Miracle-dz/UniFAR-FTUs huggingface dataset:
Multiple Local Synaptic Modifications at Specific Sensorimotor Connections after Learning Are Associated with Behavioral Adaptations That Are Components of a Global Response Change

Learning causes local changes in synaptic connectivity and coordinated, global changes affecting many aspects of behavior. How do local synaptic changes produce global behavioral changes? In the hermaphroditic mollusc Aplysia, after learning that food is inedible, memory is expressed as bias to reject a food and to reduce responses to that food. We now show that memory is also expressed as an increased bias to reject even a nonfood object. The increased bias to rejection is partially explained by changes in synaptic connections from primary mechanoafferents to five follower neurons with well defined roles in producing different feeding behaviors. Previously, these mechanoafferents had been shown to play a role in memory consolidation. Connectivity changes differed for each follower neuron: the probability that cells were connected changed; excitation changed to inhibition and vice versa; and connection amplitude changed. Thus, multiple neural changes at different sites underlie specific aspects of a coordinated behavioral change. Changes in the connectivity between mechanoafferents and their followers cannot account for all of the behavioral changes expressed after learning, indicating that additional synaptic sites are also changed. Access to the circuit controlling feeding can help determine the logic and cellular mechanisms by which multiple local synaptic changes produce an integrated, global change in behavior. SIGNIFICANCE STATEMENT How do local changes in synapses affect global behavior? Studies on invertebrate preparations usually examine synaptic changes at specific neural sites, producing a specific behavioral change. However, memory may be expressed by multiple behavioral changes. We report that a change in behavior after learning in Aplysia is accomplished, in part, by regulating connections between mechanoafferents and their synaptic followers. For some followers, the connection probabilities change; for others, the connection signs are reversed; in others, the connection strength is modified. Thus, learning produces changes in connectivity at multiple sites, via multiple synaptic mechanisms that are consistent with the observed behavioral change.
Trends and Innovations in Biosensors for COVID‐19 Mass Testing

Fast and widespread diagnosis is crucial to fighting against the outbreak of COVID‐19. This work surveys the landscape of available and emerging biosensor technologies for COVID‐19 testing. Molecular diagnostic assays based on quantitative reverse transcription polymerase chain reaction are used in most clinical laboratories. However, the COVID‐19 pandemic has overwhelmed testing capacity and motivated the development of fast point‐of‐care tests and the adoption of isothermal DNA amplification. Antigenic and serological rapid tests based on lateral‐flow immunoassays suffer from low sensitivity. Advanced digital systems enhance performance at the expense of speed and the need for large equipment. Emerging technologies, including CRISPR gene‐editing tools, benefit from high sensitivity and specificity of molecular diagnostics and the easy use of lateral‐flow assays. DNA sequencing and sample pooling strategies are highlighted to bring out the full capacity of the available biosensor technologies and accelerate mass testing.
C. elegans MAGU-2/Mpp5 homolog regulates epidermal phagocytosis and synapse density

Abstract Synapses are dynamic connections that underlie essential functions of the nervous system. The addition, removal, and maintenance of synapses govern the flow of information in neural circuits throughout the lifetime of an animal. While extensive studies have elucidated many intrinsic mechanisms that neurons employ to modulate their connections, increasing evidence supports the roles of non-neuronal cells, such as glia, in synapse maintenance and circuit function. We previously showed that C. elegans epidermis regulates synapses through ZIG-10, a cell-adhesion protein of the immunoglobulin domain superfamily. Here we identified a member of the Pals1/MPP5 family, MAGU-2, that functions in the epidermis to modulate phagocytosis and the number of synapses by regulating ZIG-10 localization. Furthermore, we used light and electron microscopy to show that this epidermal mechanism removes neuronal membranes from the neuromuscular junction, dependent on the conserved phagocytic receptor CED-1. Together, our study shows that C. elegans epidermis constrains synaptic connectivity, in a manner similar to astrocytes and microglia in mammals, allowing optimized output of neural circuits.
Measuring recognition memory in zebrafish larvae: issues and limitations

