Miracle-dz/UniFAR-FTUs huggingface dataset:
A general theory for temperature dependence in biology

At present, there is no simple, complete, and first principles-based model for quantitatively describing the full range of observed biological temperature responses. Here, we derive a theory exhibiting these features based on the Eyring-Evans-Polanyi theory governing chemical reaction rates, and which is applicable across all scales from the micro to the macro. Assuming only that the conformational entropy of molecules changes with temperature, we derive a theory for the temperature dependence which takes the form of an exponential function modified by a power-law. Our framework leads to six deductions applicable to any biological trait that depends on temperature, and elucidates novel aspects of universal temperature responses across the tree of life, from quantum to classical scales. All predictions are well supported by data for a wide variety of biological rates and steady states, from molecular to ecological scales and across multiple taxonomic groups. In addition, we provide novel explanations of several empirical relationships including optimal values in temperature response curves. One-Sentence Summary We derive a simple and universal formulae to characterize temperature responses of biological processes across the tree of life.
Kinase activity of TBK1 is required for its binding to STING, but not for its recruitment to the Golgi

Stimulator of interferon genes (STING) is an innate immune protein for DNA pathogens. In response to the emergence of DNA in the cytosol, STING relocates from the endoplasmic reticulum (ER) to the Golgi and induces the type I interferon response through cytosolic TANK-binding kinase 1 (TBK1). The molecular mechanism underlying TBK1 activation by STING remains poorly understood. Here we report a cell system by which STING and TBK1 are simultaneously monitored. The system utilizes STING/TBK1-double knockout (KO) cells, fluorescent protein-tagged TBK1 and STING, and super-resolution microscopy. After STING stimulation, TBK1 is directly recruited to the trans-Golgi network (TGN), not to the other parts of the Golgi. The recruitment of TBK1 does not require its kinase activity. C-terminal STING variants (ΔC9 and L373A), in which the TBK1-STING binding interface is mutated or deleted, induce the recruitment of TBK1. These results indicate that the kinase activity of TBK1 or the C-terminal motif of STING is not required for its recruitment to TGN, but rather for the formation of the stable STING signalling complex at TGN.
Woody species do not differ in dormancy progression: Differences in time to budbreak due to forcing and cold hardiness

Budbreak is one of the most observed and studied phenological phases in perennial plants. Two dimensions of exposure to temperature are generally used to model budbreak: accumulation of time spent at low temperatures (chilling); and accumulation of heat units (forcing). These two effects have a well-established negative correlation: the more chilling, the less forcing required for budbreak. Furthermore, temperate plant species are assumed to vary in amount of chilling required to complete endodormancy and begin the transition to breaking bud. Still, prediction of budbreak remains a challenge. The present work demonstrates across a wide range of species how bud cold hardiness must be accounted for to study dormancy and accurately predict time to budbreak. Cold hardiness defines the path length to budbreak, meaning the difference between the cold hardiness buds attain during the winter, and the cold hardiness at which deacclimated buds are predicted to open. This distance varies among species and throughout winter within a species. Increases in rate of cold hardiness loss (deacclimation) measured throughout winter show that chilling controls deacclimation potential – the proportion of the maximum rate response attained at high chill accumulation – which has a sigmoid relationship to chilling accumulation. For forcing, rates of deacclimation increase non-linearly in response to temperature. Comparisons of deacclimation potential show a dormancy progresses similarly for all species. This observation suggests that comparisons of physiologic and genetic control of dormancy requires an understanding of cold hardiness dynamics and the necessity for an update of the framework for studying dormancy and its effects on spring phenology.
Eye movements reveal spatiotemporal dynamics of visually-informed planning in navigation

