Miracle-dz/UniFAR-FTUs huggingface dataset:
Fluorescence Lifetime Imaging for Quantification of Targeted Drug Delivery in Varying Tumor Microenvironments

Rationale Trastuzumab (TZM) is a monoclonal antibody that targets the human epidermal growth factor receptor (HER2) and is clinically used for the treatment of HER2-positive breast tumors. However, the tumor microenvironment can limit the access of TZM to the HER2 targets across the whole tumor and thereby compromise TZM’s therapeutic efficacy. An imaging methodology that can non-invasively quantify the binding of TZM-HER2, which is required for therapeutic action, and distribution within tumors with varying tumor microenvironments is much needed. Methods We performed near-infrared (NIR) fluorescence lifetime (FLI) Forster Resonance Energy Transfer (FRET) to measure TZM-HER2 binding, using in vitro microscopy and in vivo widefield macroscopy, in HER2 overexpressing breast and ovarian cancer cells and tumor xenografts, respectively. Immunohistochemistry was used to validate in vivo imaging results. Results NIR FLI FRET in vitro microscopy data show variations in intracellular distribution of bound TZM in HER2-positive breast AU565 and AU565 tumor-passaged XTM cell lines in comparison to SKOV-3 ovarian cancer cells. Macroscopy FLI (MFLI) FRET in vivo imaging data show that SKOV-3 tumors display reduced TZM binding compared to AU565 and XTM tumors, as validated by ex vivo immunohistochemistry. Moreover, AU565/XTM and SKOV-3 tumor xenografts display different amounts and distributions of TME components, such as collagen and vascularity. Therefore, these results suggest that SKOV-3 tumors are refractory to TZM delivery due to their disrupted vasculature and increased collagen content. Conclusion Our study demonstrates that FLI is a powerful analytical tool to monitor the delivery of antibody drug tumor both in cell cultures and in vivo live systems. Especially, MFLI FRET is a unique imaging modality that can directly quantify target engagement with potential to elucidate the role of the TME in drug delivery efficacy in intact live tumor xenografts.
Adsorption-driven deformation and landing-footprints of the RBD proteins in SARS-CoV-2 variants onto biological and inanimate surfaces

Respiratory viruses, carried through airborne microdroplets, frequently adhere to surfaces, including plastics and metals. However, our understanding of the interactions between viruses and materials remains limited, particularly in scenarios involving polarizable surfaces. Here, we investigate the role of receptor-binding domain (RBD) mutations on the adsorption of SARS-CoV-2 to hydrophobic and hydrophilic surfaces employing molecular simulations. To contextualize our findings, we contrast the interactions on inanimate surfaces with those on native-biological interfaces, specifically the ACE2 receptor. Notably, we identify a twofold increase in structural deformations for the protein’s receptor binding motif onto the inanimate surfaces, indicative of enhanced shock-absorbing mechanisms. Furthermore, the distribution of amino acids (landing-footprints) on the inanimate surface reveals a distinct regional asymmetry relative to the biological interface. In spite of the H-bonds formed at the hydrophilic substrate, the simulations consistently show a higher number of contacts and interfacial area with the hydrophobic surface, with the WT RBD adsorbed more strongly than the delta or omicron RBDs. In contrast, the adsorption of delta and omicron to hydrophilic surfaces was characterized by a distinctive hopping-pattern. The novel shock-absorbing mechanisms identified in the virus adsorption on inanimate surfaces could lead current experimental efforts in the design of virucidal surfaces.
Creation and Validation of the First Infinium DNA Methylation Array for the Human Imprintome

