bluuebunny/crossref_metadata_2025 huggingface dataset:
DeepHBV: A deep learning model to predict hepatitis B virus (HBV) integration sites
Authors: Wu Canbiao , Guo Xiaofang , Li Mengyuan , Fu Xiayu , Hou Zeliang , Zhai Manman , Shen Jingxian , Qiu Xiaofan , Cui Zifeng , Xie Hongxian , Qin Pengmin , Weng Xuchu , Hu Zheng , Liang Jiuxing
Published: January 2021

Hepatitis B virus (HBV) is one of the main causes for viral hepatitis and liver cancer. Previous studies showed HBV can integrate into host genome and further promote malignant transformation. In this study, we developed an attention-based deep learning model DeepHBV to predict HBV integration sites by learning local genomic features automatically. We trained and tested DeepHBV using the HBV integration sites data from dsVIS database. Initially, DeepHBV showed AUROC of 0.6363 and AUPR of 0.5471 on the dataset. Adding repeat peaks and TCGA Pan Cancer peaks can significantly improve the model performance, with an AUROC of 0.8378 and 0.9430 and an AUPR of 0.7535 and 0.9310, respectively. On independent validation dataset of HBV integration sites from VISDB, DeepHBV with HBV integration sequences plus TCGA Pan Cancer (AUROC of 0.7603 and AUPR of 0.6189) performed better than HBV integration sequences plus repeat peaks (AUROC of 0.6657 and AUPR of 0.5737). Next, we found the transcriptional factor binding sites (TFBS) were significantly enriched near genomic positions that were paid attention to by convolution neural network. The binding sites of AR-halfsite, Arnt, Atf1, bHLHE40, bHLHE41, BMAL1, CLOCK, c-Myc, COUP-TFII, E2A, EBF1, Erra and Foxo3 were highlighted by DeepHBV attention mechanism in both dsVIS dataset and VISDB dataset, revealing the HBV integration preference. In summary, DeepHBV is a robust and explainable deep learning model not only for the prediction of HBV integration sites but also for further mechanism study of HBV induced cancer.

Author summary

Hepatitis B virus (HBV) is one of the main causes for viral hepatitis and liver cancer. Previous studies showed HBV can integrate into host genome and further promote malignant transformation. In this study, we developed an attention-based deep learning model DeepHBV to predict HBV integration sites by learning local genomic features automatically. The performance of DeepHBV model significantly improves after adding genomic features, with an AUROC of 0.9430 and an AUPR of 0.9310. Furthermore, we enriched the transcriptional factor binding sites of proteins by convolution neural network. In summary, DeepHBV is a robust and explainable deep learning model not only for the prediction of HBV integration sites but also for the further study of HBV integration mechanism.
Distinguishing gene flow between malaria parasite populations
Authors: Brown Tyler S. , Taylor Aimee R. , Arogbokun Olufunmilayo , Buckee Caroline O. , Chang Hsiao-Han
Published: January 2021

Measuring gene flow between malaria parasite populations in different geographic locations can provide strategic information for malaria control interventions. Multiple important questions pertaining to the design of such studies remain unanswered, limiting efforts to operationalize genomic surveillance tools for routine public health use. This report evaluates numerically the ability to distinguish different levels of gene flow between malaria populations, using different amounts of real and simulated data, where data are simulated using parameters that approximate different epidemiological conditions. Specifically, usingPlasmodium falciparumwhole genome sequence data and sequence data simulated for a metapopulation with different migration rates and effective population sizes, we compare two estimators of gene flow, explore the number of genetic markers and number of individuals required to reliably rank highly connected locations, and describe how these thresholds change given different effective population sizes and migration rates. Our results have implications for the design and implementation of malaria genomic surveillance efforts.
Choosing optimal trigger points forex situ, in totoconservation of single population threatened species
Authors: Brown Kaitlyn , Tambyah Tamara , Fenwick Jack , Burke Aidan , Grant Patrick , Hegarty-Cremer Solene , Muller Joshua , Bode Michael
Published: January 2021

Many endangered species exist in only a single population, and almost all species that go extinct will do so from their last remaining population. Understanding how to best conserve these single population threatened species (SPTS) is therefore a distinct and important task for threatened species conservation science. As a last resort, managers of SPTS may consider taking the entire population into captivity –ex situ, in totoconservation. In the past, this choice has been taken to the great benefit of the SPTS, but it has also lead to catastrophe. Here, we develop a decision-support tool for planning when to trigger this difficult action. Our method considers the uncertain and ongoing decline of the SPTS, the possibility that drasticex situaction will fail, and the opportunities offered by delaying the decision. Specifically, these benefits are additional time for ongoingin situactions to succeed, and opportunities for the managers to learn about the system. To illustrate its utility, we apply the decision tool to four retrospective case-studies of declining SPTS. As well as offering support to this particular decision, our tool illustrates why trigger points for difficult conservation decisions should be formulated in advance, but must also be adaptive. A trigger-point for theex situ, in totoconservation of a SPTS, for example, will not take the form of a simple threshold abundance.
Microtubule-associated ROP interactors both delimit and transduce ROP signaling and regulate microtubule dynamics
Authors: Feiguelman Gil , Cui Xiankui , Sternberg Hasana , Fu Ying , Yalovsky Shaul
Published: January 2021

