Miracle-dz/UniFAR-FTUs huggingface dataset:
Connectivity by the Frontal Aslant Tract (FAT) explains local functional specialization of the superior and inferior frontal gyri in humans while choosing predictive over reactive strategies: a tractography-guided TMS study

Predictive and reactive behaviors represent two mutually exclusive strategies for successfully completing a sensorimotor task. It is thought that predictive actions are based on the medial premotor system, in the superior frontal gyrus (SFG) and reactive stimulus-response behaviors rely on a lateral premotor system, in the inferior frontal gyrus (IFG). The frontal aslant tract (FAT), a white matter tract connecting SFG and IFG, is a possible neural substrate of the predictive/reactive interactions. We used diffusion-weighted imaging (DWI) of 17 male and female healthy human volunteers, to dissect 3 sub-bundles of fibers belonging to the left FAT (bundles 1, 2 and 3), arising ventrally from 1) the ventral precentral gyrus, 2) midway between the PCG and pars opercularis (POp) and 3) the POp and terminating dorsally in 3 different parts of the SFG, in a caudal-rostral order. We applied online transcranial magnetic stimulation (TMS) to 6 spots, corresponding to the medial and lateral terminations of bundles 1-3 during the fixed-duration set period of a delayed reaction task, that can be solved using a predictive (anticipatory) strategy or with a reactive strategy. Results showed that TMS changed the frequency of predictive/reactive strategies only when applied over 2 spots, the SFG and IFG terminations of bundle 2. Importantly, the effects of TMS were opposite when applied to the SFG or to the IFG. Our data show that the SFG and the IFG have opposite roles in producing predictive or reactive behavior and that reciprocal integration or competition is probably mediated by the FAT. Significance Statement As is well-known by athletes at starting blocks, interaction with the world can occur with a predictive strategy (anticipating a GO-signal) or a reactive strategy (waiting for the GO-signal to be manifest) and they are mutually exclusive. Here we showed, by using non-invasive brain stimulation (TMS), that two specific cortical regions in the superior frontal gyrus (SFG) and the inferior frontal gyrus (IFG) have opposite roles in facilitating a predictive or a reactive strategy. Importantly these two very distant regions but with highly interconnected functions are specifically connected by a small white matter bundle, which probably mediates the competition between predictive and reactive strategies. More generally, we show that the implementing anatomical connectivity in TMS studies strongly reduces spatial noise.
Artificial Alzheimer’s – visualizing the process of memory decay, confusion and death in a simple Neural Network Model of Associative Memory

This paper analyzes the behaviour of Alzheimer’s disease simulation in artificial neural networks and thereby suggests a new possible diagnosis for Alzheimer. Alzheimer’s disease is one of the most common diseases, increasing severity over time. Despite its high prevalence and thousands of yearly publications in this area, no cure has been found to date and early detection is one of the most important factor towards fighting the disease and possibly finding a cure. This paper analyses the behaviour of simulated Alzheimer in Hopfield memories and observes that the main factor influenced by the loss of connections is the time needed to recognize distorted symbols - while the recognition performance stays surprisingly high for a long time. Hence, I suggest a new early diagnosis approach which is based on slightly distorted elements (e.g., characters) and measures the time needed to perform the task, instead of just focusing on the subject’s recognition performance. This insight could have a large impact to future diagnose setups, once being validated in a clinical study.
Non-invasive vagus nerve stimulation in a hungry state decreases heart rate variability

