Miracle-dz/UniFAR-FTUs huggingface dataset:
LPCAT2 controls chemoresistance in colorectal cancer

ABSTRACT Lipid droplets (LD) are now-well recognized as playing a role in cancer progression, however their potential role in chemoresistance remains largely unknown, particularly in colorectal cancer (CRC). We recently highlighted that LD accumulate in CRC cells under the control of lysophosphatidylcholine acyltransferase 2 (LPCAT2) enzyme expression. We also showed that chemotherapy-induced LD accumulation counteracts intrinsic and extrinsic cancer cell death activation.
Coriolus versicolor biomass increases dendritic arborization of newly-generated neurons in mouse hippocampal dentate gyrus

Brain cognitive reserve refers to the ability of the brain to manage different challenges that arise throughout life, making it resilient to neuropathology. Hippocampal adult neurogenesis has been considered to be a relevant contributor for brain cognitive reserve and brain plasticity. Coriolus versicolor (CV), a common healthful mushroom, has been receiving increasing attention by its antitumoral, anti-inflammatory, antioxidant, antibacterial, and immunomodulatory properties, including in the hippocampus. Herein, we evaluated whether CV biomass oral administration for 2.5 months enhances hippocampal neurogenic reserve under normal/physiological conditions, by quantifying hippocampal dentate gyrus (DG) granular cell layer (GCL) and subgranular zone (SGZ) volumes, proliferation, number and dendritic complexity features of hippocampal newly-generated neurons. We also analyzed β-catenin levels in DG newly-generated immature neurons, because it plays a major role in neurogenesis. Although no differences were observed in the volume of GCL and SGZ layers, in proliferation and in the number of newly-generated neurons of controls and CV-administered mice, we found that CV administration promotes a significant increase in dendritic length and branching and total dendritic volume of immature neurons, suggesting a positive effect of oral CV administration in the hippocampal neurogenic reserve. We also observed that β-catenin levels are increased both in the nucleus and cytoplasm of DG immature neurons, suggesting that Wnt/β-catenin signalling may play an important role in the CV positive effect on the differentiation of these cells. These data unveil a so far unexplored neurogenic potential of CV supplementation, which emerges as a possible preventive strategy for different neurological conditions.
In vitro molecular study of wound healing using biosynthesized bacteria nanocellulose/silver nanocomposite assisted by bioinformatics databases

Background In recent years, bacterial nanocellulose (BNC) based nanocomposites have been developed to promote healing property and antibacterial activity of BNC wound dressing. Molecular study can help to better understanding about interaction of genes and pathways involved in healing progression. Objectives The aim of this study was to prepare bacterial nanocellulose/silver (BNC/Ag) nanocomposite films as ecofriendly wound dressing in order to assess their physical, cytotoxicity and antimicrobial properties. The in vitro molecular study was performed to evaluate expression of genes involved in healing of wounds after treatment with BNC/Ag biofilms. Study design, materials, and methods Silver nanoparticles were formed by using Citrullus colocynthis extract within new isolated bacterial nanocellulose (BNC) RM1. The nanocomposites were characterized using X-ray diffraction, Fourier transform infrared, and field emission scanning electron microscopy. Besides, swelling property and Ag release profile of the nanocomposites were studied. The ability of nanocomposites to promote wound healing of human dermal fibroblast cells in vitro was studied. Bioinformatics databases were used to identify genes with important healing effect. Key genes which interfered with healing were studied by quantitative real time PCR. Results Spherical silver nanoparticles with particle size ranging from 20 to 50 nm were synthesized and impregnated within the structure of BNC. The resulting nanocomposites showed significant antibacterial activities with inhibition zones ranging from 7±0.25 to 16.24±0.09 mm against skin pathogenic bacteria. Moreover, it was compatible with human fibroblast cells (HDF) and could promote in vitro wound healing after 48h. Based on bioinformatics databases, the genes of TGF-β1, MMP2, MMP9, CTNNB1, Wnt4, hsa-miR-29b-3p and hsa-miR-29c-3p played important role in wound healing. The nanocomposites had an effect in expression of the genes in healing. Thus, the BNC/Ag nanocomposite can be used to heal wound in a short period and simple manner. Conclusion This eco-friendly nanocomposite with excellent antibacterial activities and healing property confirming its utility as potential wound dressings.
Differentiation of Sendai Virus-Reprogrammed iPSC into β Cells, Compared with Human Pancreatic Islets and Immortalized β Cell Line

