Miracle-dz/UniFAR-FTUs huggingface dataset:
Loss of tristetraprolin activates NF-κB induced phenotypic plasticity and primes transition to lethal prostate cancer

Phenotypic plasticity is a hallmark of cancer and increasingly realized as a mechanism of resistance in androgen indifferent prostate tumors. It is critical to identify mechanisms and actionable targets driving phenotypic plasticity. Here, we report that loss of tristetraprolin (TTP, gene ZFP36), an RNA binding protein that regulates mRNA stability increases NF-κB activation and is associated with higher rates of aggressive disease and early recurrence in primary prostate cancer (PCa). We examined the clinical and biological impact of ZFP36 loss combined with PTEN loss, a known driver of PCa. Combined loss of PTEN and ZFP36 expression was associated with increased risk of recurrence in multiple independent primary PCa cohorts, and significantly reduced overall survival and time to progression following castration in genetically engineered mouse models. ZFP36 loss alters the cell state that is driven by PTEN loss, demonstrated by positive enrichment of gene sets including EMT, inflammation, TNFα/NF-κB, IL6-JAK/STAT3. ZFP36 loss also induces enrichment of multiple gene sets involved in cell migration, chemotaxis, and proliferation. Use of the NF-κB inhibitor dimethylaminoparthenolide induced significant therapeutic responses in tumors with PTEN and ZFP36 co-loss and reversed castration resistance. This work identifies a novel molecular mechanism driving phenotypic plasticity and castration resistance through loss of ZFP36 expression, that can be reversed by inhibition of NF-κB activity.
Statistical Learning Emerges from Temporally Preparing What Action to Perform Where

Statistical learning is the ability to exploit regularities of our world to predict what will happen when. Recently, we developed the Whac-A-Mole (WAM) paradigm to study whether participants can capitalize upon regularities embedded in complex temporal structures. Although participants were unaware of any regularity in WAM, we found better performance for targets with regular versus irregular intervals. Under the framework of statistical learning, this performance benefit can be understood to arise from distilling these regular intervals and predicting regular target onsets in a manner impossible for irregular targets. Intriguingly, here we instead found that this performance benefit emerges from preparation to a range of other temporal properties that we initially considered to be random. Participants temporally prepared, in parallel, for different actions to perform and locations to attend, without evidence that regular targets were responded to differently than irregular ones. With more time to prepare, participants gave faster and more accurate responses. Using a recent model of temporal preparation, f MTP, we illustrate that such complex temporal adaptation can arise from the memory processes underlying temporal preparation. In a broader sense, our results closely relate to theoretical work showing that statistical learning can emerge from general memory processes.
A single-molecule method for measuring fluorophore labeling yields for the study of membrane protein oligomerization in membranes

Membrane proteins are often structured as higher-order oligomers. Yet, the role of these specific assemblies is not always apparent, raising the question of whether differential oligomerization states can be linked to modulation of function. To better understand this hypothetical regulatory mechanism, there is an ongoing effort to quantify equilibrium reactions of membrane proteins in membranes. Single-molecule photobleaching analysis is particularly useful for this as it provides a binary readout of fluorophores attached to protein subunits at dilute conditions. The subunit capture method adds consideration of the Poisson probability of protein partitioning into liposomes from large equilibrium membranes. If the liposome size distribution is known, then the capture statistics can be modeled with accuracy to quantify oligomerization as a function of membrane density to obtain binding isotherms, as was demonstrated for the dimeric chloride/proton antiporter CLC-ec1. However, any quantification of stoichiometry also critically requires knowing the probability that a subunit is fluorescently labeled. Since labeling uncertainty is often unavoidable, we tested an alternate approach to estimate labeling yields using the photobleaching probability of an intrinsic dimeric control, the disulfide cross-linked R230C/L249C CLC-ec1. By iterative fitting of the experimental dimeric photobleaching probability distribution to a dimer model while varying labeling parameters, we predict the labeling yields measured by direct absorbance measurements of the purified protein before reconstitution. Finally, the average predicted labeling yield over multiple samples is used to estimate the dissociation constant of CLC-ec1 dimerization reactions, eliminating the need to quantify fluorophore labeling a priori. This approach can be generalized to study dimerization reactions where an irreversible dimeric control can be prepared. Thus, our study maps out a new method for quantifying fluorophore occupancy in samples that cannot be purified directly and improves quantification of membrane protein stoichiometry in membranes.
Heart rate variability during mindful breathing meditation

