Miracle-dz/UniFAR-FTUs huggingface dataset:
The interpretation of computational model parameters depends on the context

Reinforcement Learning (RL) models have revolutionized the cognitive and brain sciences, promising to explain behavior from simple conditioning to complex problem solving, to shed light on developmental and individual differences, and to anchor cognitive processes in specific brain mechanisms. However, the RL literature increasingly reveals contradictory results, which might cast doubt on these claims. We hypothesized that many contradictions arise from two commonly-held assumptions about computational model parameters that are actually often invalid: That parameters generalize between contexts (e.g., tasks, models) and that they capture interpretable (i.e., unique, distinctive) neurocognitive processes. To test this, we asked 291 participants aged 8-30 years to complete three learning tasks in one experimental session, and fitted RL models to each. We found that some parameters (exploration / decision noise) showed significant generalization: they followed similar developmental trajectories, and were reciprocally predictive between tasks. However, generalization was significantly below ceiling. Furthermore, other parameters (learning rates, forgetting) did not show evidence of generalization, and sometimes even opposite developmental trajectories. Interpretability was low for all parameters. We conclude that the systematic study of context factors (e.g., reward stochasticity; task volatility) will be necessary to enhance the generalizability and interpretability of computational cognitive models. Highlights Computational cognitive modeling often makes two implicit assumptions: 1) Model parameters generalize between studies and models. 2) Parameters are interpretable, i.e., neurally, cognitively, and/or mechanistically specific. We empirically investigate these assumptions in Reinforcement Learning (RL), using a large developmental dataset featuring three different learning tasks in a within-participant design. We find that no parameters generalize between tasks in terms of absolute parameter values. However, RL decision noise/exploration parameters generalize in terms of between-participant variation, showing similar age trajectories across tasks. Interpretability was low for all parameters, especially those related to learning and memory. Even for parameters that showed generalization, the degree of generalization was significantly lower than in an artificial sample with perfect generalization for most parameters, revealing a relative lack of generalization. These findings are in accordance with previous claims about the developmental trajectory of decision noise/exploration parameters, but suggest that claims about the development of learning rates or Forgetting might not be generalizable: these parameters are unlikely to capture the same neuro-cognitive processes across different tasks. We suggest ways forward to improve the generalizability and interpretability of model parameters, in particular by focusing more on task context.
ErpY-like lipoprotein of Leptospira outsmart host complement regulation by acquiring complement regulators, activating alternate pathway, and intervening membrane attack complex

The survival of pathogenic Leptospira in the host pivots on its proficiency to circumvent the immune response. These pathogens evade the complement system in serum by enticing and amassing the serum complement regulators onto their surface. ErpY-like lipoprotein, a surface-exposed protein of Leptospira spp. , is conserved and exclusively present in the pathogenic spirochete. The recombinant form of this protein is comprehended to interact with multiple extracellular matrix (ECM) components and serum proteins like soluble complement regulators factor H (FH) and factor I (FI). Here, we document that the supplementation of recombinant ErpY-like protein (40 µg/mL) in the host (humans) serum augments the viability of E. coli and saprophytic L. biflexa by more than 2-fold. Pure complement regulators FH and FI, when bound to rErpY-like protein, preserve their respective cofactor and protease activity mandated to cleave the complement component C3b. The supplementation of rErpY-like protein (40 µg/mL) in serum ensued in ∼90 % reduction of membrane attack complex (C5b-9/MAC) deposition through alternate complement pathway (AP) activation. However, rErpY-like protein could moderately reduce (∼16%) MAC deposition in serum through the classical pathway (CP). In addition, the rErpY-like protein solely activated the AP, suggesting its role in the rapid consumption and depletion of the complement components. Blocking the pathogenic L. interrogans surface with anti-rErpY resulted in an increase in MAC formation on the bacterial surface, indicating a specific role of the ErpY-like lipoprotein in complement-mediated immune evasion. This study underscores the role of the ErpY-like lipoprotein of Leptospira in complement evasion.
Late-in-life treadmill-training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts

