Miracle-dz/UniFAR-FTUs huggingface dataset:
Neuro-Cognitive Multilevel Causal Modeling: A Framework that Bridges the Explanatory Gap between Neuronal Activity and Cognition

Explaining how neuronal activity gives rise to cognition arguably remains the most significant challenge in cognitive neuroscience. We introduce neuro-cognitive multilevel causal modeling (NC-MCM), a framework that bridges the explanatory gap between neuronal activity and cognition by construing cognitive states as (behaviorally and dynamically) causally consistent abstractions of neuronal states. Multilevel causal modeling allows us to interchangeably reason about the neuronal- and cognitive causes of behavior while maintaining a physicalist (in contrast to a strong dualist) position. We introduce an algorithm for learning cognitive-level causal models from neuronal activation patterns and demonstrate its ability to learn cognitive states of the nematode C. elegans from calcium imaging data. We show that the cognitive-level model of the NC-MCM framework provides a concise representation of the neuronal manifold of C. elegans and its relation to behavior as a graph, which, in contrast to other neuronal manifold learning algorithms, supports causal reasoning. We conclude the article by arguing that the ability of the NC-MCM framework to learn causally interpretable abstractions of neuronal dynamics and their relation to behavior in a purely data-driven fashion is essential for understanding more biological systems whose complexity prohibits the development of hand-crafted computational models.
Bayesian Fluorescence Framework for integrative modeling of biomolecules

Fluorescence spectroscopic and imaging techniques, such as fluorescence-correlation spectroscopy, image correlation spectroscopy, time-resolved fluorescence spectroscopy, and intensity-based spectroscopy, can provide sparse time-dependent positional and inter-fluorophore distance information for macromolecules and their complexes in vitro and in living cells. Here, we formulated a Bayesian framework for processing and using the fluorescence data for interpreting by static and dynamic models of biomolecules. We introduce Bayesian Fluorescence Framework (BFF) as part of the open-source Integrative Modeling Platform (IMP) software environment, facilitating the development of modeling protocols based in part on fluorescence data. BFF improves the accuracy, precision, and completeness of the resulting models by formulating the modeling problem as a sampling problem dependent on general and flexible libraries of (i) atomic and coarse-grained molecular representations of single-state models, multi-state models, and dynamic processes, (ii) Bayesian data likelihoods and priors, as well as (iii) sampling schemes. To illustrate the framework, we apply it to a sample synthetic single-molecule FRET dataset of the human transglutaminase 2. We show how to integrate time-resolved fluorescence intensities, fluorescence correlation spectroscopy curves, and fluorescence anisotropies to simultaneously resolve dynamic structures, state populations, and molecular kinetics. As BFF is part of IMP, fluorescence data can be easily integrated with other data types to solve challenging modeling problems. Statement of Significance Bayesian Framework for Fluorescence (BFF) is software that implements a probabilistic framework for processing experimental fluorescence data to provide input information for Bayesian integrative structure modeling. BFF facilitates constructing integrative modeling protocols based in part on fluorescence data by reducing the required fluorescence spectroscopy and microscopy domain knowledge. In addition, it improves the precision and accuracy of the resulting models.
Single nuclei sequencing reveals C4 photosynthesis is based on rewiring of ancestral cell identity networks

In multicellular systems changes to the patterning of gene expression drive modifications in cell function and trait evolution. One striking example is found in more than sixty plant lineages where compartmentation of photosynthesis between cell types allowed the evolution of the efficient C4 pathway from the ancestral C3 state. The molecular events enabling this transition are unclear. We used single nuclei sequencing to generate atlases for C3 rice and C4 sorghum during photomorphogenesis. Our analysis revealed that initiation of photosynthesis gene expression is conditioned by cell identity. In both species a conserved cistrome defines each cell type, and photosynthesis genes switching expression from mesophyll in rice to bundle sheath in sorghum acquire hallmarks of bundle sheath identity. The sorghum bundle sheath has also acquired gene networks associated with C3 guard cells. We conclude C4 photosynthesis is based on rewiring in cis that exapts cell identity networks of C3 plants.
ATR promotes mTORC1 activation via de novo cholesterol synthesis in p16-low cancer cells

