Miracle-dz/UniFAR-FTUs huggingface dataset:
Pioneer activity distinguishes activating from non-activating pluripotency transcription factor binding sites

Genome-wide transcriptional activity involves the binding of many transcription factors to thousands of sites in the genome. Determining which sites are directly driving transcription remains a challenge. Here we use acute protein depletion of the pioneer transcription factors OCT4 and SOX2 to establish their functionality in maintaining chromatin accessibility. We show that thousands of accessible sites are lost within an hour of protein depletion, indicating rapid turnover of these sites in the absence of pioneer factors. To understand the relationship with transcription we performed nascent transcription analysis and found that open chromatin sites that are maintained by SOX2 are highly predictive of gene expression, in contrast to SOX2 binding sites that do not maintain accessibility. We use CRISPR-Cas9 genome editing in the Klf2 locus to functionally validate a predicted regulatory element. We conclude that the regulatory activity of SOX2 is exerted largely at sites where it maintains accessibility and that other binding sites are largely dispensable for gene regulation.
Distinguishing strategic orienting toward memory age from retrieval difficulty: An ERP study

We Roxana Botezatu, and Steve Hackley for helpful feedback on an earlier version of this article. The authors report no conflicts of interest. ABSTRACT A well-established finding in episodic memory research is that the likelihood of successful retrieval is a ffected by the ‘age’ of the targeted memory (i.e. based on the duration of the encoding-retrieval interval). Although such findings are usually interpreted in terms of the memory trace changing in quality or accessibility over time, there is growing evidence that retrieval also depends on how well search attempts can be strategically oriented. Here, we investigated the strategic orienting of retrieval processing, as indexed by event-related brain potentials (ERPs), when retrieval was aimed toward candidate memories of different ages. As retrieving remote versus recent memories is associated with increased difficulty, the current study was designed to dissociate the difficulty and memory age effects. Subjects encoded two lists of pictures separated by one week, with the items in each list presented once or four times. A series of memory tests targeting pictures from only one week-by-repetition condition at a time were then completed, while new pictures and those from the other conditions were rejected. Consistent with previous results, new-item ERPs were more positive over posterior scalp when recent compared to remote lists were targeted. Importantly, this difference remained when difficulty was matched, and the ERP correlates of difficulty were distinct in both timing and polarity from those of orienting. Together, these findings provide further support for the idea that the age of a targeted memory alone can lead to the adoption of retrieval orienting strategies.
Unbiased Classification of the Human Brain Proteome Resolves Distinct Clinical and Pathophysiological Subtypes of Cognitive Impairment

The hallmark amyloid-β and tau deposition of Alzheimer’s disease (AD) represents only a fraction of its diverse pathophysiology. Molecular subtyping using large-scale -omic strategies can help resolve this biological heterogeneity. Using quantitative mass spectrometry, we measured ~8,000 proteins across >600 dorsolateral prefrontal cortex tissues from Religious Orders Study and Rush Memory and Aging Project participants with clinical diagnoses of no cognitive impairment, mild cognitive impairment (MCI), and AD dementia. Unbiased classification of MCI and AD cases based on individual proteomic profiles resolved three classes with expression differences across numerous cell types and biological ontologies. Two classes displayed molecular signatures atypical of those previously observed in AD neurodegeneration, such as elevated synaptic and decreased inflammatory markers. In one class, these atypical proteomic features were associated with clinical and pathological hallmarks of cognitive resilience. These results promise to better define disease heterogeneity within AD and meaningfully impact its diagnostic and therapeutic precision.
Phenotypic similarity is a measure of functional redundancy within homologous gene families

Robustness to the impact of mutation can mitigate phenotypes that have the potential to inform gene function. This robustness is often encoded into the genome through gene duplication, among other mechanisms. Duplication is a source of structurally similar genes that can retain some functional overlap as they diverge, and as such contribute to functional redundancy in the face of mutation. While redundancies have been explored in groups of two or three paralogs by generating double and triple mutants, it is unclear to what extent larger homologous gene families contribute to robustness through functional redundancy. Here, we used phenotypic similarity as an indicator of functional redundancy to explore the extent to which homologous gene families contribute to redundancy in function. We hypothesize that, since functional redundancy is more likely to occur within gene families where genes are structurally similar, mutant strains within the same gene families would be more phenotypically similar. We generated 265 single-gene disruptions in four homologous gene families of Myxococcus xanthus, used time-lapse microscopy to generate time series of multicellular development, and developed an image analysis pipeline to compare phenotypic characteristics among different strains. We show that mutant strains cluster by gene family in the phenotypic feature space with principal component analysis, demonstrating that families of homologs can contain extensive functional redundancy networks.
The mammalian forelimb diversity as a morphological gradient of increasing evolutionary versatility

