Miracle-dz/UniFAR-FTUs huggingface dataset:
Transfer from Pediatric to Adult Care Is Hardly Child’s Play

In this issue of The Journal , Chang and colleagues describe patterns of rheumatologic/nephrologic care and changes in healthcare use and medication adherence among patients with childhood-onset systemic lupus erythematosus (SLE) during their transfer from pediatric to adult care1. The most salient of their findings was a 26% rate of loss to follow-up, defined as more than 12 months between last pediatric visit and first adult visit, or end of enrollment. Consequently, and not surprisingly, ambulatory visits declined (although interestingly, there was no signal for increased acute care use). Medication adherence was poor across groups, regardless of whether the transfer was deemed a “success. ” Taken together, Chang, et al ’s findings reinforce the overarching themes of the literature on pediatric transition to adult care, not to mention the anecdotal — but remarkably consistently held — impressions of physicians who practice in this space: that the period of transition from pediatric to adult care is littered with landmines, quilted with quagmires. Some find their way to adult care and succeed; many others, however, fail dramatically and with dire consequences. Other groups have reported that only 50% of pediatric rheumatology patients transition successfully to adult care2,3. Surely, we could forge a less perilous path. And while patients with childhood-onset SLE, like those in the Chang study, reflect a particularly vulnerable group, with complex and potentially fatal multisystemic disease, the challenges associated with transfer from pediatric to adult care transcend diagnosis or specialty. Themes are consistent among chronic diseases of onset in childhood that persist into adulthood regardless of whether the young patient has SLE, juvenile idiopathic arthritis (JIA), diabetes, or sickle cell disease4,5,6. The unique challenges associated with care of these patients are … Address correspondence to Dr. A. Steiman, Sinai Health System, Medicine, 60 Murray St., Suite 2-223, Toronto, ON M5T 3L9, Canada. Email: amanda.steiman{at}sinaihealthsystem.ca.
Ultrasensitivity and bistability in covalent modification cycles with positive autoregulation

Switch-like behaviours in biochemical networks are of fundamental significance in biological signal processing, and exist as two distinct types: ultra-sensitivity and bistability. Here we propose two new models of a reversible covalent-modification cycle with positive autoregulation (PAR) - a motif structure that is thought to be capable of both ultrasensitivity and bistability in different parameter regimes. These new models appeal to a modelling framework that we call complex complete, which accounts fully for the molecular complexities of the underlying signalling mechanisms. Each of the two new models encodes a specific molecular mechanism for PAR. We demonstrate that the modelling simplifications for PAR models that have been used in previous work, which rely on a Michaelian approximation for the enzyme-mediated reactions, are unable to accurately recapitulate the qualitative signalling responses supported by our ‘full’ complex-complete models. Strikingly, we show that the parameter regimes in which ultrasensitivity and bistability obtain in the complex-complete framework contradict the predictions made by the Michaelian simplification. Our results highlight the critical importance of accurately representing the molecular details of biochemical signalling mechanisms, and strongly suggest that the Michaelian approximation may be inadequate for predictive models of enzyme-mediated chemical reactions with added regulations.
Exploring epitope and functional diversity of anti-SARS-CoV2 antibodies using AI-based methods

Since the beginning of the COVID19 pandemics, an unprecedented research effort has been conducted to analyze the antibody responses in patients, and many trials based on passive immunotherapy — notably monoclonal antibodies — are ongoing. Twenty-one antibodies have entered clinical trials, 6 having reached phase 2/3, phase 3 or having received emergency authorization. These represent only the tip of the iceberg, since many more antibodies have been discovered and represent opportunities either for diagnosis purposes or as drug candidates. The main problem facing laboratories willing to develop such antibodies is the huge task of analyzing them and choosing the best candidate for exhaustive experimental validation. In this work we show how artificial intelligence-based methods can help in analyzing large sets of antibodies in order to determine in a few hours the best candidates in few hours. The MAbCluster method, which only requires knowledge of the amino acid sequences of the antibodies, allows to group the antibodies having the same epitope, considering only their amino acid sequences and their 3D structures (actual or predicted), and to infer some of their functional properties. We then use MAbTope to predict the epitopes for all antibodies for which they are not already known. This allows an exhaustive comparison of the available epitopes, but also gives a synthetic view of the possible combinations. Finally, we show how these results can be used to predict which antibodies might be affected by the different mutations arising in the circulating strains of the virus, such as the N501Y mutation that has started to spread in Great-Britain.
High-energy X-ray diffraction of a hydrous silicate liquid under conditions of high pressure and temperature in a modified hydrothermal diamond anvil cell

