Miracle-dz/UniFAR-FTUs huggingface dataset:
Dissecting Succulence: Crassulacean Acid Metabolism and Hydraulic Capacitance are Independent Adaptations in Clusia Leaves

Succulence is found across the world as an adaptation to water-limited niches. The fleshy organs of succulent plants develop via enlarged photosynthetic chlorenchyma and/or achlorophyllous water storage hydrenchyma cells. The precise mechanism by which anatomical traits contribute to drought tolerance is unclear, as the effect of succulence is multifaceted. Large cells are believed to provide space for nocturnal storage of malic acid fixed by crassulacean acid metabolism (CAM), whilst also buffering water potentials by elevating hydraulic capacitance (CFT). Furthermore, the effect of CAM and elevated CFT on growth and water conservation have not been compared, despite the assumption that these adaptations often occur together. We assessed the relationship between succulent anatomical adaptations, CAM and CFT, across the genus Clusia. In addition, we simulated the effects of CAM and CFT on growth and water conservation during drought using the Photo3 model. Within Clusia leaves, CAM and CFT are independent traits: CAM requires large palisade chlorenchyma cells, whereas hydrenchyma tissue governs interspecific differences in CFT. In addition, our model suggests that CAM supersedes CFT as a means to maximise CO2 assimilation and minimise transpiration during drought. Our study challenges the assumption that CAM and CFT are mutually dependent traits within succulent leaves.
Different patterns of visual processing for shapes in V1 of mouse and monkey

Recently, mice became a popular research model for the visual system including objects processing. However, while primates use their fovea to inspect objects at high resolution, mice have low visual acuity and lack a foveal region. Thus, how objects are encoded in the visual cortex of mice and whether monkeys and mice use similar neural mechanisms to discriminate between shapes, is unknown. Using voltage sensitive dye imaging, we investigated spatio-temporal patterns of population response in the primary visual cortex (V1) of mice and monkeys to shape contours. Neural responses in mice showed blurred spatial patterns, low correlation to the original stimuli and only subtle spatial differences between the shapes. In contrast, the neural responses in monkey’s V1 fovea, showed prominent differences between the shapes at sub-degree resolution with high resemblance to the original shapes, in agreement with a topographic code. Furthermore, the spatial patterns of neural synchronization in monkey’s V1 suggested contour binding by synchrony, but not in mice V1. Finally, monkey’s V1 responses at larger eccentricities, resembled more to those in mice. These results may suggest that to discriminate between shapes, mice rely on neural processing of low-level cues, whereas monkeys rely more on a topographic code.
Extensive heterogeneity of the HIV-1 infected CD4+ T-cell reservoir revealed by single-cell viral ASAPseq

Defining the long-lived HIV reservoir during antiretroviral therapy remains a challenge for HIV cure research. To determine if unifying cell surface or genomic features can be identified in unperturbed HIV-1 infected CD4+ T-cells, we developed single-cell viral ASAPseq, which leverages scATACseq and surface marker profiling to define HIV-infected cells via the presence of integrated proviral DNA. Here, we employed this strategy to define infected CD4+ T-cells both in vitro and ex vivo from blood and lymph nodes of, respectively, treated and untreated people living with HIV. In each setting, we identified HIV-infected cells with both novel and known surface markers associated with provirus. We also uncovered epigenetic profiles and transcription factor motifs enriched in HIV-infected cells that more deeply define the reservoir. Our data highlight the broad heterogeneity of the HIV reservoir and create a foundation for a multiomic atlas to develop targeted elimination strategies. experimentally and in vivo infected memory CD4+ T cells at single-cell resolution with cellular identity. With our multidimensional dataset, we highlight the heterogeneity of HIV+ cells and the variation of surface and epigenetic markers between and across infection contexts. Together, our extensive characterization of HIV infection using ASAPseq results in a multimodal single-cell dataset of cell surface protein composition, epigenetic landscape, and potential regulatory mechanisms to accelerate our understanding of the HIV reservoir for targeted therapy. cells at single-cell resolution with simultaneous surface antigen and epigenetic data. With this unparalleled resolution via ASAPseq compared to currently published techniques for studying the HIV reservoir, we uncovered both known and novel surface markers of HIV infection as well as accessible transcription factor motifs that may regulate or be indicative of HIV infection. Our study paves the way for future unmanipulated studies of the HIV reservoir. Furthermore, this approach can also be applied for lentiviral-based immunotherapy and other latent infections that involve nuclear, viral DNA. Our strategy and data are the start of a multiomic atlas of HIV infected cells with phenotypic and epigenetic characteristics - thus contributing towards the united goal of identifying the HIV reservoir for a targeted, functional cure of HIV. Live/Dead staining with FACS CD8 BV570 RPA-T8) for a 10 minute stain in the dark at room 1ml FACS buffer added x for Cells permeabilized with 250μl of BD Cytofix/Cytoperm for 18 minutes in the dark at room 1ml BD Perm/Wash and cells cells were resuspended in staining solution containing anti-p24 FITC (Beckman and BD Perm/Wash Buffer for a final staining volume of 50μl. Cells were stained in the dark for 1 hour at room temperature. Cells 1ml BD Perm/Wash Buffer and fixed with 350ul of 1% paraformaldehyde. Data on a BD FACS cytometer and analyzed using
Integrative Conformational Ensembles of Sic1 Using Different Initial Pools and Optimization Methods