Recognition memory is the capacity to recognize previously encountered objects, events or places. This ability is crucial for many fitness-related activities, and it appears very early in the development of several species. In the laboratory, recognition memory is most often investigated using the novel object recognition test (NORt), which exploits the tendency of most vertebrates to explore novel objects over familiar ones. Despite that the use of larval zebrafish is rapidly increasing in research on brain, cognition and neuropathologies, it is unknown whether larvae possess recognition memory and whether the NORt can be used to assess it. Here, we tested a NOR procedure in zebrafish larvae of 7-, 14- and 21-days post-fertilization (dpf) to investigate when recognition memory first appears during ontogeny. Overall, we found that larvae explored a novel stimulus longer than a familiar one. This response was fully significant only for 14-dpf larvae. A control experiment evidenced that larvae become neophobic at 21-dpf, which may explain the poor performance at this age. The preference for the novel stimulus was also affected by the type of stimulus, being significant with tri-dimensional objects varying in shape and bi-dimensional geometrical figures but not with objects differing in colour. Further analyses suggest that lack of effect for objects with different colours was due to spontaneous preference for one colour. This study highlights the presence of recognition memory in zebrafish larvae but also revealed non-cognitive factors that may hinder the application of NORt paradigms in the early developmental stages of zebrafish.
Stabilization of β-Catenin by Genetic Defects in Melanoma Cell Lines

Signal transduction by β-catenin involves its posttranslational stabilization and downstream coupling to the Lef and Tcf transcription factors. Abnormally high amounts of β-catenin were detected in 7 of 26 human melanoma cell lines. Unusual messenger RNA splicing and missense mutations in the β-catenin gene (CTNNB1) that result in stabilization of the protein were identified in six of the lines, and the adenomatous polyposis coli tumor suppressor protein (APC) was altered or missing in two others. In the APC-deficient cells, ectopic expression of wild-type APC eliminated the excess β-catenin. Cells with stabilized β-catenin contained a constitutive β-catenin-Lef-1 complex. Thus, genetic defects that result in up-regulation of β-catenin may play a role in melanoma progression.
Chitosan: A natural substitute of EDTA solution for final irrigation in endodontics treatment

Background: The purpose of this study was to assess the quantity of the chelated calcium ions and the smear layer removal efficiency after root canal final irrigation with three different solutions.Materials and Methods: Forty-five teeth were instrumented with rotary-files, then randomly divided into 3 equal groups (n = 15) depending on the final irrigation solution; group I: 17% ethylenediaminetetraacetic acid (EDTA), group II: 0.2% chitosan, and group III: 10% trisodium citrate. According to the time of application, every group was divided into 3 subgroups (1 min, 5 min, and 24 h). The quantification analysis of chelated calcium ions was performed by flame atomic absorption spectrometry (FAAS). Then, the presence of smear layer was examined by splitting the samples longitudinally and using scanning electron microscopy (SEM) to examine coronal, middle, and apical root canal levels. One-way analysis of variance (ANOVA) test was used for the evaluation of treatment effect. Kruskal–Wallis test was executed to detect a significant difference between groups, while Mann–Whitney U test has determined the difference between each two groups for smear layer.Results: Both 17% EDTA and 0.2% chitosan had not been statistically significant difference for smear layer removal efficiency and observed calcium ion concentrations. Although, they were more efficient of 10% trisodium citrate with a significant difference (P < 0.05). Conclusion: The application time of the chelators' solutions must not exceed 5 min to completely remove smear layer, and 0.2% chitosan is a natural substitute for 17% EDTA with a safety application for 24 h.
Effectiveness of robust optimization in volumetric modulated arc therapy using 6 and 10 MV flattening filter-free beam therapy planning for lung stereotactic body radiation therapy with a breath-hold technique