In situ high-energy X-ray diffraction measurements were made for the first time on a water-saturated silicate melt at high pressure and temperature. A modified hydrothermal diamond anvil cell (HDAC), designed to minimize the path length of the X-ray beam within a diamond anvil and to increase the solid angle of the diffracted beam, was used to reduce high background contributions and extend X-ray diffraction data collection in Q space. Quantitative differential pair distribution function (PDF) analysis of X-ray diffraction data show that the first measurable (Si–O) peak is 0.095 Å greater in length in the hydrous melt than in the starting glass. Contributions from the H2O O–O correlations, as well as from the second nearest neighbor O–O correlations within the silicate melt, are evident within the second peak of the differential PDF. The procedure described opens new opportunities to directly investigate volatile-rich melts at high pressure and temperature.
The replication of the human respiratory syncytial virus in a T cell line has multiple ineffective steps

Human respiratory syncytial virus is the most frequent cause of severe respiratory disease in children. The main targets of HRSV infection are epithelial cells of the respiratory tract and the great majority of the studies regarding HRSV infection are done in respiratory cells. Recently, the interest on respiratory virus infection of lymphoid cells has been growing, but details of the interaction of HRSV with lymphoid cells remain unknown. Therefore, this study was done to assess the relationship of HRSV with A3.01 cells, a CD4+ T cell line. We found by flow cytometry and fluorescent focus assay that A3.01 cells are susceptible but virtually not permissive to HRSV infection. De-quenching experiments revealed that the fusion process of HRSV in A3.01 cells is reduced in comparison to HEp-2 cells, an epithelial cell lineage. Quantification of viral RNA by qPCR determined that the replication of HRSV in A3.01 cells was modest. Western blot and quantitative flow cytometry analyses demonstrated that the production of HRSV proteins in A3.01 was significantly lower than in HEp-2 cells. Additionally, we found by fluorescence in situ hybridization that the inclusion body-associated granules (IBAG’s) are almost absent in HRSV inclusion bodies in A3.01 cells. We also assessed the intracellular trafficking of HRSV proteins and found that HRSV proteins co-localized partially with the secretory pathway in A3.01 cells, but these HRSV proteins and viral filaments are present only scarcely at the plasma membrane. HRSV infection of A3.01 CD4+ T cells is virtually unproductive as compared to HEp-2 cells, with virion production hampered by low fusion, hypofunctional inclusion bodies, altered trafficking of viral proteins to the plasma membrane.
tert-Butyl Carbamate at 100K

A cryogenic determination of the title compound, C5H11NO2, confirms an earlier 295 K determination. The C—N distance is 1.3374 (9) A. Intermolecular N—H⋯O(carbonyl) hydrogen bonds have lengths 2.9434 (12) and 3.0368 (11) A.
Genome Wide Characterization, Identification And Expression Analysis Of Erf Gene Family In Cotton