Intrinsically disordered proteins play key roles in regulatory protein interactions, but their detailed structural characterization remains challenging. Here we calculate and compare conformational ensembles for the disordered protein Sic1 from yeast, starting from initial ensembles that were generated either by statistical sampling of the conformational landscape, or by molecular dynamics simulations. Two popular, yet contrasting optimization methods were used, ENSEMBLE and Bayesian Maximum Entropy, to achieve agreement with experimental data from nuclear magnetic resonance, small-angle X-ray scattering and single-molecule Förster resonance energy transfer. The comparative analysis of the optimized ensembles, including secondary structure propensity, inter-residue contact maps, and the distributions of hydrogen bond and pi interactions, revealed the importance of the physics-based generation of initial ensembles. The analysis also provides insights into designing new experiments that can maximally discriminate among the optimized ensembles. Overall, differences between ensembles optimized from different priors were greater than when using the same prior with different optimization methods. Generating increasingly accurate, reliable and experimentally validated ensembles for disordered proteins is an important step towards a mechanistic understanding of their biological function and involvement in various diseases.
Aberrant MYCN expression drives oncogenic hijacking of EZH2 as a transcriptional activator in peripheral T-cell lymphoma

Peripheral T cell lymphoma (PTCL) is a heterogeneous group of hematological cancers arising from the malignant transformation of mature T cells. In a cohort of 28 PTCL cases, we identified recurrent overexpression of MYCN, a member of the MYC family of oncogenic transcription factors. Approximately half of all PTCL cases was characterized by a MYC expression signature. Inducible expression of MYCN in lymphoid cells in a mouse model caused T cell lymphoma that recapitulated human PTCL with a MYC expression signature. Integration of mouse and human expression data identified EZH2 as a key downstream target of MYCN. Remarkably, EZH2 was found to be an essential co-factor for the transcriptional activation of the MYCN-driven gene expression program, which was independent of methyltransferase activity, but dependent on phosphorylation by CDK1. MYCN-driven T cell lymphoma was sensitive to EZH2 degradation or CDK1 inhibition, which displayed synergy with FDA-approved HDAC inhibitors. Key points - Transcriptomic analysis of PTCL tumors reveals recurrent MYCN overexpression and the presence of a MYC signature in 50% of PTCL cases - EZH2 is a transcriptional cofactor for the MYCN-driven gene expression program, which confers sensitivity to HDAC inhibition
Predicting the UV Spectrum of Oligodeoxynucleotide by 2D-Matlab

A 2D-Matlab model was developed to predict the UV absorbance spectra and thus concentration of oligodeoxynucleotide samples. This model will be valuable for researchers designing experiments involving oligodeoxynucleotides. Initial data was acquired from UV absorbance spectra of oligodeoxynucleotides 23, 24 and 34 bases long. The model, which would predict the concentration of DNA from the R260 value, is shown to predict absorbance spectra and the extinction coefficient of DNA as shown when compared across a range of concentrations.
RNA helicase DDX5 mediates adaptive response to multi-kinase inhibitors in liver cancer

