Miracle-dz/UniFAR-FTUs huggingface dataset:
Beyond the Mevalonate Pathway: Control of Post-Prenylation Processing by Mutant p53

Missense mutations in the TP53 gene are among the most frequent alterations in human cancer. Consequently, many tumors show high expression of p53 point mutants, which may acquire novel activities that contribute to develop aggressive tumors. An unexpected aspect of mutant p53 function was uncovered by showing that some mutants can increase the malignant phenotype of tumor cells through alteration of the mevalonate pathway. Among metabolites generated through this pathway, isoprenoids are of particular interest, since they participate in a complex process of posttranslational modification known as prenylation. Recent evidence proposes that mutant p53 also enhances this process through transcriptional activation of ICMT, the gene encoding the methyl transferase responsible for the last step of protein prenylation. In this way, mutant p53 may act at different levels to promote prenylation of key proteins in tumorigenesis, including several members of the RAS and RHO families. Instead, wild type p53 acts in the opposite way, downregulating mevalonate pathway genes and ICMT. This oncogenic circuit also allows to establish potential connections with other metabolic pathways. The demand of acetyl-CoA for the mevalonate pathway may pose limitations in cell metabolism. Likewise, the dependence on S-adenosyl methionine for carboxymethylation, may expose cells to methionine stress. The involvement of protein prenylation in tumor progression offers a novel perspective to understand the antitumoral effects of mevalonate pathway inhibitors, such as statins, and to explore novel therapeutic strategies.
Genome- and Proteome-Wide Analysis of Lysine Acetylation in Vibrio vulnificus Vv180806 Reveals Its Regulatory Roles in Virulence and Antibiotic Resistance

Infection with Vibrio vulnificus is notorious for its atypical clinical manifestations and irreversible disease progression. Lysine acetylation is a conserved post-translational modification (PTM) that plays a critical regulatory role in diverse cellular processes. However, little is known about the role of lysine acetylation on the pathogenesis of V. vulnificus. Here, we report the complete genome sequence and a global profile for protein lysine acetylation of V. vulnificus Vv180806, a highly cefoxitin resistant strain isolated from a mortality case. The assembled genome comprised two circular chromosomes and one circular plasmid; it contained 4,770 protein-coding genes and 153 RNA genes. Phylogenetic analysis revealed genetic homology of this strain with other V. vulnificus strains from food sources. Of all the proteins in this strain, 1,924 (40.34%) were identified to be acetylated at 6,626 sites. The acetylated proteins were enriched in metabolic processes, binding functions, cytoplasm, and multiple central metabolic pathways. Moreover, the acetylation was found in most identified virulence factors of this strain, suggesting its potentially important role in bacterial virulence. Our work provides insights into the genomic and acetylomic features responsible for the virulence and antibiotic resistance of V. vulnificus, which will facilitate future investigations on the pathogenesis of this bacterium.
Occurrence of Aflatoxigenic Aspergillus Species in Peanut Varieties in Busia and Kisii Central Districts, Kenya

Recent studies have shown that peanuts in Kenya are highly contaminated with aflatoxins, however, information gaps exist on the characterization of the Aspergillus species that produce aflatoxins. Therefore, this gap necessitated the determination of the Aspergillus species producing aflatoxins in peanuts from the main growing districts of Busia and Kisii central. One hundred and two (102) peanuts samples were collected from farmers’ in each district and Aspergillus species were isolated using the dilution plate technique on modified Rose Bengal Agar. Phenotypical characterization of the identified Aspergillus flavus isolates from the samples was determined using the procedure of Mellon and Cotty. This study identified 5 Aspergillus species as contaminants in peanut analyzed. They were Aspergillus flavus L-strain, Aspergillus flavus S-strain, Aspergillus parasiticus, Aspergillus niger and Aspergillus tamari. Overall, the occurrence of Aspergillus flavus L-strain and A. flavus S-strain was significantly higher than other species identified (H = 15.55, df = 4, P = 0.004) in peanuts from the two districts. Aspergillus flavus L-strain was the most common isolate (58.8%) in peanut from Busia district while A. flavus S-strain was the most common strain (60.2%) in peanuts from Kisii central district. However, A. flavus S-strain was the most dominant species (F = 3.15, df = 25, P = 0.031) with an overall mean occurrence of 45.1%. The confirmation of occurrence of other species that produce toxins such as A. niger and A. tamarii which also produces cyclopiazonic acid, points to the need of screening peanuts for other carcinogenic mycotoxins.
Serotonergic Modulation of Locomotor Activity From Basal Vertebrates to Mammals