Vagus nerve signals from the gut to brain carry information about nutrients and drive food reward. Such signals are disrupted by consuming large amounts of high-calorie foods, necessitating greater food intake to elicit a similar neural response. Non-invasive vagus nerve stimulation (nVNS) via a branch innervating the ear is a candidate treatment for obesity in humans. There is disagreement on the optimal location of nVNS in the ear for experimental and clinical studies. There are also no studies comparing nVNS in hungry and full states. We aimed to compare ear position(s) for nVNS and explore the effects of nVNS during hungry and full states on proxies for autonomic outflow (heart-rate variability) and efferent metabolism (gastric frequency and resting energy expenditure). In a within-subject design, 14 participants (10 women, on average 29.4 +/- 6.7 years old) received nVNS in four different locations (cymba conchae, tragus, earlobe, or tragus AND cymba conchae) on separate days. In each session, participants were asked to consume a palatable chocolate flavored milk. With electrography on the abdomen and indirect calorimetry in a canopy, we measured electro-cardiogram, electro-gastrogram and resting energy expenditure for 15 minutes before and at least 35 minutes after consumption of the palatable drink. We also collected ratings of the palatable drink and internal and other states. Pre-drink consumption (in a hungry state) we observed no differences in the effect of location of acute nVNS on resting energy expenditure and gastric frequency. However, nVNS in cymba conchae decreases heart-rate variability and ratings of how much participants want to consume the drink. After drink consumption and with continued nVNS, gastric frequency is unchanged, and resting energy expenditure increases regardless of stimulation location. Heart-rate variability decreases in all locations, except cymba conchae. We also observe a trend for an increase in gastric frequency in late post-drink consumption time-points in cymba conchae. These results suggest that nVNS in the cymba conchae in a hungry state has a similar acute effect on vagal tone as food consumption: to decrease heart rate variability. This effect then negates the usual postprandial effects of a decrease in heart rate variability as seen in the other nVNS locations. This suggests that nVNS in cymba conchae may act primarily on vagal afferent autonomic (and only modestly on metabolic output) in a similar way as food consumption does. Highlights We measured autonomic outflow and efferent metabolism before and after consumption We manipulated the location of nVNS stimulation in the outer ear The different locations were earlobe, cymba conchae, tragus, cymba conchae+tragus nVNS in cymba conchae decreases pre-consumption heart-rate variability and wanting nVNS in other locations decreases post-consumption heart-rate variabilty
Oxidative Stress Induced Senescence Gives Rise to Transcriptionally Distinct Physiological States

As people age, the risk of cardiovascular disease, diabetes, cancer, and Alzheimer’s disease increases, making age itself the greatest risk factor for many human diseases. Thus, understanding the aging process can have profound consequences for human health. One striking feature of the aging process is the accumulation of senescent cells with age. When cells become damaged, they can enter a state of senescence which is a permanent cell cycle exit associated with the secretion of inflammatory cytokines. In mouse models of aging, the destruction of senescent cells with senolytic drugs delays age-associated decline and extends healthy lifespan. Yet, despite the wealth of accumulated knowledge, we do not entirely understand the biology of senescent cells. Prior work has shown that senescence is associated with increased variation in gene expression, suggesting that there may exist distinct transcriptional signatures of senescence. Understanding the different transcriptional physiological states of senescent cells would allow us to better treat them with cell-type-specific senolytic drugs. Here, we performed large-scale single-cell RNA-sequencing time series experiments to understand the development of transcriptional heterogeneity among senescent cell types. Our approach allowed us to observe and classify different transcriptional signatures of senescent cells as they emerged through time. We found that upon entering oxidative stress-induced senescence, separate subpopulations of cells were reproducibly adopting two distinct transcriptional states, one of which was associated with stress response and the second one with tissue remodeling. Our data suggest that a combination of senolytic drugs may be needed to more effectively eliminate senescent cells by targeting physiologically distinct sub-populations.
Museum specimens of a landlocked pinniped reveal recent loss of genetic diversity and unexpected population connections