Evidence suggests that ICR proteins function as adaptors that mediate ROP signaling. Here, we studied the functions of ICR2 and its homologs ICR5 and ICR3. We showed that ICR2 is a microtubule-associated protein that regulates microtubule dynamics. ICR2 can retrieve activated ROPs from the plasma membrane, and it is recruited to a subset of ROP domains. Secondary cell wall pits in the metaxylem oficr2andicr5 Arabidopsissingle mutants andicr2/icr5double andicr2/icr5/icr3triple mutants were denser and larger than those in wild-type Col-0 seedlings, implicating these three ICRs in restriction of ROP function. Theicr2but not theicr5mutants developed split root hairs further implicating ICR2 in restriction of ROP signaling. Taken together, our results show that ICR2, and likely also ICR5 and ICR3, have multiple functions as ROP effectors and as regulators of microtubule dynamics.
Computing the Riemannian curvature of image patch and single-cell RNA sequencing data manifolds using extrinsic differential geometry
Authors: Sritharan Duluxan , Wang Shu , Hormoz Sahand
Published: January 2021

Most high-dimensional datasets are thought to be inherently low-dimensional, that is, datapoints are constrained to lie on a low-dimensional manifold embedded in a high-dimensional ambient space. Here we study the viability of two approaches from differential geometry to estimate the Riemannian curvature of these low-dimensional manifolds. The intrinsic approach relates curvature to the Laplace-Beltrami operator using the heat-trace expansion, and is agnostic to how a manifold is embedded in a high-dimensional space. The extrinsic approach relates the ambient coordinates of a manifold’s embedding to its curvature using the Second Fundamental Form and the Gauss-Codazzi equation. Keeping in mind practical constraints of real-world datasets, like small sample sizes and measurement noise, we found that estimating curvature is only feasible for even simple, low-dimensional toy manifolds, when the extrinsic approach is used. To test the applicability of the extrinsic approach to real-world data, we computed the curvature of a well-studied manifold of image patches, and recapitulated its topological classification as a Klein bottle. Lastly, we applied the approach to study single-cell transcriptomic sequencing (scRNAseq) datasets of blood, gastrulation, and brain cells, revealing for the first time the intrinsic curvature of scRNAseq manifolds.
Cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy
Authors: Henkel Nicholas D. , Smail Marissa A. , Wu Xiaojun , Enright Heather A. , Fischer Nicholas , Eby Hunter M. , Carney Paul R. , McCullumsmith Robert E. , Shukla Rammohan
Published: January 2021

We probed a transcriptomic dataset of pilocarpine-induced TLE using various ontological, machine-learning, and systems-biology approaches. We showed that, underneath the complex and penetrant changes, moderate-to-subtle upregulated homeostatic and downregulated synaptic changes associated with the dentate gyrus and hippocampal subfields could not only predict TLE but various other forms of epilepsy. At the cellular level, pyramidal neurons and interneurons showed disparate changes, whereas the proportion of non-neuronal cells increased steadily. A probabilistic Bayesian network demonstrated an aberrant and oscillating physiological interaction between oligodendrocytes and interneurons in driving seizures. Validating the Bayesian inference, we showed that the cell types driving the seizures were associated with known antiepileptic and epileptic drugs. These findings provide predictive biomarkers of epilepsy, insights into the cellular connections and causal changes associated with TLE and a drug discovery method focusing on these events.
Local Shifts in Inflammatory and Resolving Lipid Mediators in Response to Tendon Overuse
Authors: Markworth James F. , Sugg Kristoffer B. , Sarver Dylan C. , Maddipati Krishna Rao , Brooks Susan V.
Published: January 2021

Tendon inflammation has been implicated in both adaptive connective tissue remodeling and overuse-induced tendinopathy. Lipid mediators control the initiation and resolution of inflammation, but their roles within tendon are largely unknown. Here we profiled local shifts in intratendinous lipid mediators via liquid chromatography-tandem mass spectrometry in response to synergist ablation-induced plantaris tendon overuse. Sixty-four individual lipid mediators were detected in homogenates of habitually loaded plantaris tendons from healthy ambulatory rats. This included many bioactive metabolites of the cyclooxygenase (COX), lipoxygenase (LOX), and epoxygenase (CYP) pathways. Synergist ablation induced a robust inflammatory response at day 3 post-surgery characterized by epitenon infiltration of polymorphonuclear leukocytes (PMNs) and macrophages (MΦ), heightened expression of inflammation-related genes, and increased intratendinous concentrations of the pro-inflammatory eicosanoids thromboxane B2(TXB2) and prostaglandin E2(PGE2). By day 7, MΦ became the predominant myeloid cell type in tendon and there were further delayed increases in other COX metabolites including PGD2, PGF2αand PGI2. Specialized pro-resolving mediators (SPMs) including protectin D1 (PD1) and resolvin D6 (RvD6), as well as related pathway markers of D-resolvins (17-HDoHE), E-resolvins (18-HEPE) and lipoxins (15-HETE) were also increased locally in response to tendon overuse, as were many anti-inflammatory fatty acid epoxides of the CYP pathway (e.g. EpETrEs). Nevertheless, intratendinous prostaglandins remained markedly increased even following 28 days of tendon overuse together with a lingering MΦ presence. These data reveal a delayed and prolonged local inflammatory response to tendon overuse characterized by an overwhelming predominance of pro-inflammatory eicosanoids and a relative lack of pro-resolving lipid mediators.
Structural and mechanistic insight into spectral tuning in flavin-binding fluorescent proteins
Authors: Röllen Katrin , Granzin Joachim , Remeeva Alina , Davari Mehdi D. , Gensch Thomas , Nazarenko Vera V. , Kovalev Kirill , Bogorodskiy Andrey , Borshchevskiy Valentin , Hemmer Stefanie , Schwaneberg Ulrich , Gordeliy Valentin , Jaeger Karl-Erich , Batra-Safferling Renu , Gushchin Ivan , Krauss Ulrich
Published: January 2021