Background: New sources of insulin-secreting cells are strongly in demand for treatment of diabetes. Induced pluripotent stem cells (iPSCs) have the potential to generate insulin-producing cells (iβ). However, the gene expression profile and secretory function of iβ still need to be validated in comparison with native β cells. Methods: Two clones of human iPSCs, reprogrammed from adult fibroblasts through integration-free Sendai virus, were differentiated into iβ and compared with donor pancreatic islets and EndoC-βH1, an immortalized human β cell line. Results: Both clones of iPSCs differentiated into insulin+ cells with high efficiency (up to 20%). iβ were negative for pluripotency markers (Oct4, Sox2, Ssea4) and positive for Pdx1, Nkx6.1, Chromogranin A, PC1/3, insulin, glucagon and somatostatin. iβ basally secreted C-peptide, glucagon and ghrelin and released insulin in response either to increasing concentration of glucose or a depolarizing stimulus. The comparison revealed that iβ are remarkably similar to donor derived islets in terms of gene and protein expression profile and similar level of heterogeneity. The ability of iβ to respond to glucose instead was more related to that of EndoC-βH1. Discussion: We demonstrated that insulin-producing cells generated from iPSCs recapitulate fundamental gene expression profiles and secretory function of native human β cells.
Anatomical and microstructural determinants of hippocampal subfield functional connectome embedding

Significance Despite the progress made by postmortem cytoarchitectonic analyses and animal electrophysiology in studying the structure and function of the hippocampal circuitry, complex anatomical challenges have prevented a detailed understanding of its substructural organization in living humans. By integrating high-resolution structural and resting-state functional neuroimaging, we demonstrate two main axes of substructural organization in the human hippocampus: one that respects its long axis and a second that follows patterns of hippocampal infolding and significantly correlates with an intracortical microstructure. Given the importance of the hippocampus for cognition, affect, and disease, our results provide an integrated hippocampal coordinate system that is relevant to cognitive neuroscience, clinical neuroimaging, and network neuroscience. The hippocampus plays key roles in cognition and affect and serves as a model system for structure/function studies in animals. So far, its complex anatomy has challenged investigations targeting its substructural organization in humans. State-of-the-art MRI offers the resolution and versatility to identify hippocampal subfields, assess its microstructure, and study topographical principles of its connectivity in vivo. We developed an approach to unfold the human hippocampus and examine spatial variations of intrinsic functional connectivity in a large cohort of healthy adults. In addition to mapping common and unique connections across subfields, we identified two main axes of subregional connectivity transitions. An anterior/posterior gradient followed long-axis landmarks and metaanalytical findings from task-based functional MRI, while a medial/lateral gradient followed hippocampal infolding and correlated with proxies of cortical myelin. Findings were consistent in an independent sample and highly stable across resting-state scans. Our results provide robust evidence for long-axis specialization in the resting human hippocampus and suggest an intriguing interplay between connectivity and microstructure.
Correlation between DCE-MRI radiomics features and Ki-67 expression in invasive breast cancer

The aim of the present study was to investigate the association between Ki-67 expression and radiomics features of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with invasive breast cancer. A total of 53 cases with low-Ki-67 expression (Ki-67 proliferation index <14%) and 106 cases with high-Ki-67 expression (Ki-67 proliferation index >14%) were investigated. A systematic approach was applied that focused on the automated segmentation of lesions and extraction of radiomics features. For each lesion 5 morphology, 4 gray-scale histogram and 6 texture features were obtained, and statistical analyzes were performed to assess the differences in these features between the low- and high-Ki-67 expressions. One morphology metric (area), 3 gray-scale histogram indexes (standard deviation, skewness and kurtosis) and 3 texture features (contrast, homogeneity and inverse differential moment) demonstrated a significant difference (P<0.05), with low-Ki-67 expression lesions tending to be smaller, clearer and heterogeneous when compared with the high-Ki-67 expressed cases. These results may provide a noninvasive means to better understand the proliferation of breast cancer.
Altered Small-World Networks in First-Episode Schizophrenia Patients during Cool Executive Function Task

