Miracle-dz/UniFAR-FTUs huggingface dataset:
Emotional behavior in aquatic organisms? Lessons from crayfish and zebrafish

Experimental animal models are a valuable tool to study the neurobiology of emotional behavior and mechanisms underlying human affective disorders. Mounting evidence suggests that various aquatic organisms, including both vertebrate (e.g., zebrafish) and invertebrate (e.g., crayfish) species, may be relevant to study animal emotional response and its deficits. Ideally, model organisms of disease should possess considerable genetic and physiological homology to mammals, display robust behavioral and physiological responses to stress, and should be sensitive to a wide range of drugs known to modulate stress and affective behaviors. Here, we summarize recent findings in the field of zebrafish‐ and crayfish‐based tests of stress, anxiety, aggressiveness and social preference, and discuss further perspectives of using these novel model organisms in translational biological psychiatry. Outlining the remaining questions in this field, we also emphasize the need in further development and a wider use of crayfish and zebrafish models to study the pathogenesis of affective disorders.
The mitochondrial calcium uniporter is crucial for the generation of fast cortical network rhythms

The role of the mitochondrial calcium uniporter (MCU) gene (Mcu) in cellular energy homeostasis and generation of electrical brain rhythms is widely unknown. We investigated this issue in mice and rats using Mcu-knockout and -knockdown strategies in vivo and in situ and determined the effects of these genetic manipulations on hippocampal gamma oscillations (30–70 Hz) and sharp wave-ripples. These physiological network states require precise neurotransmission between pyramidal cells and inhibitory interneurons, support spike-timing and synaptic plasticity and are associated with perception, attention and memory. Absence of the MCU resulted in (i) gamma oscillations with decreased power (by >40%) and lower synchrony, including less precise neural action potential generation (‘spiking'), (ii) sharp waves with decreased incidence (by about 22%) and decreased fast ripple frequency (by about 3%) and (iii) lack of activity-dependent pyruvate dehydrogenase dephosphorylation. However, compensatory adaptation in gene expression related to mitochondrial function and glucose metabolism was not detected. These data suggest that the neuronal MCU is crucial for the generation of network rhythms, most likely by influences on oxidative phosphorylation and perhaps by controlling cytoplasmic Ca2+ homeostasis. This work contributes to an increased understanding of mitochondrial Ca2+ uptake in cortical information processing underlying cognition and behaviour.
Innovation in Flow Cytometry Analysis: A New Paradigm Delineating Normal or Diseased Bone Marrow Subsets Through Machine Learning

Multiparameter ﬂ ow cytometry (MFC) has become an undisputed method for the diagnosis and follow-up of hematopoietic malignancies through the analysis of leukocyte subpopulations. 1 Although a lot of experience has been acquired in the routine application of this method, subjective approaches still remain the rule, responsible for the lack of standardization frequently perceived for this technique. The emergence of software allowing ﬁ nally for unsupervised assessment of normal hematopoietic differentiation, a long-nurtured dream, ﬁ nally rose from the development of mass cytometry (MC). 2 Here we report how the application of such novel software, in combination with ﬂ ow data analysis classical tools, allows for a better and original exploration of normal hematopoiesis pathways and, ultimately, disease and minimal residual disease (MRD) assessment. A classical widely used representation of MFC is the CD45/side scatter (SSC) biparametric histogram upon which various subsets, identi ﬁ ed through a series of supervised gates, can be backgated. 3 In this type of representation, immature progenitors are typically low SSC intermediate CD45 + cells and maturation toward the granulocytic, lymphoid or monocytic lineages can be appreciated as a continuum. However, a more precise delineation of maturation subsets cannot be performed with these approaches relying on arbitrary thresholds never directly considering all simultaneously acquired parameters together. The separation of pathological subsets in disease is hampered by the same subjective appreciations, in spite of efforts at harmonization. 4,5
Starter consortia for on-farm cocoa fermentation and their quality attributes