During the last 50 years, the serotonergic (5-HT) system was reported to exert a complex modulation of locomotor activity. Here, we focus on two key factors that likely contribute to such complexity. First, locomotion is modulated directly and indirectly by 5-HT neurons. The locomotor circuitry is directly innervated by 5-HT neurons in the caudal brainstem and spinal cord. Also, indirect control of locomotor activity results from ascending projections of 5-HT cells in the rostral brainstem that innervate multiple brain centers involved in motor action planning. Second, each approach used to manipulate the 5-HT system likely engages different 5-HT-dependent mechanisms. This includes the recruitment of different 5-HT receptors, which can have excitatory or inhibitory effects on cell activity. These receptors can be located far or close to the 5-HT release sites, making their activation dependent on the level of 5-HT released. Here we review the activity of different 5-HT nuclei during locomotor activity, and the locomotor effects of 5-HT precursors, exogenous 5-HT, selective 5-HT reuptake inhibitors (SSRI), electrical or chemical stimulation of 5-HT neurons, genetic deletions, optogenetic and chemogenetic manipulations. We highlight both the coherent and controversial aspects of 5-HT modulation of locomotor activity from basal vertebrates to mammals. This mini review may hopefully inspire future studies aiming at dissecting the complex effects of 5-HT on locomotor function.
Augmenting Anticancer Immunity Through Combined Targeting of Angiogenic and PD-1/PD-L1 Pathways: Challenges and Opportunities

Cancer immunotherapy (CIT) with antibodies targeting the programmed cell death 1 protein (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis have changed the standard of care in multiple cancers. However, durable antitumor responses have been observed in only a minority of patients, indicating the presence of other inhibitory mechanisms that act to restrain anticancer immunity. Therefore, new therapeutic strategies targeted against other immune suppressive mechanisms are needed to enhance anticancer immunity and maximize the clinical benefit of CIT in patients who are resistant to immune checkpoint inhibition. Preclinical and clinical studies have identified abnormalities in the tumor microenvironment (TME) that can negatively impact the efficacy of PD-1/PD-L1 blockade. Angiogenic factors such as vascular endothelial growth factor (VEGF) drive immunosuppression in the TME by inducing vascular abnormalities, suppressing antigen presentation and immune effector cells, or augmenting the immune suppressive activity of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. In turn, immunosuppressive cells can drive angiogenesis, thereby creating a vicious cycle of suppressed antitumor immunity. VEGF-mediated immune suppression in the TME and its negative impact on the efficacy of CIT provide a therapeutic rationale to combine PD-1/PD-L1 antibodies with anti-VEGF drugs in order to normalize the TME. A multitude of clinical trials have been initiated to evaluate combinations of a PD-1/PD-L1 antibody with an anti-VEGF in a variety of cancers. Recently, the positive results from five Phase III studies in non-small cell lung cancer (adenocarcinoma), renal cell carcinoma, and hepatocellular carcinoma have shown that combinations of PD-1/PD-L1 antibodies and anti-VEGF agents significantly improved clinical outcomes compared with respective standards of care. Such combinations have been approved by health authorities and are now standard treatment options for renal cell carcinoma, non-small cell lung cancer, and hepatocellular carcinoma. A plethora of other randomized studies of similar combinations are currently ongoing. Here, we discuss the principle mechanisms of VEGF-mediated immunosuppression studied in preclinical models or as part of translational clinical studies. We also discuss data from recently reported randomized clinical trials. Finally, we discuss how these concepts and approaches can be further incorporated into clinical practice to improve immunotherapy outcomes for patients with cancer.
Children’s Reality Status Judgments of Digital Media: Implications for a COVID-19 World and Beyond