Objective To determine the role of RNA helicase DDX5 in sorafenib/multi-tyrosine kinase inhibitor (mTKI) response. Sorafenib and mTKIs downregulate DDX5 in vitro and preclinical hepatocellular carcinoma (HCC) models. In turn, sorafenib-mediated DDX5 downregulation activates Wnt/β-catenin and non-canonical NF-κB signaling, resulting in ferroptosis escape and mTKI resistance. Design and Results Molecular, pharmacologic and bioinformatic approaches were employed in human HCC cell lines, preclinical HCC models, and HCCs from TCGA. Earlier studies linked sorafenib effectiveness to ferroptosis. Herein we demonstrate sorafenib/mTKIs downregulate DDX5 in vitro and in vivo. To understand the effect of DDX5 downregulation, we compared TCGA-derived HCCs expressing low vs. high DDX5 focusing on ferroptosis-related genes. Glutathione Peroxidase 4 (GPX4), a key ferroptosis regulator, was significantly overexpressed in DDX5LOW HCCs. Importantly, DDX5-knockdown (DDX5KD) HCC cell lines lacked lipid peroxidation by GPX4 inhibition, indicating DDX5 downregulation suppresses ferroptosis. RNAseq of wild type vs. DDX5KD cells untreated or treated with sorafenib, identified a unique set of genes repressed by DDX5 and upregulated by sorafenib. This set significantly overlaps genes from Wnt/β-catenin and non-canonical NF-κB pathways, including NF-κB inducing Kinase required for non-canonical NF-κB activation. Pharmacologic inhibition of these pathways in combination with sorafenib reduced DDX5KD cell viability. Mechanistically, sorafenib-mediated NIK expression induced NRF2 transcription, while DDX5KD extended NRF2 half/life by stabilizing p62/SQSTM1, enhancing GPX4 expression and ferroptosis escape. Conclusion Sorafenib/mTKI-mediated DDX5 downregulation results in adaptive mTKI resistance by enhancing NRF2 expression, leading to ferroptosis escape. We propose inhibition of the pathways leading to NRF2 expression will enhance the therapeutic effectiveness of sorafenib/mTKIs. What is already known on this topic – In advanced HCC, mTKIs/sorafenib, offer limited survival benefits due to resistance. Combination of VEGF (bevacizumab) and PD-L1 antibody (atezolizumab) has led to its adoption as first line treatment; however, mTKIs are still widely used in patients with contra-indications to bevacizumab; also, in atezolizumab/bevacizumab failure, mTKIs are the gold standard in second or later-line systemic therapy, emphasizing the importance of delineating the mechanism of mTKI resistance. What this study adds – We show mTKIs and sorafenib downregulate the RNA helicase DDX5. This downregulation of DDX5 by sorafenib enables activation of Wnt/β-catenin and non-canonical NF-κB pathways, leading to expression of genes that enable escape from ferroptotic cell death. How this study might affect research, practice or policy The Wnt/β-catenin and non-canonical NF-κB pathways activated by sorafenib/DDX5 downregulation can serve as druggable targets to enhance the anti-cancer effect of mTKIs by inducing ferroptosis, thereby opening-up new therapeutic directions against mTKI resistance.
An ACE2-dependent Sarbecovirus in Russian bats is resistant to SARS-CoV-2 vaccines

Spillover of sarbecoviruses from animals to humans has resulted in outbreaks of severe acute respiratory syndrome SARS-CoVs and the ongoing COVID-19 pandemic. Efforts to identify the origins of SARS-CoV-1 and −2 has resulted in the discovery of numerous animal sarbecoviruses – the majority of which are only distantly related to known human pathogens and do not infect human cells. The receptor binding domain (RBD) on sarbecoviruses engages receptor molecules on the host cell and mediates cell invasion. Here, we tested the receptor tropism and serological cross reactivity for RBDs from two sarbecoviruses found in Russian horseshoe bats. While these two viruses are in a viral lineage distinct from SARS-CoV-1 and −2, one virus, Khosta-2, was capable of using human ACE2 to facilitate cell entry. Viral pseudotypes with a recombinant, SARS-CoV-2 spike encoding for the Khosta 2 RBD were resistant to both SARS-CoV-2 monoclonal antibodies and serum from individuals vaccinated for SARS-CoV-2. Our findings further demonstrate that sarbecoviruses circulating in wildlife outside of Asia also pose a threat to global health and ongoing vaccine campaigns against SARS-CoV-2 ONE SENTENCE SUMMARY European bat coronaviruses that are only distantly related to SARS-CoV-2 but use the same cell entry route, escape the immune response against SARS-CoV-2 vaccines, driving the need for broader vaccines.
Avaliando a Qualidade do Software de um Projeto Distribuído: um Relato de Experiência