Abstract A starter consortium of Saccharomyces cerevisiae (Y), Lactobacillus plantarum (LAB), and Acetobacter aceti (AAB) was defined to ferment the Cocoa beans (Theobroma cacao). Emphasis was laid to optimize the microbial concentration with a functional ratio of selected cultures. A central composite rotatable design (CCRD) was employed to study the effect of inoculum size (0–20% w/v) with alcohol, titrable acidity, polyphenols, anthocyanin, cut test, and sensory as response variables. The significant (p < 0.05) response surface models with high coefficients of determination values (R2) ranging from 0.82 to 0.93 were considered for the experimental data, which represented the polynomial response models for describing the constraints. Based on the design, the concentration of consortia ranged 9.03X103 CFU/g of Y, 5.9X104 CFU/g of LAB, and 7.0X104 CFU/g of AAB. The graphical optimization of superimposed contour plots fulfilled the desired metabolites; alcohol (Y1) ≤ 11 mg/g, titrable acidity (Y2) ≥ 0.25%, polyphenols (Y3) ≤ 4.0 mg/g, anthocyanin (Y4) ≤ 14 mg/g, sensory (Y5) ≥ 6.0, and cut test (Y6)≥95%. Thus, validation through a field trial was confirmed to adopt the techno-economic feasibility on-farm process with precise inoculums. The effect of starter consortia on Cocoa fermentation and quality was found to be significant.
The IKs Ion Channel Activator Mefenamic Acid Requires KCNE1 and Modulates Channel Gating in a Subunit-Dependent Manner

The pairing of KCNQ1 and KCNE1 subunits together mediates the cardiac slow delayed rectifier current (IKs), which is partly responsible for cardiomyocyte repolarization and physiologic shortening of the cardiac action potential. Mefenamic acid, a nonsteroidal anti-inflammatory drug, has been identified as an IKs activator. Here, we provide a biophysical and pharmacological characterization of mefenamic acid’s effect on IKs. Using whole-cell patch clamp, we show that mefenamic acid enhances IKs activity in both a dose- and stoichiometry-dependent fashion by changing the slowly activating and deactivating IKs current into an almost linear current with instantaneous onset and slowed tail current decay, sensitive to the IKs blocker (3R,4S)-(+)-N-[3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy) chroman-4-yl]-N-methylmethanesulfonamide (HMR1556). Both single channels, which reveal no change in the maximum conductance, and whole-cell studies, which reveal a dramatically altered conductance-voltage relationship despite increasingly longer interpulse intervals, suggest mefenamic acid decreases the voltage sensitivity of the IKs channel and shifts channel gating kinetics toward more negative potentials. Modeling studies revealed that changes in voltage sensor activation kinetics are sufficient to reproduce the dose and frequency dependence of mefenamic acid action on IKs channels. Mutational analysis showed that mefenamic acid’s effect on IKs required residue K41 and potentially other surrounding residues on the extracellular surface of KCNE1, and explains why the KCNQ1 channel alone is insensitive to up to 1 mM mefenamic acid. Given that mefenamic acid can enhance all IKs channel complexes containing different ratios of KCNQ1 to KCNE1, it may provide a promising therapeutic approach to treating life-threatening cardiac arrhythmia syndromes. SIGNIFICANCE STATEMENT The channels which generate the cardiac slow delayed rectifier K+ current (IKs) are composed of KCNQ1 and KCNE1 subunits. Due to the critical role played by IKs in heartbeat regulation, enhancing IKs current has been identified as a promising therapeutic strategy to treat various heart rhythm diseases. Most IKs activators, unfortunately, only work on KCNQ1 alone and not the physiologically relevant IKs channel. We have demonstrated that mefenamic acid can enhance IKs in a dose- and stoichiometry-dependent fashion, regulated by its interactions with KCNE1.
MicroRNA-107 inhibits proliferation and invasion of laryngeal squamous cell carcinoma cells by targeting CACNA2D1 in vitro