Even prior to the COVID-19 crisis, one of the children’s most common screen activities was using the video-sharing platform YouTube, with many children preferring YouTube over television. The pandemic has significantly increased the amount of time many children spend on YouTube—watching videos for both entertainment and education. However, it is unclear how children conceptualize the people they see on YouTube. Prior to the pandemic, children 3–8 years old (N = 117) were recruited to participate. Children were told that they would see pictures taken from videos and answer questions about them. Children saw three physical photos with the same image of a man and a bird and were told that the photo was (a) from a video on the experimenter’s phone, (b) from a video on television, or (c) from a video on YouTube. They were asked whether the person in the photo was real or not real, which video would be best for learning, and which video they would prefer to watch. Findings indicated that children were marginally less likely to believe that people on YouTube are real than people in a video on a phone, with no difference between beliefs about people on YouTube and television. Notably, these beliefs were similar across the age range tested here. Across all ages, children preferred to watch YouTube more than phone videos and believed that YouTube possessed greater educational value than both phone and television videos.
Multi-Omics Analysis to Characterize Cigarette Smoke Induced Molecular Alterations in Esophageal Cells

Though smoking remains one of the established risk factors of esophageal squamous cell carcinoma, there is limited data on molecular alterations associated with cigarette smoke exposure in esophageal cells. To investigate molecular alterations associated with chronic exposure to cigarette smoke, non-neoplastic human esophageal epithelial cells were treated with cigarette smoke condensate (CSC) for up to 8 months. Chronic treatment with CSC increased cell proliferation and invasive ability of non-neoplastic esophageal cells. Whole exome sequence analysis of CSC treated cells revealed several mutations and copy number variations. This included loss of high mobility group nucleosomal binding domain 2 (HMGN2) and a missense variant in mediator complex subunit 1 (MED1). Both these genes play an important role in DNA repair. Global proteomic and phosphoproteomic profiling of CSC treated cells lead to the identification of 38 differentially expressed and 171 differentially phosphorylated proteins. Bioinformatics analysis of differentially expressed proteins and phosphoproteins revealed that most of these proteins are associated with DNA damage response pathway. Proteomics data revealed decreased expression of HMGN2 and hypophosphorylation of MED1. Exogenous expression of HMGN2 and MED1 lead to decreased proliferative and invasive ability of smoke exposed cells. Immunohistochemical labeling of HMGN2 in primary ESCC tumor tissue sections (from smokers) showed no detectable expression while strong to moderate staining of HMGN2 was observed in normal esophageal tissues. Our data suggests that cigarette smoke perturbs expression of proteins associated with DNA damage response pathways which might play a vital role in development of ESCC.
Generation of Neural Progenitor Cells From Canine Induced Pluripotent Stem Cells and Preliminary Safety Test in Dogs With Spontaneous Spinal Cord Injuries