There is evidence for a progressive decline of protein quality control mechanisms during the process of cardiac aging. This enables the accumulation of protein aggregates and damaged organelles that contribute to age-associated cardiac dysfunction. Macroautophagy (referred to as autophagy) is the process by which post-mitotic cells such as cardiomyocytes clear defective proteins and organelles. We hypothesized that late-in-life exercise training improves autophagy, protein aggregate clearance, and function that is otherwise dysregulated in hearts from old vs adult mice. As expected, 24-month old male C57BL/6J mice (old) exhibited : (i) repressed autophagosome formation and protein aggregate accumulation in the heart; (ii) systolic and diastolic dysfunction; and (iii) reduced exercise capacity, vs. 8-month old (adult) mice (all p< .05). Separate cohorts of 21 month old mice completed a 3-month progressive resistance treadmill-running program (old-ETR) that improved (all < .05) : (i) body composition; (ii) exercise capacity; and (iii) soleus muscle citrate synthase activity, vs. age-matched mice that did not train (old-SED). Importantly, (iv) protein expression of autophagy markers indicated trafficking of the autophagosome to the lysosome increased, (v) protein aggregate clearance improved, and (vi) overall function was enhanced (all p<0.05), in hearts from old-ETR vs. old- SED mice. Dietary maneuvers and pharmacological interventions shown to elevate basal autophagy are reported to mitigate / reverse age-associated cardiac dysfunction. Here we show the first evidence that a physiological intervention initiated late-in-life improves autophagic flux, protein aggregate clearance, and overall function in mouse hearts.
Identifying and classifying goals for scientific knowledge

Motivation Science progresses by posing good questions, yet work in biomedical text mining has not focused on them much. We propose a novel idea for biomedical natural language processing: identifying and characterizing the questions stated in the biomedical literature. Formally, the task is to identify and characterize ignorance statements, statements where scientific knowledge is missing or incomplete. The creation of such technology could have many significant impacts, from the training of PhD students to ranking publications and prioritizing funding based on particular questions of interest. The work presented here is intended as the first step towards these goals. Results We present a novel ignorance taxonomy driven by the role ignorance statements play in the research, identifying specific goals for future scientific knowledge. Using this taxonomy and reliable annotation guidelines (inter-annotator agreement above 80%), we created a gold standard ignorance corpus of 60 full-text documents from the prenatal nutrition literature with over 10,000 annotations and used it to train classifiers that achieved over 0.80 F1 scores. Availability Corpus and source code freely available for download at https://github.com/UCDenver-ccp/Ignorance-Question-Work. The source code is implemented in Python. Contact Mayla.Boguslav@CUAnshcutz.edu
Decomposition of the SARS-CoV-2-ACE2 interface reveals a common trend among emerging viral variants