Abstract. Several companies are implementing distributed software development and with the benefits come great challenges such as the difficulty of team management and communication problems. As a solution, we need to adapt the traditional methodology of software development. In this context, this paper describes how the quality was maintained during a distributed development project. For this reason, a case study was conducted in order to investigate how the Scrum best practices were adapted. At the end of the project, a set of lessons learned was identified to maintain the quality of distributed software development in a practical and efficient way.
Towards Incremental FSM-based Testing of Software Product Lines

Software Product Line (SPL) is an approach which offers several benefits for organizations, such as significant reductions in the development and maintenance costs, reduced time-to-market, and personalized software products. In SPLs, the testing activity presents challenges due to characteristics of their development process. The cost of testing SPL is usually higher than the cost of testing traditional systems. SPLs foster the reuse of artifacts that include requirement specifications, code and models. Among different models used in an SPL, state-based models, such as Finite State Machines, are promising candidates to support the test case generation. Therefore, we propose a strategy to reuse test cases generated for different products of an SPL. Test cases are derived from Finite State Machines representing products instantiated from an SPL. The test cases generated for a product are reused when testing further products instantiated from the same SPL, in order to reduce the size of additional test cases. We illustrate our strategy in a case study using two SPLs of embedded system applications.
MM-SQAP: Method for Modeling Software Quality Assurance Process

This experience report describes MM-SQAP (Method for Modeling Software Quality Assurance Process). This method was defined and applied in a financial company in order to establish its software quality assurance process. The results obtained with this application demonstrated its feasibility. The application of MM-SQAP in other areas, in different domains, will make it more flexible than its original version.
Elemental and Isotopic Signatures of Bulk Sedimentary Organic Matter in Shenhu Area, Northern South China Sea

Hydrate-bearing sediments provide excellent materials for studying the primary sources and diagenetic alterations of organic matter. In this study, the elemental and isotopic signatures of total organic carbon (TOC), total inorganic carbon (TIC), total nitrogen (TN), and total sulfur (TS) are systematically investigated in three hydrate-bearing sediment cores (∼240 m) retrieved from the Shenhu area, South China Sea. All sediment layers from three sites are with low TOC content (average 0.35%) with marine and terrestrial mixed sources (-23.6‰ < δ13Corg < -21.4‰). However, the generally low δ15N (2.49–5.31‰) and C/N ratios (4.35–8.2) and their variation with depth cannot be explained by the terrestrial sources (Pearl River) and marine sources, binary end-member mixing processes. Contribution from lateral allochthonous organic matter from the mountainous river is considered after excluding other possible factors and ingeniously elucidating the organic matter origins. Furthermore, specific layers in W01B and W02B exhibit elevated S/C ratios (up to 2.39), positive bias of δ34S-TS (up to +29.7‰), and negative excursion of δ13C-TIC (up to -8.29‰), which are the characteristics of sustained occurrence of sulfate-driven anaerobic oxidation of methane. The occurrence of coupled carbon–sulfur anomaly may be accompanied by deep hydrocarbon leakage and the formation of hydrate with high saturation.
cAMP-Dependent Synaptic Plasticity at the Hippocampal Mossy Fiber Terminal