Advances in stem cell technology, including the use of induced pluripotent stem cells (iPSC) to produce neurons and glial cells, offer new hope for patients with neurological disease and injuries. Pet dogs with spinal cord injuries provide an important spontaneous animal model for evaluating new approaches to stem cell therapy. Therefore, studies were conducted to identify optimal conditions for generating neural progenitor cells (NPC) from canine induced pluripotent stem cells (iPSC) for preliminary evaluation in animals with spinal cord injury. We found that canine NPC could be induced to differentiate into mature neural cells, including glia and neurons. In addition, canine NPC did not form teratomas when injected in NOD/SCID mice. In a pilot study, two dogs with chronic spinal cord injury underwent fluoroscopically guided intrathecal injections of canine NPC. In follow-up MRI evaluations, tumor formation was not observed at the injection sites. However, none of the animals experienced meaningful clinical or electrophysiological improvement following NPC injections. These studies provide evidence that canine iPSC can be used to generate NPC for evaluation in cellular therapy of chronic spinal cord injury in the dog spontaneous injury model. Further refinements in the cell implantation procedure are likely required to enhance stem cell treatment efficacy.
Characterization of Bottom-up Microservice Composition Evolution. An Approach Based on the Choreography of BPMN Fragments

Microservices need to be composed in order to provide their customers with valuable services. To do so, event-based choreographies are used many times since they help to maintain a lower coupling among microservices. However, this solution rises the composition complexity since the control flow is distributed across microservices and it is difficult to analyze and understand the big picture of it. To improve this problem, a previous work presented an approach that proposed creating the big picture of a composition in a BPMN model, splitting it into BPMN fragments, and distributing these fragments among micro-services. A tool-supported architecture was also proposed to achieve that both descriptions of a composition (the big picture and the split one) coexist in a sys-tem. In the current work, we present a first step to face the problem of evolving microservice compositions that are created and deployed with our approach. To do so, we need to consider that we can evolve a microservice composition from (1) its big picture (top-down approach) and (2) a particular BPMN fragment (bottom-up approach). We pay special attention to the bottom-up approach and pre-sent a characterization of the changes that can be done, analyze the impact that each of them has on the global composition, and propose compensation actions that maintain the integrity of the composition when possible.
B-Mode and Doppler Ultrasonography in a Murine Model of Ehrlich Solid Carcinoma With Different Growth Patterns

Ehrlich solid carcinoma (ESC) is one of the tumor models used in cancer research. Although it is widely used, it has no ultrasonographic descriptions. In this study, serial B-mode and Doppler ultrasonographic examinations were performed for 23 days for ESCs inoculated into 18 Swiss albino mice. The growth patterns were analyzed, and on the basis of their growth curve, the tumors were classified into two groups: fast growth (FG) and slow growth (SG). Ultrasonographic characteristics of the tumor’s capsule, margins, echogenicity, echotexture, vascular index (VI), distribution of vascular flow, and Doppler indices such as the resistive index, pulsatility index, and peak systolic velocity (SV) were analyzed and compared between the two groups. A high VI and earlier blood flow were noted in the FG group (p<0.05). Additionally, SV was higher in the FG group than in the SG group (13.28 ± 0.38 cm/s vs. 8.43 ± 0.26 cm/s). In contrast, a change in echogenicity and flow distribution patterns were observed, especially in FG tumors. Therefore, ESC presented with few ultrasonographic differences between FG and SG tumors, especially vascularization during the initial stages of tumor growth.
How to Design Optimal Accelerated rTMS Protocols Capable of Promoting Therapeutically Beneficial Metaplasticity

Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, Netherlands, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht, Netherlands, Centre for Integrative Neuroscience, Faculty of Psychology and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands
Pallet Handling System with an Autonomous Forklift for Outdoor Fields

In Japan, the aging and depopulation of its workforce are issues. Therefore, the development of autonomous agricultural robots is required for saving manpower and labor. In this paper, we described an autonomous pallet handling system for forklift, which can automatically unload and convey pallets for harvesting vegetables outdoors. Because of inserting the forks into a narrow pallet hole, accurate pallet posture estimation and accurate control of a forklift and the forks are required. The system can detect the pallet by deep learning based object detection from an image. Based on the results of object detection and measurement by horizontal 3D light detection and ranging (LiDAR), the system accurately estimates a distance as well as horizontal and vertical deviation between the forklift and the pallet in the outside field. The forklift is controlled by sliding mode control (SMC) which is robust to disturbances. Furthermore, the vertical LiDAR scans the pallet for precisely adjusting the height of the fork. The system requires the environment with no or little preparation for the automation process. We confirmed the effectiveness of the system through an experiment. The experiment is assumed that the forklift unloads the pallet from the vehicle as the real task of agriculture. The experimental results indicated the suitability of the system in real agricultural environments.
A17 Amacrine Cells and Olfactory Granule Cells: Parallel Processors of Early Sensory Information