Aim The Saimaa ringed seal (Pusa hispida saimensis) is endemic to Lake Saimaa in Finland. The subspecies is thought to have originated when parts of the ringed seal population of the Baltic region were trapped in lakes emerging due to post-glacial bedrock rebound around 9,000 years ago. During the 20th century, the population experienced a drastic human-induced bottleneck. Today encompassing a little over 400 seals with extremely low genetic diversity, it is classified as endangered. Our main aim was to evaluate the role of the 20th century bottleneck in the erosion of genetic diversity in the Saimaa seal population. We also evaluated connections with other ringed seals from the Baltic Sea, Lake Ladoga, North America, Svalbard and the White Sea. Location Lake Saimaa, Finland, together with the Baltic Sea and the Arctic Ocean. Methods We sequenced sections of the mitochondrial control region from 60 up to 125 years old museum specimens of the Saimaa ringed seal. The generated dataset was combined with publicly available sequences. We studied how genetic variation has changed through time in this subspecies, and how it is phylogenetically related to other ringed seal populations. Results We observed temporal fluctuations in haplotype frequencies and loss of haplotypes accompanied by a recent reduction in female effective population size. In apparent contrast with the traditionally held view of the Baltic origin of the population, the Saimaa ringed seal mtDNA variation shows also affinities to North American ringed seals. Main conclusions Our results suggest that the Saimaa ringed seal has experienced recent genetic drift associated with small population size. The results further suggest that extant Baltic ringed seals do not represent well the ancestral population of the Saimaa ringed seal, which calls for re-evaluation of the deep history of this subspecies.
A novel strategy for dynamic modeling of genome-scale interaction networks

Background Modern medicine is equipped with huge amounts of big biological datasets and a wide range of computational methods to understand the molecular events underlying complex disorders. The recent availability of omics data allows a holistic view towards the interactions of various biomolecule types. However, the constructed maps are static, ignoring the dynamicity of molecular processes. On the other hand, the dynamic models of biological systems are commonly generated in small scales. Hence, the construction of large scale dynamic models that can quantitatively predict the time-course cellular behaviors is a big challenge. This study was aimed at developing a pipeline for automatic construction of such models from time-course experimental data. Results Information of interactions between input genes is retrieved from SIGNORE 2.0 database and an interaction network is constructed which then is translated to biochemistry language and converted to a biochemical reactions network. In the next step, a large-scale ODE system is constructed by generating the ODE equivalent of each biochemical reaction. To estimate the kinetics parameters of the ODE model, a novel large-scale parameter approximation method is proposed. This method gives an estimation of system parameters by fitting model outputs to time-course experimental measurements. The total pipeline is provided as a MATLAB toolbox called SPADAN, standing for Systematic Protein Association Dynamic ANalyzer. Using multilayer time-series experimental data, the performance of the pipeline was checked by modeling 4379 regulatory interactions between 768 molecules in colon cancer cells exposed to chemotherapy agents. Conclusion Starting from time-series experimental data, SPADAN automatically constructs map of interactions, generates an ODE system, and performs a parameter approximation procedure. It constructs genome-scale dynamic models, filling the gap between large-scale static and small-scale dynamic modeling strategies. This simulation approach allows for holistic quantitative predictions which is critical for the simulation of therapeutic interventions in precision medicine.
Western diet-induced shifts in the maternal microbiome are associated with altered microRNA expression in baboon placenta and fetal liver

