Miracle-dz/UniFAR-FTUs huggingface dataset:
A comparison of data integration methods for single-cell RNA sequencing of cancer samples

Tumours are routinely profiled with single-cell RNA sequencing (scRNA-seq) to characterize their diverse cellular ecosystems of malignant, immune, and stromal cell types. When combining data from multiple samples or studies, batch-specific technical variation can confound biological signals. However, scRNA-seq batch integration methods are often not designed for, or benchmarked, on datasets containing cancer cells. Here, we compare 5 data integration tools applied to 171,206 cells from 5 tumour scRNA-seq datasets. Based on our results, STACAS and fastMNN are the most suitable methods for integrating tumour datasets, demonstrating robust batch effect correction while preserving relevant biological variability in the malignant compartment. This comparison provides a framework for evaluating how well single-cell integration methods correct for technical variability while preserving biological heterogeneity of malignant and non-malignant cell populations.
Specific telomere protection ensured by FOXO3a upon genotoxic stress and during aging

Longevity is determined by diverse signaling pathways including telomere protection and homeostasis master regulators like FOXO3a. We previously showed that the telomeric repeat binding factor 2 (TRF2) expression decreases with age in human skeletal muscle and that, surprisingly, its loss in myofibers does not trigger telomere deprotection. We reveal here that in TERF2-compromised myotubes, FOXO3a is recruited to telomeres where it acts as a protective factor against ATM-dependent DNA damage activation. Moreover, we show that FOXO3a-telomere association increases with age in human skeletal muscle biopsies. In mitotic fibroblasts, the telomere protective properties of FOXO3a are operative if the cells are treated with bleomycin. The telomere function of FOXO3a does not require its Forkhead DNA binding domain but the CR2C. Overall, these findings demonstrate a direct connection between two key longevity pathways, FOXO3a and telomere protection. This unveils an unexpected higher level of integration in the regulation of longevity signaling pathway.
Relative model selection can be sensitive to multiple sequence alignment uncertainty

Background Multiple sequence alignments (MSAs) represent the fundamental unit of data inputted to most comparative sequence analyses. In phylogenetic analyses in particular, errors in MSA construction have the potential to induce further errors in downstream analyses such as phylogenetic reconstruction itself, ancestral state reconstruction, and divergence time estimation. In addition to providing phylogenetic methods with an MSA to analyze, researchers must also specify a suitable evolutionary model for the given analysis. Most commonly, researchers apply relative model selection to select a model from candidate set and then provide both the MSA and the selected model as input to subsequent analyses. While the influence of MSA errors has been explored for most stages of phylogenetics pipelines, the potential effects of MSA uncertainty on the relative model selection procedure itself have not been explored. Results We assessed the consistency of relative model selection when presented with multiple perturbed versions of a given MSA. We find that while relative model selection is mostly robust to MSA uncertainty, in a substantial proportion of circumstances, relative model selection identifies distinct best-fitting models from different MSAs created from the same set of sequences. We find that this issue is more pervasive for nucleotide data compared to amino-acid data. However, we also find that it is challenging to predict whether relative model selection will be robust or sensitive to uncertainty in a given MSA. Conclusions We find that that MSA uncertainty can affect virtually all steps of phylogenetic analysis pipelines to a greater extent than has previously been recognized, including relative model selection.
Multiscale model of the physiological control of myocardial perfusion to delineate putative metabolic feedback mechanisms

Coronary blood flow is tightly regulated to ensure that myocardial oxygen delivery meets local metabolic demand via the concurrent action of myogenic, neural, and metabolic mechanisms. While several competing hypotheses exist, the specific nature of the local metabolic mechanism(s) remains poorly defined. To gain insights into the viability of putative metabolic feedback mechanisms and into the coordinated action of parallel regulatory mechanisms, we applied a multi-scale modeling framework to analyze experimental data on coronary pressure, flow, and myocardial oxygen delivery in the porcine heart in vivo. The modeling framework integrates a previously established lumped-parameter model of myocardial perfusion used to account for transmural hemodynamic variations and a simple vessel mechanics model used to simulate the vascular tone in each of three myocardial layers. Vascular tone in the resistance vessel mechanics model is governed by input stimuli from the myogenic, metabolic, and autonomic control mechanisms. Seven competing formulations of the metabolic feedback mechanism are implemented in the modeling framework, and associated model simulations are compared to experimental data on coronary pressures and flows under a range of experimental conditions designed to interrogate the governing control mechanisms. Analysis identifies a maximally likely metabolic mechanism among the seven tested models, in which production of a metabolic signaling factor is proportional to MVO2 and delivery proportional to flow. Finally, the identified model is validated based on comparisons of simulations to data on the myocardial perfusion response to conscious exercise that were not used for model identification.
Microalgal protein AstaP is a potent carotenoid solubilizer and delivery module with a broad carotenoid binding repertoire

