Miracle-dz/UniFAR-FTUs huggingface dataset:
Local continual reassessment methods for dose finding and optimization in drug-combination trials

Due to the limited sample size and large dose exploration space, obtaining a desirable dose combination is a challenging task in the early development of combination treatments for cancer patients. Most existing designs for optimizing the dose combination are model-based, requiring significant efforts to elicit parameters or prior distributions. Model-based designs also rely on intensive model calibration and may yield unstable performance in the case of model misspecification or sparse data. We propose to employ local, underparameterized models for dose exploration to reduce the hurdle of model calibration and enhance the design robustness. Building upon the framework of the partial ordering continual reassessment method, we develop local data-based continual reassessment method designs for identifying the maximum tolerated dose combination, using toxicity only, and the optimal biological dose combination, using both toxicity and efficacy, respectively. The local data-based continual reassessment method designs only model the local data from neighboring dose combinations. Therefore, they are flexible in estimating the local space and circumventing unstable characterization of the entire dose-exploration surface. Our simulation studies show that our approach has competitive performance compared to widely used methods for finding maximum tolerated dose combination, and it has advantages over existing model-based methods for optimizing optimal biological dose combination.
A climatology of satellite-derived cloud properties over marine stratocumulus regions

Satellite data on cloud properties obtained during the First ISCCP Regional Experiment (FIRE) (where ISCCP stands for Interantional Satellite Cloud Climatology Project) were analyzed using a methodology used in the 1987 FIRE Intensive Field Observations (IFO) measurements, in order to link the small-scale IFO results to the ISCCP large-scale bulk cloud properties and to provide a detailed climatology for climate modeling. The preliminary results of the analysis delineated some of the features common to all four major subtropical marine stratus areas analyzed. The differences observed between the areas were greatest for the values of cloud optical depths.
How well do high resolution models reproduce tropical convection

Cascade is a multi-institution project studying the temporal and spatial organization of tropical convective systems. While cloud resolving numerical models can reproduce the observed diurnal cycle of such systems they are sensitive to the chosen resolution. As part of this effort, we are comparing results from the Met. Office Unified Model to data from the Global Earth Radiation Budget satellite instrument over the African Monsoon Interdisciplinary Analyses region of North Africa. We use a variety of mathematical techniques to study the outgoing radiation and the evolution of properties such as the cloud size distribution. The effectiveness of various model resolutions is tested with a view to determining the optimum balance between resolution and the need to reproduce the observations.
Recruitment Promotion via Twitter: A Network-centric Approach of Analyzing Community Engagement Using Social Identity

With the proliferation of online technologies, social media recruitment has become an essential part of any company’s outreach campaign. A social media platform can provide marketing posts with access to a large pool of candidates and at a low cost. It also provides the opportunity to quickly customize and refine messages in response to the reception. With online marketing, the key question is: which communities are attracted by recruitment tweets on social media? In this work, we profile the Twitter accounts that interact with a set of recruitment tweets by the U.S. Army’s Recruitment Command through a network-centric perspective. By harnessing how users signal their affiliations through user information, we extract and analyze communities of social identities. From Social Identity Theory, these social identities can be critical drivers of behavior, like the decision to enlist in the military. With this framework, we evaluate the effectiveness of the U.S. Army’s recruitment campaign on Twitter, observing that these campaigns typically attract communities with military exposure like veterans or those that identify with professional careers and fitness (e.g., student, professionals, athletes). The campaign also attracts, but at a much lower level, interaction from those in the digital industries—data scientists, cybersecurity professionals, and so forth. When analyzing the accounts in terms of their degree of automation, we find a set of intent-unknown bot accounts interacting with the tweets, and that many of the recruitment accounts are perceived as automated accounts. These observations can aid in campaign refinement: targeting the digital community and getting a broader reach for online recruitment publicity campaigns.
Structural insights into the complex of oncogenic KRas4BG12V and Rgl2, a RalA/B activator

The work reports the KRas4BG12V oncogenic mutation alters the binding kinetics with Rgl2, a RalA/B activator, and the V12 resides at the KRas4B(G12V)•Rgl2 complex interface in the crystal structure. About a quarter of total human cancers carry mutations in Ras isoforms. Accumulating evidence suggests that small GTPases, RalA, and RalB, and their activators, Ral guanine nucleotide exchange factors (RalGEFs), play an essential role in oncogenic Ras-induced signalling. We studied the interaction between human KRas4B and the Ras association (RA) domain of Rgl2 (Rgl2RA), one of the RA-containing RalGEFs. We show that the G12V oncogenic KRas4B mutation changes the interaction kinetics with Rgl2RA. The crystal structure of the KRas4BG12V: Rgl2RA complex shows a 2:2 heterotetramer where the switch I and switch II regions of each KRasG12V interact with both Rgl2RA molecules. This structural arrangement is highly similar to the HRasE31K:RALGDSRA crystal structure and is distinct from the well-characterised Ras:Raf complex. Interestingly, the G12V mutation was found at the dimer interface of KRas4BG12V with its partner. Our study reveals a potentially distinct mode of Ras:effector complex formation by RalGEFs and offers a possible mechanistic explanation for how the oncogenic KRas4BG12V hyperactivates the RalA/B pathway.
The changing role of a video-on-demand service in the strategies of public service media: A production study of Danish TV 2 Play and its impact on the production culture of the schedulers, 2016–2022

