bluuebunny/crossref_metadata_2025_split huggingface dataset:
Missing interactions: the current state of multispecies connectivity analysis
Authors: Wood Sylvia L.R. , Martins Kyle T. , Dumais-Lalonde Véronique , Tanguy Olivier , Maure Fanny , Denis Annick St. , Rayfield Bronwyn , Martin Amanda E. , Gonzalez Andrew 
Published: November 2021

AbstractDesigning effective habitat and protected area networks, which sustain species-rich communities is a critical conservation challenge. Recent decades have witnessed the emergence of new computational methods for analyzing and prioritizing the connectivity needs of multiple species. We argue that the goal of multispecies connectivity prioritizations be the long-term persistence of a set of species in a landscape and suggest the index of metapopulation capacity as one metric by which to assess and compare the effectiveness of proposed network designs. Here we present a review of the literature based on 77 papers published between 2010 and 2020, in which we assess the current state and recent advances in multispecies connectivity analysis in terrestrial ecosystems. We summarize the four most employed analytical methods, compare their data requirements, and provide an overview of studies comparing results from multiple methods. We explicitly look at approaches for integrating multiple species considerations into reserve design and identify novel approaches being developed to overcome computational and theoretical challenges posed by multispecies connectivity analyses. We conclude that, while advances have been made over the past decade, the field remains nascent in its ability to integrate multiple species interactions into analytical approaches to connectivity. Furthermore, the field is hampered in its ability to provide robust connectivity assessments for lack of a clear definition and goal for multispecies connectivity, as well as a lack of common metrics for their comparison.
An ex vivo culture model of kidney podocyte injury reveals mechanosensitive, synaptopodin-templating, sarcomere-like structures
Authors: Jiang Shumeng , Alisafaei Farid , Yuan Hong , Peng Xiangjun , Huang Yin-Yuan , Miner Jeffrey H. , Genin Guy M. , Suleiman Hani Y. 
Published: November 2021

AbstractChronic kidney diseases are widespread and incurable. The biophysical mechanisms underlying them are unclear, in part because material systems for reconstituting the microenvironment of the relevant kidney cells are limited. A critical question is how kidney podocytes (glomerular epithelial cells) regenerate the foot processes of the filtration apparatus following injury. Recently identified sarcomere-like structures (SLSs) with periodically spaced myosin IIA (a contractile protein) and synaptopodin (an actin-associated protein) appear in injured podocytes in vivo. We hypothesized that SLSs template synaptopodin in the initial stages of recovery, and tested this hypothesis by developing an ex vivo culture system that models both kidney physiology and pathophysiology. SLSs were observed in vitro for the first time as podocytes migrated out of harvested kidney glomeruli onto micropatterns of physiologically relevant proteins. SLSs emerged over two days, and cells formed foot process-like extensions from these periodically spaced proteins. SLS distributions and morphology were sensitive to actomyosin inhibitors, substrate stiffness, and extracellular matrix proteins associated with pathology. These results indicate a role for mechanobiological factors in podocyte recovery from injury, and suggest SLSs as a target for therapeutic intervention.
Age-dependent increased sag amplitude in human pyramidal neurons dampens baseline cortical activity
Authors: Guet-McCreight Alexandre , Chameh Homeira Moradi , Mahallati Sara , Wishart Margaret , Tripathy Shreejoy J. , Valiante Taufik A. , Hay Etay 
Published: November 2021

AbstractAging involves various neurobiological changes, although their effect on brain function in humans remains poorly understood. The growing availability of human neuronal and circuit data provides opportunities for uncovering age-dependent changes of brain networks and for constraining models to predict consequences on brain activity. Here we found increased sag voltage amplitude in human middle temporal gyrus layer 5 pyramidal neurons from older subjects, and captured this effect in biophysical models of younger and older pyramidal neurons. We used these models to simulate detailed layer 5 microcircuits and found lower baseline firing in older pyramidal neuron microcircuits, with minimal effect on response. We then validated the predicted reduced baseline firing using extracellular multi-electrode recordings from human brain slices of different ages. Our results thus report changes in human pyramidal neuron input integration properties and provide fundamental insights on the neuronal mechanisms of altered cortical excitability and resting state activity in human aging.
Tubular obstruction induced polycystin upregulation is pro-fibrotic and induced a severe cystic phenotype in adult mice with autosomal dominant polycystic kidney disease: the coexistence of polycystin loss and gain function in ADPKD
Authors: Wu Ming , Wang Yanzhe , Jing Ying , Chen Dongping , Xing Yufeng , Bai Yanfang , Huang Di , Zhou Yijing , Hu Jinghua , Zhuang Shougang , Ye Chaoyang 
Published: November 2021

