Miracle-dz/UniFAR-FTUs huggingface dataset:
Cryo-EM structure of monomeric CXCL12-bound CXCR4 in active state

CXC chemokine receptor 4 (CXCR4) and its chemokine ligand CXCL12 are crucial to embryonic development, bone marrow retention of hematopoietic progenitor cells, cancer metastasis, angiogenesis and HIV-1 infection. Yet the structural basis for CXCR4 recognition of full-length CXCL12 remains unknown despite available structures of CXCR4 in complex with small molecule antagonists and a viral chemokine. Here we present a cryo-EM structure of monomeric CXCL12-CXCR4 in complex with heterotrimeric Gi proteins at a resolution of 2.65 Å. The CXCL12-CXCR4 interaction at their N termini is stabilized by a polar interaction between the PC motif (C28NT in CXCR4) and CXC motif (the unique P10 in CXCL12). The N terminal 8 amino acids in CXCL12 insert into the transmembrane binding pocket (chemokine recognition site 2, CRS2) of CXCR4 with S4 defining an upward turn of V3, P2 and K1. Polar interactions involving C186ECL2 and D187ECL2, along with hydrogen bonding with E2887,39 and D2626,58 stabilize the N terminus of CXCL12 in CRS2. Hydrophobic interactions between side chains aligning CRS2 and P2, L5 and S6 of CXCL12 further strengthen its binding to the receptor. CXCL12 inserts deep into the binding pocket, and the 3. 2Å distance measured between V3 and the ‘toggle switch’ W6.48 for G protein activation is among the shortest of all chemokine-receptor pairs. Our findings provide structural insights into the recognition mechanism of CXCR4 for its chemokine ligand CXCL12.
De novo design of drug-binding proteins with predictable binding energy and specificity

The de novo design of small-molecule-binding proteins has seen exciting recent progress; however, the ability to achieve exquisite affinity for binding small molecules while tuning specificity has not yet been demonstrated directly from computation. Here, we develop a computational procedure that results in the highest affinity binders to date with predetermined relative affinities, targeting a series of PARP1 inhibitors. Two of four designed proteins bound with affinities ranging from < 5 nM to low μM, in a predictable manner. X-ray crystal structures confirmed the accuracy of the designed protein-drug interactions. Molecular dynamics simulations informed the role of water in binding. Binding free-energy calculations performed directly on the designed models are in excellent agreement with the experimentally measured affinities, suggesting that the de novo design of small-molecule-binding proteins with tuned interaction energies is now feasible entirely from computation. We expect these methods to open many opportunities in biomedicine, including rapid sensor development, antidote design, and drug delivery vehicles. One Sentence Summary We use informatic sampling to design low nM drug-binding proteins, and physics-based calculations to accurately predict affinities.
USING VALUES TO PREDICT TOURIST MOTIVATION: AN APPLICATION TO SPECIAL EVENTS IN CULTURAL TOURISM AT THE WINNIPEG FRINGE THEATRE FESTIVAL

Using the Winnipeg Fringe Theatre Festival in Manitoba, Canada as the context, the purpose of this paper is to examine the relationship between personal values and motivations for attending a festival. More specifically the work had two primary research questions. First, what are the dominant tourist values and tourist motivations for visitors to the Winnipeg Fringe Festival? Second, what is the relationship between visitors’ values and their motivations for attending the festival? Visitors rated self-respect (M = 6.30), fun and enjoyment in life (M = 6.26), warm relationship with others (M = 6.19), and self-fulfillment (M = 6.15) as the top personal values based on Kahle’s (1983) LOV scale. Strongest motivations for attending the festival were: to be entertained (M = 6.45), to learn something new (M = 5.31), to go to the Fringe to be with others who enjoy the same thing (M = 5.19), to spend time with friends (M = 5.03), and to attend a cultural event not normally having an opportunity to go to (M = 4.93). Treating the top five motivation items as separate dependent variables, a series of stepwise regression analyses were conducted. The nine personal value items explained between 8% and 13% of the variance in the five motivation items. Belonging explained the most variance across the five regression analyses. Implications for the festival as well as future research endeavors are highlighted in the closing of the paper.
TGM6, a helminth secretory product, mimics TGF-β binding to TβRII to antagonize TGF-β signaling in fibroblasts