Background Differentially methylated imprint control regions (ICRs) regulate the monoallelic expression of imprinted genes. Their epigenetic dysregulation by environmental exposures throughout life results in the formation of common chronic diseases. Unfortunately, existing Infinium methylation arrays lack the ability to profile these regions adequately. Whole genome bisulfite sequencing (WGBS) is the unique method able to profile these regions, but it is very expensive and it requires not only a high coverage but it is also computationally intensive to assess those regions. Findings To address this deficiency, we developed a custom methylation array containing 22,819 probes. Among them, 9,757 probes map to 1,088 out of the 1,488 candidate ICRs recently described. To assess the performance of the array, we created matched samples processed with the Human Imprintome array and WGBS, which is the current standard method for assessing the methylation of the Human Imprintome. We compared the methylation levels from the shared CpG sites and obtained a mean R2 = 0.569. We also created matched samples processed with the Human Imprintome array and the Infinium Methylation EPIC v2 array and obtained a mean R2 = 0.796. Furthermore, replication experiments demonstrated high reliability (ICC: 0.799-0.945). Conclusions Our custom array will be useful for replicable and accurate assessment, mechanistic insight, and targeted investigation of ICRs. This tool should accelerate the discovery of ICRs associated with a wide range of diseases and exposures, and advance our understanding of genomic imprinting and its relevance in development and disease formation throughout the life course.
Temporal and spatial patterns of remotely sensed litterfall in tropical and subtropical forests of Taiwan

Litterfall is important for returning nutrients and carbon to the forest floor, and microbes decompose the litterfall to release CO2 into the atmosphere. Litterfall is a pivotal component in the forest biogeochemical cycle, which is sensitive to climate variability and plant physiology. In this study, we combined field litterfall estimates and time series (2001–2011) climate (the Moderate Resolution Imaging Spectroradiometer (MODIS) land surface temperature (LST) and Tropical Rainfall Measuring Mission (TRMM) precipitations) and green vegetation (MODIS photosynthetically active vegetation cover (PV)) variables to estimate regional annual litterfall in tropical/subtropical forests in Taiwan. We found that time series MODIS LST‐ and PV‐derived metrics, the annual accumulated MODIS LST, and coefficient of variation of PV, respectively, but not the TRMM precipitation variables were salient factors for the estimation (r2 = 0.548 and p < 0.001). The mean (±standard deviation) annual litterfall was 5.1 ± 1.2 Mg ha−1 yr−1 during the observation period. The temporal dynamics of the litterfall revealed that typhoons and consecutive drought events might affect the litterfall temporal variation. Overall, the annual litterfall decreased along the elevation gradient, which may reflect a change in the vegetation type. The northeast and northwest facing slopes yielded the highest amount of annual litterfall (≥5.9 Mg ha−1 yr−1), which was in contrast with the southern aspect (5.1 Mg ha−1 yr−1). This variation may be associated with the dryness of the microclimate influenced by solar radiation. This study demonstrates the feasibility of utilizing time series MODIS LST and PV data to predict large‐scale field litterfall, which may facilitate large‐scale monitoring of biogeochemical cycles in forest ecosystems.
Superiority of chromosomal compared to plasmid-encoded compensatory mutations

Plasmids are important vectors of horizontal gene transfer in microbial communities but can impose a burden on the bacteria that carry them. Such plasmid fitness costs are thought to arise principally from conflicts between chromosomal- and plasmid-encoded molecular machineries, and thus can be ameliorated by compensatory mutations (CMs) that reduce or resolve the underlying causes. CMs can arise on plasmids (i.e. plaCM) or on chromosomes (i.e. chrCM), with contrasting predicted effects upon plasmid success and subsequent gene transfer because plaCM can also reduce fitness costs in plasmid recipients, whereas chrCM can potentially ameliorate multiple distinct plasmids. Here, we develop theory and a novel experimental system to directly compare the ecological effects of plaCM and chrCM that arose during evolution experiments between Pseudomonas fluorescens SBW25 and its sympatric mercury resistance megaplasmid pQBR57. We show that while plaCM was predicted to succeed under a broader range of parameters in mathematical models, experimentally chrCM dominated under all conditions, including those with numerous recipients, due to a more efficacious mechanism of compensation, and advantages arising from transmission of costly plasmids to competitors (plasmid ‘weaponisation’). We show analytically the presence of a mixed Rock-Paper-Scissors regime for plaCM, driven by trade-offs with horizontal transmission, that explains the observed failure of plaCM to dominate even in competition against an uncompensated plasmid. Our results reveal broader implications of plasmid-bacterial evolution for plasmid ecology, demonstrating the importance of compensatory mutations for resistance gene spread. One consequence of the superiority of chrCM over plaCM is the likely emergence in microbial communities of compensated bacteria that can act as ‘hubs’ for plasmid accumulation and dissemination.
Gaze and Arrows: does the Gaze Following Patch in the posterior temporal cortex differentiate social and symbolic spatial cues?