Goal-oriented navigation is widely understood to depend upon internal maps. Although this may be the case in many settings, humans tend to rely on vision in complex, unfamiliar environments. To study the nature of gaze during visually-guided navigation, we tasked humans to navigate to transiently visible goals in virtual mazes of varying levels of difficulty, observing that they took near-optimal trajectories in all arenas. By analyzing participants’ eye movements, we gained insights into how they performed visually-informed planning. The spatial distribution of gaze revealed that environmental complexity mediated a striking trade-off in the extent to which attention was directed towards two complimentary aspects of the world model: the reward location and task-relevant transitions. The temporal evolution of gaze revealed rapid, sequential prospection of the future path, evocative of neural replay. These findings suggest that the spatiotemporal characteristics of gaze during navigation are significantly shaped by the unique cognitive computations underlying real-world, sequential decision making.
Biosynthetic heme of malaria parasite induces cerebral pathogenesis by regulating hemozoin formation and griseofulvin can prevent cerebral malaria

Heme-biosynthetic pathway of malaria parasite is dispensable for asexual stages, but essential for sexual and liver stages. Despite having backup mechanisms to acquire hemoglobin-heme, pathway intermediates and/or enzymes from the host, asexual parasites express heme pathway enzymes and synthesize heme. Here we show heme synthesized in asexual stages promotes cerebral pathogenesis by enhancing hemozoin formation. Hemozoin is a parasite molecule associated with inflammation, aberrant host-immune responses, disease severity and cerebral pathogenesis. The heme pathway knockout parasites synthesize less hemozoin, and mice infected with knockout parasites are completely protected from cerebral malaria and death due to anaemia is delayed. Biosynthetic heme regulates food vacuole integrity and the food vacuoles from knockout parasites are compromised in pH, lipid unsaturation and proteins, essential for hemozoin formation. Targeting parasite heme synthesis by griseofulvin - a FDA-approved drug, prevents cerebral malaria in mice and provides a new adjunct therapeutic option for cerebral and severe malaria.
Understanding double descent through the lens of principal component regression

Several recent papers have studied the double descent phenomenon: a classic U-shaped empirical risk curve when the number of parameters is smaller or equal to the number of data points, followed by a decrease in empirical risk (referred to as “second descent”) as the number of features is increased past the interpolation threshold (the minimum number of parameters needed to have 0 training error). In a similar vein as several recent papers on double descent, we concentrate here on the special case of over-parameterized linear regression, one of the simplest model classes that exhibit double descent, with the aim of better understanding the nature of the solution in the second descent and how it relates to solutions in the first descent. In this paper, we show that the final second-descent model (obtained using all features) is equivalent to the model estimated using principal component (PC) regression when all PCs of training data are included. It follows that many properties of double descent can be understood through the relatively simple and well-characterized lens of PC regression. In particular, we will identify a set of conditions that will guarantee final second-descent performance to be better than the best first-descent performance: it is the scenario in which PC regression using all features does not suffer from over-fitting and can be guaranteed to outperform any other first-descent model (any linear regression model using no more features than training data points). We will also discuss how this work relates to transfer learning, semi-supervised learning, few-shot learning, as well as theoretical concepts in neuroscience.
Reconciling contrast invariance and non-linear computation in cortical circuits

Network selectivity for orientation is invariant to changes in the stimulus contrast in the primary visual cortex. Similarly, the selectivity for odor identity is invariant to changes in odorant concentration in the piriform cortex. Interestingly, invariant network selectivity appears robust to local changes in synaptic strength induced by synaptic plasticity, even though: i) synaptic plasticity can potentiate or depress connections between neurons in a feature-dependent manner, and ii) in networks with balanced excitation and inhibition, synaptic plasticity is a determinant for the network non-linearity. In this study, we investigate whether network contrast invariance is consistent with a variety of synaptic states and connectivities in balanced networks. By using mean-field models and spiking network simulations, we show how the synaptic state controls the non-linearity in the network response to contrast and how it can lead to the emergence of contrast-invariant or contrast-dependent selectivity. Different forms of synaptic plasticity sharpen or broaden the network selectivity, while others do not affect it. Our results explain how the physiology of individual synapses is linked to contrast-invariant selectivity at the network level.
Fascin limits Myosin activity within Drosophila border cells to control substrate stiffness and promote migration