Maternal consumption of a high-fat, Western-style diet (WD) disrupts the maternal/infant microbiome and contributes to developmental programming of the immune system and nonalcoholic fatty liver disease (NAFLD) in the offspring. Epigenetic changes, including non-coding miRNAs in the fetus and/or placenta may also underlie this risk. We previously showed that obese nonhuman primates (NHP) fed a WD during pregnancy results in the loss of beneficial maternal gut microbes and dysregulation of cellular metabolism and mitochondrial dysfunction in the fetal liver, leading to a perturbed postnatal immune response with accelerated NAFLD in juvenile offspring. Here, we investigated associations between WD-induced maternal metabolic and microbiome changes, in the absence of obesity, and miRNA and gene expression changes in the placenta and fetal liver. After ∼8-11 months of maternal WD feeding (mWD), dams were similar in body weight but exhibited mild, systemic inflammation (elevated CRP and neutrophil count) and dyslipidemia (increased triglycerides and cholesterol) compared with dams fed a control diet. The maternal gut microbiome was mainly comprised of Lactobacillales and Clostridiales, with significantly decreased alpha diversity (P = 0.0163) in WD-fed dams but no community-wide differences (P = 0.26). At 0.9 gestation, mRNA expression of IL6 and TNF in mWD-exposed placentas trended higher, while increased triglycerides, expression of pro-inflammatory CCR2, and histological evidence for fibrosis were found in mWD-exposed fetal livers. In the mWD-exposed fetus, hepatic expression levels of miR-204-5p and miR-145-3p were significantly downregulated, whereas in mWD-exposed placentas, miR-182-5p and miR-183-5p were significantly decreased. Notably, miR-1285-3p expression in the liver and miR-183-5p in the placenta were significantly associated with inflammation and lipid synthesis pathway genes, respectively. Blautia and Ruminococcus were significantly associated with miR-122-5p in liver, while Coriobacteriacea and Prevotellacea were strongly associated with miR-1285-3p in the placenta; both miRNAs are implicated in pathways mediating postnatal growth and obesity. Our findings demonstrate that mWD shifts the maternal microbiome, lipid metabolism, and inflammation prior to obesity and are associated with epigenetic changes in the placenta and fetal liver. These changes may underlie inflammation, oxidative stress, and fibrosis patterns that drive NAFLD and metabolic disease risk in the next generation.
Understanding implicit sensorimotor adaptation as a process of proprioceptive re-alignment

Multiple learning processes contribute to successful goal-directed actions in the face of changing physiological states, biomechanical constraints, and environmental contexts. Amongst these processes, implicit sensorimotor adaptation is of primary importance, ensuring that movements remain well-calibrated and accurate. A large body of work on reaching movements has emphasized how adaptation centers on an iterative process designed to minimize visual errors. The role of proprioception has been largely neglected, thought to play a passive role in which proprioception is affected by the visual error but does not directly contribute to adaptation. Here we present an alternative to this visuo-centric framework, arguing that that implicit adaptation can be understood as minimizing a proprioceptive error, the distance between the perceived hand position and its intended goal. We use this proprioceptive re-alignment model (PReMo) to re-examine many phenomena that have previously been interpreted in terms of learning from visual errors, as well as offer novel accounts for unexplained phenomena. We discuss potential challenges for this new perspective on implicit adaptation and outline a set of predictions for future experimentation.
Genomic screening reveals UBA1 as a potent and druggable target in c-MYC-high TNBC models

Triple negative breast cancer (TNBC) accounts for over 30% of all breast cancer-related deaths, despite accounting for only 10%–15% of total breast cancer cases. Targeted therapy development has largely stalled in TNBC, underlined by a lack of traditionally druggable addictions like receptor tyrosine kinases (RTKs). Here, through full genome CRISPR/Cas9 screening of TNBC models, we have uncovered the sensitivity of TNBCs to the depletion of the Ubiquitin-Like Modifier Activating Enzyme 1 (UBA1). Targeting UBA1 with the first in-class UBA1 inhibitor TAK-243 induced unresolvable ER-stress and activating transcription factor 4 (ATF4)-mediated upregulation of pro-apoptotic NOXA, leading to cell death. In five patient derived xenograft models (PDXs) of TNBC, TAK-243 therapy led to tumor inhibition or frank tumor regression. In an intracardiac metastatic model of TNBC, TAK-243 markedly reduced metastatic burden. Importantly, there was an order of magnitude greater sensitivity of TNBC lines to TAK-243 compared to normal tissue-derived cells. Lastly, c-MYC expression correlates with TAK-243 sensitivity and cooperates with TAK-243 to induce a stress response and cell death. We posit UBA1 is an important new target in TNBC expressing high levels of c-MYC. Significance Genomic screening of TNBC cell lines revealed broad sensitivity to depletion of the E1 ubiquitin enzyme, UBA1. Disrupting UBA1 with the first in-class inhibitor TAK-243 in TNBC models induces ER-stress through an ATF4-NOXA axis that is dependent on c-MYC, leading to apoptosis, in vitro and in vivo, primary tumor growth inhibition and metastatic inhibition.
Domestication of different varieties in the cheese-making fungus Geotrichum candidum