Abstract This article highlights and discusses the main findings from three different media production studies (2016, 2019, and 2022) investigating the changing production culture of the schedulers in public service media. The inclusion of a broadcaster video-on-demand (BVoD) service in the broadcaster's portfolio affected the production culture. First, the article argues that profound changes happened to the organisational framing of the BVoD service's status and its impact on the production practices. Second, the article shows the BVoD service's impact on the content priorities among the schedulers at TV 2 in Denmark and third, how the public service branding of TV 2 became more explicit in the production culture. However, across these three points of impact and the shifts in the strategic focus at TV 2, the business model at TV 2 and its interplay with the public service obligations runs as an undercurrent.
Nucleotide sharing through gap junctions buffers replication stress

Cell proliferation underlying tissue growth and homeostasis, requires high levels of metabolites such as deoxynucleotides (dNTPs). The dNTP pool is known to be tightly cell-autonomously regulated through the de novo synthesis and salvage pathways. Here, we reveal that nucleotides can be provided to cells non-autonomously by surrounding cells of the tissue. Drosophila adult intestinal stem cells are highly sensitive to nucleotide depletion whereas wing progenitor cells are not. While adult intestinal stem cells lack gap junctions and their associated capacity to buffer dNTP pools, wing progenitor cells share nucleotides through connections to surrounding cells via gap junctions, allowing buffering of replication stress induced by nucleotide pool depletion. These findings have broad implications, suggesting that gap junction connectivity may define how sensitive cells are to changes in intracellular dNTP levels and replication stress.
Achieving Institutional Isomorphism in International Franchising through Knowledge Transfer: Evidence from the Food and Beverage Industry in Cambodia

ABSTRACT This study evaluates franchising decisions in the food and beverage industry by incorporating an institutional perspective and an organizational learning perspective to account for both economic and social factors. Adopting a qualitative approach, multiple-case-study analysis is conducted on international franchise brands in the food and beverage industry. The results indicate how each type of franchise network – underdeveloped, developing, and developed – achieves coercive and mimetic isomorphism and how that leads to distinctive implications for both the franchisor and the franchisee. This research fills the gap in the franchising literature by providing insights into knowledge-transfer practices and institutional isomorphism.
High-amplitude network co-fluctuations linked to variation in hormone concentrations over the menstrual cycle

Abstract Many studies have shown that the human endocrine system modulates brain function, reporting associations between fluctuations in hormone concentrations and brain connectivity. However, how hormonal fluctuations impact fast changes in brain network organization over short timescales remains unknown. Here, we leverage a recently proposed framework for modeling co-fluctuations between the activity of pairs of brain regions at a framewise timescale. In previous studies we showed that time points corresponding to high-amplitude co-fluctuations disproportionately contributed to the time-averaged functional connectivity pattern and that these co-fluctuation patterns could be clustered into a low-dimensional set of recurring “states. ” Here, we assessed the relationship between these network states and quotidian variation in hormone concentrations. Specifically, we were interested in whether the frequency with which network states occurred was related to hormone concentration. We addressed this question using a dense-sampling dataset (N = 1 brain). In this dataset, a single individual was sampled over the course of two endocrine states: a natural menstrual cycle and while the subject underwent selective progesterone suppression via oral hormonal contraceptives. During each cycle, the subject underwent 30 daily resting-state fMRI scans and blood draws. Our analysis of the imaging data revealed two repeating network states. We found that the frequency with which state 1 occurred in scan sessions was significantly correlated with follicle-stimulating and luteinizing hormone concentrations. We also constructed representative networks for each scan session using only “event frames”—those time points when an event was determined to have occurred. We found that the weights of specific subsets of functional connections were robustly correlated with fluctuations in the concentration of not only luteinizing and follicle-stimulating hormones, but also progesterone and estradiol.
Engineered BCL6 BTB Domain of the Bcl-2 Protein Family shows Dynamic Structural Behavior: Insights from Molecular Dynamics Simulations