Determining the molecular origin of spectral tuning in photoactive biological systems is instrumental for understanding their function. Spectral-tuning efforts for flavin-binding fluorescent proteins (FbFPs), an emerging class of fluorescent reporters, are limited by their dependency on protein-bound flavins, whose structure and hence electronic properties, cannot be altered by mutation. To address those shortcomings, we here present the photophysical, computational and structural characterization of structurally uncharacterized blue-shifted FbFPs, carrying a previously described lysine substitution within their flavin-binding pocket. X-ray structures reveal displacement of the lysine away from the chromophore and opening up of the structure as cause for the blue shift. Site-saturation mutagenesis and high-throughput screening, yielded a red-shifted variant, in which the lysine side chain of the blue-shifted variant is stabilized in close distance to the flavin by a secondary mutation, mechanistically accounting for the red shift. Thus, a single secondary mutation in a blue-shifted variant is sufficient to generate a red-shifted FbFP. Using spectroscopy, X-ray crystallography and quantum mechanics molecular mechanics calculations, we provide a firm structural and functional understanding of spectral tuning in FbFPs. We also show that the identified blue- and red-shifted variants allow for two-color microscopy based on spectral separation. In summary, the generated blue- and red-shifted variants represent promising new tools that should find application in life sciences.
The Application of Countercurrent Chromatography for the study of Bacteriophages
Authors: Friedersdorff Jessica C A , Bright Colin , Rooke David , Creevey Christopher J , Kingston-Smith Alison H
Published: January 2021

1.

Bacteriophages (phages) are viruses that target bacteria, with the ability to lyse and kill host bacterial cells. Due to this, they have been of some interest as a therapeutic since their discovery in the early 1900s, but with the recent increase in antibiotic resistance, phages have seen a resurgence in attention. Current methods of isolation and purification of phages can be long and tedious, with caesium chloride concentration gradients the gold standard for purifying a phage fraction. Isolation of novel phages requires centrifugation and ultrafiltration of mixed samples, such as water sources, effluent or faecal samples etc, to prepare phage filtrates for further testing. We propose countercurrent chromatography as a novel and alternative approach to use when studying phages, as a scalable and high-yield method for obtaining phage fractions. However, the full extent of the usefulness and resolution of separation with this technique has not been researched; it requires optimisation and ample testing before this can be revealed. Here we present an initial study to determine survivability of two phages, T4 and ϕX174, using only water as a mobile phase in a Spectrum Series 20 HPCCC. Both phages were found to remain active once eluted from the column. Phages do not fully elute from the column and sodium hydroxide is necessary to flush the column between runs to deactivate remaining phages.
Biotechnological exploitation ofSaccharomyces jureiand its hybrids in craft beer fermentation uncovers new aroma combinations
Authors: Giannakou Konstantina , Visinoni Federico , Zhang Penghan , Nathoo Nishan , Jones Paul , Cotterrell Mark , Vrhovsek Urska , Delneri Daniela
Published: January 2021

Hybridization is an important evolutionary mechanism to bring about novel phenotypes and may produce new hybrids with advantageous combinations of traits of industrial importance. Within theSaccharomycesgroup,Saccharomyces jureiis a newly discovered species and its biotechnological potential has not yet been fully explored. This yeast was found to be able to grow well in synthetic wort and at low temperatures, qualities necessary in good candidates for fermentated bevarages. Here, we analysed its fermentation and aroma profile and created novel non-GMO hybrids betweenS. jureiandS. cerevisiaeale yeasts to develop new starter strains with interesting flavours for the craft beer industry. Pilot beer fermentations with specific hybrids showed a good fermentation performance, similar to the ale parent strain, while presenting a better sugar attenuation and a more complex flavour profile. This study exploits the genetic diversity of yeasts and show how inter-specific hybridisation and clone selection can be effectively used in brewing to create new products and to eliminate or increase specific traits.
A global cancer data integrator reveals principles of synthetic lethality, sex disparity and immunotherapy
Authors: Yogodzinski Christopher , Arab Abolfazl , Pritchard Justin R. , Goodarzi Hani , Gilbert Luke A.
Published: January 2021