The murine helminth parasite Heligmosomoides polygyrus expresses a family of proteins structurally related to TGF-β Mimic 1 (TGM1), a secreted five domain protein that activates the TGF-β pathway and converts naïve T lymphocytes to immunosuppressive Tregs. TGM1 signals through the TGF-β type I and type II receptors, TβRI and TβRII, with domains 1-2 and 3 binding TβRI and TβRII, respectively, and domains 4-5 binding CD44, a co-receptor abundant on T cells. TGM6 is a homologue of TGM1 that is co-expressed with TGM1, but lacks domains 1 and 2. Herein, we show that TGM6 binds TβRII through domain 3, but does not bind TβRI, or other type I or type II receptors of the TGF-β family. In TGF-β reporter assays in fibroblasts, TGM6, but not truncated TGM6 lacking domains 4 and 5, potently inhibits TGF-β- and TGM1-induced signaling, consistent with its ability to bind TβRII but not TβRI or other receptors of the TGF-β family. However, TGM6 does not bind CD44 and is unable to inhibit TGF-β and TGM1 signaling in T cells. To understand how TGM6 binds TβRII, the X-ray crystal structure of the TGM6 domain 3 bound to TβRII was determined at 1.4 Å. This showed that TGM6 domain 3 binds TβRII through an interface remarkably similar to the TGF-β:TβRII interface. These results suggest that TGM6 has adapted its domain structure and sequence to mimic TGF-β binding to TβRII and function as a potent TGF-β and TGM1 antagonist in fibroblasts. The coexpression of TGM6, along with the immunosuppressive TGMs that activate the TGF-β pathway, may prevent tissue damage caused by the parasite as it progresses through its life cycle from the intestinal lumen to submucosal tissues and back again.
An exploratory computational analysis in mice brain networks of widespread epileptic seizure onset locations along with potential strategies for effective intervention and propagation control

Mean-field models have been developed to replicate key features of epileptic seizure dynamics. However, the precise mechanisms and the role of the brain area responsible for seizure onset and propagation remain incompletely understood. In this study, we employ computational methods within The Virtual Brain framework and the Epileptor model to explore how the location and connectivity of an Epileptogenic Zone (EZ) in a mouse brain are related to focal seizures (seizures that start in one brain area and may or may not remain localized), with a specific focus on the hippocampal region known for its association with epileptic seizures. We then devise computational strategies to confine seizures (prevent widespread propagation), simulating medical-like treatments such as tissue resection and the application of an anti-seizure drugs or neurostimulation to suppress hyperexcitability. Through selectively removing (blocking) specific connections informed by the structural connectome and graph network measurements or by locally reducing outgoing connection weights of EZ areas, we demonstrate that seizures can be kept constrained around the EZ region. We successfully identified the minimal connections necessary to prevent widespread seizures, with a particular focus on minimizing surgical or medical intervention while simultaneously preserving the original structural connectivity and maximizing brain functionality.
Transmittance Variations Analysis in Sunglasses Lenses Post Sun Exposure

The hypothesis that sunglass ultraviolet (UV) protection can degrade with Sun exposure has never been proven experimentally. No sunglasses standards take into account UV transmittance changes after long Sun exposure. We selected 12 sunglass lenses and measured transmittance values from 280 nm to 780 nm. After 50 hours of exposure, new transmittance measurements were taken and transmittance variations inferior to 0.2% were observed. The exposition continues longer and more lenses will be tested to obtain conclusive results. We hope to obtain experimental data to confirm UV protection loss hypothesis and obtain a relation between Sun and solar simulator exposition
A new guest to the blood feast: a novel symbiotic lineage associated with a haematophagous leech from the genus Haementeria