Apoptosis is crucially regulated by the Bcl-6 protein, and mutations in this protein can have a significant impact on many malignancies. In this study, we used molecular dynamics simulations to examine the effects of specific mutations (Q8C, R67C, and N84C) in the crystal structure of the BCL6 BTB domain in a compound with pyrazole-pyrimidine ligand. We concentrated on comprehending the dynamics of these alterations and their possible effects on the emergence of cancer. To explore the structural and dynamic changes induced by these mutations, we performed in silico simulations using the GROMACS software suite (version 5.2, 2020.1) on Google Colab’s Tesla T4 GPU. The crystal structure of the BCL6 BTB domain in complex with the pyrazole-pyrimidine ligand (PDB ID: 5N20) served as the wild-type reference structure. Mutations were imposed using the Rotamer functions of Chimera. The simulations were carried out for a total duration of 20 ns using a time step of 2 femtoseconds (0.002 ps). The Trajectory profiles of the BCL6 BTB domain protein and its three mutations, Q8C, R67C and N84C, were shown to differ from each other. Based on the analysis of RMSD, RMSF, and Rg, it was determined that the mutant 2 (R67C) protein exhibited increased instability and greater flexibility. In contrast, mutant 3 (N84C) demonstrates a heightened level of compactness and greater stability compared to the remaining protein mutant. PCA also provides information regarding the structural dynamics of these mutants. In addition, the SASA and SASA autocorrelation provides a distinct view of the solvent accessibility of these proteins.
Calcification and trophic responses of Mesophotic reefs to carbonate chemistry variability

Mesophotic coral ecosystems (MCEs) are extensions of adjacent shallow water coral reefs. Accessibility to these ecosystems is challenging due to their depth limits (∼ 30 – 150 m) and as a result, scientific knowledge of these reef systems is limited. It has been posited that the depth limits of MCEs diminish anthropogenic effects experienced by shallow reef systems. A lack of empirical measurements to date has made this hypothesis impossible to determine for mesophotic reef metabolism. The alkalinity anomaly technique was utilized to determine rates of net ecosystem calcification (NEC) and net ecosystem production (NEP) from 30, 40 and 60 m mesophotic reefs during a 15-month period. Seawater chemistry was determined to be chemically conducive for calcification (average aragonite saturation Ωaragonite of 3.58, average calcite saturation Ωcalcite of 5.44) with estimates of NEC indicating these reef systems were net accretive and within global average values for shallow coral reefs (< 30 m). The strongest periods of calcification occurred in late summer and were coupled with strong autotrophic signals. These episodes were followed by suppressed calcification and autotrophy and in the case of the 60 m reefs, a switch to heterotrophy. Whilst there was variability between the three reefs depths, the overall status of the mesophotic system was net autotrophic. This determination was the opposite of trophic status estimates previously described for adjacent shallow reefs. Whilst there were periods of net dissolution, the mesophotic reef system was net accretive (i.e., gross calcification > gross CaCO3 dissolution). The measured inorganic carbon chemistry and estimates of NEC and NEP represent the first such biogeochemical measurements for MCEs. The values established by this study demonstrate just how close these understudied ecosystems are in terms of the known boundary thresholds for low saturation state reefs. Making predictions on how these ecosystems will respond to future climatic conditions, will require greater sampling effort over long times scales to decouple the environmental controls exerted on such ecosystems.
Pseudomonas aeruginosa MipA-MipB envelope proteins act as new sensors of polymyxin

Due to the rising incidence of antibiotic resistant infections, the last-line antibiotics polymyxins have resurged in the clinics in parallel with new bacterial strategies of escape. The Gram-negative opportunistic pathogen Pseudomonas aeruginosa develops resistance to colistin/polymyxin by distinct molecular mechanisms, mostly through modification of the lipid A component of the LPS by proteins encoded within the arnBCDATEF-ugd (arn) operon. In this work, we characterized a polymyxin-induced operon, named mipBA, notably present in P. aeruginosa strains devoid of the arn operon. We showed that mipBA is activated by ParR/ParS two-component regulatory system in response to polymyxin. MipA and MipB localize to bacterial outer membrane and form a complex in vitro. Structural modeling revealed that the lipoprotein MipB adopts a β-lactamase fold with two additional C-terminal domains,while MipA folds as an outer-membrane β-barrel, harboring an internal negatively charged channel, able to host a polymyxin molecule. Nano differential scanning fluorimetry (DSF) showed that polymyxin stabilized MipA protein in vitro. Mass spectrometry-based quantitative proteomics on whole bacterial membranes demonstrated that the ΔmipBA mutant synthesized less MexXY-OprA proteins in response to polymyxin compared to the wild-type strain, as a consequence of impaired transcriptional activation of the mex operon. We propose MipA/MipB to act as membrane (co)sensors working in concert to activate ParS histidine kinase and help the bacterium to cope with polymyxin-mediated envelope stress through synthesis of the efflux pomp, MexXY-OprA.
A scalable, low-cost phenotyping strategy to assess tuber size, shape, and the colorimetric features of tuber skin and flesh in potato breeding populations

