Miracle-dz/UniFAR-FTUs huggingface dataset:
Macro, Micro, and Molecular. Changes of the Osteochondral Interface in Osteoarthritis Development

Osteoarthritis (OA) is a long-term condition that causes joint pain and reduced movement. Notably, the same pathways governing cell growth, death, and differentiation during the growth and development of the body are also common drivers of OA. The osteochondral interface is a vital structure located between hyaline cartilage and subchondral bone. It plays a critical role in maintaining the physical and biological function, conveying joint mechanical stress, maintaining chondral microenvironment, as well as crosstalk and substance exchange through the osteochondral unit. In this review, we summarized the progress in research concerning the area of osteochondral junction, including its pathophysiological changes, molecular interactions, and signaling pathways that are related to the ultrastructure change. Multiple potential treatment options were also discussed in this review. A thorough understanding of these biological changes and molecular mechanisms in the pathologic process will advance our understanding of OA progression, and inform the development of effective therapeutics targeting OA.
Limited reciprocal surrogacy of bird and habitat diversity and inconsistencies in their representation in Romanian protected areas

Because it is impossible to comprehensively characterize biodiversity at all levels of organization, conservation prioritization efforts need to rely on surrogates. As species distribution maps of relished groups as well as high-resolution remotely sensed data increasingly become available, both types of surrogates are commonly used. A good surrogate should represent as much of biodiversity as possible, but it often remains unclear to what extent this is the case. Here, we aimed to address this question by assessing how well bird species and habitat diversity represent one another. We conducted our study in Romania, a species-rich country with high landscape heterogeneity where bird species distribution data have only recently started to become available. First, we prioritized areas for conservation based on either 137 breeding bird species or 36 habitat classes, and then evaluated their reciprocal surrogacy performance. Second, we examined how well these features are represented in already existing protected areas. Finally, we identified target regions of high conservation value for the potential expansion of the current network of reserves (as planned under the new EU Biodiversity Strategy for 2030). We found that bird species were a better surrogate for habitat diversity than vice versa. Highly ranked areas based on habitat diversity were represented better than areas based on bird species, which varied considerably between species. Our results highlight that taxonomic and environmental (i.e., habitat types) data may perform rather poorly as reciprocal surrogates, and multiple sources of data are required for a full evaluation of protected areas expansion.
PKC-ε Regulates Vesicle Delivery and Focal Exocytosis for Efficient IgG-mediated Phagocytosis

PKC-ε is required for membrane addition during IgG-mediated phagocytosis; its role in this process is ill-defined. High resolution imaging revealed that PKC-ε exits the Golgi and enters phagosomes on vesicles that then fuse. TNF-α and PKC-α colocalize at the Golgi and on vesicles that enter the phagosome. Loss of PKC-ε and TNF-α delivery upon nocodazole treatment confirmed vesicular transport on microtubules. That TNF-α+ vesicles are not delivered in macrophages from PKC-ε null mice, or upon dissociation of the Golgi-associated pool of PKC-ε, implicates Golgi-tethered PKC-ε as a driver of Golgi-to-phagosome trafficking. Finally, we established that PKC-ε’s regulatory domain is sufficient for delivery of TNF-α+ vesicles to the phagosome. These studies reveal a novel role for PKC-ε in focal exocytosis: its regulatory domain drives Golgi-derived vesicles to the phagosome while catalytic activity is required for their fusion. This is one of the first examples of a PKC requirement for vesicular trafficking and describes a novel function for a PKC regulatory domain. Summary Golgi-tethered PKC-ε regulates vesicle trafficking along phagosomally-directed microtubules and vesicle fusion into forming phagosomes. Unexpectedly, the regulatory domain is sufficient for vesicle delivery. Graphical Abstract PKC-ε is required for Golgi-to-phagosome trafficking. Golgi-tethered PKC-ε+ vesicles carry TNF-α to IgG phagosomes. Dissociation of PKC-ε from the Golgi with PIK93 or expression of hSac1-K2A prevents vesicle delivery. The regulatory domain of PKC-ε (εRD) is sufficient for vesicle delivery, but not fusion. Created with BioRender.com
The length scale of multivalent interactions is evolutionarily conserved in fungal and vertebrate phase-separating proteins