In this article, we discuss Heart Rate Variability (HRV) measured during mindful breathing meditation. We provide a pedagogical computation of 2 commonly used HRV metrics, i.e. the root mean square of successive differences (RMSSD) and the standard deviation of RR intervals (SDRR), in terms of Fourier components. It is shown that the RMSSD preferentially weights higher frequency Fourier modes, making it unsuitable as a biosignal for mindful breathing meditation which encourages slow breathing. We propose a new metric called the autonomic balance index (ABI) which uses Respiratory Sinus Arrhythmia to quantify the fraction of HRV contributed by the parasympathetic nervous system. We apply this metric to HRV data collected during two different meditation techniques, and show that the ABI is significantly elevated during mindful breathing, making it a good signal for biofeedback during meditation sessions.
Greater resistance to footshock punishment in female C57BL/6J mice responding for ethanol

Background One characteristic of alcohol use disorder (AUD) is compulsive drinking, or drinking despite negative consequences. When quinine is used to model such aversion-resistant drinking, female rodents typically are more resistant to punishment than males. Using an operant response task where C57BL/6J responded for ethanol (EtOH) mixed with quinine, we previously demonstrated that female mice tolerate higher concentrations of quinine in EtOH than males. Here, we aimed to determine if this female vulnerability to aversion-resistant drinking behavior is similarly observed when footshock punishment is used. Methods Male and female C57BL/6J mice were trained to respond for 10% EtOH in an operant task on a fixed ratio 3 schedule. After consistent responding, mice were tested in a punishment session using either a 0.25 mA or 0.35 mA footshock. To assess footshock sensitivity, a subset of mice underwent a flinch, jump, vocalize test in which behavioral responses to increasing amplitudes of footshock (0.05 – 0.95 mA) were assessed. In a separate cohort of mice, males and females were trained to respond for 2.5% sucrose and responses were punished using a 0.25 mA footshock. Results Males and females continued to respond for 10% EtOH when paired with a 0.25 mA footshock. Females alone continued to respond for EtOH when a 0.35 mA footshock was delivered. Both males and females reduced responding for 2.5% sucrose when punished with a 0.25 mA footshock. Finally, footshock sensitivity in the flinch, jump, vocalize test did not differ by sex. Conclusions Females continue to respond for 10% EtOH despite a 0.35 mA footshock and this behavior is not due to differences in footshock sensitivity between males and females. These results suggest that female C57BL/6J mice are generally more resistant to punishment in an operant self-administration paradigm. These results add to the literature characterizing aversion-resistant alcohol drinking behaviors in females.
SARS-CoV-2 entry route impacts a range of downstream viral and cellular processes

SARS-CoV-2 entry is promoted by both cell-surface TMPRSS2 and endolysosomal cathepsins. To investigate the impact of differentially routed virions on host and viral processes, lung epithelial cells expressing distinct combinations of entry factors were infected with authentic viruses. Entry route determined early rates of viral replication and transcription, egress and inhibitor sensitivity, with differences observed between virus strains. Transcriptional profiling revealed that induction of innate immunity was correlated to viral genome and transcript abundance in infected cells. Surface entry triggered early activation of antiviral responses, reducing cumulative virion production, while endolysosomal entry delayed antiviral responses and prolonged virus shedding due to extended cell viability. The likely molecular footprints of escape from antiviral effector targeting were also recorded in viral genomes and correlated with entry route-dependent immune status of cells. TMPRSS2 orthologues from diverse mammals, but not zebra fish, facilitated infection enhancement, which was more pronounced for ancestral strains. Leveraging RNA-seq and scRNA-seq datasets from SARS-CoV-2 infected hamsters, we validate aspects of our model in vivo. In summary, we demonstrate that distinct cellular and viral processes are linked to viral entry route, collectively modulating virus shedding, cell-death rates and viral genome evolution.
Intra-peritoneal transplantation for efficient and easy generation of experimental acute myeloid leukemia in mice

