infected mice and reduced the proportion of Th2 cells and Th17 cells. Immunology multiplex assay further showed that myricetin attenuated S. japonicum-induced rise in the plasma levels of IL-4, IL-5, IL-10, IL-13, and IL-17A in infected mice while increasing the plasma contents of IFN-γ, IL-12, and IL-7. In conclusion, our study provides the first direct evidence that myricin possesses potent anti-schistosome activities in vitro and in vivo, and offers new insights into the mechanisms of action by myricetin. The present findings suggest that myricetin could be further explored as a therapeutic agent for S. japonicum.
Effects of Carbon/Nitrogen Ratio on Growth, Intestinal Microbiota and Metabolome of Shrimp (Litopenaeus vannamei)

Increasing the C/N ratio of input feed has been reported as a practical approach for improving water quality and enhancing shrimp growth through changing the bacterial community of rearing water. However, little is known about the effects of different C/N ratios of feed input on the intestinal microbiota and metabolome of shrimp. In the present study, the effects of three different C/N ratio levels (CN6, CN10, and CN15) maintained by adding sucrose on the growth, intestinal microbiota and metabolome of Litopenaeus vannamei, and bioflocs formation were investigated after 17 days of feeding. The results indicated that higher C/N ratio (10 and 15), especially CN15, of feed input significantly enhance the length and weight of shrimp individuals accompanied by a significant accumulation of bioflocs, compared to that of CN6. The increase of C/N ratio input decreased the α-diversity of the intestinal microbiota and changed the microbial community structure through increasing the relative abundance of Actinobacteria, Rhodobacteraceae (mainly consist of Roseobacter and Paracoccus groups), Alteromonadaceae, and inhibiting the growth of Cyanobacteria, certain Rhodobacteraceae, Mycoplasmataceae and Vibrio. The change of microbial community caused by increasing C/N ratio input was closely associated with various bioactive metabolites of flavonoids, benzenoids, prenol lipids, and indole derivatives, which are benefit for shrimp growth either as an antimicrobial agent or as a nutrient component. Overall, this study demonstrated that manipulating high C/N ratio of feed input helps to the growth of shrimp through increasing the relative abundance of potential beneficial bacteria and the accumulation of various bioactive metabolites to suppress the growth of detrimental bacteria.
Comparison of Clinical Characteristics Between Febrile and Afebrile Seizures Associated With Acute Gastroenteritis in Childhood

Background: Acute gastroenteritis (AGE) accompanied by seizures is not a rare scenario in childhood. We investigated the clinical features of children with febrile or afebrile seizures during AGE and aimed to identify the impact of fever in this situation-related seizure. Methods: We retrospectively reviewed the medical charts of children admitted due to seizures associated with mild AGE between January 2008 and December 2017. These consecutive patients were divided into two groups: an “afebrile group” whose diagnosis was compatible with “benign convulsion with mild gastroenteritis (CwG)” and a “febrile group” who had a fever within 24 h of the onset of an AGE-related seizure. We compared the two groups' clinical and laboratory characteristics, electroencephalograms (EEG), neuroimaging, and outcomes. Results: Of the children suffering from AGE and seizures, 41 were afebrile and 30 were febrile, with a mean age of 32.2 ± 27.6 months. The gender, seizure semiology, frequency, duration of seizures, the time interval between AGE symptoms onset and first seizure, and levels of serum sodium, and hepatic enzymes were significantly different between the two groups. The most frequently identified enteropathogen was rotavirus (33%), especially in the male and febrile subjects. Afebrile patients had more EEG abnormalities initially, but all returned to normal later. All cases had an uneventful outcome. Of note, seizure clusters (≥2 episodes) occurred more frequently in the afebrile patients who had a duration of AGE symptoms lasting 2 days or more, or white blood cell counts ≥ 10,000/μL (p-values: 0.05 and 0.04, respectively). In comparison with seven similar studies, all showed more seizure clusters, partial seizures, and a shorter interval between AGE onset and seizures in afebrile patients than in febrile patients. Contrarily, afebrile patients had longer seizure duration and lower serum hepatic transaminases than febrile patients. Conclusion: Although fever partially influenced the clinical features of AGE-related seizures, febrile CwG might have pathophysiology distinctly different from that of febrile seizures. Comprehensive knowledge in discerning febrile and afebrile CwG can help to avoid unnecessary diagnostics tests, and anticonvulsants use.
Pulmonary Resection for Metastasis of Hepatocellular Carcinoma Recurring After Liver Transplant: An Italian Multicenter Experience