One key feature of proteins that form liquid droplets by phase separation inside a cell is the presence of multiple sites – multivalency – that mediate interactions with other proteins. We know little about the variation of multivalency on evolutionary time scales. Here, we investigated the long-term evolution (∼600 million years) of multivalency in fungal mRNA decapping subunit 2 protein (Dcp2), and in the FET protein family. We found that multivalency varies substantially among the orthologs of these proteins. However, evolution has maintained the length scale at which sequence motifs that enable protein-protein interactions occur. That is, the total number of such motifs per hundred amino acids is higher and less variable than expected by neutral evolution. To help explain this evolutionary conservation, we developed a conformation classifier using machine-learning algorithms. This classifier demonstrates that disordered segments in Dcp2 and FET proteins tend to adopt compact conformations, which is necessary for phase separation. Thus, the evolutionary conservation we detected may help proteins preserve the ability to undergo phase separation. Altogether, our study reveals that the length scale of multivalent interactions is an evolutionarily conserved feature of two classes of phase-separating proteins in fungi and vertebrates.
Meta-analytic maps of brain activity evoked by cognitive function diverge from resting state networks

Spontaneous human brain activity is organized into resting state networks (RSN), complex patterns of synchronized activity that account for the majority of brain metabolism. The correspondence between these patterns and those elicited by task performance suggests that spontaneous brain activity originates from the stream of ongoing cognitive processing. Here we investigate a large number of meta-analytic activation maps obtained from Neurosynth (www.neurosynth.org) to establish that task-rest similarity can be inflated by two potential sources of bias. Applying a hierarchical module detection algorithm to a network representation of activation map similarity, we showed that the correspondence between RSN and task-evoked activity tends to hold only for the largest spatial scales. Second, we established that this correspondence is biased by the inclusion of maps related to neuroanatomical terms (e.g. “parietal”, “occipital”, “cingulate”, etc.). Our results challenge the cognitive origin of spontaneous brain activity, suggesting that anatomically-constrained homeostatic processes could also play an important role in the inception and shaping of human resting state activity fluctuations.
Modelling segregation of bidisperse granular mixtures varying simultaneously in size and density for free surface flows

Abstract Flowing granular materials segregate due to differences in particle size (driven by percolation) and density (driven by buoyancy). Modelling the segregation of mixtures of large/heavy particles and small/light particles is challenging due to the opposing effects of the two segregation mechanisms. Using discrete element method (DEM) simulations of combined size and density segregation we show that the segregation velocity is well described by a model that depends linearly on the local shear rate and quadratically on the species concentration for free surface flows. Concentration profiles predicted by incorporating this segregation velocity model into a continuum advection–diffusion–segregation transport model match DEM simulation results well for a wide range of particle size and density ratios. Most surprisingly, the DEM simulations and the segregation velocity model both show that the segregation direction for a range of size and density ratios depends on the local species concentration. This leads to a methodology to determine the combination of particle size ratio, density ratio and particle concentration for which a bidisperse mixture will not segregate.
Increasing the Diversity of the Teacher Workforce: Socio-Political Challenges to Reducing Inequalities in Access to Teacher Education Programs