Objective There is an unmet need for novel therapies to treat acute myeloid leukemia (AML) and the associated relapse that involves leukemia stem cells (LSCs). An experimental AML rodent model to test therapies based on successfully transplanting these cells via retro-orbital injections in recipient mice is fraught with challenges. The aim of this study was to develop an easy, reliable, and consistent method to generate a robust murine model of AML using an intra-peritoneal route. Methods Bone marrow cells were transduced with a retrovirus expressing human MLL-AF9 fusion oncoprotein. Efficiency of lineage negative (Lin−) and Lin−Sca-1+c-Kit+ (LSK) populations as donor LSCs in the development of primary AML was tested. We developed a new method to generate AML by intra-peritoneal injection and discuss the pros and cons of intra-peritoneal and retro-orbital injections in serial transplantations. Results Both Lin− and LSK cells transduced with human MLL-AF9 virus engrafted well in the bone marrow and spleen of recipients, leading to a full-blown AML. Intra-peritoneal injection of donor cells established AML in recipients upon serial transplantation.Infiltration of AML cells was detected in the blood, bone marrow, spleen, and liver of recipients by flow cytometry, qPCR, and histological analyses. Conclusions Intra-peritoneal injection is an efficient method of AML induction using serial transplantation of donor cells. Delayed homing to bone marrow, seen in intra-peritoneal injection that impedes the progression of AML, can be easily overcome by increasing the number of transplanted donor cells. Increasing the number of transplanted donor cells can also help shorten the duration of onset of AML. Sorting of LSK population within donor cells is not necessary in the generation of MLL-AF9-induced primary AML given that Lin− population are equally efficient as LSK donor cells in primary transplantation of AML in mice.
Protein Geometry, Function and Mutation

This survey for mathematicians summarizes several works by the author on protein geometry and protein function with applications to viral glycoproteins in general and the spike glycoprotein of the SARS-CoV-2 virus in particular. Background biology and biophysics are sketched. This body of work culminates in a postulate that protein secondary structure regulates mutation, with backbone hydrogen bonds materializing in critical regions to avoid mutation, and disappearing from other regions to enable it.
Human activities impact microbial communities of Amazon Mangroves

Mangroves provide a unique ecological environment for complex microbial communities. They are particularly important in controlling the chemical environment of the ecosystem. Microbial diversity analyses of these ecosystems help us understand the environmental dynamics and the changes due to impacts. Amazonian mangroves are distributed across Amapá, Pará and Maranhão states occupying an area of 9,000 km2 and correspond to 70% of the mangroves in Brazil, in which studies on microbial biodiversity are extremely rare. The present study aimed to determine changes in microbial community structure along the PA-458 highway that divided the mangrove. Mangrove samples were collected from three zones, (i) under anthropogenic actions, (ii) in the process of recovery and (ii) preserved. Total DNA was extracted, submitted for 16S rDNA amplification and sequenced on the Illumina MiSeq platform. Reads were analyzed using USEARCH tools and packages available in R Platform. The most abundant phyla were Proteobacteria, followed by Firmicutes and Bacteroidetes in all three mangrove locations. Genera such as Desulfuromonas, Desulfatiglans, Collinsella, Dorea, Dialister were not found in the impacted mangrove. The impacted mangrove proved to be ecologically different from other mangroves. Our results show that human impact in the mangrove areas has resulted in loss of biodiversity, caused by the construction of the PA-458 highway, reducing the support and maintenance of habitat life and the ecosystem’s resilience to disturbance.
The hologenome of Osedax frankpressi reveals the genetic interplay for the symbiotic digestion of vertebrate bone