Advances in cancer biology are increasingly dependent on integration of heterogeneous datasets. Large scale efforts have systematically mapped many aspects of cancer cell biology; however, it remains challenging for individual scientists to effectively integrate and understand this data. We have developed a new data retrieval and indexing framework that allows us to integrate publicly available data from different sources and to combine publicly available data with new or bespoke datasets. Beyond a database search, our approach empowered testable hypotheses of new synthetic lethal gene pairs, genes associated with sex disparity, and immunotherapy targets in cancer. Our approach is straightforward to implement, well documented and is continuously updated which should enable individual users to take full advantage of efforts to map cancer cell biology.
In Vivo Sublayer Analysis Of Human Retinal Inner Plexiform Layer Obtained By Visible-Light Optical Coherence Tomography
Authors: Ghassabi Zeinab , Kuranov Roman V. , Wu Mengfei , Tayebi Behnam , Wang Yuanbo , Rubinoff Ian , Liu Xiaorong , Wollstein Gadi , Schuman Joel S. , Zhang Hao F. , Ishikawa Hiroshi
Published: January 2021

Purpose

Growing evidence suggests, in glaucoma, the dendritic degeneration of subpopulation of the retinal ganglion cells (RGCs) may precede RGCs soma death. Since different RGCs synapse in different IPL sublayers, visualization of the lamellar structure of the IPL could enable both clinical and fundamental advances in glaucoma understanding and management. In this pilot study, we investigated whether visible-light optical coherence tomography (vis-OCT) could detect the difference in the inner plexiform layer (IPL) sublayers thicknesses between small cohorts of healthy and glaucomatous subjects.

Method

We investigated vis-OCT retinal images from nine healthy and five glaucomatous subjects. Four of the healthy subjects were scanned three times each in two separate visits, and five healthy and five glaucoma subjects were scanned three times during a single visit. Raster speckle-reduction scans (3 by 3 by 1.2 mm^3: horizontal; vertical; axial directions with 8192×8×1024 samplings, respectively) of the superior macular were acquired. IPL sublayers were then manually segmented using averaged A-line profiles.

Results

The mean ages of glaucoma and healthy subjects are 59.6 +/- 13.4 and 45.4 +/- 14.4 years (p =0.02, Wilcoxon rank-sum test), respectively. The visual field mean deviation (MD) are −26.4 to −7.7 dB in glaucoma patient and −1.6 to 1.1 dB in healthy subjects (p =0.002). The mean circumpapillary retinal nerve fiber layer (RNFL) thicknesses are 59.6 +/- 9.1 μm in glaucoma and 99.2 +/- 16.2 μm in healthy subjects (p=0.004). Median coefficients of variation (CVs) of intra-session repeatability for the entire IPL and three sublayers are 3.1%, 5.6%, 6.9%, and 5.6% in healthy subjects and 1.8%, 6.0%, 7.7%, and 6.2% in glaucoma patients, respectively. The mean entire IPL thicknesses are 36.2 +/- 1.5 μm in glaucomatous and 40.1 +/- 1.7 micrometer in healthy eyes (p=0.003, Mixed-effects model). We found that the middle sublayer thickness was responsible for the majority of the difference (14.2 +/- 1.8 μm in glaucomatous and 17.5 +/- 1.4 in healthy eyes, p<0.01).

Conclusions

IPL sublayer analysis revealed that the middle sublayer could be responsible for the majority of IPL thinning in glaucoma. Vis-OCT quantified IPL sublayers with good repeatability in both glaucoma and healthy subjects. Visualization of the IPL sublayers may enable the investigation of lamella-specific changes in the IPL in glaucoma and may help elucidate the response of different types of RGCs to the disease.
An “individualist” model of an active genome in a developing embryo
Authors: Huang Shao-Kuei , Dutta Sayantan , Whitney Peter H. , Shvartsman Stanislav Y. , Rushlow Christine A.
Published: January 2021

The earlyDrosophilaembryo provides unique experimental advantages for addressing fundamental questions of gene regulation at multiple levels of organization, from individual gene loci to the whole genome. UsingDrosophilaembryos undergoing the first wave of genome activation, we detected discrete “speckles” of RNA Polymerase II (Pol II), and showed that they overlap with transcribing loci. We characterized the spatial distribution of Pol II speckles and quantified how this distribution changes in the absence of the primary driver ofDrosophilagenome activation, the pioneer factor Zelda. Although the number and size of Pol II speckles were reduced, indicating that Zelda promotes Pol II speckle formation, we observed a uniform distribution of distances between active genes in the nuclei of both wildtype andzeldamutant embryos. This suggests that the topologically associated domains identified by Hi-C studies do little to spatially constrain groups of transcribed genes at this time. We provide evidence that linear genomic distance between transcribed genes is the primary determinant of measured physical distance between the active loci. Furthermore, we show active genes can have distinct Pol II pools even if the active loci are in close proximity. In contrast to the emerging model whereby active genes are clustered to facilitate co-regulation and sharing of transcriptional resources, our data support an “individualist” model of gene control at early genome activation inDrosophila. This model is in contrast to a “collectivist” model where active genes are spatially clustered and share transcriptional resources, motivating rigorous tests of both models in other experimental systems.
Controlled spatial organization of bacterial clusters reveals cell filamentation is vital forXylella fastidiosabiofilm formation
Authors: Anbumani Silambarasan , da Silva Aldeliane M. , Fischer Eduarda Regina , de Souza e Silva Mariana , von Zuben Antônio A.G. , Carvalho Hernandes F. , de Souza Alessandra A. , Janissen Richard , Cotta Monica A.
Published: January 2021