A key regulator of collective cell migrations, which drive development and cancer metastasis, is substrate stiffness. Increased substrate stiffness promotes migration and is controlled by Myosin. Using Drosophila border cell migration as a model of collective cell migration, we identify, for the first time, that the actin bundling protein Fascin limits Myosin activity in vivo. Loss of Fascin results in: increased activated Myosin on the border cells and their substrate, the nurse cells; decreased border cell Myosin dynamics; and increased nurse cell stiffness as measured by atomic force microscopy. Reducing Myosin restores on-time border cell migration in fascin mutant follicles. Further, Fascin’s actin bundling activity is required to limit Myosin activation. Surprisingly, we find that Fascin regulates Myosin activity in the border cells to control nurse cell stiffness to promote migration. Thus, these data shift the paradigm from a substrate stiffness-centric model of regulating migration, to uncover that collectively migrating cells play a critical role in controlling the mechanical properties of their substrate in order to promote their own migration. This new means of mechanical regulation of migration is likely conserved across contexts and organisms, as Fascin and Myosin are common regulators of cell migration.
Single-cell dissection of the human cerebrovasculature in health and disease

Despite the importance of the blood-brain barrier in maintaining normal brain physiology and in understanding neurodegeneration and CNS drug delivery, human cerebrovascular cells remain poorly characterized due to their sparsity and dispersion. Here, we perform the first single-cell characterization of the human cerebrovasculature using both ex vivo fresh-tissue experimental enrichment and post mortem in silico sorting of human cortical tissue samples. We capture 31,812 cerebrovascular cells across 17 subtypes, including three distinct subtypes of perivascular fibroblasts as well as vasculature-coupled neurons and glia. We uncover human-specific expression patterns along the arteriovenous axis and determine previously uncharacterized cell type-specific markers. We use our newly discovered human-specific signatures to study changes in 3,945 cerebrovascular cells of Huntington’s disease patients, which reveal an activation of innate immune signaling in vascular and vasculature-coupled cell types and the concomitant reduction to proteins critical for maintenance of BBB integrity. Finally, our study provides a comprehensive resource molecular atlas of the human cerebrovasculature to guide future biological and therapeutic studies.
Maternal Obesity Dysregulates Fetal Hematopoietic Stem and Progenitor Cell Development in Rhesus Macaques

Infants from obese moms have an increased susceptibility to immune dysregulation. However, the mechanisms by which maternal obesity alters fetal hematopoiesis remain largely unknown. Here, we determined the impact of maternal consumption of an obesogenic western-style diet (WSD) on hematopoietic development in fetal rhesus macaques using a combination of phenotypic, functional, and genomic assays. We demonstrate that maternal WSD resulted in accelerated fetal growth and altered fetal hematopoiesis. Specifically, single-cell RNA sequencing analysis of fetal bone marrow HSPCs showed that maternal WSD altered the transcriptional program of the common lymphoid progenitors and decreased the frequencies of bone marrow B-cells and NK-cells. Despite an expansion of monocyte progenitors in FBM, fetal blood monocytes from the WSD group demonstrated a blunted response to bacterial lipopolysaccharide. Furthermore, maternal WSD led to poor engraftment of fetal HSPCs in nonlethally irradiated immunodeficient NOD/SCID/IL2rγ-/-mice. Collectively, this study demonstrates that maternal WSD dysregulates fetal HSPC development.
Association of Resting Heart Rate and Heart Rate Variability With Proximal Suicidal Risk in Patients With Diverse Psychiatric Diagnoses