Carotenoids are lipophilic substances with many biological functions, from coloration to photoprotection. Being potent antioxidants, carotenoids have multiple biomedical applications, including the treatment of neurodegenerative disorders and retina degeneration. Nevertheless, the delivery of carotenoids is substantially limited by their poor solubility in the aqueous phase. Natural water-soluble carotenoproteins can facilitate this task, necessitating studies on their ability to uptake and deliver carotenoids. One such promising carotenoprotein, AstaP (Astaxanthin-binding protein), was recently identified in eukaryotic microalgae, but its structure and functional properties remained largely uncharacterized. By using a correctly folded recombinant protein, here we show that AstaP is an efficient carotenoid solubilizer that can stably bind not only astaxanthin but also zeaxanthin, canthaxanthin, and, to a lesser extent, β-carotene, i.e. carotenoids especially valuable to human health. AstaP accepts carotenoids provided as acetone solutions or embedded in membranes, forming carotenoid-protein complexes with an apparent stoichiometry of 1:1. We successfully produced AstaP holoproteins in specific carotenoid-producing strains of Escherichia coli, proving it is amenable to cost-efficient biotechnology processes. Regardless of the carotenoid type, AstaP remains monomeric in both apo- and holoforms, while its rather minimalistic mass (∼20 kDa) makes it an especially attractive antioxidant delivery module. In vitro, AstaP transfers different carotenoids to the liposomes and to unrelated proteins from cyanobacteria, which can modulate their photoactivity and/or oligomerization. These findings expand the toolkit of the characterized carotenoid-binding proteins and outline the perspective of the use of AstaP as a unique monomeric antioxidant nanocarrier with an extensive carotenoid-binding repertoire.
Scaling up to meet new challenges of brain and behaviour through deep brain electrophysiology in freely moving sheep

While rodents are arguably the easiest animals to use for studying brain function, relying on them as model species for translational research comes with its own sets of limitations. Here, we propose sheep as a practical large animal species for in vivo brain function studies performed in naturalistic settings. To demonstrate their experimental usefulness, we performed proof-of-principle deep brain electrophysiological recording experiments from unrestrained sheep. Recordings were made from cortex and hippocampus both whilst sheep performed goal-directed behaviours (two-choice discrimination tasks), and across states of vigilance that included natural sleep. Hippocampal and cortical oscillatory rhythms were consistent with those seen in rodents and non-human primates, and included cortical alpha oscillations during immobility, hippocampal theta oscillations (5-6Hz) during locomotion and hippocampal sharp wave ripple oscillations (∼150 Hz) during immobility. Moreover, we found clear examples of neurons whose activity was modulated by task, speed of locomotion, spatial position, reward and vigilance states. Recordings were conducted over a period of many months. Due to the exceptional stability of individual electrodes we were able to record from some neurons repeatedly across the span of a month. Together these experiments demonstrate that sheep are an excellent experimental animal model to use in longitudinal electrophysiological and imaging studies, particularly those requiring a large brained mammal, large scale recordings across distributed neuronal networks, experimentation outside the confounds of the traditional laboratory, or all the above concomitantly.
A Cell Culture Model of BK Polyomavirus Persistence, Genome Recombination, and Reactivation

BK polyomavirus (BKPyV) generally establishes a persistent subclinical infection in healthy individuals but can cause severe disease in transplant recipients. While an in vitro model to study acute replication exists, no practical model with which to study BKPyV persistence is currently available. ABSTRACT BK polyomavirus (BKPyV) is a small nonenveloped DNA virus that establishes a ubiquitous, asymptomatic, and lifelong persistent infection in at least 80% of the world's population. In some immunosuppressed transplant recipients, BKPyV reactivation causes polyomavirus-associated nephropathy and hemorrhagic cystitis. We report a novel in vitro model of BKPyV persistence and reactivation using a BKPyV natural host cell line. In this system, viral genome loads remain constant for various times after establishment of persistent infection, during which BKPyV undergoes extensive random genome recombination. Certain recombination events result in viral DNA amplification and protein expression, resulting in production of viruses with enhanced replication ability. IMPORTANCE BK polyomavirus (BKPyV) generally establishes a persistent subclinical infection in healthy individuals but can cause severe disease in transplant recipients. While an in vitro model to study acute replication exists, no practical model with which to study BKPyV persistence is currently available. We established a BKPyV persistence model in cell culture. Our model reveals that the virus can persist for various periods of time before random recombination of the viral genome leads to enhanced replication.
Does the rainbow trout ovarian fluid guide the spermatozoon on its way to the egg?