Background and aim: Liver transplantation (LT) is a validated treatment for hepatocellular carcinoma (HCC). HCC recurrence occurred between 8 and 20% of patients and lung is the most frequent site. Pulmonary metastases resection (PMR) prolongs survival, however in LT-setting the impact on survival is unclear. To give new lights on this issue, we report the experience of three Italian LT Centers. Methods: All consecutive HCC transplanted patients in three Italian LT Centers, who developed pulmonary metastasis from HCC (PM-HCC), as first metastasis, from 2008 to 2018, were included whenever treated with PMR. Results: Twenty-five patients were enrolled (median age 58 yrs, 84% male, 3% cirrhotics). HCC recurred after 34 months (9–306) since LT and PMR was performed after 2.4 months (0–43.1). A total of 28 PMR (19 single resections; 9 multiple resections; 16 right; 2 left) have been performed on 24 patients while in one case percutaneous microwave ablation (MWA) was preferred. Four patients have been re-operated due to pulmonary HCC-recurrence after surgery. The majority of surgical resection type was wedge resection (26, 89%). Surgical access was: video-assisted thoracic surgery (VATS) in 17 cases (59%); thoracotomy in 11 (38%); MWA in 1 (3%). The 48% of nodule was in right lower lobe. Perioperative in-hospital mortality and 30 days mortality were nil; median surgical time 90 min (50–365); median post-operative overall stay 5 days (2–11). Post-operative ICU treatment was necessary in 1 case (3%) for 3 days; blood transfusions in 2 cases (7%). Overall, 5 complications (2 bleeding; 1 AKI; 1 major cardiac; 1 wound dehiscence) occurred, with an overall complications rate of 23%. Eight (32%) patients died during a follow-up after HCC recurrence of 32 months (7–213): 7 for HCC progression, 1 for severe liver failure due to chronic rejection. The 1 and 5 year cumulative probability of OS from recurrence were 100 and 43% (95%CI 12–74), respectively, with a median OS of 51 months (95%CI 24–78). Conclusion: Selected patients with isolated pulmonary HCC-recurrence after LT and with preserved hepatic function showed that a pulmonary metastasectomy could be efficacious in managing a PM-HCC and could give an opportunity for long-term survival.
Supplemental Clostridium butyricum Modulates Lipid Metabolism Through Shaping Gut Microbiota and Bile Acid Profile of Aged Laying Hens

Probiotic Clostridium butyricum could affect lipid metabolism in broilers. However, it is not clear whether C. butyricum could improve lipid metabolism through shaping gut microbiota and bile acid (BA) profile of laying hens. We aimed to evaluate the contributions of gut microbiota and BA profile to the potential effect of C. butyricum on lipid metabolism of aged laying hens. A total of 192 60-week-old Hy-Line Brown laying hens were divided into two groups (eight replicates per group). Birds were fed a basal diet supplemented with 0 or 2.7 g/kg C. butyricum (1.0 × 109 CFU/g). Samples were collected at the end of week 8 of the experiment. The results showed elevated (P < 0.05) concentrations of glucagon-like peptide 1, insulin and thyroid hormones in serum responded to C. butyricum addition, which also decreased (P < 0.05) hepatic free fatty acids contents, as well as increased (P < 0.05) the expression of hepatic acyl-CoA oxidase, farnesoid X receptor (FXR) and PPARα. C. butyricum addition increased (P < 0.05) Bacteroidetes abundance but tended to decrease (P < 0.10) Firmicutes abundance in the ileum. Besides, C. butyricum addition resulted in higher (P < 0.05) abundances of Clostridia (Clostridiales) and Prevotellaceae, concurrent with an increasing trend (P < 0.10) of Bifidobacteriaceae abundance and decreased the abundances of several harmful bacteria such as Klebsiella (P < 0.05). Regarding ileal BA profile, there was a reduced (P < 0.05) content of tauro-α-muricholic acid, increased (P < 0.05) contents of tauroursodeoxycholic acid and lithocholic acid, along with increasing trends (P < 0.10) of glycochenodeoxycholic acid and hyodeoxycholic acid contents due to C. butyricum addition, which also increased (P < 0.05) ileal FXR expression. Collectively, supplemental C. butyricum accelerated hepatic fatty acid oxidation, and shaped gut microbiota and BA profile, thus reducing fat deposition in the liver of aged laying hens.
Psychophysiological Effects of Downregulating Negative Emotions: Insights From a Meta-Analysis of Healthy Adults