The Gaze Following Patch (GFP) is located in the posterior temporal cortex and has been described as a cortical module dedicated to processing other people’s gaze direction in a domain-specific manner. Thus, it appears to be the neural correlate of Baron-Cohen’s Eye-Direction Detector (EDD) which is one of the core modules in his Mindreading System - a neurocognitive model for the Theory of Mind concept. Inspired by Jerry Fodor’s ideas on the modularity of the mind, Baron-Cohen proposed that, among other things, the individual modules are domain-specific. In the case of the EDD this means that it exclusively processes eye-like stimuli to extract gaze direction and that other stimuli, that may carry directional information as well, are processed elsewhere. If the GFP is indeed EDD’s neural correlate it must meet this expectation. To test this, we compared the GFP’s BOLD activity during gaze-direction following with the activity during arrow-direction following. Contrary to the expectation based on the assumption of domain specificity we did not find a differentiation between gaze and arrow-direction following. In fact, we were not able to reproduce the GFP as presented in previous studies. A possible explanation is that in the present study – unlike previous work –, the gaze stimuli did not contain an obvious change of direction that represented a visual motion. Hence, the critical stimulus component responsible for the identification of the GFP in previous experiments might have been visual motion.
Multi-state kinetics of the syringe-like injection mechanism of Tc toxins

Tc toxins are virulence factors of many insects and human pathogenic bacteria. They attach as soluble prepores to receptors on host cells and following acidification in the late endosome, perforate the cell membrane like a syringe to translocate toxic enzymes into the host cell through their pore-forming channel. Although this complex transformation has been structurally well studied, the functional aspects of this large-scale rearrangement, such as the reaction pathway with possible intermediate states and the resulting temporal evolution have remained elusive. Here, we used an integrated biophysical approach to monitor the prepore-to-pore transition and found that it takes ∼28 h when induced by high pH in the absence of other factors. In the presence of liposomes, an increasingly high pH or receptors, such as heparin or Vsg, the probability to transform prepores to pores increases by a factor of up to 4. This effect can also be mimicked by biotinylation or site-directed mutagenesis of the shell, demonstrating that shell destabilization is a crucial step in prepore-to-pore transition. We show that shell opening is a heterogeneous process with transition times ranging from 60 ms to 1.6 s and resolve three sequential intermediate states: an initial transient intermediate during shell destabilization, a first stable intermediate where the receptor-binding domains on the shell rearrange and a second stable intermediate with an open shell. In contrast, the ejection of the pore-forming channel from the open shell is highly cooperative with a transition time of < 60 ms. This detailed knowledge of the Tc toxin mechanism of action, even in the absence of receptors, is important for the future application of Tc toxins as biomedical devices or biopesticides.
Recruitment of the m6A/Am demethylase FTO to target RNAs by the telomeric zinc finger protein ZBTB48

Fat mass and obesity-associated protein (FTO) can remove both the N6-methyladenosine (m6A) and N6, 2′-O-dimethyladenosine (m6Am) methylation marks that function in multiple aspects of posttranscriptional regulation. Here, we demonstrate that ZBTB48, a C2H2-zinc finger protein that functions in telomere maintenance, associates with FTO and binds both mRNA and the telomere-associated regulatory RNA TERRA to regulate the functional interactions of FTO with target transcripts. Specifically, depletion of ZBTB48 affects targeting of FTO to sites of m6A/m6Am modification, changes cellular m6A/m6Am levels and, consequently, alters decay rates of target RNAs. ZBTB48 ablation also accelerates growth of HCT-116 colorectal cancer cells and modulates FTO-dependent regulation of Metastasis-associated protein 1 (MTA1) transcripts by controlling the binding to MTA1 mRNA of the m6A reader IGF2BP2. Our findings thus uncover a previously unknown mechanism of posttranscriptional regulation in which ZBTB48 co-ordinates RNA-binding of the m6A/m6Am demethylase FTO to control expression of its target RNAs.
Computational and neural evidence for altered fast and slow learning from losses in gambling disorder