Similarly to other strict blood-feeders, leeches from the Haementeria genus (Hirudinida: Glossiphoniidae) have established a symbiotic association with bacteria harboured intracellularly in oesophageal bacteriomes. Previous genome sequence analyses of these endosymbionts revealed co-divergence with their hosts, a strong genome reduction, and a simplified metabolism largely dedicated to the production of B vitamins, which are nutrients lacking from a blood diet. Candidatus Providencia siddallii has been identified as the obligate nutritional endosymbiont of a monophyletic clade of Mexican and South American Haementeria spp. Nonetheless, given a lack of molecular investigations, the identity of the symbiont housed in the bacteriomes of its sister clade of Central and South American congeners remained unknown. In this work, we report on a novel bacterial endosymbiont found in a representative from this Haementeria clade. We found that this symbiont lineage has evolved from within the Pluralibacter genus, known mainly from clinical, but also environmental strains. Similarly to Ca. Providencia siddallii, the Haementeria-associated Pluralibacter symbiont displays clear signs of genome reduction, accompanied by an A+T-biased sequence composition. Genomic analysis of its metabolic potential revealed a retention of pathways related to B vitamin biosynthesis, supporting its role as a nutritional endosymbiont. Finally, comparative genomics of both Haementeria symbiont lineages suggests that the ancient Providencia symbiont was likely replaced by the novel Pluralibacter one, thus constituting the first reported case of nutritional symbiont replacement in a leech without morphological changes in the bacteriome.
A computational procedure for predicting excipient effects on protein-protein affinities

Protein-protein interactions lie at the center of much biology and are a challenge in formulating biological drugs such as antibodies. A key to mitigating protein association is to use small molecule additives, i.e. excipients that can weaken protein-protein interactions. Here, we develop a computationally efficient model for predicting the viscosity-reducing effect of different excipient molecules by combining atomic-resolution MD simulations, binding polynomials and a thermodynamic perturbation theory. In a proof of principle, this method successfully rank orders four types of excipients known to reduce the viscosity of solutions of a particular monoclonal antibody. This approach appears useful for predicting effects of excipients on protein association and phase separation, as well as the effects of buffers on protein solutions. TOC Graphic
Svedala kommuns behov av klimatanpassning för översvämningar samt kvalificerade åtgärder

The effects of climate change and urbanization will increase the risk of flooding in urban areas due to increased precipitation and larger amount of impervious surfaces. Svedala, a municipality in southern Sweden and its storm water recipient Segea is one area that will be at greater risks in the future. The aim of this study is to compile information about flood risks in Svedala to identify the need for climate adaptation measures regarding flooding. My study shows that there is a need for Svedala to implement climate adaptation measures within many sectors in the municipality, including infrastructure and buildings. Furthermore the storm water sewer system is in great need for adaptation as the storm water capacity is undersized with repeated sewer overflows. To identify suitable climate adaptation measures to Svedala, climate adaptation plans from other Swedish municipalities and scientific literature were reviewed and evaluated. The results show many suitable measures to reduce the risk of flooding in Svedala. Some of the measures stands out by its quality to handle multiple risk areas, as: construction of green infrastructure and urban wetlands and less impervious surfaces. My conclusion is that the risk of flooding in Svedala will decrease if they implement the identified measures from this thesis. Furthermore my thesis can be used as a basis for a climate adaptation plan regarding flood risks in Svedala. (Less)
Solar‐Induced Fluorescence Helps Constrain Global Patterns in Net Biosphere Exchange, as Estimated Using Atmospheric CO2 Observations