DNA damage and cellular metabolism are intricately linked with bidirectional feedback. Two of the main effectors of the DNA damage response and control of cellular metabolism are ATR and mTORC1, respectively. Prior work has placed ATR upstream of mTORC1 during replication stress, yet the direct mechanism for how mTORC1 is activated in this context remain unclear. We previously published that p16-low cells have mTORC1 hyperactivation, which in part promotes their proliferation. Using this model, we found that ATR, but not ATM, is upstream of mTORC1 activation via de novo cholesterol synthesis and is associated with increased lanosterol synthase (LSS). Indeed, p16-low cells showed increased cholesterol abundance. Additionally, knockdown of either ATR or LSS decreased mTORC1 activity. Decreased mTORC1 activity due to ATR knockdown was rescued by cholesterol supplementation. Finally, using both LSS inhibitors and multiple FDA-approved de novo cholesterol synthesis inhibitors, we found that the de novo cholesterol biosynthesis pathway is a metabolic vulnerability of p16-low cells. Together, our data provide new evidence coupling the DNA damage response and cholesterol metabolism and demonstrate the feasibility of using FDA-approved cholesterol-lowering drugs in tumors with loss of p16.
Assessment of resting state structural-functional relationships in perisylvian region during the early weeks after birth

This study investigates the structural-functional (S-F) relationships of perisylvian region in the first weeks after birth during rest. Previous joint S-F studies of the perisylvian development were mainly conducted on individual structural and functional features and outperformed non-joint studies. By using a weighted combination of features, a joint S-F study can advance understanding of the perisylvian development in neonates, thereby offering valuable markers for predicting neurodevelopmental disorders. To this purpose, we used 390 structural and 89 functional features for each region of interest (ROI) in perisylvian. Structural features include morphological and myelination features of cortical regions, and functional features include functional connectivity (FC) between each ROI and other brain regions. Subsequently, the S-F hybrid marker for each ROI is produced using the sparse canonical correlation analysis (SCCA). In addition, the significance and consistency of the contribution of each structural and functional feature in the hybrid marker are examined using statistical tests. The findings indicated the correlation between the FC of each ROI with other brain regions, and the myelination of that ROI or other brain regions, while no correlation was observed between the FC and the morphological features of the cortical regions. Furthermore, in the hybrid markers, auditory regions show greater contributions of FC and myelination compared to higher-order regions such as Broca area, suggesting their early development in infants. Additionally, regions such as insula and cingulate gyrus have not only FC but also jointly S-F relationships with most of the perisylvian sub-regions. Therefore, the hybrid markers outperform individual joint markers by introducing additional S-F relationships for characterizing the normal development of the perisylvian region in neonates.
The mycobacterial glycoside hydrolase LamH enables capsular arabinomannan release and stimulates growth

Mycobacterial glycolipids are important cell envelope structures that drive host-pathogen interactions. Arguably, the most important amongst these are lipoarabinomannan (LAM) and its precursor, lipomannan (LM), which are both trafficked out of the bacterium to the host via unknown mechanisms. An important class of exported LM/LAM is the capsular derivative of these molecules which is devoid of its lipid anchor. Here, we describe the identification of a glycoside hydrolase family 76 enzyme that we term LamH which specifically cleaves α-1,6-mannoside linkages within LM and LAM, driving its export to the capsule releasing its phosphatidyl-myo-inositol mannoside lipid anchor. Unexpectedly, we found that the catalytic activity of this enzyme is important for efficient exit from stationary phase cultures where arabinomannan acts as a signal for growth phase transition. Finally, we demonstrate that LamH is important for Mycobacterium tuberculosis survival in macrophages. These data provide a new framework for understanding the biological role of LAM in mycobacteria.
Evaluation of short-term hair follicle storage conditions for maintenance of RNA integrity

Hair follicles provide an easily accessible tissue for interrogating gene expression in mammals. RNAlater® is a liquid storage solution that stabilises and preserves cellular RNA, eliminating the need to immediately process or freeze tissue specimens. The manufacturer advises storage of samples at 2-8°C overnight before transfer to –20°C. This study aimed to evaluate RNA integrity in hair follicle samples collected from horses, stabilized in RNAlater®, and stored under three short-term storage conditions. Mane hair samples complete with follicles were collected from three horses at a single time point. Approximately 15 hairs were placed in each of three 2 mL tubes containing 0.75ml RNAlater® solution. Test group A was stored at 4°C for 24-h, then decanted and stored at -20°C. Test groups B and C were stored at 4°C and 19°C (room temperature) respectively for 7 days, then decanted and stored at -20°C. RNA was isolated from all samples and RNA quantity and quality were measured. One-way ANOVA revealed no difference in RNA concentration (A:516 +/-125 ng/ml, B:273+/-93 ng/ml, C:476+/-176 ng/ml;P = 0.4293) or quality (A:9.5 +/-0.19, B:9.8+/-0.09, C:9.2+/-0.35 RIN; P = 0.3193) between the test groups. There were no group differences in mean Cycle Threshold values from qPCR validation assays confirming high-quality template cDNA. The results suggest that storage of hair follicles for one week in RNAlater® at cool or room temperature conditions will not compromise RNA integrity and will permit extended transport times from remote sampling locations without the need for freezing.
Regulation of NRF2 by Phosphoinositides and Small Heat Shock Proteins