Domestication is an excellent model for studying adaptation processes, involving recent adaptation and diversification, convergence following adaptation to similar conditions, as well as degeneration of unused functions. Geotrichum candidum is a fungus used for cheese making and is also found in other environments such as soil and plants. By analyzing whole-genome data from 98 strains, we found that all strains isolated from cheese formed a monophyletic clade. Within the cheese clade, we identified three genetically differentiated populations and we detected footprints of recombination and admixture. The genetic diversity in the cheese clade was similar as that in the wild clade, suggesting the lack of strong bottlenecks. Commercial starter strains were scattered across the cheese clade, thus not constituting a single clonal lineage. The cheese populations were phenotypically differentiated from other populations, with a slower growth on all media, even cheese, a prominent production of typical cheese volatiles and a lower proteolytic activity. One of the cheese clusters encompassed all soft goat cheese strains, suggesting an effect of cheese-making practices on differentiation. Another of the cheese populations seemed to represent a more advanced stage of domestication, with stronger phenotypic differentiation from the wild clade, harboring much lower genetic diversity, and phenotypes more typical of cheese fungi, with denser and fluffier colonies and a greater ability of excluding cheese spoiler fungi. Cheese populations lacked two beta lactamase-like genes present in the wild clade, involved in xenobiotic clearance, and displayed higher contents of transposable elements, likely due to relaxed selection. Our findings suggest the existence of genuine domestication in G. candidum, which led to diversification into different varieties with contrasted phenotypes. Some of the traits acquired by cheese strains indicate convergence with other, distantly related fungi used for cheese maturation.
PhiDsc: Protein functional mutation Identification by 3D Structure Comparison

Selective pressures that trigger cancer formation and progression shape the mutational landscape of somatic mutations in cancer. Given the limits within which cells are regulated, a growing tumor has access to only a finite number of pathways that it can alter. As a result, tumors arising from different cells of origin often harbor identical genetic alterations. Recent expansive sequencing efforts have identified recurrent hotspot mutated residues in individual genes. Here, we introduce PhiDsc, a novel statistical method developed based on the hypothesis that, functional mutations in a recurrently aberrant gene family can guide the identification of mutated residues in the family’s individual genes, with potential functional relevance. PhiDsc combines 3D structural alignment of related proteins with recurrence data for their mutated residues, to calculate the probability of randomness of the proposed mutation. The application of this approach to the RAS and RHO protein families returned known mutational hotspots as well as previously unrecognized mutated residues with potentially altering effect on protein stability and function. These mutations were located in, or in proximity to, active domains and were indicated as protein-altering according to six in silico predictors. PhiDsc is freely available at https://github.com/hobzy987/PhiDSC-DALI.
Flight test procedures

The planning and conduct of flight experiments is an important part of the system identification process. To be most effective it is important that such experiments should be designed and performed specifically for the purposes of system identification. In the case of helicopters and other forms of rotorcraft especially, satisfactory parameter estimates are seldom obtained from flight experiments which have some other primary objective. This section of the AGARD Advisory Report 280 reviews the procedures for the planning of flight tests, addresses issues assocaited with the selection of test inputs, discusses the conduct of flight tests and discussed procedures to be followed in terms of activities acrried out after flight tests have been completed.
Fun with FUN

The notions of scientific community and research field are central elements for researchers and the articles they publish. We propose to explore the evolution of the FUN conference community since its creation from the articles listed in DBLP, authors, program committees, and advertised themes, by means of a novel symmetric embedding, and carefully crafted software tools. Our results make it possible on the one hand to better understand the evolution of the community, and on the other hand to easily integrate new themes or researchers during future editions. 2012 ACM Subject Classification Information systems → Similarity measures; Information systems → Information extraction