At present, little is known about brain functional connectivity and its small-world topologic properties in first-episode schizophrenia (SZ) patients during cool executive function task. In this paper, the Trail Making Test-B (TMT-B) task was used to evaluate the cool executive function of first-episode SZ patients and electroencephalography (EEG) data were recorded from 14 first-episode SZ patients and 14 healthy controls during this cool executive function task. Brain functional connectivity between all pairs of EEG channels was constructed based on mutual information (MI) analysis. The constructed brain functional networks were filtered by three thresholding schemes: absolute threshold, mean degree, and a novel data-driven scheme based on orthogonal minimal spanning trees (OMST), and graph theory was then used to study the topographical characteristics of the filtered brain graphs. Results indicated that the graph theoretical measures of the theta band showed obvious difference between SZ patients and healthy controls. In the theta band, the characteristic path length was significantly longer and the cluster coefficient was significantly smaller in the SZ patients for a wide range of absolute threshold T. However, the cluster coefficient showed no significant changes, and the characteristic path length was still significantly longer in SZ patients when calculated as a function of mean degree K. Interestingly, we also found that only the characteristic path length was significantly longer in SZ patients compared with healthy controls after using the OMST scheme. Pearson correlation analysis showed that the characteristic path length was positively correlated with executive time of TMT-B for the combined SZ patients and healthy controls (r = 0.507, P = 0.006), but not for SZ patients alone (r = 0.072, P = 0.612). The above results suggested a less optimal organization of the brain network and could be useful for understanding the pathophysiologic mechanisms underlying cool executive dysfunction in first-episode SZ patients.
Splenectomy during cytoreductive surgery in epithelial ovarian cancer

Background The aim of the study was to analyze the underlying causes and application of splenectomy in patients with epithelial ovarian cancer (EOC) and assess its effect on the surgical satisfaction and prognosis of these patients. Materials and methods Clinical data of patients with ovarian epithelial cancer treated with cytoreductive surgery were collected from 2000 to 2015 at Peking Union Medical College Hospital. Results A total of 2,882 patients underwent ovarian cancer cytoreductive surgery at Peking Union Medical College Hospital between 2000 and 2015, of whom 38 (1.3%) also underwent spleen resections. Of these 38 patients, one underwent splenectomy due to intraoperative trauma, whereas the remaining 37 patients underwent splenectomy due to splenic metastasis. Among these 37 patients, 27 underwent resection due to direct tumor spread in the spleen and 10 underwent resection due to hematogenous metastasis. For subsequent first-line chemotherapy, 22 patients were platinum sensitive and 15 were platinum resistant. Overall median survival and the postsplenectomy median survival time were 106 and 75 months, respectively. The overall median survival in secondary cytoreduction was 101 months compared with 20.3–56 months in literature reviews. Univariate analysis revealed that platinum resistance to first-line chemotherapy, suboptimal surgery, and hematogenous metastasis influenced survival. Chemosensitivity and residual disease were identified as independent risk factors by multivariate analysis. We also report a literature review concerning the efficacy and safety of splenectomy during cytoreductive surgery in EOC. Conclusion Approximately 1.3% of patients with EOC underwent spleen resection during initial cytoreductive surgery and more often during recytoreductive surgery. Tumor involvement was the most common indication for splenectomy, and rare patients underwent splenectomy due to intraoperative trauma. Most patients achieved optimal surgery, and thus their overall survival and postsplenectomy survival rates were longer. The prognosis of patients was closely related to chemosensitivity and presence of residual tumors. Splenectomy should be attempted in all patients with splenic involvement in whom optimal cytoreductive surgery was achievable, no matter in primary or secondary cytoreduction.
Treatment patterns and outcomes for patients with advanced melanoma in US oncology clinical practices.