Assessing psychophysiological responses of emotion regulation is a cost-efficient way to quantify emotion regulation and to complement subjective report that may be biased. Previous studies have revealed inconsistent results complicating a sound interpretation of these findings. In the present study, we summarized the existing literature through a systematic search of articles. Meta-analyses were used to evaluate effect sizes of instructed downregulation strategies on common autonomic (electrodermal, respiratory, cardiovascular, and pupillometric) and electromyographic (corrugator activity, emotion-modulated startle) measures. Moderator analyses were conducted, with moderators including study design, emotion induction, control instruction and trial duration. We identified k = 78 studies each contributing multiple sub-samples and performed 23 meta-analyses for combinations of emotion regulation strategy and psychophysiological measure. Overall, results showed that effects of reappraisal and suppression on autonomic measures were highly inconsistent across studies with rather small mean effect sizes. Electromyography (startle and corrugator activity) showed medium effect sizes that were consistent across studies. Our findings highlight the diversity as well as the low level of standardization and comparability of research in this area. Significant moderation of effects by study design, trial duration, and control condition emphasizes the need for better standardization of methods. In addition, the small mean effect sizes resulting from our analyses on autonomic measures should be interpreted with caution. Findings corroborate the importance of multi-channel approaches.
The Biotherapeutic Potential of Lactobacillus reuteri Characterized Using a Target-Specific Selection Process

A growing body of clinical and experimental data supports the view that the efficacy of probiotics is strain-specific and restricted to particular pathological conditions, which means that newly isolated probiotic strains need to be targeted to a specific disease. Following national and international guidelines, we used a conventional in vitro experimental approach to characterize a novel strain of Lactobacillus reuteri, LMG P-27481, for safety (sensitivity to antibiotics and genome analysis) and putative efficacy (resistance to gastro-intestinal transit, adhesiveness, induction of cytokines, and release of antimicrobial metabolites). In vitro assays, which were carried out to examine the probiotic’s effect on diarrhea (lactose utilization, inhibition of pathogens such as bacteria and Rotavirus), showed that it was more efficacious with respect to well-known reference strains in antagonizing Clostridioides difficile (CD). Data confirming that the probiotic can effectively treat CD colitis was gained from in vivo trials involving mice conditioned with large spectrum antibiotics before they were subjected to CD challenge. Two out of the three antibiotic-treated groups received daily LMG P-27481 for different time durations in order to simulate a preventive approach (LMG P-27481 administered prior to CD challenge) or an antagonistic one (LMG P-27481 administered after CD challenge). Both approaches significantly reduced, with respect to the untreated controls, CD DNA concentrations in caecum and C. difficile toxin titers in the gut lumen. In addition, LMG P-27481 supplementation significantly mitigated body weight loss and the extent of inflammatory infiltrate and tissue damage. The study results, which need to be confirmed by in vivo clinical trials, have demonstrated that the L. reuteri LMG P-27481 strain is a promising probiotic candidate for the treatment of CD infection.
Neural Processing Mechanism of Mental Calculation Based on Cerebral Oscillatory Changes: A Comparison Between Abacus Experts and Novices

Background: Abacus experts could mentally calculate fast some mathematical operations using multi-digit numbers. The temporal dynamics of abacus mental calculation are still unknown although some behavioral and neuroimaging studies have suggested a visuospatial and visuomotor neural process during abacus mental calculation. Therefore, this contribution aims to clarify the significant similarities and the differences between experts and novices by investigating calculation-induced neuromagnetic responses based on cerebral oscillatory changes. Methods: Twelve to 13 healthy abacus experts and 17 non-experts participated in two experimental paradigms using non-invasive neuromagnetic measurements. In experiments 1 and 2, the spatial distribution of oscillatory changes presented mental calculations and temporal frequency profiles during addition while examining multiplication tasks. The MEG data were analyzed using synthetic aperture magnetometry (SAM) with an adaptive beamformer to calculate the group average of the spatial distribution of oscillatory changes and their temporal frequency profiles in source-level analyses. Results: Using a group average of the spatial distribution of oscillatory changes, we observed some common brain activities in both right-handed abacus experts and non-experts. In non-experts, we detected the right dorsolateral prefrontal cortex (DLPFC) and bilateral Intraparietal sulcus (IPS); whereas in experts, detected the bilateral parieto-occipital sulcus (POS), right inferior frontal gyrus (IFG), and left sensorimotor areas mainly. Based on the findings generated, we could propose calculation processing models for both abacus experts and non- experts conveniently. Conclusion: The proposed model of calculation processing in abacus experts and novices revealed that the novices could calculate logically depending on numerical processing in the left IPS. In contrast, abacus experts are utilizing spatial processing using a memorized imaginary abacus, which distributed over the bilateral hemispheres in the IFG and sensorimotor areas.