Cross-border migration leads to a diversification of societies, which is reflected in the education system, where classrooms are composed of students with heterogeneous cultural, linguistic, socio-economic characteristics. However, this diversity is only to a limited extent reflected in the teacher population, even though teachers from different backgrounds can bring specific intercultural competencies, have more positive attitudes toward multicultural heterogeneity and act as role models. To facilitate the diversification of the teaching profession, it is imperative that the cohorts of students entering teacher education programs represent the diversity of societies, however studies have shown students with migration backgrounds or from families with lower socio-economic status are underrepresented in such programs. This study considered the demographic constellation of applicants for admission into the teacher education program in Luxembourg (2015–2019) and investigated to what extent the admission process (dis)advantages certain groups. Results revealed that although applicants come from diverse backgrounds, proficiency in the country’s native languages poses a disadvantage for students with migration backgrounds. In addition, applicants coming from more privileged families stand a better chance of being admitted. Results are interpreted within the framework of social mobility and social reproduction. Implications for the admission to the teachers’ education program are discussed.
Reinforcement learning modeling reveals a reward-history-dependent strategy underlying reversal learning in squirrel monkeys

Insight into psychiatric disease and development of therapeutics relies on behavioral tasks that study similar cognitive constructs in multiple species. The reversal learning task is one popular paradigm that probes flexible behavior, aberrations of which are thought to be important in a number of disease states. Despite widespread use, there is a need for a high-throughput primate model that can bridge the genetic, anatomic, and behavioral gap between rodents and humans. Here, we trained squirrel monkeys, a promising preclinical model, on an image-guided deterministic reversal learning task. We found that squirrel monkeys exhibited two key hallmarks of behavior found in other species: integration of reward history over many trials and a side-specific bias. We adapted a reinforcement learning model and demonstrated that it could simulate monkey-like behavior, capture training-related trajectories, and provide insight into the strategies animals employed. These results validate squirrel monkeys as a model in which to study behavioral flexibility.
Exploitation of sulfated glycosaminoglycan status for precision medicine of platinums in triple-negative breast cancer

Triple negative breast cancer (TNBC) is a subtype of breast cancer lacking targetable biomarkers. TNBC is known to be most aggressive, and when metastatic is often drug resistant and uncurable. Biomarkers predicting response to therapy improve treatment decisions and allow personalized approaches for TNBC patients. This study explores sulfated glycosaminoglycan (sGAG) levels as a predictor of TNBC response to platinum therapy. sGAG levels were quantified in three distinct TNBC tumor models including cell line-derived, patient-derived xenograft (PDX) tumors, and isogenic models deficient in sGAG biosynthesis. The in vivo antitumor efficacy of Triplatin, a sGAG-directed platinum agent, was compared in these models to the clinical platinum agent, carboplatin. We determined that >40% of TNBC PDX tissue microarray samples have high levels of sGAGs. The in vivo accumulation of Triplatin in tumors as well as antitumor efficacy of Triplatin positively correlated with sGAG levels on tumor cells, whereas carboplatin followed the opposite trend. In carboplatin-resistant tumor models expressing high levels of sGAGs, Triplatin decreased primary tumor growth, reduced lung metastases and inhibited metastatic growth in lungs, liver, and ovaries. sGAG levels served as a predictor of Triplatin sensitivity in TNBC. Triplatin may be particularly beneficial in treating patients with chemotherapy-resistant tumors who have evidence of residual disease after standard neoadjuvant chemotherapy. More effective neoadjuvant and adjuvant treatment will likely improve clinical outcome of TNBC. Significance TNBC is a heterogenous disease, often defined by the absence of a therapeutic target. Our recent results show sGAGs may provide a viable biomarker for Triplatin in patients with TNBC, producing a significant advantage over carboplatin in this setting. Selective precision medicine agents, such as Triplatin, that are active against chemotherapy-resistant disease and exploit molecular biomarkers like sGAGs may significantly benefit patients in this setting.
Gender Differences in Psychosocial Predictors of Sexual Activity and HIV Testing Among Youth in Kenya