ERF is a subfamily of AP2/EREBP superfamily, contained single AP2 domain. The overexpression of ERF genes steered to abiotic stress tolerance and pathogen resistance in transgenic plants. Here, a genome-wide analysis of ERF gene family within two diploid species (G. arboreum & G. raimondii) and two tetraploid species (G. barbadense, G. hirsutum) was performed. A total of 118, 120, 213, 220 genes contained sequence single AP2 domain were identified in G. arboreum, G. raimondii, G. barbadense and G. hirsutum respectively. The identified genes were unevenly distributed across 13/26 chromosomes of A and D genomes of cotton. Genome comparison revealed that segmental duplication may have played crucial roles in the expansion of the cotton ERF gene family, and tandem duplication also played a minor role. Analysis of RNA-Seq data indicated that cotton ERF gene expression levels varied across different tissues and in response to different abiotic stress. Overall, our results could provide valuable information for better understanding the evolution of cotton ERF genes and lays a foundation for future investigation in cotton.
Multi-scale annotations of chromatin states in 127 human cell-types

Genome-wide profiling of chromatin states has been widely used to characterize the biological function of non-coding genomic sequences in a cell-type specific manner. However, the systematic, comprehensive annotations of chromatin states from experimental data are challenging and require not just extensive biological knowledge but also sophisticated computational modeling. Previously we developed a hierarchical hidden Markov model, named diHMM, to systematically annotate chromatin states at multiple scales based on the combination of histone mark and chromatin regulator binding profiles. Here, we have improved the method by optimizing computational efficiency and using an ensemble-clustering approach to achieve a unified annotation by integrating information from cell-type-specific models. We then applied this improved method to generate a unified multi-scale chromatin state map in 127 human cell types, based on public data generated by the Epigenome Roadmap and ENCODE consortia. We found cell types with similar origin are typically associated with similar chromatin states, but cultured cell lines have distinct structures than primary cells. The contribution of enhancer elements to gene regulation is mediated by the broader context of domain-state organization. Distinct domain-state patterns are associated with various 3D chromatin structures. As such, we have demonstrated the utility of the multi-scale chromatin state map in characterizing the biological function of the human genome.
Distinct VIP interneurons in the cingulate cortex encode anxiogenic and social stimuli

A hallmark of higher-order cortical regions is their functional heterogeneity, but it is not well understood how these areas encode such diverse information. The anterior cingulate cortex (ACC), for example, is important in both emotional regulation and social cognition. Previous work shows activation of the ACC to anxiety-related and social stimuli, but it is unknown how subpopulations or microcircuits within the ACC simultaneously encode these distinct stimuli. One type of inhibitory interneuron, which is positive for vasoactive intestinal peptide (VIP), is known to alter the activity of many cells in local cortical microcircuits, but it is unknown whether the activity of VIP cells in the ACC (VIPACC) encodes anxiety-related or social information. Using in vivo calcium imaging and miniscopes in freely behaving mice to monitor VIPACC activity, we identified distinct, non-overlapping subpopulations of VIPACC that preferentially activated to either anxiogenic, anxiolytic, social, or non-social stimuli. We determined that stimulus-selective cells encode the animal’s behavioral states and VIP interneuron clusters may co-activate, improving this encoding. Finally, we used trans-synaptic tracing to show that VIPACC receive widespread inputs from regions implicated in emotional regulation and social cognition. These findings demonstrate not only that the ACC is not homogeneous in its function, but also that there is marked functional heterogeneity even within disinhibitory interneuron populations. This work contributes to our understanding of how the cortex encodes information across diverse contexts and provides insight into the complexity of neural processes involved in anxiety and social behavior.
Berberine and Obatoclax Inhibit SARS-Cov-2 Replication in Primary Human Nasal Epithelial Cells In Vitro