Cyclic adenosine monophosphate (cAMP) is a crucial second messenger involved in both pre- and postsynaptic plasticity in many neuronal types across species. In the hippocampal mossy fiber (MF) synapse, cAMP mediates presynaptic long-term potentiation and depression. The main cAMP-dependent signaling pathway linked to MF synaptic plasticity acts via the activation of the protein kinase A (PKA) molecular cascade. Accordingly, various downstream putative synaptic PKA target proteins have been linked to cAMP-dependent MF synaptic plasticity, such as synapsin, rabphilin, synaptotagmin-12, RIM1a, tomosyn, and P/Q-type calcium channels. Regulating the expression of some of these proteins alters synaptic release probability and calcium channel clustering, resulting in short- and long-term changes to synaptic efficacy. However, despite decades of research, the exact molecular mechanisms by which cAMP and PKA exert their influences in MF terminals remain largely unknown. Here, we review current knowledge of different cAMP catalysts and potential downstream PKA-dependent molecular cascades, in addition to non-canonical cAMP-dependent but PKA-independent cascades, which might serve as alternative, compensatory or competing pathways to the canonical PKA cascade. Since several other central synapses share a similar form of presynaptic plasticity with the MF, a better description of the molecular mechanisms governing MF plasticity could be key to understanding the relationship between the transcriptional and computational levels across brain regions.
Hyperdense Artery Sign in Patients With Acute Ischemic Stroke–Automated Detection With Artificial Intelligence-Driven Software

Background Hyperdense artery sign (HAS) on non-contrast CT (NCCT) can indicate a large vessel occlusion (LVO) in patients with acute ischemic stroke. HAS detection belongs to routine reporting in patients with acute stroke and can help to identify patients in whom LVO is not initially suspected. We sought to evaluate automated HAS detection by commercial software and compared its performance to that of trained physicians against a reference standard. Methods Non-contrast CT scans from 154 patients with and without LVO proven by CT angiography (CTA) were independently rated for HAS by two blinded neuroradiologists and an AI-driven algorithm (Brainomix®). Sensitivity and specificity were analyzed for the clinicians and the software. As a secondary analysis, the clot length was automatically calculated by the software and compared with the length manually outlined on CTA images as the reference standard. Results Among 154 patients, 84 (54.5%) had CTA-proven LVO. HAS on the correct side was detected with a sensitivity and specificity of 0.77 (CI:0.66–0.85) and 0.87 (0.77–0.94), 0.8 (0.69–0.88) and 0.97 (0.89–0.99), and 0.93 (0.84–0.97) and 0.71 (0.59–0.81) by the software and readers 1 and 2, respectively. The automated estimation of the thrombus length was in moderate agreement with the CTA-based reference standard [intraclass correlation coefficient (ICC) 0.73]. Conclusion Automated detection of HAS and estimation of thrombus length on NCCT by the tested software is feasible with a sensitivity and specificity comparable to that of trained neuroradiologists.
Evolution of HLA-B Pharmacogenomics and the Importance of PGx Data Integration in Health Care System: A 10 Years Retrospective Study in Thailand

Background: The HLA-B is the most polymorphic gene, play a crucial role in drug-induced hypersensitivity reactions. There is a lot of evidence associating several risk alleles to life-threatening adverse drug reactions, and a few of them have been approved as valid biomarkers for predicting life-threatening hypersensitivity reactions. Objectives: The objective of this present study is to present the progression of HLA-B pharmacogenomics (PGx) testing in the Thai population during a 10‐year period, from 2011 to 2020. Methods: This was a retrospective observational cohort study conducted at the Faculty of Medicine Ramathibodi Hospital. Overall, 13,985 eligible patients who were tested for HLA-B risk alleles between periods of 2011–2020 at the study site were included in this study. Results: The HLA PGx testing has been increasing year by year tremendously, 94 HLA-B testing was done in 2011; this has been raised to 2,880 in 2020. Carbamazepine (n = 4,069, 33%), allopurinol (n = 4,675, 38%), and abacavir (n = 3,246, 26%) were the most common drugs for which the HLA-B genotyping was performed. HLA-B*13:01, HLA-B*15:02 and HLA-B*58:01 are highly frequent, HLA-B*51:01 and HLA-B*57:01 are moderately frequent alleles that are being associated with drug induced hypersensitivity. HLA-B*59:01 and HLA-B*38:01 theses alleles are rare but has been reported with drug induced toxicity. Most of the samples were from state hospital (50%), 36% from private clinical laboratories and 14% from private hospitals. Conclusion: According to this study, HLA-B PGx testing is increasing substantially in Thailand year after year. The advancement of research in this field, increased physician awareness of PGx, and government and insurance scheme reimbursement assistance could all be factors. Incorporating PGx data, along with other clinical and non-clinical data, into clinical decision support systems (CDS) and national formularies, on the other hand, would assist prescribers in prioritizing therapy for their patients. This will also aid in the prediction and prevention of serious adverse drug reactions.