Our previous studies have confirmed that α2δ1 has the potential to function as a cancer stem cell marker, and CACNA2D1 is the coding gene of α2δ1. But it is unclear how microRNAs regulate the expression of the CACNA2D1 gene in laryngeal cancer cells. We detected the expressions of α2δ1 protein, microRNA-107, and CACNA2D1 in 40 pairs of laryngeal cancer tissues and adjacent normal tissues. Laryngeal squamous cell carcinoma cells, TU212 and TU686, were cultured and transfected in the blank control group, the agomiR negative control group, the agomiR-107 group, the antagomiR negative control group, or the antagomiR-107 group, and the dual-luciferase reporter assay was employed to assess the regulatory effect of microRNA-107 on CACNA2D1. Then, the effects of microRNA-107 on the biological function of laryngeal squamous cell carcinoma cells were detected by qRT-PCR, Western blot, MTT, cell migration/invasion assay, and cell colony-formation assay. Our data suggested that the protein level of α2δ1, encoded by CACNA2D1, in laryngeal carcinoma tissues was higher than that in adjacent normal tissues, while the expression of microRNA-107 was significantly decreased in laryngeal carcinoma tissues. The dual-luciferase reporter gene assay confirmed that microRNA-107 bound to the 3′-UTR two positions (202-209, 902-908) of CACNA2D1 mRNA. Moreover, the expression of CACNA2D1 and α2δ1 protein were significantly decreased in TU212 and TU686 cells transfected with microRNA-107 expression vectors (P < 0.05), and proliferation, clone formation, migration, and invasion of these cells were also reduced. Furthermore, after knocking down microRNA-107, exactly opposite results were obtained. Overexpression of microRNA-107 can inhibit the proliferation and invasion of laryngeal carcinoma cells in vitro.
Activated leukocyte cell adhesion molecule regulates B lymphocyte migration across central nervous system barriers

Activated leukocyte cell adhesion molecule mediates B lymphocyte migration across central nervous system barriers. Crossing barriers Increasing evidence supports a critical role for B lymphocytes in multiple sclerosis (MS). Extravasation of B lymphocytes into the central nervous system promotes disease initiation and progression, and B lymphocyte–targeting therapies have shown potential benefits in experimental models and clinical trials. However, the mechanisms mediating B lymphocyte extravasation are unclear. Now, Michel et al. show that the adhesion molecule ALCAM promoted B lymphocyte extravasation. ALCAM-expressing B cells were increased in serum and brain of patients with MS, and the frequency of ALCAM-expressing B lymphocytes correlated with disease severity in a mouse model of autoimmune encephalomyelitis. Blocking ALCAM reduced disease severity in mice. The presence of B lymphocyte–associated oligoclonal immunoglobulins in the cerebrospinal fluid is a classic hallmark of multiple sclerosis (MS). The clinical efficacy of anti-CD20 therapies supports a major role for B lymphocytes in MS development. Although activated oligoclonal populations of pathogenic B lymphocytes are able to traffic between the peripheral circulation and the central nervous system (CNS) in patients with MS, molecular players involved in this migration have not yet been elucidated. In this study, we demonstrated that activated leukocyte cell adhesion molecule (ALCAM/CD166) identifies subsets of proinflammatory B lymphocytes and drives their transmigration across different CNS barriers in mouse and human. We also showcased that blocking ALCAM alleviated disease severity in animals affected by a B cell–dependent form of experimental autoimmune encephalomyelitis. Last, we determined that the proportion of ALCAM+ B lymphocytes was increased in the peripheral blood and within brain lesions of patients with MS. Our findings indicate that restricting access to the CNS by targeting ALCAM on pathogenic B lymphocytes might represent a promising strategy for the development of next-generation B lymphocyte–targeting therapies for the treatment of MS.
Concordant location of accessory pathways and tricuspid valve in AV discordance