Vertebrate limb morphology often reflects the environment, due to variation in locomotor requirements and other ecological traits. However, proximal and distal limb segments may evolve differently to each other, reflecting an anatomical gradient of functional specialization that has been suggested to be impacted by the timing of bone condensation during ontogeny. Here we explore whether the temporal sequence of bone condensation predicts variation in the capacity of evolution to generate morphological diversity between proximal and distal forelimb segments across more than 600 species of mammals. Our findings are consistent with the hypothesis that late developing distal limb elements should display greater morphological variation than more proximal limb elements, which condense earlier during morphogenesis. Distal limb elements, belonging to the autopod, not only exhibit higher diversity of form, but are also more integrated and, on average, show greater evolutionary versatility than intermediate and upper limb segments. Our findings indicate that the macroevolutionary patterns of proximal and distal limb segments are not the same, suggesting that strong functional selection, combined with the higher potential of development to generate variation in more distal limb structures, facilitate the evolution of high autopodial disparity in mammals.
Anticipation of Appetitive Operant Action Induces Sustained Dopamine Release in the Nucleus Accumbens

The mesolimbic dopamine system is implicated in signaling reward-related information as well as in actions that generate rewarding outcomes. These implications are commonly investigated in either pavlovian or operant reinforcement paradigms, where only the latter requires instrumental action. To parse contributions of reward- and action-related information to dopamine signals, we directly compared the two paradigms: male rats underwent either pavlovian or operant conditioning while dopamine release was measured in the nucleus accumbens, a brain region central for processing this information. Task conditions were identical with the exception of the operant-lever response requirement. Rats in both groups released the same quantity of dopamine at the onset of the reward-predictive cue. However, only the operant-conditioning group showed a subsequent, sustained plateau in dopamine concentration throughout the entire 5 s cue presentation (preceding the required action). This dopamine ramp was unaffected by probabilistic reward delivery, occurred exclusively before operant actions, and was not related to task performance or task acquisition as it persisted throughout the 2 week daily behavioral training. Instead, the ramp flexibly increased in duration with longer cue presentation, seemingly modulating the initial cue-onset-triggered dopamine release, that is, the reward prediction error (RPE) signal, as both signal amplitude and sustainment diminished when reward timing was made more predictable. Thus, our findings suggest that RPE and action components of dopamine release can be differentiated temporally into phasic and ramping/sustained signals, respectively, where the latter depends on the former and presumably reflects the anticipation or incentivization of appetitive action, conceptually akin to motivation. SIGNIFICANCE STATEMENT It is unclear whether the components of dopamine signals that are related to reward-associated information and reward-driven approach behavior can be separated. Most studies investigating the dopamine system use either pavlovian or operant conditioning, which both involve the delivery of reward and necessitate appetitive approach behavior. Thus, used exclusively, neither paradigm can disentangle the contributions of these components to dopamine release. However, by combining both paradigms in the same study, we find that anticipation of a reward-driven operant action induces a modulation of reward-prediction-associated dopamine release, producing so-called dopamine ramps. Therefore, our findings provide new insight into dopamine ramps and suggest that dopamine signals integrate reward and appetitive action in a temporally distinguishable, yet dependent, manner.
Conserved and transcript-specific functions of the RESC factors, RESC13 and RESC14, in kinetoplastid RNA editing

Uridine insertion/deletion RNA editing is an extensive post-transcriptional modification of mitochondrial mRNAs in kinetoplastid organisms, including Trypanosoma brucei. This process is carried out using trans-acting gRNAs and complex protein machinery. The essential RNA Editing Substrate Binding Complex (RESC) serves as the scaffold that modulates protein and RNA interactions during editing, and contains the Guide RNA Binding Complex (GRBC), the RNA Editing Mediator Complexes (REMCs), and organizer proteins. Despite the importance of RESC in editing, the functions of each protein comprising this complex are not completely understood. Here, we further define the roles of a REMC protein, RESC13, and a RESC organizer, RESC14, using high-throughput sequencing on two large pan-edited mRNAs, A6 and COIII. When comparing our analyses to that of a previously published small pan-edited mRNA, RPS12, we find that RESC13 has conserved functions across the three transcripts with regards to editing initiation, gRNA utilization, gRNA exchange, and restricting the formation of long mis-edited junctions that likely arise from its ability to modulate RNA structure. However, RESC13 does have transcript-specific effects on the types of long junctions whose formation it restricts. RESC14 has a conserved effect on gRNA utilization across the three transcripts analyzed, but has transcript-specific effects on editing initiation, gRNA exchange, and junction formation. Our data suggest that transcript-specific effects of both proteins are due to differences in transcript length and sequences as well as transcript-specific protein interactions. These findings highlight the importance of studying multiple transcripts to determine the function of editing factors.
Interdependent progression of bidirectional sister replisomes in E. coli