Solar‐induced chlorophyll fluorescence (SIF) shows enormous promise as a proxy for photosynthesis and as a tool for modeling variability in gross primary productivity and net biosphere exchange (NBE). In this study, we explore the skill of SIF and other vegetation indicators in predicting variability in global atmospheric CO2 observations, and thus global variability in NBE. We do so using a 4‐year record of CO2 observations from NASA's Orbiting Carbon Observatory 2 satellite and using a geostatistical inverse model. We find that existing SIF products closely correlate with space‐time variability in atmospheric CO2 observations, particularly in the extratropics. In the extratropics, all SIF products exhibit greater skill in explaining variability in atmospheric CO2 observations compared to an ensemble of process‐based CO2 flux models and other vegetation indicators. With that said, other vegetation indicators, when multiplied by photosynthetically active radiation, yield similar results as SIF and may therefore be an effective structural SIF proxy at regional to global spatial scales. Furthermore, we find that using SIF as a predictor variable in the geostatistical inverse model shifts the seasonal cycle of estimated NBE and yields an earlier end to the growing season relative to other vegetation indicators. These results highlight how SIF can help constrain global‐scale variability in NBE.
Pre-training with pseudo-labeling for regulatory sequence prediction

Predicting molecular processes using deep learning is a promising approach to provide biological insights for non-coding SNPs identified in genome-wide association studies. However, most deep learning methods rely on supervised learning which requires DNA sequences associated with functional data, and whose amount is severely limited by the finite size of the human genome. Conversely, the amount of mammalian DNA sequences is growing exponentially due to ongoing large-scale sequencing projects, but in most cases without functional data. To alleviate the limitations of supervised learning, we propose a novel semi-supervised learning based on pseudo-labeling, which allows to explot unannotated DNA sequences from numerous genomes during model pre-training. The approach is very flexible and can be used to train any neural architecture including state-of-the-art models, and shows in certain situations strong predictive performance improvements compared to standard supervised learning in most cases.
Sunshine duration as a proxy of the atmospheric aerosol content

One of the most important radiative properties of aerosols is their optical thickness (AOD), which is closely linked to the total burden of atmospheric aerosols. On the contrary, we do avail of long time series of sunshine duration (SD) measurements, which is defined as the total time length of those sub-periods for which the direct solar irradiance exceeds a certain threshold. In the past, the Campbell-Stokes sunshine recorder (CSSR) has been the most common instrument for measuring SD. Specifically, SD is obtained measuring the length of the burn produced on a cardboard. The principal goal of the present thesis is to investigate the suitability of sunshine observations, as well as the width of the burn on the cards, for detecting changes in atmospheric aerosol load for both high time resolution and long time scales. The initial hypothesis is that an increase of AOD reduces both SD and the burn width. Una de les propietats radiatives mes importants dels aerosols atmosferics es el seu espessor optic (AOD), que esta molt vinculat a la carrega total d’aerosols en l’atmosfera. Per altra banda, existeixen llargues series temporals d’insolacio (SD), que es defineix com la suma de subperiodes en que la irradiancia solar directa excedeix un cert llindar. En el passat, l’heliograf Campbell-Stokes ha estat l’instrument mes comu per la mesura de SD, obtinguda a partir de la longitud de la cremada produida en una banda de cartolina. L’objectiu principal d’aquesta tesi ha estat investigar la idoneitat de la utilitzacio de mesures de SD, aixi com l’amplada de les cremades en les cartolines, per tal de detectar canvis en la carrega d’aerosols atmosferics, tant en alta resolucio temporal com en llargues escales temporals, partint de la hipotesis de que un augment de l’AOD redueix tant la mesura de SD com l’ample de la cremada.
News without the buzz: reading out weak theta rhythms in the hippocampus

Local field potentials (LFPs) reflect the collective dynamics of neural populations, yet their exact relationship to neural codes remains unknown1. One notable exception is the theta rhythm of the rodent hippocampus, which seems to provide a reference clock to decode the animal’s position from spatiotemporal patterns of neuronal spiking2 or LFPs3. But when the animal stops, theta becomes irregular4, potentially indicating the breakdown of temporal coding by neural populations. Here we show that no such breakdown occurs, introducing an artificial neural network that can recover position-tuned rhythmic patterns (pThetas) without relying on the more prominent theta rhythm as a reference clock. pTheta and theta preferentially correlate with place cell and interneuron spiking, respectively. When rats forage in an open field, pTheta is jointly tuned to position and head orientation, a property not seen in individual place cells but expected to emerge from place cell sequences5. Our work demonstrates that weak and intermittent oscillations, as seen in many brain regions and species, can carry behavioral information commensurate with population spike codes.
Single-molecule FRET and molecular dynamics simulations reveal early activation steps of MET receptor by Listeria monocytogenes