Objectively measurable biomarkers have not been applied for suicide risk prediction. Resting heart rate (HR) and heart rate variability (HRV) showed potential as trans-diagnostic markers associated with suicide. This study aimed to investigate the associations of resting HR and HRV on proximal suicide risk in patients with diverse psychiatric diagnoses. This chart review study used the medical records of psychiatric patients who visited the outpatient clinic at an academic tertiary hospital. A total of 1,461 patients with diverse psychiatric diagnoses was included in the analysis. Proximal suicide risk was measured using the Mini-International Neuropsychiatric Interview (MINI) suicidal score. Linear regression analyses with the MINI suicidal score as a dependent variable and binary logistic regression analyses with moderate-to-high suicide risk (MINI suicidal risk score ≥6) as a dependent variable were conducted to explore the effects of resting HR and HRV parameters on acute suicide risk after adjusting for age, sex, presence of major depressive disorder (MDD) and bipolar disorder (BD), severity of depression and anxiety severity. We found that 55 (34.6%) patients in the MDD group, 40 (41.7%) in the BD group and 36 (3.9%) in the others group reported moderate-to-high suicide risk. Linear regression analysis revealed that both resting HR and root-mean-square of successive difference (RMSSD) had significant associations with the MINI suicidal score (P = 0.037 with HR, P = 0.003 with RMSSD). In logistic regression, only RMSSD showed a significant association with moderate-to-high suicide risk (P = 0.098 with HR, P = 0.019 with RMSSD), which remained significant in subgroup analysis with patients who reported any suicide-related symptom (MINI suicidal score >0; n = 472; P = 0.017 with HR, P = 0.012 with RMSSD). Our study findings suggest the potential for resting HR and RMSSD as biomarkers for proximal suicide risk prediction. Further research with longitudinal evaluation is needed to confirm our study findings.
Species-Specific Differences in Sperm Chromatin Decondensation Between Eutherian Mammals Underlie Distinct Lysis Requirements

Sperm present a highly particular DNA condensation that is acquired during their differentiation. Protamines are key elements for DNA condensation. However, whereas the presence of protamine 1 (P1) is conserved across mammalian species, that of protamine 2 (P2) has evolved differentially, existing only few species that use both protamines for sperm DNA condensation. In addition, altered P1/P2 ratios and alterations in the expression of P1 have previously been associated to infertility and DNA damage disorders. On the other hand, different methods evaluating DNA integrity, such as Sperm Chromatin Dispersion (SCD) and Comet tests, need a previous complete DNA decondensation to properly assess DNA breaks. Related with this, the present study aims to analyze the resilience of sperm DNA to decodensation in different eutherian mammals. Sperm samples from humans, horses, cattle, pigs and donkeys were used. Samples were embedded in low melting point agarose and treated with lysis solutions to induce DNA decondensation and formation of sperm haloes. The treatment consisted of three steps: (1) incubation in SDS + DTT for 30 min; (2) incubation in DTT + NaCl for 30 min; and (3) incubation in DTT + NaCl with or without proteinase K for a variable time of 0, 30, or 180 min. How incubation with the third lysis solution (with or without proteinase K) for 0, 30, and 180 min affected DNA decondensation was tested through analyzing core and halo diameters in 50 sperm per sample. Halo/core length ratio was used as an indicator of complete chromatin decondensation. While incubation time with the third lysis solution had no impact on halo/core length ratios in species having P1 and P2 (human, equine and donkey), DNA decondensation of pig and cattle sperm, which only present P1, significantly (P < 0.05) increased following incubation with the third lysis solution for 180 min. In addition, the inclusion of proteinase K was found to accelerate DNA decondensation. In conclusion, longer incubations in lysis solution including proteinase K lead to higher DNA decondensation in porcine and bovine sperm. This suggests that tests intended to analyze DNA damage, such as halo or Comet assays, require complete chromatin deprotamination to achieve high sensitivity in the detection of DNA breaks.
The Immune Microenvironment in Human Papilloma Virus-Induced Cervical Lesions—Evidence for Estrogen as an Immunomodulator