The morphological plasticity of bacteria to form filamentous cells commonly represents an adaptive strategy induced by stresses. In contrast, for diverse pathogens filamentous cells have been observed during biofilm formation, with function yet to be elucidated. To identify prior hypothesized quorum sensing as trigger of such cell morphogenesis, spatially controlled cell adhesion is pivotal. Here, we demonstrate highly-selective cell adhesion of the biofilm-forming phytopathogenXylella fastidiosato gold-patterned SiO2substrates with well-defined geometries and dimensions. The consequent control of both cell density and distances between cell clusters using these patterns provided evidence of quorum sensing governing filamentous cell formation. While cell morphogenesis is induced by cell cluster density, filamentous cell growth is oriented towards neighboring cell clusters and distance-dependent; large interconnected cell clusters create the early biofilm structural framework. Together, our findings and investigative platform could facilitate therapeutic developments targeting biofilm formation mechanisms ofX. fastidiosaand other pathogens.
A Novel Approach to Study Gamma-Band Coherence inEx VivoHippocampal Slices from a Mouse Model of Bipolar Disorder
Authors: Rodríguez Díaz Jean C. , Jenkins Paul M. , Pritchett Dominique L. , Jones Kevin S.
Published: January 2021

Oscillations play crucial roles in many cognitive processes such as memory formation and attention. GABAergic interneurons can synchronize neuronal activity leading to gamma oscillations (30-60 Hz). Abnormalities in oscillatory activity in the hippocampus have been implicated in the pathology of some mental health disorders including schizophrenia and bipolar disorder, however the neurobiological mechanism underlying these abnormal oscillations are not yet fully understood. We set out to develop a reliable approach to study gamma oscillations inex vivohippocampal preparations using perforated microelectrode arrays. Perforated microelectrode arrays allow for the simultaneous measurement of electrical activity at multiple sites while allowing solutions to pass through the brain section. We obtained extracellular electrophysiological recordings from acute sections of mouse hippocampus situated on a 60-channel, perforated microelectrode arrays (pMEAs). Bath application of kainate rapidly induced and maintained oscillatory activity in the CA1 and CA3 regions of the hippocampus. Kainate-induced oscillations were quickly abolished by the GABAA receptor antagonist, bicuculline. Furthermore, we employed this approach on a mouse model of bipolar disorder. Sections prepared from mutant mice exhibited an increase in the coherence of gamma power within CA1 despite a reduction in gamma band power.
Beyond coral-algal regimes: high taxonomic resolution surveys and trait-based analyses reveal multiple benthic regimes
Authors: Reverter Miriam , Jackson Matthew , Rohde Sven , Moeller Mareen , Bara Robert , Lasut Markus T. , Reinach Marco Segre , Schupp Peter J.
Published: January 2021

As coral reef communities change and reorganise in response to anthropogenic and climate disturbances, there is a growing need of detecting and understanding the different emerging species regimes and their contribution to key ecosystem processes. Using a case study on coral reefs at the epicentre of tropical marine biodiversity (North Sulawesi), we explored how application of different biodiversity approaches (i.e. use of major taxonomic categories, high taxonomic resolution categories and trait-based approaches) affects the detection of distinct fish and benthic community assemblages. Our results show that using major categories (family level or above) to study coral reef communities fails to identify distinct regimes. We also show that for detection of different benthic regimes, especially communities dominated by non-coral organisms, monitoring of only scleractinian coral communities is insufficient, and that all types of benthic organisms (e.g. sponges, ascidians, soft corals, algae etc.) need to be considered. We have implemented for the first time, the use of a trait-based approach to study the functional diversity of whole coral reef benthic assemblages, which allowed us to detect five different community regimes, only one of which was dominated by scleractinian corals. We circumvented the challenge that for some benthic groups (e.g. sponges, ascidians or some soft corals) visual identification up to the species level is not possible, by identifying and categorising traits that can be applied to groups of similar organisms instead of specific species. Furthermore, by the parallel study of benthic and fish communities we provide new insights into key processes and functions that might dominate or be compromised in the different community regimes.
Eye tracking impairments in children with protein-energy malnutrition
Authors: Almeida Natalia L. , Silva Jessica B. S. , Silva Nayara P. , Fernandes Thiago P. , Santos Natanael A.
Published: January 2021