The human growth factor receptor MET is a receptor tyrosine kinase involved in cell proliferation, migration, and survival. MET is also hijacked by the intracellular pathogen Listeria monocytogenes. Its invasion protein, internalin B (InlB), binds to MET and promotes the formation of a signaling dimer that triggers the internalization of the pathogen. Here, we use a combination of structural biology, modeling, molecular dynamics simulations, and in situ single-molecule Förster resonance energy transfer (smFRET) experiments to elucidate the early events in MET activation by Listeria. Simulations show that InlB binding stabilizes MET in a conformation that promotes dimer formation. smFRET identifies the organization of the in situ signaling dimer. Further MD simulations of the dimer model are in quantitative agreement with smFRET. We accurately describe the structural dynamics underpinning an important cellular event and introduce a powerful methodological pipeline applicable to studying the activation of other plasma membrane receptors.
Symmetry. Saddle Points, and Global Optimization Landscape of Nonconvex Matrix Factorization

We propose a general theory for studying the geometry of nonconvex objective functions with underlying symmetric structures. In specific, we characterize the locations of stationary points and the null space of the associated Hessian matrices via the lens of invariant groups. As a major motivating example, we apply the proposed general theory to characterize the global geometry of the low-rank matrix factorization problem. In particular, we illustrate how the rotational symmetry group gives rise to infinitely many nonisolated strict saddle points and equivalent global minima of the objective function. By explicitly identifying all stationary points, we divide the entire parameter space into three regions: ($\mathcal{R}_{1}$) the region containing the neighborhoods of all strict saddle points, where the objective has negative curvatures; ($\mathcal{R}_{2}$) the region containing neighborhoods of all global minima, where the objective enjoys strong convexity along certain directions; and ($\mathcal{R}_{3}$) the complement of the above regions, where the gradient has sufficiently large magnitudes. We further extend our result to the matrix sensing problem. This allows us to establish strong global convergence guarantees for popular iterative algorithms with arbitrary initialization.
Power of Artificial Neural Networks and Taguchi's Orthogonal Arrays in Software Effort and Cost Estimation

In this paper we provide an overview of the research conducted on three novel models for estimating effort and costs in software project implementation. All three models utilize different architectures of artificial neural networks (ANNs) constructed based on Taguchi's orthogonal vector plans. The idea behind the conducted research is to optimize these novel models to avoid experiment repetition and reduce training time when estimating software projects. The structure of the proposed models could be improved by employing different encoding functions and clustering techniques for input data, aiming to mitigate the heterogeneous nature observed in various sets of real projects. Additionally, studies suggest the homogenization of input values across projects, leading to higher reliability and accuracy in the obtained results. Optimization with the Taguchi method, coupled with increased coverage of a wide range of industrial projects, results in the efficient and successful completion of various software projects, bringing benefits to the modern software industry.
A Case Study on the Quality of Static Analysis Bug Reports

Finding bugs in software using automated tools has enjoyed generous attention for as long as humans wrote software. With the increase in computing capacity and advancement in compiler theory, static analyzer tools like the Clang Static Analyzer have been an unexpandable part of several software development projects. The Clang Static Analyzer, like many other tools of its kind, employs heuristics, which may lead to reports on correct code – so-called false positives . The evaluation and the potential fixing of the reports cannot be automated, requiring valuable time from the most expensive and least available resource during development, a human expert. While the finding of bugs stands in the focus of academic research, the intelligible presentation of those findings to the user was less frequently discussed. In our paper, we survey several reports emitted by the Clang Static Analyzer to understand what makes a bug report hard to understand. Our study aims to pave the way for further research to fix the problems discussed here.
Evaluation of cultivation, legume undersowing and nitrogen interventions on wheat development

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