Neurons typically receive synaptic input in their dendritic arbor, integrate inputs in their soma, and send output action potentials through their axon, following Cajal’s law of dynamic polarization. Two notable exceptions are retinal amacrine cells and olfactory granule cells (GCs), which flout Cajal’s edict by providing synaptic output from the same dendrites that collect synaptic input. Amacrine cells, a diverse cell class comprising >60 subtypes, employ various dendritic input/output strategies, but A17 amacrine cells (A17s) in particular share further interesting functional characteristics with GCs: both receive excitatory synaptic input from neurons in the primary glutamatergic pathway and return immediate, reciprocal feedback via GABAergic inhibitory synapses to the same synaptic terminals that provided input. Both neurons thereby process signals locally within their dendrites, shaping many parallels, signaling pathways independently. The similarities between A17s and GCs cast into relief striking differences that may indicate distinct processing roles within their respective circuits: First, they employ partially dissimilar molecular mechanisms to transform excitatory input into inhibitory output; second, GCs fire action potentials, whereas A17s do not. Third, GC signals may be influenced by cortical feedback, whereas the mammalian retina receives no such retrograde input. Finally, A17s constitute just one subtype within a diverse class that is specialized in a particular task, whereas the more homogeneous GCs may play more diverse signaling roles via multiple processing modes. Here, we review these analogies and distinctions between A17 amacrine cells and granule cells, hoping to gain further insight into the operating principles of these two sensory circuits.
An early warning dropout model in higher education degree programs: A case study in Ecuador

Worldwide, a significant concern of universities is to reduce academic dropout rate. Several initiatives have been made to avoid this problem; however, it is essential to recognize at-risk students as soon as possible. In this paper, we propose a new predictive model that can identify the earliest moment of dropping out of a student of any semester in any undergraduate course. Unlike most available models, our solution is based on academic information alone, and our evidence suggests that by ignoring socio-demographics or pre-college entry information, we obtain more reliable predictions, even when a student has only one academic semester finished. Therefore, our prediction can be used as part of an academic counseling tool providing the performance factors that could influence a student to leave the institution. With this, the counselors can identify those students and take better decisions to guide them and finally, minimize the dropout in the institution. As a case study, we used the students’ data of all undergraduate programs from 2000 until 2019 from a public high education university in Ecuador.
Characterization of a Novel Peptide from Pathogenic Leptospira and Its Cytotoxic Effect

Leptospirosis is a zoonotic infectious disease caused by pathogenic Leptospira species. Virulence proteins have been shown to be key determinants of the pathogenesis of pathogenic Leptospira. A specific peptide at a mass-to-charge ratio of 7000 Da was identified in Leptospira whole cells using matrix-assisted laser/desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. This peptide was specifically present in pathogenic Leptospira and in clinical isolates. We report here the characterization of this specific peptide using a proteomics approach. This peptide was significantly matched to a hypothetical conserved L. interrogans protein (LA2458) with a calculated molecular weight of 7140.136 Da containing a tellurite-resistance domain at its C terminus (TerB-C). The amino acid sequences revealed the presence of hydrophobic transmembrane portions and two linear B-cell epitopes. Despite its low abundance, this synthetic peptide demonstrated dose-dependent cytotoxicity toward African green monkey kidney (Vero) cells via the apoptosis pathway. The concentration of the peptide 100 µM induced about 50% of cell death after a 24 h exposure. This peptide could be useful for the diagnosis of leptospirosis and the study of pathogenesis.