Atrio-ventricular (A-V) discordance is an uncommon form of congenital heart disease.1 In patients with this abnormality, the right atrium is connected to the morphological left ventricle through the mitral valve and the left atrium to the morphological right ventricle through the tricuspid valve. A-V discordance is a 'sine qua non' feature of congenitally corrected transposition of the great arteries (cc-TGA). However, A-V discordance can also be associated with other congenital heart malformations, such as double outlet right ventricle. In cc-TGA, the concomitant ventriculo-arterial discordance (double discordance) physiologically corrects the pulmonary and systemic circulation, so that they remain in series. Thus, these patients are acyanotic and often remain asymptomatic until adulthood.2 This is more likely to occur when systemic right ventricular function is preserved and in the absence of concomitant severe defects such as ventricular septal defect, pulmonary outflow tract obstruction or systemic tricuspid valve regurgitation. However, patients with A-V discordance frequently present with arrhythmias even if they do not suffer from other congenital abnormalities. Conduction system disorders, A-V nodal reentrant tachycardia, and accessory A-V pathways (AP) account for a high incidence of arrhythmias in these patients. Why do these patients develop these arrhythmias even in the presence of near normal circulation? To answer this question, we need to understand the developmental abnormalities that occur as result of the peculiar anatomical arrangement in these patients. We will now discuss how the abnormal embryological development underlies the arrhythmias that arise in patients with A-V discordance. This article is protected by copyright. All rights reserved.
Quality Measurement of Serious Illness Communication: Recommendations for Health Systems Based on Findings from a Symposium of National Experts.

Background: Communication between clinicians and patients fundamentally shapes the experience of serious illness. There is increasing recognition that health systems should routinely implement structures and processes to assure high-quality serious illness communication (SIC) and measure the effectiveness of their efforts on key outcomes. The absence, underdevelopment, or limited applicability of quality measures related specifically to SIC, and their limited application only to those seen by specialist palliative and hospice care teams, hinder efforts to improve care planning, service delivery, and health outcomes for all seriously ill patients. Objective: We convened an expert stakeholder symposium and subsequently surveyed participants to consider challenges, opportunities, priorities, and strategies to improve quality measurement specific to SIC. Results: We identified several barriers and opportunities to improving quality measurement of SIC. These include issues related to the definition of SIC, methodological challenges related to measuring SIC and related outcomes, underutilization of technologies that can facilitate measurement, and measurement development, and dissemination. Conclusions: Patients, clinicians, and health systems increasingly align around the importance of high-quality communication in serious illness. We offer recommendations for various stakeholder groups to advance SIC quality measurement. Enthusiasm and a sense of urgency among health systems to drive and measure communication improvements inform our proposal for a set of example measures for implementation now.
Regulating ENaC's gate.

Epithelial Na+ channels (ENaCs) are members of a family of cation channels that function as sensors of the extracellular environment. ENaCs are activated by specific proteases in the biosynthetic pathway and at the cell surface that remove imbedded inhibitory tracts, which allows channels to transition to higher open probability states. Resolved structures of ENaC and an acid sensing ion channel revealed highly organized extracellular regions. Within the periphery of ENaC subunits are unique domains formed by anti-parallel ß strands containing the inhibitory tracts and protease cleavage sites. ENaCs are inhibited by Na+ binding to specific extracellular site(s) that promotes channel transition to a lower open probability state. Specific inositol phospholipids and channel modification by cys-palmitoylation enhance channel open probability. How these regulatory factors interact in a concerted manner to influence channel open probability is an important question that has not been resolved. These various factors are reviewed, and the impact of specific factors on human disorders is discussed.
Understanding osteoarthritis pathogenesis: a multiomics system-based approach.