AIM To describe recent evolution in treatment patterns and outcomes for advanced melanoma (AMel). METHODS This retrospective observational study analyzed de-identified electronic health record data from the Flatiron Health database for 1140 adult patients who initiated first-line therapy for AMel from 1 January 2014 to 30 June 2016 with follow-up through 28 February 2017. RESULTS The most common first-line regimens were ipilimumab-based therapies (34%), anti-PD-1 monotherapy (26%) and BRAF/MEK inhibitor(s) (20%). First-line ipilimumab-based and BRAF inhibitor regimens decreased after the third quarter of 2014 (3Q2014), and by 2Q2016, 55 and 91% of BRAF-mutant and BRAF wild-type cohorts, respectively, received a first-line anti-PD-1 regimen. Median overall survival from first-line initiation for all patients was 18.8 months (95% CI: 16.3-23.3). CONCLUSION Results illustrate changing paradigms of therapy and real-world patient outcomes for AMel.
Genome-scale analysis of Acetobacterium bakii reveals the cold adaptation of psychrotolerant acetogens by post-transcriptional regulation

Acetogens synthesize acetyl-CoA via CO2 or CO fixation, producing organic compounds. Despite their ecological and industrial importance, their transcriptional and post-transcriptional regulation has not been systematically studied. With completion of the genome sequence of Acetobacterium bakii (4.28-Mb), we measured changes in the transcriptome of this psychrotolerant acetogen in response to temperature variations under autotrophic and heterotrophic growth conditions. Unexpectedly, acetogenesis genes were highly up-regulated at low temperatures under heterotrophic, as well as autotrophic, growth conditions. To mechanistically understand the transcriptional regulation of acetogenesis genes via changes in RNA secondary structures of 5′-untranslated regions (5′-UTR), the primary transcriptome was experimentally determined, and 1379 transcription start sites (TSS) and 1100 5′-UTR were found. Interestingly, acetogenesis genes contained longer 5′-UTR with lower RNA-folding free energy than other genes, revealing that the 5′-UTRs control the RNA abundance of the acetogenesis genes under low temperature conditions. Our findings suggest that post-transcriptional regulation via RNA conformational changes of 5′-UTRs is necessary for cold-adaptive acetogenesis.
Identification of botanicals with potential therapeutic use against methicillin‐resistant Staphylococcus aureus (MRSA) infections

Staphylococcus aureus is an opportunistic pathogen. Over‐ and improper‐use of pharmaceuticals against S. aureus has led to the development of antibiotic resistance, including methicillin‐resistant S. aureus (MRSA). This study examined the efficacy of botanical extracts as an alternative form of treatment to S. aureus and MRSA, including penicillin/methicillin‐resistant S. aureus (PenR), and multidrug resistant S. aureus (MDR). Initial screening of botanicals was done via a minimum inhibitory concentration procedure. In addition, a temporal growth curve was performed in order to quantify the growth of the bacteria in the presence of the extracts. Results demonstrated 13 botanicals that had varying activities against S. aureus, PenR, and MDR. These botanicals were separated into mild, moderate, and highly efficacious based on the concentration needed to inhibit bacterial growth. These results propose a comparison of botanical‐derived antimicrobial extracts that may be utilized against S. aureus and different antibiotic resistant strains of MRSA.
The Effectiveness of Psychosocial and Behavioral Interventions for Informal Dementia Caregivers: Meta-Analyses and Meta-Regressions.