Reactive oxygen species (ROS) are generated by aerobic metabolism, and their deleterious effects are buffered by the cellular antioxidant response, which prevents oxidative stress. The nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of the antioxidant response. Basal levels of NRF2 are kept low by ubiquitin-dependent degradation of NRF2 by E3 ligases, including the Kelch-like ECH-associated protein 1 (KEAP1). Here, we show that the stability and function of NRF2 is regulated by the type I phosphatidylinositol phosphate kinase g (PIPKIg), which binds NRF2 and transfers its product phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) to NRF2. PtdIns(4,5)P2 binding recruits the small heat shock protein HSP27 to the complex. Silencing PIPKIg or HSP27 destabilizes NRF2, reduces expression of its target gene HO-1, and sensitizes cells to oxidative stress. These data demonstrate an unexpected role of phosphoinositides and HSP27 in regulating NRF2 and point to PIPKIg and HSP27 as drug targets to destabilize NRF2 in cancer. In brief Phosphoinositides are coupled to NRF2 by PIPKIγ, and HSP27 is recruited and stabilizes NRF2, promoting stress-resistance.
Lack of chromokinesin Klp-19 creates a more rigid midzone and affects force transmission during anaphase in C. elegans

Recent studies have highlighted the significance of the spindle midzone – the region positioned between chromosomes – in ensuring proper chromosome segregation. By combining advanced 3D electron tomography and cutting-edge light microscopy we have discovered a previously unknown role of the regulation of microtubule dynamics within the spindle midzone of C. elegans. Using Fluorescence recovery after photobleaching and a combination of second harmonic generation and two-photon fluorescence microscopy, we found that the length of the antiparallel microtubule overlap zone in the spindle midzone is constant throughout anaphase, and independent of cortical pulling forces as well as the presence of the microtubule bundling protein SPD-1. Further investigations of SPD-1 and the chromokinesin KLP-19 in C. elegans suggest that KLP-19 regulates the overlap length and functions independently of SPD-1. Our data shows that KLP-19 plays an active role in regulating the length and turn-over of microtubules within the midzone as well as the size of the antiparallel overlap region throughout mitosis. Depletion of KLP-19 in mitosis leads to an increase in microtubule length in the spindle midzone, which also leads to increased microtubule – microtubule interaction, thus building up a more robust microtubule network. The spindle is globally stiffer and more stable, which has implications for the transmission of forces within the spindle affecting chromosome segregation dynamics. Our data shows that by localizing KLP-19 to the spindle midzone in anaphase microtubule dynamics can be locally controlled allowing the formation of a functional midzone.
The Immunoglobulin-Like Cell Adhesion Molecule Nectin and Its Associated Protein

Most but not all phyla include examples of species that are able to regenerate large sections of the body plan. The mechanisms underlying regeneration on this scale are currently being studied in a variety of contexts in both vertebrates and invertebrates. Regeneration generally involves the formation of a wound epithelium after transection or injury, followed by the generation of regenerative progenitor cells and morphogenesis to give the regenerate. Common mechanisms may exist in relation to each of these aspects. For example, the initial proliferation of progenitor cells often depends on the nerve supply, whereas morphogenesis reflects the generation of positional disparity between adjacent cells—the principle of intercalation. These mechanisms are reviewed here across a range of contexts. We also consider the evolutionary origins of regeneration and how regeneration may relate to both agametic reproduction and to ontogeny. 525 Click here for quick links to Annual Reviews content online, including: • Other articles in this volume • Top cited articles • Top downloaded articles • Our comprehensive search Further ANNUAL REVIEWS A nn u. R ev . C el l D ev . B io l. 20 08 . 2 4: 52 554 9. D ow nl oa de d fr om w w w . a nn ua lr ev ie w s. or g by C am br id ge U ni ve rs ity o n 01 /0 2/ 11 . F or p er so na l u se o nl y. ANRV356-CB24-21 ARI 3 September 2008 17:38
This is a wonderful initiative and I urge all states and territories to invest in their kids ’ futures by embracing KidsMatter Early Childhood

“The Australian Psychological Society is proud to be an integral partner in the successful pilot of the KidsMatter Early Childhood mental health initiative for children in early childhood education and care services. KidsMatter Early Childhood helps services and families to promote positive child development and has been proven to reduce social and emotional difficulties in children most at risk. In addition, the initiative was shown to increase the capacity of services and families to support children’s social and emotional development so it benefits the health and wellbeing of children in the long-term. The Australian Psychological Society also wishes to thank the early childhood education and care services and families participating in the pilot for their commitment to the initiative and to children’s mental health and wellbeing. ”
Signature-Based Small Molecule Screening Identifies Cytosine Arabinoside as an EWS/FLI Modulator in Ewing Sarcoma