Tuber size, shape, colorimetric characteristics, and defect susceptibility are all factors that influence the acceptance of new potato cultivars. Despite the importance of these characteristics, our understanding of their inheritance is substantially limited by our inability to precisely measure these features quantitatively on the scale needed to evaluate breeding populations. To alleviate this bottleneck, we developed a low-cost, semi-automated workflow to capture data and measure each of these characteristics using machine vision. This workflow was applied to assess the phenotypic variation present within 189 F1 progeny of the A08241 breeding population. Our results provide an example of quantitative measurements acquired using machine vision methods that are reliable, heritable, and can be used to understand and select upon multiple traits simultaneously in structured potato breeding populations.
Indirect Inference: Which Moments to Match?

The standard approach to indirect inference estimation considers that the auxiliary parameters, which carry the identifying information about the structural parameters of interest, are obtained from some recently identified vector of estimating equations. In contrast to this standard interpretation, we demonstrate that the case of overidentified auxiliary parameters is both possible, and, indeed, more commonly encountered than one may initially realize. We then revisit the “moment matching” and “parameter matching” versions of indirect inference in this context and devise efficient estimation strategies in this more general framework. Perhaps surprisingly, we demonstrate that if one were to consider the naive choice of an efficient Generalized Method of Moments (GMM)-based estimator for the auxiliary parameters, the resulting indirect inference estimators would be inefficient. In this general context, we demonstrate that efficient indirect inference estimation actually requires a two-step estimation procedure, whereby the goal of the first step is to obtain an efficient version of the auxiliary model. These two-step estimators are presented both within the context of moment matching and parameter matching.
Detecting inbreeding depression in structured populations

Measuring inbreeding as well as its consequences on fitness is central for many areas in biology including human genetics and the conservation of endangered species. However, there is no consensus on the most appropriate method, neither for quantification of inbreeding itself nor for the model to estimate its effect on specific traits. In this project, we simulated traits based on simulated genomes from a large pedigree and empirical whole-genome sequences of human data from populations with various sizes and structure (from the 1,000 Genomes project). We compare the ability of various inbreeding coefficients (F) to quantify the strength of inbreeding depression: allele sharing, two versions of the correlation of uniting gametes which differ in the weight they attribute to each locus and two identical-by-descent segments-based estimators. We also compare two models: the standard linear model and a linear mixed model including a genetic relatedness matrix (GRM) as random effect to account for the non-independence of observations. We find linear mixed models give better results in scenarios with population or family structure. Within the mixed models, we compare three different GRM matrices and show that in homogeneous populations, there is little difference among the different F and GRM for inbreeding depression quantification. However, as soon as strong population or family structure is present, the strength of inbreeding depression can be most efficiently estimated only if (i) the phenotypes are regressed on inbreeding coefficient based on a weighted version of the correlation of uniting gametes, which gives more weight to common alleles and (ii) with the GRM obtained from an allele sharing relatedness estimator.
Evolutionary conservation of secondary structures in the lncRNAs of plants

LncRNAs are essential regulators of eukaryotic gene expression. They exert their gene regulatory functions by interacting with DNA, RNA, and protein. These functions are considered at least in part associated with their capacity to fold into complex three-dimensional structures. The conservation of lncRNA structure in mammalian genomes has been assessed in several studies, however, very little is known about the conservation of lncRNA structures in plants. Here, we analyze the structural conservation of lncRNAs in Brassicaceae, using a whole genome alignment of 16 Brassicaceae species. We found that 44.2% (1925 of 4354) of the intergenic lncRNAs (lincRNAs) and 75.1% (1549 of 2060) of the natural antisense transcripts (NATs) of Arabidopsis thaliana have conserved structural motifs in at least 2 of the 16 species. Also, 3612 lncRNAs have conserved structural motifs in multiple species; 2264 of which are tissue-specific, and 841 can be associated with a function by a co-expression network in A. thaliana. Indeed, we find evidence for the conservation of structural motifs in several lncRNAs with known functions, including, lncCOBRA1, FLORE, IPS1, ELENA1 and COOLAIR. The latter was shown previously to have a conserved structure. Overall, we have identified numerous lncRNAs with conserved structures in Brassicaceae that warrant further experimental exploration in vivo to understand whether these lncRNAs and their conserved structures are of biological significance.