Bidirectional DNA replication complexes initiated from the same origin remain colocalized in a factory configuration for part or all of their lifetimes. However, there is little evidence that sister replisomes are functionally interdependent, and the consequence of factory replication is unknown. Here, we investigated the functional relationship between sister replisomes in E. coli, which naturally exhibits both factory and solitary configurations in the same replication cycle. Using an inducible transcription factor roadblocking system, we found that blocking one replisome caused a significant decrease in overall progression and velocity of the sister replisome. Remarkably, progression was impaired only if the block occurred while sister replisomes were still in a factory configuration – blocking one fork had no significant effect on the other replisome when sister replisomes were physically separate. Disruption of factory replication also led to increased fork stalling and requirement of fork restart mechanisms. These results suggest that physical association between sister replisomes is important for establishing an efficient and uninterrupted replication program. We discuss the implications of our findings on mechanisms of replication factory structure and function, and cellular strategies of replicating problematic DNA such as highly transcribed segments.
Changing Point and Parameter Instability with Heteroskedastic Models

The hypothesis of structural stability that the regression coefficients do not change over time is central to all applications of linear regression models. It is rather surprising that existing theory as well as practice focuses on testing for structural change under homoskedasticity – that is, regression coefficients may change, but the variances remain the same. Since structural change can, and often does, involve changes in variances, this is a puzzling gap in the literature. Our main focus in this paper is to utilize a newly developed test (MZ) by Maasoumi et al. (2010) that tests simultaneously for break in regression coefficients as well as in variance. Currently the sup F test is most widely used for structural change. This has certain optimality properties shown by Andrews (1993). However, this test assumes homoskedasticity across the structural change. We introduce the sup MZ test which caters to unknown breakpoints, and also compare it to the sup F. Our Monte Carlo results show that sup MZ test incurs only a low cost in case of homoskedasticity while having hugely better performance in case of heteroskedasticity. The simulation results are further supported by providing a real world application. In real world data sets, we find that structural change often involves heteroskedasticity. In such cases, the sup F test can fail to detect structural breaks and give misleading results, while the sup MZ test works well. We conclude that the sup MZ test is superior to current methodology for detecting structural change.
Towards Cybersecurity by Design: A multi-level reference model for requirements-driven smart grid cybersecurity

This paper provides a first step towards a reference model for end-to-end cybersecurity by design in the electricity sector. The envisioned reference model relies, among others, on the integrated consideration of two currently fragmented, but complementary, reference models: NISTIR 7628 and powerLang. As an underlying language architecture of choice, we rely on multi-level modeling, specifically on the Flexible Meta Modeling and Execution Language (FMML x ), as multi-level modeling supports a natural integration across different abstraction levels inherent to reference models. This paper’s contributions are a result of one full consideration of Wieringa’s engineering cycle: for problem investigation, we describe the problems the reference model should address; for treatment design, we contribute the requirements the reference model should fulfill; for treatment implementation, we provide reference model’s fragments implemented in an integrated modeling and programming environment. Finally, for treatment evaluation, we perform expert interviews to check, among others, the artefact’s relevance and utility.
Union selection effects - some inconsistent models

We show that some of the models which have been used in the South African literature to estimate union selection effects are logically inconsistent. This is a much more serious problem than a failure to identify the coefficient. It implies that the model cannot be true in any possible state of the world. Unfortunately the offending specification is becoming entrenched in the literature.
Universal self-similar dynamics of relativistic and nonrelativistic field theories near nonthermal fixed points

We investigate universal behavior of isolated many-body systems far from equilibrium, which is relevant for a wide range of applications from ultracold quantum gases to high-energy particle physics. The universality is based on the existence of nonthermal fixed points, which represent nonequilibrium attractor solutions with self-similar scaling behavior. The corresponding dynamic universality classes turn out to be remarkably large, encompassing both relativistic as well as nonrelativistic quantum and classical systems. For the examples of nonrelativistic (Gross-Pitaevskii) and relativistic scalar field theory with quartic self-interactions, we demonstrate that infrared scaling exponents as well as scaling functions agree. We perform two independent nonperturbative calculations, first by using classical-statistical lattice simulation techniques and second by applying a vertex-resummed kinetic theory. The latter extends kinetic descriptions to the nonperturbative regime of overoccupied modes. Our results open new perspectives to learn from experiments with cold atoms aspects about the dynamics during the early stages of our universe.
S0033291720003797jra 1948..1958