New viral variants of the SARS-CoV-2 virus show enhanced infectivity compared to wild type, resulting in an altered pandemic situation in affected areas. These variants are the B.1. 1.7 (United Kingdom), B.1. 1.7 with the additional E484K mutation, the B.1. 351 variant (South Africa) and the P.1 variant (Brazil). Understanding the binding modalities between these viral variants and the host cell receptor ACE2 allows depicting changes, but also common motifs of virus-host cell interaction. The trimeric spike protein expressed at the viral surface contains the receptor-binding domain (RBD) that forms the molecular interface with ACE2. All the above-mentioned variants carry between one and three amino acid exchanges within the interface-forming region of the RBD, thereby altering the binding interface with ACE2. Using molecular dynamics simulations and decomposition of the interaction energies between the RBD and ACE2, we identified phenylalanine 486, glutamine 498, threonine 500 and tyrosine 505 as important interface-forming residues across viral variants. We also suggest a reduced binding energy between RBD and ACE2 in viral variants with higher infectivity, attributed to residue-specific differences in electrostatic interaction energy. Importantly, individual amino acid exchanges not only influence the affected position, but also alter the conformation of surrounding residues and affect their interaction potential as well. We demonstrate how computational methods can help to identify changed as well as common motifs across viral variants. These identified motifs might play a crucial role, in the strategical development of therapeutic interventions against the fast mutating SARS-CoV-2 virus. Significance Statement The COVID-19 pandemic caused by the SARS-CoV-2 virus has significantly changed our lives. To date, there is a lack of neutralizing drugs that specifically target SARS-CoV-2. Hope lies in newly developed vaccines that effectively prevent severe cases of acute respiratory syndrome. However, emerging viral variants escape vaccine-induced immune-protection. Therefore, identification of appropriate molecular targets across viral variants is important for the development of second- and third-generation vaccines and inhibitory antibodies. In this study, we identify residues across viral variants that are important for viral binding to the host cell. As such residues cannot be replaced without diminishing infectivity of the virus, these residues represent primary targets for intervention, for example by neutralizing antibodies.
Diverse Genetic Determinants of Nitrofurantoin Resistance in UK Escherichia coli

Antimicrobial resistance in enteric or urinary Escherichia coli is a risk factor for invasive E. coli infections. Due to widespread trimethoprim resistance amongst urinary E. coli and increased bacteraemia incidence, a national recommendation to prescribe nitrofurantoin for uncomplicated urinary tract infection was made in 2018. Nitrofurantoin resistance is reported in <6% urinary E. coli isolates in the UK. However, mechanisms underpinning nitrofurantoin resistance in these isolates remain unknown. This study aimed to identify genetic determinants of nitrofurantoin resistance in a local E. coli collection and assess their prevalence in a larger dataset of E. coli genomes. Deleterious point mutations and gene-inactivating insertion sequences in both chromosomal nitroreductase genes nfsA and nfsB were identified in genomes of nine nitrofurantoin-resistant urinary E. coli isolates collected from north west London. Eight types of genetic alterations were identified when comparing sequences of nfsA, nfsB, and the associated gene ribE in 12,412 E. coli genomes collected from across the UK. Evolutionary analysis revealed homoplasic mutations and explained the order of stepwise mutations. An algorithm was developed to predict nitrofurantoin susceptibility and predictions for 20 accessible isolates were experimentally validated. Only one genome carrying oqxAB, a mobile gene complex associated with reduced nitrofurantoin susceptibility, was identified. In conclusion, mutations and insertion sequences in nfsA and nfsB are leading causes of nitrofurantoin resistance in UK E. coli. As nitrofurantoin exposure increases in human populations, the prevalence of nitrofurantoin resistance in carriage E. coli isolates and those from urinary and bloodstream infections should be monitored. Importance This study expands knowledge about the genetic basis of nitrofurantoin resistance in E. coli isolates using whole-genome sequencing and genomic analysis. We report novel and previously known deleterious mutations of chromosomal genes nfsA, nfsB, and ribE as well as the interruption of nfsA and nfsB by insertion sequences, recapitulating the roles of oxygen-insensitive nitroreductases in the development of nitrofurantoin resistance in E. coli. We revealed and categorised the genotypic diversity in these three genes in a large collection of UK E. coli genomes. A scoring algorithm is provided to predict nitrofurantoin susceptibility from genotypes. Our predictions suggest that acquired nitrofurantoin resistance is not of immediate concern in the UK. However, experimental validation of predictions suggested the involvement of mechanisms other than alterations in nfsA, nfsB, or ribE in determining nitrofurantoin susceptibility, emphasising the need for monitoring nitrofurantoin resistance amongst E. coli.
Levelling out differences in aerobic glycolysis neutralizes the competitive advantage of oncogenic PIK3CA mutant progenitors in the esophagus