Abstract We investigated the feasibility of a robust optimization with 6 MV X-ray (6X) and 10 MV X-ray (10X) flattening filter-free (FFF) beams in a volumetric modulated arc therapy (VMAT) plan for lung stereotactic body radiation therapy (SBRT) using a breath-holding technique. Ten lung cancer patients were selected. Four VMAT plans were generated for each patient; namely, an optimized plan based on the planning target volume (PTV) margin and a second plan based on a robust optimization of the internal target volume (ITV) with setup uncertainties, each for the 6X- and 10X-FFF beams. Both optimized plans were normalized by the percentage of the prescription dose covering 95% of the target volume (D95%) to the PTV (1050 cGy × 4 fractions). All optimized plans were evaluated using perturbed doses by specifying user-defined shifted values from the isocentre. The average perturbed D99% doses to the ITV, compared to the nominal plan, decreased by 369.1 (6X-FFF) and 301.0 cGy (10X-FFF) for the PTV-based optimized plan, and 346.0 (6X-FFF) and 271.6 cGy (10X-FFF) for the robust optimized plan, respectively. The standard deviation of the D99% dose to the ITV were 163.6 (6X-FFF) and 158.9 cGy (10X-FFF) for the PTV-based plan, and 138.9 (6X-FFF) and 128.5 cGy (10X-FFF) for the robust optimized plan, respectively. Robust optimized plans with 10X-FFF beams is a feasible method to achieve dose certainty for the ITV for lung SBRT using a breath-holding technique.
Bleeding risk of ticagrelor compared to clopidogrel in intensive care unit patients with acute coronary syndrome: A propensity-score matching analysis

Background Intensive care unit (ICU) patients with the most severe forms of acute coronary syndrome (ACS) require invasive therapies such as extracorporeal life support. The risk of bleeding in ICU patients with ACS treated with a dual antiplatelet therapy of aspirin and ticagrelor is unknown. The primary objective of this study was to compare the bleeding risk of ticagrelor and clopidogrel in ICU patients with ACS. Methods and findings We conducted a retrospective study based on a propensity score and a proportional hazards model. All patients with ACS hospitalized in the ICU of a French university hospital between January 2013 and January 2017 were included in the study. Bleeding during ICU stay was defined as all Thrombolysis in myocardial infarction (TIMI) major or minor events. A total of 155 patients were included in the study. According to propensity score matching, 57 patients treated with aspirin and ticagrelor were matched with 57 patients treated with aspirin and clopidogrel. Median (first-third quartile) Simplified Acute Physiology Score II was 61.5 (41.0–85.0). Bleeding during ICU stay occurred in 12 patients (21.1%) treated with clopidogrel and in 35 patients (61.4%) treated with ticagrelor (p<0.0001). This significant association was found for both TIMI major bleeding (12.3% vs. 35.1%, p = 0.004) and TIMI minor bleeding (8.8% vs. 26.3%, p = 0.01). The relative risk of bleeding occurrence during ICU stay was 2.60 (confidence interval 95%: 1.55–4.35) for ticagrelor compared to clopidogrel. No significant difference in ICU mortality was found between the two groups (45.6% in the clopidogrel group vs. 29.8% in the ticagrelor group, p = 0.08). Conclusions Bleeding complications are frequent and serious in ICU patients with ACS. A dual antiplatelet therapy of aspirin and ticagrelor is associated with a higher risk of bleeding compared to a dual antiplatelet therapy of aspirin and clopidogrel.
The miR-1224-5p/ELF3 Axis Regulates Malignant Behaviors of Pancreatic Cancer via PI3K/AKT/Notch Signaling Pathways

Purpose Aberrant expression of microRNAs contributes to the progression of pancreatic cancer by targeting downstream genes. A novel regulatory axis, miR-1224-5p/ELF3, was identified by bioinformatic analysis and experimental verification. Studies of the underlying molecular mechanisms behind this axis lead to a better understanding of the development of pancreatic cancer. Materials and Methods The differential expression of miR-1224-5p and ELF3 was verified based on Gene Expression Omnibus (GEO) datasets and clinical samples. The relationship between miR-1224-5p and ELF3 was demonstrated by luciferase assay and Western blot. The related signaling pathways of the miR-1224-5p/ELF3 axis in pancreatic cancer were investigated by gene set enrichment analysis (GSEA) and verified by Western blot. An analysis between ELF3 expression and immune infiltration was performed. Cellular and animal experiments were utilized to explore the effects of miR-1224-5p and ELF3 in pancreatic cancer. Results Suppressed expression of miR-1224-5p in pancreatic tumor tissues and cancer cells was identified first. Furthermore, miR-1224-5p is correlated with clinicopathological features, and decreased expression of miR-1224-5p indicates poor prognosis. miR-1224-5p serves as a tumor suppressor and inhibits malignant behaviors of pancreatic cancer based on in vivo and in vitro assays. The putative target gene ELF3 was predicted by bioinformatic analysis and confirmed by dual-luciferase reporter assay. Overexpression of ELF3 can improve the malignant behaviors of pancreatic cancer and demonstrates poor prognosis and advanced clinical stage. The inhibitory role of miR-1224-5p in pancreatic cancer is manifested by its direct targeting of ELF3. A negative correlation between ELF3 expression and immune cell infiltration was identified, suggesting an immunosuppressive state resulting from ELF3 overexpression. The PI3K/AKT/Notch signaling pathways and epithelial-to-mesenchymal transition (EMT) are important underlying mechanisms. Conclusion The miR-1224-5p/ELF3 axis may serve as a new diagnostic, therapeutic, and prognostic biomarker in pancreatic cancer. The related PI3K/AKT/Notch/EMT signaling pathways greatly promote the elucidation of the progression of pancreatic cancer.
Identifying Therapies to Combat Epithelial Mesenchymal Plasticity-Associated Chemoresistance to Conventional Breast Cancer Therapies Using An shRNA Library Screen