Sub-Saharan Africa (SSA) carries a disproportionate burden of HIV in the world relative to its population. Youth are at particular risk. Understanding HIV risk factors, as well as factors affecting HIV testing among SSA youth, is important given that HIV testing, linkage to care, and viral suppression are part of the global strategy to end HIV. Because young women face disparate sexual and reproductive health outcomes, exploring gender differences related to HIV risk, and testing is vital. Using existing program evaluation data from a larger project, the purpose of this study was to explore gender differences related to sexual activity and HIV testing among youth in SSA. Participant data from 581 youth ages 13–24 in Kenya was analyzed using descriptive statistics, analysis of covariance, and binomial logistic regression. Findings revealed that young men were more likely to report sexual activity than young women. Age was a predictor of sexual activity for all youth. However, among psychosocial variables, depression predicted sexual activity for young women while stress predicted sexual activity for young men. Although there were no gender differences in HIV testing after controlling for demographic and psychosocial variables, there were some differences between young women and young men with regard to predictors of HIV testing. Age and full-time self-employment predicted HIV testing among young women, while part-time self-employment, education, and substance abuse risk predicted HIV testing among young men. Findings suggest a need for gender and youth friendly strategies for addressing the HIV treatment cascade and care continuum.
Outcomes of COVID-19 Admissions in the New York City Public Health System and Variations by Hospitals and Boroughs During the Initial Pandemic Response

Introduction: In the initial pandemic regional differences may have existed in COVID-19 hospitalizations and patient outcomes in New York City. Whether these patterns were present in public hospitals is unknown. The aim of this brief study was to investigate COVID-19 hospitalizations and outcomes in the public health system during the initial pandemic response. Methods: A retrospective review was conducted on COVID-19 admissions in New York City public hospitals during the exponential phase of the pandemic. All data were collected from an integrated electronic medical records system (Epic Health Systems, Verona, WI). Overall, 5,422 patients with at least one admission each for COVID-19 were reviewed, with a study of demographic characteristics (including age, gender, race, BMI), pregnancy status, comorbidities, facility activity, and outcomes. Data related to hospitalization and mortality trends were also collected from City of New York website. These data often involved more than one facility and/or service line resulting in more location or treatment facility counts than patients due to utilization of services at more than one location and transfers between locations and facilities. Results: Higher mortality was associated with increasing age with the highest death rate (51.9%) noted in the age group >75 years (OR 7.88, 95%CI 6.32–10.08). Comorbidities with higher mortality included diabetes (OR 1.5, 95% CI 1.33–1.70), hypertension (OR 1.62, 95% CI 1.44–1.83), cardiovascular conditions (OR 1.66, 95% CI 1.47–1.87), COPD (OR 1.86, 95% CI 1.39–2.50). It was deduced that 20% of all New York City COVID-19 positive admissions were in public health system during this timeframe. A high proportion of admissions (21.26%) and deaths (19.93%) were at Elmhurst Hospital in Queens. Bellevue and Metropolitan Hospitals had the lowest number of deaths, both in borough of Manhattan. Mortality in public hospitals in Brooklyn was 29.9%, Queens 28.1%, Manhattan 20.4%. Conclusion: Significant variations existed in COVID-19 hospitalizations and outcomes in the public health system in New York City during the initial pandemic. Although outcomes are worse with older age and those with comorbidities, variations in hospitals and boroughs outside of Manhattan are targets to investigate and strategize efforts.
Immunolocalization studies of vimentin and ACE2 on the surface of cells exposed to SARS-CoV-2 Spike proteins