Background: Malnutrition is characterized by impaired nutrient ingestion and absorption, and it is still one of the most substantial causes of morbidity and mortality in children worldwide. To the best of our knowledge, this is the first study investigating eye tracking in children with protein-energy malnutrition (PEM). We sought to investigate how PEM may affect eye movement. Methods: Twenty children without PEM (mean age = 10.8; SD = 1.0 years) and 18 children with PEM (mean age = 10.9; SD = 1.2 years). Here we used three types of tests or stimuli: one formed by a maze and two by seven errors games (boats and elephants). Results: Our results indicated that children with PEM had impaired performance on all of the tests used here. These data suggest that the nutritional impairments during the first year of life, the critical period in visual system development, can have direct impact on eye movement patterns. Conclusions: Our findings must be replicated so that neurophysiological patterns of PEM can be precisely understood. However, this study has repercussions in several areas of knowledge.
Bottom-up inputs are required for the establishment of top-down connectivity onto cortical layer 1 neurogliaform cells
Authors: Ibrahim Leena A , Huang Shuhan , Fernandez-Otero Marian , Sherer Mia , Vemuri Spurti , Xu Qing , Machold Robert , Rudy Bernardo , Fishell Gord
Published: January 2021

Higher order feedback projections to sensory cortical areas converge on layer 1 (L1), the primary site for integration of top-down information via the apical dendrites of pyramidal neurons and L1 GABAergic interneurons. Here, we investigated the contribution of early thalamic inputs onto L1 interneurons for the establishment of top-down inputs in the primary visual cortex. We find that bottom-up thalamic inputs predominate during early L1 development and preferentially target neurogliaform cells. We find that these projections are critical for the subsequent strengthening of feedback inputs from the anterior cingulate cortex. Enucleation or selective removal of thalamic afferents blocked this phenomenon. Notably, while early activation of anterior cingulate afferents resulted in a premature strengthening of these top-down inputs to neurogliaform cells, this was also dependent on thalamic inputs. Our results demonstrate that the proper establishment of top-down feedback inputs critically depends on bottom-up inputs from the thalamus during early postnatal development.
Dicer promotes genome stability via the bromodomain transcriptional co-activator Brd4
Authors: Gutbrod MJ , Roche B , Steinberg JI , Lakhani AA , Chang K , Schorn AJ , Martienssen RA
Published: January 2021

RNA interference is essential for transcriptional silencing and genome stability, but conservation of this role in mammals has been difficult to demonstrate.Dicer1-/-mouse embryonic stem cells have microRNA-independent proliferation defects, and we conducted a CRISPR-Cas9 screen to restore viability. We identified suppressor mutations in transcriptional activators, H3K9 methyltransferases, and chromosome segregation factors, strongly resembling Dicer suppressors in fission yeast. Suppressors rescued chromosomal defects, and reversed strand-specific transcription of major satellite repeats inDicer1-/-. The strongest suppressors were inBrd4, and in the transcriptional elongator/histone acetyltransferaseElp3. Using viable mutants and pharmaceutical inhibitors, we demonstrate that deletion of specific residues inBrd4rescue genome instability defects ofDicer1-/-in both mammalian cells and fission yeast, implicating Dicer in coordinating transcription and replication of satellite repeats.

Replication and segregation defects inDicer1-/-stem cells depend on centromeric transcription byBrd4, and are deeply conserved in fission yeast.
Unveiling unexpected complexity and multipotentiality of early heart fields
Authors: Zhang Qingquan , Carlin Daniel , Zhu Fugui , Cattaneo Paola , Ideker Trey , Evans Sylvia M. , Bloomekatz Joshua , Chi Neil C.
Published: January 2021

Complex organs are composed of a multitude of specialized cell types which assemble to form functional biological structures. How these cell types are created and organized remains to be elucidated for many organs including the heart, the first organ to form during embryogenesis. Here, we show the ontogeny of mammalian mesoderm at high-resolution single cell and genetic lineage/clonal analyses, which revealed an unexpected complexity of the contribution and multi-potentiality of mesodermal progenitors to cardiac lineages creating distinct cell types forming specific regions of the heart. Single-cell transcriptomics ofMesp1lineage-traced cells during embryogenesis and corresponding trajectory analyses uncovered unanticipated developmental relationships between these progenitors and lineages including two mesodermal progenitor sources contributing to the first heart field (FHF), an intraembryonic and a previously uncharacterized extraembryonic-related source, that produce distinct cardiac lineages creating the left ventricle. Lineage-tracing studies revealed that these extraembryonic-related FHF progenitors reside at the extraembryonic-intraembryonic interface in gastrulating embryos and generate cardiac cell types that form the epicardium and the dorsolateral regions of the left ventricle and atrioventricular canal myocardium. Clonal analyses further showed that these progenitors are multi-potent, creating not only cardiomyocytes and epicardial cell types but also extraembryonic mesoderm. Overall, these results reveal unsuspected multiregional origins of the heart fields, and provide new insights into the relationship between intraembryonic cardiac lineages and extraembryonic tissues and the associations between congenital heart disease and placental insufficiency anomalies.
Does land use matter? Carbon consequences of alternative land use futures in New England
Authors: MacLean Meghan Graham , Duveneck Matthew , Plisinski Joshua , Morreale Luca , Laflower Danelle , Thompson Jonathan
Published: January 2021