Background: Breast cancer (BC) is a heterogeneous disease for which the commonly used chemotherapeutic agents primarily include the anthracyclines (doxorubicin, epirubicin), microtubule inhibitors (paclitaxel, docetaxel, eribulin), and alkylating agents (cyclophosphamide). While these drugs can be highly effective, metastatic tumours are frequently refractory to treatment or become resistant upon tumour relapse. Methods: We undertook a cell polarity/epithelial mesenchymal plasticity (EMP)-enriched short hairpin RNA (shRNA) screen in MDA-MB-468 breast cancer cells to identify factors underpinning heterogeneous responses to three chemotherapeutic agents used clinically in breast cancer: Doxorubicin, docetaxel, and eribulin. shRNA-transduced cells were treated for 6 weeks with the EC10 of each drug, and shRNA representation assessed by deep sequencing. We first identified candidate genes with depleted shRNA, implying that their silencing could promote a response. Using the Broad Institute’s Connectivity Map (CMap), we identified partner inhibitors targeting the identified gene families that may induce cell death in combination with doxorubicin, and tested them with all three drug treatments. Results: In total, 259 shRNAs were depleted with doxorubicin treatment (at p < 0.01), 66 with docetaxel, and 25 with eribulin. Twenty-four depleted hairpins overlapped between doxorubicin and docetaxel, and shRNAs for TGFB2, RUNX1, CCDC80, and HYOU1 were depleted across all the three drug treatments. Inhibitors of MDM/TP53, TGFBR, and FGFR were identified by CMap as the top pharmaceutical perturbagens and we validated the combinatorial benefits of the TGFBR inhibitor (SB525334) and MDM inhibitor (RITA) with doxorubicin treatment, and also observed synergy between the inhibitor SB525334 and eribulin in MDA-MB-468 cells. Conclusions: Taken together, a cell polarity/EMP-enriched shRNA library screen identified relevant gene products that could be targeted alongside current chemotherapeutic agents for the treatment of invasive BC.
Synergy between Photodynamic Therapy and Dactinomycin Chemotherapy in 2D and 3D Ovarian Cancer Cell Cultures

In this study we explored the efficacy of combining low dose photodynamic therapy using a porphyrin photosensitiser and dactinomycin, a commonly used chemotherapeutic agent. The studies were carried out on compressed collagen 3D constructs of two human ovarian cancer cell lines (SKOV3 and HEY) versus their monolayer counterparts. An amphiphilc photosensitiser was employed, disulfonated tetraphenylporphine, which is not a substrate for ABC efflux transporters that can mediate drug resistance. The combination treatment was shown to be effective in both monolayer and 3D constructs of both cell lines, causing a significant and synergistic reduction in cell viability. Compared to dactinomycin alone or PDT alone, higher cell kill was found using 2D monolayer culture vs. 3D culture for the same doses. In 3D culture, the combination therapy resulted in 10 and 22 times higher cell kill in SKOV3 and HEY cells at the highest light dose compared to dactinomycin monotherapy, and 2.2 and 5.5 times higher cell kill than PDT alone. The combination of low dose PDT and dactinomycin appears to be a promising way to repurpose dactinomycin and widen its therapeutic applications.
Two pathogenic races of Melampsora larici-populina in north-western Europe

Three collections of Melampsora larici-populina Kleb. originating from Belgium, France and the Netherlands were compared for their pathogenicity on eleven poplar clones. Qualitative type reactions suggest the existence of two pathogenic races designated E1 and E2. E2 is able to infect some clones previously considered to be resistant.
Loss of Kex2 Affects the Candida albicans Cell Wall and Interaction with Innate Immune Cells