The marine annelid Osedax has evolved a unique heterotrophic symbiosis that allows it to feed exclusively on sunken bones. Yet, the genetic and physiological principles sustaining this symbiosis are poorly understood. Here we show that Osedax frankpressi has a small, AT-rich genome shaped by extensive gene loss. While the Oceanospirillales endosymbiont of Osedax is enriched in genes for carbohydrate and nitrogen metabolism, O. frankpressi has undergone genetic changes to accommodate bone digestion, including the expansion of matrix metalloproteases, and a loss of pathways to synthesize amino acids that are abundant in collagen. Unlike other symbioses, however, innate immunity genes required to acquire and control the endosymbionts are reduced in O. frankpressi. These findings reveal Osedax has evolved an alternative genomic toolkit to bacterial symbiosis where host-symbiont co-dependence has favoured genome simplicity in the host to exploit the nutritionally unbalanced diet of bones. Teaser Genome reduction and adaptations for collagen digestion underpin the symbiosis of Osedax worms to exploit decaying bones.
Novel transient cell clusters provide a possible link between early neural activity and angiogenesis in the neonatal mouse retina

Developing neurons become spontaneously active while growing blood vessels begin to irrigate their surroundings. However, surprising little is known about early interactions between neural activity and angiogenesis. In the neonatal mouse retina, spontaneous waves of impulses sweep across the ganglion cell layer (GCL), just underneath the growing superficial vascular plexus. We discovered clusters of transient auto-fluorescent cells in the GCL, forming an annulus that co-localizes with the frontline of the growing plexus. Blood vessel density is highest within cluster areas, suggesting their involvement in angiogenesis. Once the clusters and blood vessels reach the retinal periphery by the end of the first postnatal week, the clusters disappear, eliminated by microglial phagocytosis. Electrical imaging suggests that they have their own electrophysiological signature. Blocking Pannexin1 (PANX1) hemi-channels with probenecid blocks the waves and the fluorescent clusters disappear following prolonged exposure to the drug. Spontaneous waves’ initiation points follow a developmental center-to-periphery progression similar to the cluster cells. We suggest that these transient cells are specialized, hyperactive neurons residing in the GCL. They generate spontaneous activity hotspots, thereby triggering waves through purinergic paracrine signaling via PANX1 hemi-channels. The strong activity generated around these hotspots triggers angiogenesis, attracting new blood vessels that provide local oxygen supply. Signaling through PANX-1 attracts microglia that establish contact with these cells, eventually leading to their elimination by phagocytosis. These cluster cells may provide the first evidence that specialized transient neuronal populations guide angiogenesis in the developing CNS through neural activity.
Deductive systems and grammars: proofs as grammatical structures

During the last fifteen years, much of the research of proof theoretical grammars has been focused on their weak generative capacity. This research culminated in Pentus’ theorem, which showed that Lambek grammars generate precisely the context-free languages. However, during the same period of time, research on other grammar formalisms has stressed the importance of “strong generative capacity,” i.e. the derivation or phrase structure trees that grammars assign to strings. The first topic of this thesis is the strong generative capacity of Lambek grammars. The proof theoretic perspective on grammars allows us to consider different notions of what “structure assigned by a Lambek grammar to a string” is taken to mean. For example, we can take any proof tree that establishes that a grammar generates a certain string or only those that are in some normal form. It can be shown that the formal properties of these notions of structure differ. The main result of this part of the thesis is that, although Lambek grammars generate context-free string languages, their derivation trees are more complex than those of context-free grammars. The latter were characterized by Thatcher as coinciding with the local tree languages, while the derivation trees of Lambek grammars include tree languages which are not regular. Even non-associative Lambek grammars, which recently have become more popular variants of categorial grammar, can be used to generate non-local tree languages. However, their normal form tree languages are always regular. Finally, categorial grammars lacking introduction rules have local derivation trees. Thus, there is a genuine hierarchy of proof theoretical grammars with respect to strong generative capacity. Additionally, we consider the semantic aspect of the proof theoretic approach to language, which is given by the correspondence between proof theory and type
Self-deprecation: Searching for a Measure Autodesprecio: en busca de una medida