Learning occurs across multiple timescales, with fast learning crucial for adapting to sudden environmental changes, and slow learning beneficial for extracting robust knowledge from multiple events. Here we asked if miscalibrated fast vs slow learning can lead to maladaptive decision-making in individuals with gambling disorder. Participants with problem gambling and a recreational gambling control group without any symptoms associated with problem gambling performed a probabilistic decision-making task involving reward-learning and loss-avoidance while being scanned with fMRI. Problem gamblers showed impaired reversal learning from losses compared to the control group, with excessive dependence on slow timescales and reduced reliance on fast timescales. fMRI data implicated the putamen, an area associated with habit, and medial prefrontal cortex (PFC) in slow loss-value encoding, with significantly more robust encoding in medial PFC in problem gamblers compared to controls. Problem gamblers also exhibited stronger loss prediction error encoding in the insular cortex. These findings suggest that individuals with problem gambling have an impaired ability to adjust their predictions following losses, manifested by a stronger influence of slow value learning. This impairment could contribute to the behavioral inflexibility of problem gamblers, particularly the persistence in gambling behavior typically observed in those individuals after incurring loss outcomes.
The molecular basis for the increased stability of the FUS-LC fibril at the anionic membrane- and air-water interfaces

Self-organization of biomolecules can lead to the formation of liquid droplets, hydrogels, and irreversible aggregates that bear immense significance in biology and diseases. Despite the considerable amount of studies conducted on biomolecular condensation in bulk solution, there is still a lack of understanding of how different surfaces regulate the condensation process. In this context, recent studies showed that, in contrast to zwitterionic lipid membranes, anionic membranes promoted the production of liquid droplets of FUsed in Sarcoma Low Complexity domain (FUS-LC) despite exhibiting no specific protein-lipid interactions. Moreover, the air-water interface led to a solid fibril-like aggregate of FUS-LC. The molecular mechanism of condensation/aggregation of proteins in response to surfaces of various charged states or levels of hydrophobicity remains to be better elucidated. Here, we address this question by investigating the stability of a small β fibril state of FUS-LC in bulk solution vs. membrane- and air-water interfaces. Our study demonstrates the stability of the FUS-LC fibril in the presence of anionic membranes over 1 µs timescale while the fibril falls apart in bulk solution. We observe that a zwitterionic membrane does not enhance the stability of the fibril and 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS) has a higher propensity to stabilize the fibril than dioleoylphosphatidylglycerol (DOPG), in qualitative agreement with experiments. We further show that the fibril becomes more stable at the air-water interface. We pinpoint interfacial solvation at the membrane- and air-water interfaces as a key factor that contributes to the stabilization of the peptide assembly.
Practical Fine-grained Privilege Separation in Multithreaded Applications

An inherent security limitation with the classic multithreaded programming model is that all the threads share the same address space and, therefore, are implicitly assumed to be mutually trusted. This assumption, however, does not take into consideration of many modern multithreaded applications that involve multiple principals which do not fully trust each other. It remains challenging to retrofit the classic multithreaded programming model so that the security and privilege separation in multi-principal applications can be resolved. This paper proposes ARBITER, a run-time system and a set of security primitives, aimed at fine-grained and data-centric privilege separation in multithreaded applications. While enforcing effective isolation among principals, ARBITER still allows flexible sharing and communication between threads so that the multithreaded programming paradigm can be preserved. To realize controlled sharing in a fine-grained manner, we created a novel abstraction named ARBITER Secure Memory Segment (ASMS) and corresponding OS support. Programmers express security policies by labeling data and principals via ARBITER's API following a unified model. We ported a widely-used, in-memory database application (memcached) to ARBITER system, changing only around 100 LOC. Experiments indicate that only an average runtime overhead of 5.6% is induced to this security enhanced version of application.
Cross-Database Liveness Detection: Insights from Comparative Biometric Analysis