The Spike protein from SARS-CoV-2 mediates docking of the virus onto cells and contributes to viral invasion. Several cellular receptors are involved in SARS-CoV-2 Spike docking at the cell surface, including ACE2 and neuropilin. The intermediate filament protein vimentin has been reported to be present at the surface of certain cells and act as a co-receptor for several viruses; furthermore, its potential involvement in interactions with Spike proteins has been proposed. Here we have explored the binding of Spike protein constructs to several cell types using low-temperature immunofluorescence approaches in live cells, to minimize internalization. Incubation of cells with tagged Spike S or Spike S1 subunit led to discrete dotted patterns at the cell surface, which showed scarce colocalization with a lipid raft marker, but consistent coincidence with ACE2. Under our conditions, vimentin immunoreactivity appeared as spots or patches unevenly distributed at the surface of diverse cell types. Remarkably, several observations including potential antibody internalization and adherence to cells of vimentin-positive structures present in the extracellular medium exposed the complexity of vimentin cell surface immunoreactivity, which requires careful assessment. Notably, overall colocalization of Spike and vimentin signals markedly varied with the cell type and the immunodetection sequence. In turn, vimentin-positive spots moderately colocalized with ACE2; however, a particular enrichment was detected at elongated structures positive for acetylated tubulin, consistent with primary cilia, which also showed Spike binding. Thus, these results suggest that vimentin-ACE2 interaction could occur at selective locations near the cell surface, including ciliated structures, which can act as platforms for SARS-CoV-2 docking.
Recovering mixtures of fast-diffusing states from short single-particle trajectories

Single particle tracking (SPT) directly measures the dynamics of proteins in living cells and is a powerful tool to dissect molecular mechanisms of cellular regulation. Interpretation of SPT with fast-diffusing proteins in mammalian cells, however, is complicated by technical limitations imposed by fast image acquisition. These limitations include short trajectory length due to photobleaching and shallow depth of field, high localization error due to the low photon budget imposed by short integration times, and cell-to-cell variability. To address these issues, we developed methods to infer distributions of diffusion coefficients from SPT data with short trajectories, variable localization accuracy, and absence of prior knowledge about the number of underlying states. We discuss advantages and disadvantages of these approaches relative to other frameworks for SPT analysis. Significance statement Single particle tracking (SPT) uses fluorescent probes to track the motions of individual molecules inside living cells, providing biologists with a close view of the cell’s inner machinery at work. Commonly used SPT imaging approaches, however, result in fragmentation of trajectories into small pieces as the probes move through the microscope’s plane of focus. This makes it challenging to extract usable biological information. This paper describes a method to reconstruct an SPT target’s dynamic profile from these trajectory fragments. The method builds on previous approaches to provide information about challenging SPT targets without discrete dynamic states while accounting for some known biases, enabling observation of previously hidden features in mammalian SPT experiments.
Spatial and ecological drivers of population structure in Alkanna tinctoria (Boraginaceae), a polyploid medicinal herb

Background and Aims Quantifying genetic variation is fundamental to understand a species’ demographic trajectory and its ability to adapt to future changes. In comparison to diploids, however, genetic variation and factors fostering genetic divergence remains poorly studied in polyploids due to analytical challenges. Here, by employing a ploidy-aware framework, we investigated the genetic structure and its determinants in polyploid Alkanna tinctoria (Boraginaceae), an ancient medicinal herb that is the source of bioactive compounds known as alkannin and shikonin (A/S). From a practical perspective, such investigation can inform biodiversity management strategies. Methods We collected 14 populations of A. tinctoria within its main distribution range in Greece and genotyped them using restriction site-associated DNA sequencing (RAD-seq). As an outgroup, we included two populations of A. sieberi. By using a ploidy-aware genotype calling based on likelihoods, we generated a dataset of 16,107 high quality SNPs. Classical and model-based analysis was done to characterize the genetic structure within and between the sampled populations. Finally, to reveal the drivers of genetic structure, we searched for associations between allele frequencies and spatial and climatic variables. Key Results We found support for a marked regional structure in A. tinctoria along a latitudinal gradient in line with phytogeographic divisions. Several analyses identified interspecific admixture affecting both mainland and island populations. Modelling of spatial and climatic variables further demonstrated a larger contribution of neutral processes and a lesser albeit significant role of selection in shaping the observed genetic structure in A. tinctoria. Conclusions Current findings provide evidence of strong genetic structure in A. tinctoria mainly driven by neutral processes. The revealed natural genomic variation in Greek Alkanna can be used to further predict variation in A/S production, whereas our bioinformatics approach should prove useful for the study of other non-model polyploid species.