Introduction: Self-depreciation is a construct rarely studied by psychology, usually considered just a facet opposite to self-esteem. However, the literature presents its relationship with mental health and well-being, indicating the relevance of further investigations. Objective: The present research aimed to develop a measure for self-deprecation. Method: Were conducted two studies, both with 200 brazilian participants (M = 21,73; SD = 5,87). In addition to the developed instrument, the second study used the Rosenberg Self-Esteem Scale, the Single-Item Self-Esteem Scale, the Single-Item Narcissism Scale and the Aggression Questionnaire. Results: Initially, exploratory factor analysis and reliability analysis were performed on the instrument, which indicated a single factor organization, explaining 35 % of the variance and obtaining the reliability of ω = 0,89. The second study sought to carry out confirmatory analysis, calibration analysis, and correla- tions between self-deprecation, self-esteem, narcissism, and aggression. The scale had a good fit index of adjustment (CFI = 0,97; TLI = 0,97; RMSEA = 0,04; and SRMR = 0,05). There was a negative correlation between self-esteem (r = -0,75) and self-deprecation, as well as a positive one with all aggression factors. Conclusions: The Self-Deprecation Scale showed evidence of factor validity and reliability. Despite this, the limitations of the study are highlighted, especially the use of convenience sampling. It is concluded that the objectives were met.
New Insight Into Introducing a (2-ℇ)-Approximation Ratio for Minimum Vertex Cover Problem

Vertex cover problem is a famous combinatorial problem, which its complexity has been heavily studied over the years and it is known that there is not any mathematical programming formulation that approximates it better than , while a -approximation for it can be trivially obtained. In this paper, by a combination of a well-known semidefinite programming formulation and a randomized procedure , along with satisfying new properties, we introduce an approximation algorithm for the vertex cover problem with a performance ratio of on arbitrary graphs, en route to answering an open question about the unique games conjecture.
Identifying Author Profiles Containing Irony or Spreading Stereotypes with SBERT and Emojis

The Profiling Irony and Stereotype Spreaders on Twitter Shared Task at CLEF 2022 asks to analyze a set of tweets from an author in order to determine whether the author spreads irony and stereotypes. Our approach is to feed all tweets from an author to SBERT a a single input batch and feed all output vectors from the model to an additive attention layer to produce a vector representation per author. This vector representation is the input to a linear binary classifier. We placed second among 40 participants with a test accuracy of 97.8. We selected the best model using 5 fold cross-validation.
Enhancing a glossectomy patient's speech via GMM-based voice conversion

In this paper, we describe the use of a voice conversion algorithm for improving the intelligibility of speech by patients with articulation disorders caused by a wide glossectomy and/or segmental mandibulectomy. As a first trial, to demonstrate the difficulty of the task at hand, we implemented a conventional Gaussian mixture model (GMM)-based algorithm using a frame-by-frame approach. We compared voice conversion performance among normal speakers and one with an articulation disorder by measuring the number of training sentences, the number of GMM mixtures, and the variety of speaking styles of training speech. According to our experiment results, the mel-cepstrum (MC) distance was decreased by 40% in all pairs of speakers as compared with that of pre-conversion measures; however, at post-conversion, the MC distance between a pair of a glossectomy speaker and a normal speaker was 28% larger than that between pairs of normal speakers. The analysis of resulting spectrograms showed that the voice conversion algorithm successfully reconstructed high-frequency spectra in phonemes /h/, /t/, /k/, /ts/, and /ch/; we also confirmed improvements of speech intelligibility via informal listening tests.
Eﬀect of Surface Form Dictionary on Eﬀectiveness in Entity Linking

This thesis aims to explore the eﬀect of using ClueWeb annotations for candidate selection and disambiguation in entity linking. We used the Rad-boud Entity Linker (REL) to test various conﬁgurations, and discovered that using these annotations can have a signiﬁcant impact on both recall and disambiguation. We think this research indicates that it is worthwhile to consider including ClueWeb annotations in the candidate selection part of entity linking systems.