PURPOSE OF REVIEW Osteoarthritis is a heterogenous, multifactorial condition regulated by complex biological interactions at multiple levels. Comprehensive understanding of these regulatory interactions is required to develop feasible advances to improve patient outcomes. Improvements in technology have made extensive genomic, transcriptomic, epigenomic, proteomic, and metabolomic profiling possible. This review summarizes findings over the past 20 months related to omics technologies in osteoarthritis and examines how using a multiomics approach is necessary for advancing our understanding of osteoarthritis as a disease to improve precision osteoarthritis treatments. RECENT FINDINGS Using the search terms 'genomics' or 'transcriptomics' or 'epigenomics' or 'proteomics' or 'metabolomics' and 'osteoarthritis' from January 1, 2018 to August 31, 2019, we identified advances in omics approaches applied to osteoarthritis. Trends include untargeted whole genome, transcriptome, proteome, and metabolome analyses leading to identification of novel molecular signatures, cell subpopulations and multiomics validation approaches. SUMMARY To address the complexity of osteoarthritis, integration of multitissue analyses by multiomics approaches with the inclusion of longitudinal clinical data is necessary for a comprehensive understanding of the disease process, and for appropriate development of efficacious diagnostics, prognostics, and biotherapeutics.
CIN III and cervical SCC with negative oncogenic HPV PCR: A case series

With the recent introduction of the renewed National Cervical Screening Program (NCSP) in Australia, utilising primary human papillomavirus (HPV) nucleic acid testing (NAT) for known oncogenic HPV types rather than cervical cytology, we reflect on three asymptomatic women with negative oncogenic HPV test results and high‐grade cervical abnormalities including cervical intraepithelial neoplasia (CIN) III and cervical squamous cell carcinoma (SCC). The two cases with CIN III had a ‘probable’ oncogenic subtype (HPV 53) identified on further testing, while the case of SCC had no HPV virus identified. These cases serve as a reminder of the need for ongoing diligence despite low‐risk screening under the new program.
A transposed-word effect in same-different judgments to sequences of words.

The present study examined transposed-word effects in a same-different matching task with sequences of 5 words. The word sequences were presented one after the other, each for 400 ms, the first in lowercase and the second in uppercase. The first sequence, the reference, was either a grammatically correct sentence or a scrambled ungrammatical sequence of the same words. The second sequence, the target, was either the same as the reference or differed either by transposing the second and third words or the third and fourth words in the first sequence or by replacing the same 2 words with different words in Experiment 1 or by a single word replacement in Experiment 2. The results showed that "same" responses were easier to make with grammatically correct references and that "different" responses were harder to make when the difference involved a transposition compared with a replacement. This transposed-word effect was found to be independent of reference grammaticality in Experiment 1. Experiment 2 again found a transposed-word effect for ungrammatical sequences, but here the effect was reduced compared with grammatical sequences. The effects found with ungrammatical sequences are taken to reflect the noisy bottom-up association of word identities to locations along a line of text, and this process combines with the influence of top-down grammatical constraints when "different" judgments are harder to make. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
Application of Interspecies Correlation Estimation (ICE) models and QSAR in estimating species sensitivity to pesticides

ABSTRACT Ecological risk assessment is challenged by the need to assess hazard to the diverse communities of organisms inhabiting aquatic and terrestrial systems. Computational approaches, such as Quantitative Structure Activity Relationships (QSAR) and Interspecies Correlation Estimation (ICE) models, are useful tools that provide estimates of acute toxicity where data are lacking or limited for ecological risk assessments (ERA). This review describes the technical basis of ICE models for use in pesticide ERA that may be used in conjunction with QSAR model estimates or surrogate species toxicity data and demonstrates the potential for improving hazard assessment. Validation and uncertainty analysis of ICE model predictions are summarized and used as guidance for selecting ICE models and evaluating toxicity predictions. A user-friendly web-based ICE modelling platform (Web-ICE) is described and demonstrated through case studies. Case studies include the development of Species Sensitivity Distributions generated from QSAR and ICE estimates, comparative sensitivity for a pesticide and its degradate, and application of ICE-estimated toxicity values for listed species assessments.