Background.Major depressive disorder (MDD) is a leading cause of morbidity and mortality. Shortfalls in treatment quantity and quality are well-established, but the specific gaps in pharmacotherapy and psychotherapy are poorly understood. This paper analyzes the gap in treatment coverage for MDD and identifies critical bottlenecks. Methods. Seventeen surveys were conducted across 15 countries by the World Health Organization-World Mental Health Surveys Initiative. Of 35 012 respondents, 3341 met DSM-IV criteria for 12-month MDD. The following components of effective treatment coverage were analyzed: (a) any mental health service utilization; (b) adequate pharmacotherapy; (c) adequate psychotherapy; and (d) adequate severity-specific combination of both. Results. MDD prevalence was 4.8% (S.E., 0.2). A total of 41.8% (S.E., 1.1) received any mental health services, 23.2% (S.E., 1.5) of which was deemed effective. This 90% gap in effective treatment is due to lack of utilization (58%) and inadequate quality or adherence (32%). Critical bottlenecks are underutilization of psychotherapy (26 percentage-points reduction in coverage), underutilization of psychopharmacology (13-point reduction), inadequate physician monitoring (13-point reduction), and inadequate drug-type (10-point reduction). High-income countries double low-income countries in any mental health service utilization, adequate pharmacotherapy, adequate psychotherapy, and adequate combination of both. Severe cases are more likely than mild-moderate cases to receive either adequate pharmacotherapy or psychotherapy, but less likely to receive an adequate combination. Conclusions. Decision-makers need to increase the utilization and quality of pharmacotherapy and psychotherapy. Innovations such as telehealth for training and supervision plus nonspecialist or community resources to deliver pharmacotherapy and psychotherapy could address these bottlenecks.
Modulation of HIF-1α/COX-2 pathway associated with attenuation of intestinal mucosa inflammatory damage by Acanthopanax senticosus polysaccharides in lipopolysaccharide-challenged piglets.

Intestinal barrier inflammatory damage is commonly accompanied by hypoxia. The hypothesis that dietary Acanthopanax senticosus polysaccharides (ASPS) might modulate HIF-1α signaling pathway and contribute to attenuate intestinal injury was tested in lipopolysaccharide (LPS)-challenged piglets. Thirty-six weaned pigs were randomly allocated to one of the following three groups: (1) basal diet+saline challenge; (2) basal diet+LPS challenge; (3) basal diet with 800 mg/kg ASPS+LPS challenge. LPS was injected at 15, 18 and 21 d, and intestinal sections were sampled following blood collection at 21 d of the trial. The results showed ASPS administration reversed (P＜0.05) LPS-induced decrease in average daily feed intake and rise (P＜0.05) of diarrhea incidence and index. Biochemical index reflecting gut barrier damage and function involving ileal pro-inflammatory cytokines (TNF-α and IL-1β) and enzymes activity (DAO and lactase), as well as circulatory D-xylose were normalized (P＜0.05) in LPS-challenged piglets receiving ASPS. ASPS also ameliorated intestinal morphological deterioration of LPS-challenged piglets, proven by elevated ileal villus height (P＜0.05) and improved appearance of epithelial villus and tight junction ultrastructure. Moreover, ASPS prevented LPS-induced amplification of inflammatory mediators, achieved by depressed mRNA abundance of TNF-α, iNOS, and concentration of IL-1β in ileum. Importantly, ileal protein expressions of HIF-1α, COX-2 and NFκB p65 were also suppressed with ASPS administration (P＜0.05). Collectively, these results suggest that the improvement of mucosal inflammatory damage and diarrhea in immune stress piglets are possibly associated with a novel finding where HIF-1α/COX-2 pathway down-regulation involved in NFκB p65-inducible releasing of inflammatory cytokines by dietary ASPS.
Alloying Behavior of Au and Au–Ge on GaAs

Although Au–Ge has often been used in making Ohmic contacts to GaAs, the alloying behavior of this system has not been well characterized and understood. In this paper the behavior of Au and Au–Ge layers on GaAs was investigated as a function of processing temperature (400–600°C) and time by backscattering and channeling‐effect measurements with 2‐MeV 4He ions. Scanning electron microscopy and current‐voltage evaluations were also made. Similarities are found in both systems: There is a deeply penetrating component of Au into the GaAs that remains essentially unaltered once the surface Au has been consumed; a disordered region near the surface is found, the amount of which increased with increased process times. No significant amount of Au is found on substitutional or tetrahedral interstitial sites within about 3000 A of the surface. The presence of the Ge does have a significant effect: Complete alloying occurs at lower temperatures, and Ohmic contacts are formed. Scanning‐electron‐microcope displays in.