Normal human tissues progressively accumulate cells carrying mutations. Activating mutations in PIK3CA generate large clones in the aging human esophagus, but the underlying cellular mechanisms are unclear. Here, we tracked mutant PIK3CA esophageal progenitor cells in transgenic mice by lineage tracing. Expression of an activating heterozygous Pik3caH1047R mutation in single progenitor cells tilts cell fate towards proliferation, generating mutant clones that outcompete their wild type neighbors. The mutation leads to increased aerobic glycolysis through the activation of Hif1α transcriptional targets compared with wild type cells. We found that interventions that level out the difference in activation of the PI3K/HIF1α/aerobic glycolysis axis between wild type and mutant cells attenuate the competitive advantage of Pik3caH1047R mutant cells in vitro and in vivo. Our results suggest that clinically feasible interventions that even out signaling imbalances between wild type and mutant cells may limit the expansion of oncogenic mutants in normal epithelia.
Toward an Emotional Individual Motor Signature

Bodily expression of felt emotion has been documented in the literature. However, it is often associated with high motor variability between individuals. This study aimed to identify individual motor signature (IMS) of emotions. IMS is a new method of motion analysis and visualization able to capture the subtle differences in the way each of us moves, seen as a kinematic fingerprint. We hypothesized that the individual motor signature would be different depending on the induced emotional state and that an emotional motor signature of joy and sadness common to all participants would emerge. For that purpose, we elicited these emotions (joy, sadness, and a neutral control emotion) in 26 individuals using an autobiographical memory paradigm, before they performed a motor improvization task (e.g., the mirror game). We extracted the individual motor signature under each emotional condition. Participants completed a self-report emotion before and after each trial. Comparing the similarity indexes of intra- and inter-emotional condition signatures, we confirmed our hypothesis and showed the existence of a specific motor signature for joy and sadness, allowing us to introduce the notion of emotional individual motor signature (EIMS). Our study indicates that EIMS can reinforce emotion discrimination and constitutes the first step in modeling emotional behavior during individual task performances or social interactions.
A Comprehensive Review of the Chemistry, Pharmacokinetics, Pharmacology, Clinical Applications, Adverse Events, and Quality Control of Indigo Naturalis

Indigo naturalis (IN), which is derived from indigo plants such as Strobilanthes cusia (Nees) Kuntze, Persicaria tinctoria (Aiton) Spach, and Isatis tinctoria L. , has been traditionally used in the treatment of hemoptysis, epistaxis, chest pain, aphtha, and infantile convulsion in China for thousands of years. Clinical trials have shown that the curative effect of IN for psoriasis and ulcerative colitis (UC) is remarkable. A total of sixty-three compounds, including indole alkaloids, terpenoids, organic acids, steroids, and nucleosides, have been isolated from IN, of which indole alkaloids are the most important. Indirubin, isolated from IN, was used as a new agent to treat leukemia in China in the 1970s. Indirubin is also an active ingredient in the treatment of psoriasis. Pharmacological studies have confirmed that IN has inhibitory effects on inflammation, tumors, bacteria, and psoriasis. Indigo, indirubin, tryptanthrin, isorhamnetin, indigodole A, and indigodole C are responsible for these activities. This review provides up-to-date and comprehensive information on IN with regard to its chemistry, pharmacokinetics, pharmacology, clinical applications, adverse events, and quality control. This review may also serve a reference for further research on IN.
Developmental Changes in Pyramidal Cell Morphology in Multiple Visual Cortical Areas Using Cluster Analysis

Neuronal morphology is characterized by salient features such as complex axonal and dendritic arbors. In the mammalian brain, variations in dendritic morphology among cell classes, brain regions, and animal species are thought to underlie known differences in neuronal function. In this work, we obtained a large dataset from http://neuromorpho.org/ comprising layer III pyramidal cells in different cortical areas of the ventral visual pathway (V1, V2, V4, TEO, and TE) of the macaque monkey at different developmental stages. We performed an in depth quantitative analysis of pyramidal cell morphology throughout development in an effort to determine which aspects mature early in development and which features require a protracted period of maturation. We were also interested in establishing if developmental changes in morphological features occur simultaneously or hierarchically in multiple visual cortical areas. We addressed these questions by performing principal component analysis (PCA) and hierarchical clustering analysis on relevant morphological features. Our analysis indicates that the maturation of pyramidal cell morphology is largely based on early development of topological features in most visual cortical areas. Moreover, the maturation of pyramidal cell morphology in V1, V2, V4, TEO, and TE is characterized by unique developmental trajectories.
Theranostic Terbium Radioisotopes: Challenges in Production for Clinical Application