Fertilization of freshwater fish occurs in an environment that may negatively affect the gametes; therefore, the specific mechanisms triggering the encounters of gametes would be highly expedient. The egg and ovarian fluid (OF) are likely the primary sources of these triggers in fish that we confirmed here for rainbow trout Oncorhynchus mykiss. The ovarian fluid significantly affected the spermatozoa performance: it supported high velocity for a more extended period and changed the motility pattern from tumbling in water to straightforward moving in the ovarian fluid. Rainbow trout OF induced a trapping chemotaxis-like effect on activated male gametes, and this effect depended on the properties of the activating media. The interaction of the spermatozoa with the attracting agents was accompanied by their “turn-and-run” behavior involving asymmetric flagellar beating and Ca2+ concentration bursts in the bent flagella segment, characteristic of the chemotactic response. Collectively, the ovarian fluid creates the optimal environment for rainbow trout spermatozoa performance, being an effective promoter of fertilization. The individual peculiarities of the egg (ovarian fluid) – sperm interaction in rainbow trout reflect the specific features of the spawning process in this species.
Rapid specialization of counter defenses enables two-spotted spider mite to adapt to novel plant hosts

Genetic adaptation, occurring over a long evolutionary time, enables host-specialized herbivores to develop novel resistance traits and to efficiently counteract the defenses of a narrow range of host plants. In contrast, physiological acclimation, leading to the suppression and/or detoxification of host defenses is hypothesized to enable broad-generalists to shift between plant hosts. However, the host adaptation mechanisms used by generalists composed of host-adapted populations are not known. Tetranychus urticae is an extreme generalist herbivore whose individual populations perform well only on a subset of potential hosts. We combined experimental evolution, Arabidopsis genetics, mite reverse genetics, and pharmacological approaches to examine mite host adaptation upon the shift of a bean-adapted population to Arabidopsis thaliana. We showed that cytochrome P450 monooxygenases are required for mite adaptation to Arabidopsis. We identified activities of two tiers of P450s: general xenobiotic-responsive P450s that have a limited contribution to mite adaptation to Arabidopsis and adaptation-associated P450s that efficiently counteract Arabidopsis defenses. In ≈25 generations of mite selection on Arabidopsis plants, mites evolved highly efficient detoxification-based adaptation, characteristic of specialist herbivores. This demonstrates that specialization to plant resistance traits can occur within the ecological timescale, enabling the two-spotted spider mite to shift to novel plant hosts.
Online employer reviews: A glimpse into the employer-brand benefits of working in the Las Vegas hotel/casino industry

Abstract Employer review websites are rising in popularity as credible sources for researching potential employers. Employer reviews can not only influence job seekers but also offer a glimpse into an organization’s employer-brand benefits. This qualitative study explored employee reviews posted on the Glassdoor and Indeed web pages of four Las Vegas hotel/casino corporations. The results revealed that three employer-brand benefits appeared in the reviews as both positive and negative attributes of employment: (1) functional, (2) economic, and (3) psychological. The findings from this study have implications for both marketing and H.R. practitioners and contribute to the growing body of employer-branding literature.
Optical Parameters of Atomically Heterogeneous Systems Created by Plasma Based Low Energy Ion Beams: Wavelength Dependence and Effective Medium Model

The article presents the irradiation effects of low energy (∼0.5 keV) inert gaseous Argon ion beams on optical constants [real (n) and imaginary (k) parts of the refractive index], dielectric constants, skin depth, and optical conductivity of copper (Cu), silver (Ag), and aluminum (Al) metallic thin films (MTF). The optical constants of pristine MTF are obtained by employing the universal Kramers-Kronig (KK) technique. The reflectivity of pristine MTF measured using UV-VIS-NIR spectrophotometry is used as an input parameter in the KK technique to determine the optical constants as a function of energy [or wavelength (λ)] of incident light ranging between ∼1–4.96 eV (or 250–1,200 nm). For the irradiated MTF, the optical constants including the skin depth (δ = λ/2πk), optical conductivity (σ = nkc/λ), and dielectric constants (ϵ 1 = n 2 − k 2 and ϵ 2 = 2nk) with varying ion fluence have been investigated by implementing the Maxwell-Garnett (MG) approximation, used to determine the effective dielectric constants of a random mixture of two different mediums. Additionally, n and k obtained from MG approximation have been compared with those obtained using the pseudo- Brewster angle technique for four different laser wavelengths (405, 532, 632.8 and 670 nm) and are found to be in good agreement with each other. It is observed that the optical constants and optical conductivity of the MTF decrease with increase in ion beam fluence, while the skin depth increases. Besides the optical constants, the behavior of skin depth, dielectric constants, and optical conductivity of the irradiated MTF with varying fluence are discussed in this article.
Single-Cell Transcriptome Profiling Reveals the Suppressive Role of Retinal Neurons in Microglia Activation Under Diabetes Mellitus