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as a new human pathogen in late 2019 and has infected an estimated 10% of the global population in less than a year. There is a clear need for effective antiviral drugs to complement current preventive measures including vaccines. In this study, we demonstrate that berberine and obatoclax, two broad-spectrum antiviral compounds, are effective against multiple isolates of SARS-CoV-2. Berberine, a plant-derived alkaloid, inhibited SARS-CoV-2 at low micromolar concentrations and obatoclax, originally developed as an anti-apoptotic protein antagonist, was effective at sub-micromolar concentrations. Time-of-addition studies indicated that berberine acts on the late stage of the viral life cycle. In agreement, berberine mildly affected viral RNA synthesis, but strongly reduced infectious viral titers, leading to an increase in the particle-to-pfu ratio. In contrast, obatoclax acted at the early stage of the infection, in line with its activity to neutralize the acidic environment in endosomes. We assessed infection of primary human nasal epithelial cells cultured on an air-liquid interface and found that SARS-CoV-2 infection induced and repressed expression of a specific set of cytokines and chemokines. Moreover, both obatoclax and berberine inhibited SARS-CoV-2 replication in these primary target cells. We propose berberine and obatoclax as potential antiviral drugs against SARS-CoV-2 that could be considered for further efficacy testing.
Maize (Zea mays L.) Nucleoskeletal Proteins Regulate Nuclear Envelope Remodeling and Function in Stomatal Complex Development and Pollen Viability

In eukaryotes, the nuclear envelope (NE) encloses chromatin and separates it from the rest of the cell. The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex physically bridges across the NE, linking nuclear and cytoplasmic components. In plants, these LINC complexes are beginning to be ascribed roles in cellular and nuclear functions, including chromatin organization, regulation of nuclei shape and movement, and cell division. Homologs of core LINC components, KASH and SUN proteins, have previously been identified in maize. Here, we characterized the presumed LINC-associated maize nucleoskeletal proteins NCH1 and NCH2, homologs of members of the plant NMCP/CRWN family, and MKAKU41, homologous to AtKAKU4. All three proteins localized to the nuclear periphery when transiently and heterologously expressed as fluorescent protein fusions in Nicotiana benthamiana. Overexpression of MKAKU41 caused dramatic changes in the organization of the nuclear periphery, including nuclear invaginations that stained positive for non-nucleoplasmic markers of the inner and outer NE, and the ER. The severity of these invaginations was altered by changes in LINC connections and the actin cytoskeleton. In maize, MKAKU41 appeared to share genetic functions with other LINC components, including control of nuclei shape, stomatal complex development, and pollen viability. Overall, our data show that NCH1, NCH2, and MKAKU41 have characteristic properties of LINC-associated plant nucleoskeletal proteins, including interactions with NE components suggestive of functions at the nuclear periphery that impact the overall nuclear architecture.
Neural excitability increases with axonal resistance between soma and axon initial segment

Significance Action potentials initiate in the axon initial segment (AIS), close to the soma. Previous experimental findings suggested that a distal shift in AIS position reduces excitability, but theoretical work predicts the opposite. A distal shift in AIS position corresponds to an elevation of axial resistance (Ra) between soma and AIS. We modified Ra and measured the voltage threshold (Vth) of action potentials in the soma of cortical neurons. Increasing Ra by mechanically pinching the axon hillock lowered Vth by ∼6 mV, whereas decreasing Ra by substituting internal ions with higher mobility elevated Vth. Thus, excitability increases with axial resistance and therefore with a distal shift of the AIS. The position of the axon initial segment (AIS) is thought to play a critical role in neuronal excitability. Previous experimental studies have found that a distal shift in AIS position correlates with a reduction in excitability. Yet theoretical work has suggested the opposite, because of increased electrical isolation. A distal shift in AIS position corresponds to an elevation of axial resistance Ra. We therefore examined how changes in Ra at the axon hillock impact the voltage threshold (Vth) of the somatic action potential in L5 pyramidal neurons. Increasing Ra by mechanically pinching the axon between the soma and the AIS was found to lower Vth by ∼6 mV. Conversely, decreasing Ra by substituting internal ions with higher mobility elevated Vth. All Ra-dependent changes in Vth could be reproduced in a Hodgkin–Huxley compartmental model. We conclude that in L5 pyramidal neurons, excitability increases with axial resistance and therefore with a distal shift of the AIS.
Cells protect chromosome-microtubule attachments, independent of biorientation, using an Astrin-PP1 and CyclinB-CDK1 feedback loop