The secretory pathway in Candida albicans involves the protein translocation into the lumen of the endoplasmic reticulum and transport to the Golgi complex, where proteins undergo posttranslational modifications, including glycosylation and proteolysis. The Golgi-resident Kex2 protease is involved in such processing and disruption of its encoding gene affected virulence and dimorphism. These previous studies were performed using cells without URA3 or with URA3 ectopically placed into the KEX2 locus. Since these conditions are known to affect the cellular fitness and the host–fungus interaction, here we generated a kex2Δ null mutant strain with URA3 placed into the neutral locus RPS1. The characterization of this strain showed defects in the cell wall composition, with a reduction in the N-linked mannan content, and the increment in the levels of O-linked mannans, chitin, and β-glucans. The defects in the mannan content are likely linked to changes in Golgi-resident enzymes, as the α-1,2-mannosyltransferase and α-1,6-mannosyltransferase activities were incremented and reduced, respectively. The mutant cells also showed reduced ability to stimulate cytokine production and phagocytosis by human mononuclear cells and macrophages, respectively. Collectively, these data showed that loss of Kex2 affected the cell wall composition, the protein glycosylation pathways, and interaction with innate immune cells.
Phylogenetic, Evolutionary and Structural Analysis of Canine Parvovirus (CPV-2) Antigenic Variants Circulating in Colombia

Canine parvovirus (CPV-2) is the causative agent of haemorrhagic gastroenteritis in canids. Three antigenic variants—CPV-2a, CPV-2b and CPV-2c—have been described, which are determined by variations at residue 426 of the VP2 capsid protein. In Colombia, the CPV-2a and CPV-2b antigenic variants have previously been reported through partial VP2 sequencing. Mutations at residues Asn428Asp and Ala514Ser of variant CPV-2a were detected, implying the appearance of a possible new CPV-2a variant in Colombia. The purpose of the present study was to characterise the full VP2 capsid protein in samples from Antioquia, Colombia. We conducted a cross-sectional study with 56 stool samples from dogs showing clinical symptoms of parvoviral disease. Following DNA extraction from the samples, VP2 amplification was performed using PCR and positive samples were sequenced. Sequence and phylogenetic analyses were performed by comparison with the VP2 gene sequences of the different CPV-2 worldwide. VP2 was amplified in 51.8% of the analysed samples. Sequencing and sequence alignment showed that 93.1% of the amplified samples belonged to the new CPV-2a antigenic variant previously. Analysing the amino acid sequences revealed that all CPV-2a contain Ala297Asn mutations, which are related to the South America I clade, and the Ala514Ser mutation, which allows characterization as a new CPV-2a sub-variant. The Colombian CPV-2b variant presented Phe267Tyr, Tyr324Ile and Thr440Ala, which are related to the Asia-I clade variants. The CPV-2c was not detected in the samples. In conclusion, two antigenic CPV-2 variants of two geographically distant origins are circulating in Colombia. It is crucial to continue characterising CPV-2 to elucidate the molecular dynamics of the virus and to detect new CPV-2 variants that could be becoming highly prevalent in the region.
The Globalisation of Cardiology and Cardiovascular Diseases in the World–Society—A Case Study with a Special Focus on Heart Failure

While there has been a shift of attention in global health towards non-communicable diseases, we still know little about the social mechanisms that have allowed these diseases to emerge as topics of global concern. We employ a sociological approach to globalisation in order to reconstruct how cardiology, with our special focus being on heart failure research, has become global, and thereby placed cardiovascular diseases on the agenda of global health. Following sociological theories of world–society and world–polity, we identify a number of preconditions that had to be met so that the globalisation of cardiology could set in. Amongst them were technological innovations, the emergence of an organisational infrastructure on the national level, the appearance of cardiological journals, and an internationally standardised nomenclature. More recently, new drugs and treatment strategies, new specialist journals, and new international standards allowed the subspeciality of heart failure to globalise. Our findings are based on the history and sociology of cardiology, and on our analysis of a broad range of other documents, including scientific articles, guidelines, and policy documents. Additionally, our analysis included two datasets, one containing information on national cardiac societies, and the other containing data on publication output in cardiology.