Globally, forests play an important role in climate change mitigation. However, land-use impacts the ability of forests to sequester and store carbon. Here we quantify the impacts of five divergent future land-use scenarios on aboveground forest carbon stocks and fluxes throughout New England. These scenarios, four co-designed with stakeholders from throughout the region and the fifth a continuation of recent trends in land use, were simulated by coupling a land cover change model with a mechanistic forest growth model to produce estimates of aboveground carbon over 50 years. Future carbon removed through harvesting and development was tracked using a standard carbon accounting methodology, modified to fit our modeling framework. Of the simulated changes in land use, changes in harvesting had the most profound and immediate impacts on carbon stocks and fluxes. In one of the future land-use scenarios including a rapid expansion of harvesting for biomass energy, this changed New England’s forests from a net carbon sink to a net carbon source in 2060. Also in these simulations, relatively small reductions in harvest intensities (e.g., 10% reduction), coupled with an increased percent of wood going into longer-term storage, led to substantial reductions in net carbon emissions (909 MMtCO2eq) as compared to a continuation of recent trends in land use. However, these projected gains in carbon storage and reduction in emissions from less intense harvesting regimes can only be realized if it is paired with a reduction in the consumption of the timber products, and their replacements, that otherwise would result in additional emissions from leakage and substitution.
Host-pathogen Immune Feedbacks Can Explain Widely Divergent Outcomes from Similar Infections
Authors: Ellner Stephen P. , Buchon Nicolas , Dörr Tobias , Lazzaro Brian P.
Published: January 2021

A longstanding question in infection biology is why two very similar individuals, with very similar pathogen exposures, may have very different outcomes. Recent experiments have found that even isogenicDrosophila melanogasterhosts, given identical inoculations of some bacterial pathogens at suitable doses, can experience very similar initial bacteria proliferation but then diverge to either a lethal infection or a sustained chronic infection with much lower pathogen load. We hypothesized that divergent infection outcomes are a natural result of mutual negative feedbacks between pathogens and the host immune response. Here we test this hypothesisin silicoby constructing process-based dynamic models for bacterial population growth, host immune induction, and the feedbacks between them, based on common mechanisms of immune system response. Mathematical analysis of a minimal conceptual model confirms our qualitative hypothesis that mutual negative feedbacks can magnify small differences among hosts into life-or-death differences in outcome. However, explaining observed features of chronic infections requires an extension of the model to include induced pathogen modifications that shield themselves from host immune responses at the cost of reduced proliferation rate. Our analysis thus generates new, testable predictions about the mechanisms underlying bimodal infection outcomes.
The kidney protects against sepsis by producing systemic uromodulin
Authors: LaFavers Kaice A. , Hage Chadi , Gaur Varun , Micanovic Radmila , Hato Takashi , Khan Shehnaz , Winfree Seth , Doshi Simit , Moorthi Ranjani N. , Twigg Homer , Wu Xue-Ru , Dagher Pierre C. , Srour Edward , El-Achkar Tarek M.
Published: January 2021

Sepsis is a significant cause of mortality in hospitalized patients. Concomitant development of acute kidney injury (AKI) increases sepsis mortality through unclear mechanisms. While electrolyte disturbances and toxic metabolite buildup during AKI could be important, it is possible that the kidney produces a protective molecule lost during sepsis with AKI. We previously demonstrated that systemic Tamm-Horsfall Protein (THP, uromodulin), a kidney-derived protein with immunomodulatory properties, falls in AKI. Using a mouse sepsis model without severe kidney injury, we show that the kidney increases circulating THP by enhancing basolateral release of THP from medullary thick ascending limb cells. In sepsis patients, changes in circulating THP are positively associated with critical illness. THP is also foundde novoin injured lungs. Genetic ablation of THP in mice leads to increased mortality and bacterial burden during sepsis. Consistent with the increased bacterial burden, the presence of THPin vitroandin vivoleads macrophages and monocytes to upregulate a transcriptional program promoting cell migration, phagocytosis and chemotaxis and treatment of macrophages with purified THP increases phagocytosis. Rescue of septic THP-/-mice with exogenous systemic THP improves survival. Together, these findings suggest that through releasing THP, the kidney modulates the immune response in sepsis by enhancing mononuclear phagocyte function and systemic THP has therapeutic potential in sepsis.

Significance Statement

Sepsis is a significant contributor to kidney injury as well as morbidity and mortality worldwide. Specific therapies to improve outcomes in sepsis with kidney injury have largely been limited to symptom management and infectious agent control, in part because it is unclear how kidney injury increases sepsis mortality. This paper describes the identification of Tamm-Horsfall protein, previously known to protect in ischemic models of AKI, as protective in preclinical models of sepsis. It demonstrates how the loss of THP leads to decreased mononuclear phagocyte function and diversity, increased pathogen burden and decreased survival. THP also increases in sepsis without severe kidney injury and concentrates in injured organs. Further study of THP in sepsis could lead to novel sepsis therapeutics.
Partition Quantitative Assessment (PQA): A quantitative methodology to assess the embedded noise in clustered omics and systems biology data
Authors: Camacho-Hernández Diego A. , Nieto-Caballero Victor E. , León-Burguete José E. , Freyre-González Julio A.
Published: January 2021