Background The presence of tumor-specific mutations in the cancer genome represents a potential opportunity for pharmacologic intervention to therapeutic benefit. Unfortunately, many classes of oncoproteins (e.g., transcription factors) are not amenable to conventional small-molecule screening. Despite the identification of tumor-specific somatic mutations, most cancer therapy still utilizes nonspecific, cytotoxic drugs. One illustrative example is the treatment of Ewing sarcoma. Although the EWS/FLI oncoprotein, present in the vast majority of Ewing tumors, was characterized over ten years ago, it has never been exploited as a target of therapy. Previously, this target has been intractable to modulation with traditional small-molecule library screening approaches. Here we describe a gene expression–based approach to identify compounds that induce a signature of EWS/FLI attenuation. We hypothesize that screening small-molecule libraries highly enriched for FDA-approved drugs will provide a more rapid path to clinical application. Methods and Findings A gene expression signature for the EWS/FLI off state was determined with microarray expression profiling of Ewing sarcoma cell lines with EWS/FLI-directed RNA interference. A small-molecule library enriched for FDA-approved drugs was screened with a high-throughput, ligation-mediated amplification assay with a fluorescent, bead-based detection. Screening identified cytosine arabinoside (ARA-C) as a modulator of EWS/FLI. ARA-C reduced EWS/FLI protein abundance and accordingly diminished cell viability and transformation and abrogated tumor growth in a xenograft model. Given the poor outcomes of many patients with Ewing sarcoma and the well-established ARA-C safety profile, clinical trials testing ARA-C are warranted. Conclusions We demonstrate that a gene expression–based approach to small-molecule library screening can identify, for rapid clinical testing, candidate drugs that modulate previously intractable targets. Furthermore, this is a generic approach that can, in principle, be applied to the identification of modulators of any tumor-associated oncoprotein in the rare pediatric malignancies, but also in the more common adult cancers.
PLUS BENZYLADENINE IN COMBINATION WITH SUCROSE IMPROVES POSTHARVEST LEAF AND INFLORESCENCE QUALITY IN Lilium ‘

The interaction between foliar treatment with 100 mg ∙dm of both gibberellic acid 4+7 (GA 4+7) and benzyladenine (BA) and vase solution containing 3% sucros e was analysed in cut Lilium ‘Alma Ata’. GA4+7+BA considerably delayed leaf senescence, suppressed an thocyanin accumulation in the leaves of plants held in the sucrose solution and improved the average longe vity of the flowers and the vase life of the stems. Sucrose in the vase solution strongly reduced the abs cission of leaves and contributed to the enlargemen t of the top flower. The number of significant interactio ns between the treatments indicated that the investi gated factors acted dependently mainly on flower quality, while their action on leaf quality was mostly indepen dent. Results show that combined treatment with growth regulators and sucrose may considerably increase postharvest quality of cut Lilium ‘Alma Ata’.
“ Where am I ? ” Finding Patients in the Process of Navigating a Complex Clinical Information Space

As a central component of healthcare quality improvement efforts in the United States, patient participation in care has become increasingly common. However, along with the benefits, increased participation often requires significant patient effort – for example, to learn enough to be able to have productive discussions with their healthcare provider. Building upon our previous work, in which we identified online health forum posts containing users’ laboratory test results and preliminarily analyzed relevant posts, here we report the results of additional qualitative analyses. The goal of this paper is to propose initial characterizations of patient information and knowledge needs in different situations. These results will inform our future work. Eventually, we hope that this line of research will offer insights that will improve patient-provider communication channels, especially those supported by healthcare technologies, as well as informal sources of support, so that they provide more personalized information that better meets patients’ needs.
Application of PDE and Mathematical Morphology in the Extraction of Cartographic Features

The aim of this paper is to apply techniques for PDE (partial differential equations) and mathematical morphology for the extraction of cartographic features in digital images of remote sensing. These images have become increasingly part of daily life in order, which appear as a strategic tool for the future. The scanned images are used in weather forecasting, forest surveys, urban planning, agricultural, oceanographic and others. These studies aim at smoothing a given image with a model of PDE, and then applying techniques of mathematical morphology for extracting the feature of interest in this case, roads. The results may contribute to the acquisition or updating of data for geographic information systems and cartographic update. The study area corresponds to an image containing a stretch of the Mario Covas Ring Road, located in region of SP (Sao Paulo), Brazil.
On existence of optimal linear encoders over non-field rings for data compression with application to computing

This note proves that, for any finite set of correlated discrete i.i. d. sources, there always exists a sequence of linear encoders over some finite non-field rings which achieves the data compression limit, the Slepian-Wolf region. Based on this, we address a variation of the data compression problem which considers recovering some discrete function of the data. It is demonstrated that linear encoder over non-field ring strictly outperforms its field counterpart for encoding some function in terms of achieving strictly larger achievable region with strictly smaller alphabet size.