Diabetic retinopathy, as one of the common complications of diabetes mellitus, is the leading cause of blindness in the working-age population worldwide. The disease is characterized by damage to retinal vasculature, which is associated with the activation of retina microglial and induces chronic neurodegeneration. Previous studies have identified the effects of activated microglial on the retinal neurons, but the cellular and molecular mechanisms underlying microglial activation is largely unknown. Here, we performed scRNA-seq on the retina of non-human primates with diabetes mellitus, and identified cell-type-specific molecular changes of the six major cell types. By identifying the ligand-receptor expression patterns among different cells, we established the interactome of the whole retina. The data showed that TNF-α signal mediated the activation of microglia through an autocrine manner. And we found TGFβ2, which was upregulated in cone dramatically by hyperglycemia, inhibited microglia activation at the early stage of diabetic retinopathy. In summary, our study is the first to profile cell-specific molecular changes and the cell-cell interactome of retina under diabetes mellitus, paving a way to dissect the cellular and molecular mechanisms underlying early-stage diabetic retinopathy.
Associations of Dietary Fat Intake With Mortality From All Causes, Cardiovascular Disease, and Cancer: A Prospective Study

The impact of fat intake on health has become a growing public concern. The existing evidence linking specific dietary fat intake with mortality is controversial. We aimed to investigate the association between fat intake and total and cause-specific mortality in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial. Intakes of saturated fatty acids (SFAs), trans-fatty acids (TFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) were assessed via food frequency questionnaires. The primary outcomes were total, cardiovascular disease (CVD), and cancer mortality. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression model adjusting for confounders. Overall, 24,141 deaths were recorded over a total 1,672,715 person-years of follow-up. There was a significant positive association between SFA consumption and total mortality (HRQ5 vs. Q1 = 1.13, 95% CI 1.05–1.22; Pfor trend < 0.001). PUFA intake was strongly inversely associated with total mortality (HRQ5 vs. Q1 = 0.79, 95% CI 0.73–0.85; Pfor trend < 0.001) and CVD mortality (HRQ5 vs. Q1 = 0.66, 95% CI 0.58–0.75; Pfor trend < 0.001). There was a similar, but to a lesser extent, association between MUFA intake and total and CVD mortality [HRQ5 vs. Q1 0.91 (95% CI: 0.84–0.99), Pfor trend = 0.044 and 0.85 (0.73–0.98), Pfor trend = 0.020, respectively]. None of these types of dietary fat were associated with cancer mortality (all Pfor trend > 0.05). In conclusion, this study observed a detrimental effect of SFA intake on total mortality; in contrast, greater consumption of PUFAs and MUFAs were associated with lower risks of all-cause death and CVD mortality.
A Proposed Probabilistic Method for Distinguishing Between Delusions and Other Environmental Judgements, With Applications to Psychotherapy

How can individuals with schizophrenia best be equipped to distinguish delusions from accurate judgements about their environment? This study presents an approach based on the principles of Bayesian probability and presents the results of a series of tests in which a simulated observer classifies randomly generated data characteristic of a simulated environment. The complexity of the data ranges from scalars to vectors of variable lengths, and the simulated observer makes its decisions based on either perfect or imperfect models of its environment. We find that when a low-dimensional observation is considered characteristic of both real observations and delusions, the prior probabilities of any observation being real or fake are of greater importance to the final decision than the attributes of the observation. However, when an observation is high-dimensional (complex), classification accuracy tends to improve toward 100% with increasing complexity of observations, as long as the patient's model of the world isn't drastically inaccurate. On the contrary, when the observer's model is sufficiently inaccurate, the accuracy rate decreases with increasing observational complexity. Overall, the results suggest applicability of the Bayesian model to the use of interventional therapy for those who suffer from psychosis.