Identifying groups that share common features among datasets through clustering analysis is a typical problem in many fields of science, particularly in post-omics and systems biology research. In respect of this, quantifying how a measure can cluster or organize intrinsic groups is important since currently there is no statistical evaluation of how ordered is, or how much noise is embedded in the resulting clustered vector. Many of the literature focuses on how well the clustering algorithm orders the data, with several measures regarding external and internal statistical measures; but none measure has been developed to statistically quantify the noise in an arranged vector posterior a clustering algorithm, i.e., how much of the clustering is due to randomness. Here, we present a quantitative methodology, based on autocorrelation, to assess this problem.
Semi-supervised Calibration of Risk with Noisy Event Times (SCORNET) Using Electronic Health Record Data
Authors: Ahuja Yuri , Liang Liang , Huang Selena , Cai Tianxi
Published: January 2021

Leveraging large-scale electronic health record (EHR) data to estimate survival curves for clinical events can enable more powerful risk estimation and comparative effectiveness research. However, use of EHR data is hindered by a lack of direct event times observations. Occurrence times of relevant diagnostic codes or target disease mentions in clinical notes are at best a good approximation of the true disease onset time. On the other hand, extracting precise information on the exact event time requires laborious manual chart review and is sometimes altogether infeasible due to a lack of detailed documentation. Current status labels – binary indicators of phenotype status during follow up – are significantly more efficient and feasible to compile, enabling more precise survival curve estimation given limited resources. Existing survival analysis methods using current status labels focus almost entirely on supervised estimation, and naive incorporation of unlabeled data into these methods may lead to biased results. In this paper we propose Semi-supervised Calibration of Risk with Noisy Event Times (SCORNET), which yields a consistent and efficient survival curve estimator by leveraging a small size of current status labels and a large size of imperfect surrogate features. In addition to providing theoretical justification of SCORNET, we demonstrate in both simulation and real-world EHR settings that SCORNET achieves efficiency akin to the parametric Weibull regression model, while also exhibiting non-parametric flexibility and relatively low empirical bias in a variety of generative settings.
Evolvability and constraint in the primate basicranium, shoulder, and hip and the importance of multi-trait evolution
Authors: Agosto Elizabeth R. , Auerbach Benjamin M.
Published: January 2021

The scapula shares developmental and functional relationships with traits of the basicranium, vertebral column, humerus, and clavicle. As a limb girdle, it also shares analogous characteristics with the pelvis. Despite these relationships, studies of primate shoulder evolution often focus on traits of the scapula in isolation. Such analyses may lead to spurious conclusions, as they implicitly model the scapula as evolving independent of other anatomical regions. Traits of the shoulder girdle share genetic covariances with each other, as well as potential covariances with dimensions of other skeletal elements. To create accurate models of shoulder evolution, it is imperative to account for the constraints imposed by these sources of covariance. Here, we use evolutionary quantitative methods to test a model in which shoulder morphological evolution is influenced by its developmental and functional covariances with the basicranium in theColobusgenus. This evolutionary relationship is also assessed with morphology of the pelvis to provide context to the evolutionary covariance among traits of the basicranium and shoulder girdle. Our results indicate potential evolutionary implications arising from covariances among the basicranium, shoulder, and pelvis. We further propose that the shoulder and basicranium may be examples of developmental, functional, and genetic covariances among traits that manifest an evolutionary suite of mutually constrained morphologies. We demonstrate novel evolutionary relationships among the shoulder girdle and basicranium that affect not only models of primate shoulder evolution but have broader implications for modeling trait evolution across the skeleton.
Developmental exposure to domoic acid disrupts startle response behavior and circuitry
Authors: Panlilio Jennifer M. , Jones Ian T. , Salanga Matthew C. , Aluru Neelakanteswar , Hahn Mark E.
Published: January 2021

Harmful algal blooms produce potent neurotoxins that accumulate in seafood and are hazardous to human health. Developmental exposure to the harmful algal bloom toxin, domoic acid (DomA), has behavioral consequences well into adulthood, but the cellular and molecular mechanisms are largely unknown. To assess these, we exposed zebrafish embryos to DomA during the previously identified window of susceptibility (2 days post-fertilization) and used the well-known startle response circuit as a tool to identify specific neuronal components that are targeted by exposure to DomA. Exposure to DomA reduced the probability of eliciting a startle after auditory/vibrational or electrical stimuli and led to the dramatic reduction of one type of startle, short latency c-start (SLC) responses. Furthermore, DomA-exposed larvae had altered kinematics of both SLC and long latency c-start (LLC) startle responses, exhibiting shallower bend angles and slower maximal angular velocities. Using vital dye staining, immunolabelling, and live imaging of transgenic lines, we determined that while the sensory inputs were intact, the reticulospinal neurons required for SLC responses were absent in most DomA-exposed larvae. Furthermore, axon tracing revealed that DomA-treated larvae also showed significantly reduced primary motor neuron axon collaterals. Overall, these results show that developmental exposure to DomA leads to startle deficits by targeting specific subsets of neurons. These findings provide mechanistic insights into the neurodevelopmental effects of excess glutamatergic signaling caused by exposure to DomA. It further provides a model for using the startle response circuit to identify neuronal populations targeted by toxin or toxicant exposures.

Summary statement

We used the zebrafish startle response as a tool to identify sensory-motor deficits and the loss of specific neural populations after developmental exposure to the harmful algal bloom toxin domoic acid.

GRAPHICAL ABSTRACT