In an era where biometric security serves as a keystone of modern identity verification systems, ensuring the authenticity of these biometric samples is paramount. Liveness detection, the capability to differentiate between genuine and spoofed biometric samples, stands at the forefront of this challenge. This research presents a comprehensive evaluation of liveness detection models, with a particular focus on their performance in cross-database scenarios, a test paradigm notorious for its complexity and real-world relevance. Our study commenced by meticulously assessing models on individual datasets, revealing the nuances in their performance metrics. Delving into metrics such as the Half Total Error Rate, False Acceptance Rate, and False Rejection Rate, we unearthed invaluable insights into the models' strengths and weaknesses. Crucially, our exploration of cross-database testing provided a unique perspective, highlighting the chasm between training on one dataset and deploying on another. Comparative analysis with extant methodologies, ranging from convolutional networks to more intricate strategies, enriched our understanding of the current landscape. The variance in performance, even among state-of-the-art models, underscored the inherent challenges in this domain. In essence, this paper serves as both a repository of findings and a clarion call for more nuanced, data-diverse, and adaptable approaches in biometric liveness detection. In the dynamic dance between authenticity and deception, our work offers a blueprint for navigating the evolving rhythms of biometric security.
On the expected efficiency of branch and bound for the asymmetric TSP

Let the costs C ( i, j ) for an instance of the asymmetric traveling salesperson problem be independent uniform [0 , 1] random variables. We consider the eﬃciency of branch and bound algorithms that use the assignment relaxation as a lower bound. We show that w.h. p. the number of steps taken in any such branch and bound algorithm is e Ω( n a ) for some small absolute constant a > 0.
Selected COSMO-2 verification results over North-eastern Italian Veneto

The regional meteorological service of the north-eastern Italian region Veneto, the Centro Meteorologico di Teolo (CMT) is part of the Regional Agency for Environmental Protection and Prevention of Veneto (ARPAV). The CMT run a dense network of automatic weather stations (AWS), counting some 200 over the entire territory, a good part of which are transmitted in near real time. Also, in 2005 a network of planetary boundary layer (PBL) profilers was installed, more precisely four passive microwave radiometers (MWR) and four SODARs [1]. These observations are used to verify the COSMO-2 over the Veneto territory, which can be thought of as a domain roughly split in four parts with distinct climatological characteristics, i.e. going from south to north (Fig. 1) there is the plain, the flat Po Valley portion of Veneto, which spans about two thirds of the area, the prealpine foothills and the prealpine chain, which is a significant barrier for southerly flows, the Val Belluna, a major Alpine valley just north of the prealpine chain, and finally the Dolomite mountains, a high and inner Alpine mountain area. In this contribution selected verification results of the screen-level temperature, the temperature profiles and the PBL mixing height is given. The data set is described in section 2, the results in section 3, while some conclusions are summarized in the final section.
Modeling Timber and Non-timber Trade-offs in Spatially-explicit Forest Planning

Forest management is inherently a multiple-objective decision making process. Timber production, recreation, wildlife habitat and watershed protection are some of the many uses of forests. Providing the public with an optimal bundle of timber and nontimber benefits is challenging because many of these benefits conflict. Modeling the conflicting objectives, quantifying the trade-offs between them, and identifying efficient management alternatives can facilitate consensus between the stakeholders that represent the various forest uses. Spatially-explicit harvest scheduling provides an excellent modeling environment for such analyses. This work evaluates several existing and one proposed multi-criteria mathematical programming techniques as applied to a two-, then to a three-objective spatially-explicit forest planning problem. The objectives of these models were (1) to maximize the net revenues of the forest, (2) to maximize the minimum amount of mature forest habitat in large patches that evolve across the landscape and over time given various harvest schedules, and (3), in the three-objective model, to minimize the perimeter of these patches. The comparison criteria were the number of efficient alternatives found, the time to find them, the ability of the user to filter the alternatives, and the potential of the techniques to handle n-objective problems. In both the twoand the three-objective case, the proposed Alpha-Delta and the traditional Weighted Method showed promising computational performance. It is recommended that these two methods should be employed in concert to make full use of their respective advantages.