Currently, research on terbium has gained a momentum owing to its four short-lived radioisotopes, 149Tb, 152Tb, 155Tb, and 161Tb, all of which can be considered in one or another field of nuclear medicine. The members of this emerging quadruplet family have appealing nuclear characteristics and have the potential to do justice to the proposed theory of theranostics nuclear medicine, which amalgamates therapeutic and diagnostic radioisotopes together. The main challenge for in vivo use of these radioisotopes is to produce them in sufficient quantity. This review discusses that, at present, neither light charged particle nor the heavy ion (HI) activation are suitable for large-scale production of neutron deficient terbium nuclides. Three technological factors like (i) enrichment of stable isotopes to a considerable level, (ii) non-availability of higher energies in commercial cyclotrons, and (iii) non-availability of the isotope separation technique coupled with commercial accelerators limit the large scale production of terbium radionuclides by light charged particle activation. If in future, the technology can overcome these hurdles, then the light charged particle activation of enriched targets would produce a high amount of useful terbium radionuclides. On the other hand, to date, the spallation reaction coupled with an online isotope separator has been found suitable for such a requirement, which has been adopted by the CERN MEDICIS programme. The therapeutic 161Tb radionuclide can be produced in a reactor by neutron bombardment on enriched 160Gd target to produce 161Gd which subsequently decays to 161Tb. The radiochemical separation is mandatory even if the ISOL technique is used to obtain high radioisotopic purity of the desired radioisotope.
Processing of Complement Coercion With Aspectual Verbs in Mandarin Chinese: Evidence From a Self-Paced Reading Study

This study examines whether Chinese complement coercion sentences with aspectual verbs will elicit processing difficulty during real-time comprehension. Complement coercion is a linguistic phenomenon in which certain verbs (e.g., start, enjoy), requiring an event-denoting complement, are combined with an entity-denoting complement (e.g., book), as in The author started a book. Previous studies have reported that the entity-denoting complement elicited processing difficulty following verbs that require event argument compared with verbs that do not (e.g., The author wrote a book). While the processing of complement coercion has been extensively studied in Indo-European languages such as English and German, it is relatively under-researched in Sino-Tibetan languages such as Mandarin Chinese. Given the fact that there are many linguistic elements behaving distinctly in the different language families, for instance, verbs with respect to their semantic properties and syntactic representations of the complement, it is meaningful to investigate whether or not the existing linguistic differences have any effect on the processing of complement coercion in Mandarin. With this research goal, we recorded self-paced reading time of 61 native Mandarin speakers to investigate the processing of the entity-denoting complement in sentences with three different verb types (aspectual verbs which require an event-denoting complement, preferred verbs which denote a preferred interpretation of the aspectual expressions, and non-preferred verbs which denote a non-preferred but plausible interpretation of the aspectual expressions), as exemplified in 顾客开始/填写/查看这份问卷 gù-kè kāi-shǐ/tián-xiě/chá-kàn zhè-fèn wèn-juàn “The customer started/filled in/checked the questionnaire. ” It was found that the entity noun complement (e.g., 这份问卷 zhè-fèn wèn-juàn “the questionnaire”) elicited significantly longer reading times in coercion sentences than non-coercion counterparts. The results are compatible with the previous findings in English that complement coercion sentences impose processing cost during real-time comprehension. The study contributes empirical evidence to coercion studies cross-linguistically.