Defects in chromosome-microtubule attachment can cause chromosomal instability, associated with infertility and aggressive cancers. Chromosome-microtubule attachment is mediated by a large macromolecular structure, the kinetochore. Kinetochore pairs are bioriented and pulled by microtubules from opposing spindle poles to ensure the equal segregation of chromosomes. Kinetochore-microtubule attachments lacking opposing-pull are detached by Aurora-B/Ipl1; yet, how mono-oriented attachments that are a prerequisite for biorientation, but lacking opposing-pull are spared is unclear. Using an RNAi-mediated screen, we uncover a unique role for the Astrin-SKAP complex in protecting mono-oriented attachments. We provide the first evidence for how a microtubule-end associated protein senses outer-kinetochore changes specific to end-on attachments and assembles into an outer kinetochore crescent to stabilise mature attachments. We find that Astrin-PP1 and Cyclin-B-CDK1 activities counteract each other to preserve mono-oriented attachments. Thus, cells are not only surveying chromosome-microtubule attachment errors, but they are also actively sensing and stabilising mature attachments independent of biorientation.
Towards understanding interindividual differences in cortical morphological brain networks

Individual-level morphological brain networks are becoming an important approach for studying human connectome; however, their interindividual differences are not well understood with respect to behavioral and cognitive relevance, individual identification, and genetic origin. Using three publicly available datasets that involved cross-sectional and longitudinal structural magnetic resonance scans of adults and children, we constructed four morphological brain networks for each of 1,451 images from 1,329 participants on the basis of cerebral surface-based, vertex-wise cortical thickness, fractal dimension, gyrification index and sulcal depth, respectively. The morphological index-dependent networks were further fused via multiplex network model, and fed into community detection. We found that the multiplex morphological brain networks 1) accounted for significant proportions of interindividual variance in and were predictive of multiple behavioral and cognitive domains, in particular Cognition and Motor domains (P < 0.05, corrected), 2) distinguished individuals from each other with high accuracies even for twin subjects (accuracies > 96%), and 3) exhibited low-moderate heritability with the highest for sulcal depth-based morphological brain networks. Intriguingly, compared with intra-module morphological connectivity, inter-module connections explained more behavioral and cognitive variance and were associated with higher heritability. Further comparisons revealed that multiplex morphological brain networks outperformed each type of single-layer morphological brain networks in the performance of behavioral and cognitive association and prediction, and individual identification. Finally, all the findings were generally reproducible over different datasets. Altogether, our findings indicate that interindividual differences in individual-level morphological brain networks are biologically meaningful, which underpins their usage as fingerprints for individualized studies in health and disease.
Novel integrative elements and genomic plasticity in ocean ecosystems

Horizontal gene transfer accelerates microbial evolution, promoting diversification and adaptation. The globally abundant marine cyanobacterium Prochlorococcus has a highly streamlined genome with frequent gene exchange reflected in its extensive pangenome. The source of its genomic variability, however, remains elusive since most cells lack the common mechanisms that enable horizontal gene transfer, including conjugation, transformation, plasmids and prophages. Examining 623 genomes, we reveal a diverse system of mobile genetic elements – cargo-carrying transposons we named tycheposons – that shape Prochlorococcus’ genomic plasticity. The excision and integration of tycheposons at seven tRNA genes drive the remodeling of larger genomic islands containing most of Prochlorococcus’ flexible genes. Most tycheposons carry genes important for niche differentiation through nutrient acquisition; others appear similar to phage parasites. Tycheposons are highly enriched in extracellular vesicles and phage particles in ocean samples, suggesting efficient routes for their dispersal, transmission and propagation. Supported by evidence for similar elements in other marine microbes, our work underpins the role of vesicle- and virus-mediated transfer of mobile genetic elements in the diversification and adaptation of microbes in dilute aquatic environments – adding a significant piece to the puzzle of what governs microbial evolution in the planet’s largest habitat.