Globally, human papilloma virus (HPV) infection is a common sexually transmitted disease. However, most of the HPV infections eventually resolve aided by the body’s efficient cell-mediated immune responses. In the vast majority of the small group of patients who develop overt disease too, it is the immune response that culminates in regression of lesions. It is therefore a rarity that persistent infection by high-risk genotypes of HPV compounded by other risk factors progresses through precancer (various grades of cervical intraepithelial neoplasia—CIN) to cervical cancer (CxCa). Hence, although CxCa is a rare culmination of HPV infection, the latter is nevertheless causally linked to >90% of cancer. The three ‘Es’ of cancer immunoediting viz. elimination, equilibrium, and escape come into vogue during the gradual evolution of CIN 1 to CxCa. Both cell-intrinsic and extrinsic mechanisms operate to eliminate virally infected cells: cell-extrinsic players are anti-tumor/antiviral effectors like Th1 subset of CD4+ T cells, CD8+ cytotoxic T cells, Natural Killer cells, etc. and pro-tumorigenic/immunosuppressive cells like regulatory T cells (Tregs), Myeloid-Derived Suppressor Cells (MDSCs), type 2 macrophages, etc. And accordingly, when immunosuppressive cells overpower the effectors e.g., in high-grade lesions like CIN 2 or 3, the scale is tilted towards immune escape and the disease progresses to cancer. Estradiol has long been considered as a co-factor in cervical carcinogenesis. In addition to the gonads, the Peyer’s patches in the gut synthesize estradiol. Over and above local production of the hormone in the tissues, estradiol metabolism by the gut microbiome: estrobolome versus tryptophan non-metabolizing microbiome, regulates free estradiol levels in the intestine and extraintestinal mucosal sites. Elevated tissue levels of the hormone serve more than one purpose: besides a direct growth-promoting action on cervical epithelial cells, estradiol acting genomically via Estrogen Receptor-α also boosts the function of the stromal and infiltrating immunosuppressive cells viz. Tregs, MDSCs, and carcinoma-associated fibroblasts. Hence as a corollary, therapeutic repurposing of Selective Estrogen Receptor Disruptors or aromatase inhibitors could be useful for modulating immune function in cervical precancer/cancer. The immunomodulatory role of estradiol in HPV-mediated cervical lesions is reviewed.
Correlates of Social Cognition and Psychopathic Traits in a Community-Based Sample of Males

Social cognition is the ability to identify, understand, and interpret mental states and emotions. Psychopathic traits are typically described in two ways; Primary: shallow affect, emotional detachment, and relationship difficulties, and Secondary Psychopathic Traits: antisocial traits, impulsiveness, and emotional dysregulation. People with high psychopathic traits tend to perform lower on measures of social cognition. This study investigated the relationship of social cognition (mentalising) to primary and secondary psychopathic traits in a non-clinical sample, and investigated the psychometric properties of the Reading the Mind in the Eyes Test (RMET) Short Forms (A and B). A community-based male sample (N = 1,000; age range 18–78) was recruited through an online platform. Psychopathic traits were measured using Levenson, Kiehl, and Fitzpatrick's Self-Report Psychopathy Scale, and stratified into Primary and Secondary Psychopathic traits. Secondary validation of the RMET Short Forms was completed investigating scale reliability, and validity. Findings suggest excellent psychometrics in a large community cohort for the RMET Short Forms (A and B), with significant negative correlations on social cognitive performance and high self-report psychopathy. The item valence within the social cognitive measure (positive, negative, and neutral affect stimuli) was also examined, and correlated significantly with both Primary and Secondary Psychopathic traits. This study provides further validation of the RMET Short Forms (A and B), and adds to the literature on the scale by investigating performance on short-form specific valence. This study further suggests that in a non-clinical community sample of males, that higher psychopathic traits correlated significantly, and negatively, with social cognitive performance.
Separation of 0.75–0.125 mm Fine Coal Using the Cylindrical Section of a 710/500 mm Three-Product Dense Medium Cyclone

ABSTRACT Dense medium cyclone is eﬀective in beneficiation of ﬁne coal with great separation precision. Small-diameter cyclones (usually 150 mm to 350 mm) are preferred in industrial applications. But the handling capacity of a small cyclone is low, which brings about the problems of maintain and operation. The separation eﬃciency of large-diameter cyclones with greater handling capability in ﬁne coal treatment is questionable. In this study, the cylindrical section of a 710/500 mm three-product cyclone was adopted to treat 0.75–0.125 mm ﬁne coal, where the cylinder-cone cyclone was a surge section. Inﬂuence of inlet pressure and feed rate were studied in an industrial environment. According to the results, the separation eﬃciency was sharp at relatively low feed pressures (110 KPa to 160 KPa). The separation eﬀect increased with the feed rate. The favorable Ecart probable (Ep) value of 0.054 was obtained at an inlet pressure of 120 KPa and a feed rate of 42 t/h. Results of the studies showed that large-diameter cyclones will be applicable for ﬁne coal treatment. These results will be signiﬁcant for fine coal with a high content of near-density material.