BACKGROUND Many psychosocial and behavioral interventions have been developed for informal dementia caregivers. Because existing meta-analyses only focused on a limited number of interventions and outcomes, how effective these interventions are overall and which interventions components are associated with larger effects has yet to be explored. OBJECTIVE To provide a comprehensive meta-analysis of the effectiveness of psychosocial and behavioral interventions on burden, depression, anxiety, quality of life, stress, and sense of competence in informal dementia caregivers. In addition, we examined if interventions which utilized more sessions and/or were delivered personally (face-to-face) had larger effect sizes. In exploratory meta-regressions, we examined seven additional moderators. METHODS The protocol was registered with PROSPERO, number CRD42017062555. We systematically searched the literature to identify controlled trials assessing the effect of psychosocial and behavioral interventions on the six outcome measures, for informal dementia caregivers. We performed six random effects meta-analyses, to assess the pooled effect sizes of the interventions. In addition, we performed separate meta-regressions, for each outcome, for each moderator. RESULTS The sample consisted of 60 studies. For all outcomes except anxiety, the pooled effects were small and in favor of the intervention group. No moderator was found to systematically predict these effects. There were no indications for publication bias or selection bias based on significance. CONCLUSION Overall, the interventions yield significant (small) effects, independent of intervention characteristics. Future research should explore options to enhance the effectiveness of interventions aimed at assisting informal caregivers.
Parallel reaction pathways and noncovalent intermediates in thymidylate synthase revealed by experimental and computational tools

Significance Thymidylate synthase (TSase) is one of the prime anticancer targets, as it generates the sole de novo source of thymidylate, a unique precursor for DNA. Fluoropyrimidines and antifolates inhibiting TSase pathways are not only components of the most widely used therapeutic regimens but also highly toxic agents leading to acquired resistance in tumor cells. To provide fresh mechanistic insight to TSase-targeted drug design, we used a combination of experiments, kinetic modeling, and quantum mechanics/molecular mechanics (QM/MM) calculations to discover formation of unexpected noncovalent intermediates prevailing in the catalysis and overstabilized covalent species corresponding to a parallel reaction pathway. These findings challenge the traditional chemical path of this enzyme and offer drug targets. Thymidylate synthase was one of the most studied enzymes due to its critical role in molecular pathogenesis of cancer. Nevertheless, many atomistic details of its chemical mechanism remain unknown or debated, thereby imposing limits on design of novel mechanism-based anticancer therapeutics. Here, we report unprecedented isolation and characterization of a previously proposed intact noncovalent bisubstrate intermediate formed in the reaction catalyzed by thymidylate synthase. Free-energy surfaces of the bisubstrate intermediates interconversions computed with quantum mechanics/molecular mechanics (QM/MM) methods and experimental assessment of the corresponding kinetics indicate that the species is the most abundant productive intermediate along the reaction coordinate, whereas accumulation of the covalent bisubstrate species largely occurs in a parallel nonproductive pathway. Our findings not only substantiate relevance of the previously proposed noncovalent intermediate but also support potential implications of the overstabilized covalent intermediate in drug design targeting DNA biosynthesis.
A New Hybrid Approach on WCET Analysis for Real-Time Systems Using Machine Learning

The notion of the Worst-Case Execution Time (WCET) allows system engineers to create safe real-time systems. This value is used to schedule all software tasks before their deadlines. Failing these deadlines will cause catastrophic events, e.g. vehicle crashes, failing to detect dangerous anomalies, etc. Different analysis methodologies exist to determine the WCET. However, these methods do not provide early insight in the WCET during development. Therefore, pessimistic assumptions are made by system designers resulting in more expensive, overqualified hardware. In this paper, an extension on the hybrid methodology is proposed which implements a predictor model using Machine Learning (ML). This new approach estimates the WCET on smaller entities of the code, so-called hybrid blocks, based on software and hardware features. As a result, the ML-based hybrid analysis provides insight of the WCET early-on in the development process and refines its estimate when more detailed features are available. In order to facilitate the extraction of code-related features, a new tool for the COBRA framework is proposed. This paper proves the potential of the ML-based hybrid approach by conducting multiple experiments based on the TACLeBench on a first prototype. A set of annotated code features were used to train and validate eight different regression models. The results already show promising estimates without tuning any hyperparameters, proving the potential of the methodology.