AbstractMutations inPKD1(encoding polycystin-1) orPKD2(encoding polycystin-2) gene cause autosomal dominant polycystic kidney disease (ADPKD), however high levels of polycystins are detected in renal tissues of ADPKD patients. Animal studies showed that loss and gain of function of polycystins are both pathogenic and can induce cystic phenotype in the kidney, which are associated with enhanced renal fibrosis. Recent studies showed that increased expression of polycystins contributes to organ fibrosis. However, the role of polycystins in renal tubulointerstitial fibrosis remains unclear. In this study, we demonstrated that polycystin-1 or polycystin-2 was highly expressed in the kidney of two different fibrotic mouse models and positively correlated with expression of collagen-I. Pharmaceutical inhibition of polycystin-2 with triptolide or genetic knockout of polycystin-2 reduced the expression of epithelial-mesenchymal transition (EMT) markers and deposition of extracellular matrix proteins in fibrotic kidneys. Similarly, conditional knockout ofPkd1gene also attenuated renal fibrosis in mouse models. Thus, we further hypothesized that inhibition of polycystins delays cyst growth by mitigating renal fibrosis. Here, we showed that polycystin-1 or polycystin-2 was up-regulated inPkd2orPkd1mice respectively and tightly correlated with the growth of renal cysts and fibrosis development. Genetic deletion of both polycystin-1 and polycystin-2 retarded cyst growth inPkd1orPkd2mice. Finally, we deleted pkd1 gene in a fibrosis triggered adult ADPKD mouse model at different time point before or after the fibrotic injury. We showed that early and long-term inactivation ofPkd1delayed fibrosis triggered renal cyst growth in adultPkd1mice as compared with mice with late and short-term inactivation ofPkd1gene. We conclude that tubular obstruction induced polycystin up-regulation is pro-fibrotic and accelerates cyst growth through enhancing renal interstitial fibrosis in ADPKD mice. Our study indicates that ADPKD is caused by both loss and gain function of polycystins. Reduction of the aberrant upregulation of polycystins in cystic kidneys is a therapeutic option for ADPKD patients.Research highlightsPolycystin1 and polycystin-2 are up-regulated in fibrotic kidneysInhibition or deletion of polycystins inhibits EMT and attenuates renal tubulointerstitial fibrosisUpregulation of polycystin1 or polycystin-2 is positively correlated with fibrosis progression and renal cyst growth in ADPKD miceDouble knockout of Pkd1 and Pkd2 gene inhibits renal cyst growth in ADPKD miceLong-term deletion of Pkd1 gene delayed fibrosis triggered renal cyst growth in ADPKD mice
The Biosynthetic Costs of Amino Acids at the Base of the Food Chain Determine Their Use in Higher-order Consumer Genomes
Authors: Ortega Javier Gómez , Tyagi Sonika , Mirth Christen K. , Piper Matthew D. W. 
Published: November 2021

ABSTRACTDietary nutrient composition is essential for shaping important fitness traits and behaviours. Many organisms are protein limited and for Drosophila melanogaster, this limitation manifests at the level of the single most limiting essential Amino Acid (AA) in the diet. The identity of this AA and its effects on female fecundity is readily predictable by a procedure called exome matching in which the sum of AAs encoded by a consumer’s exome is used to predict the relative proportion of AAs required in its diet. However, the exome matching calculation does not weight AA contributions to the overall profile by protein size or expression. Here we update the exome matching calculation to include these weightings. Surprisingly, although nearly half of the transcriptome is differentially expressed when comparing male and female flies, we found that creating transcriptome-weighted exome matched diets for each sex did not enhance their fecundity over that supported by exome matching alone. These data indicate that while organisms may require different amounts of dietary protein across conditions, the relative proportion of the constituent AAs remains constant. Interestingly, we also found remarkable conservation of exome matched AA profiles across taxa and that the composition of these profiles could be explained by the metabolic costs of microbial AA synthesis. Thus, it appears that bioenergetic constraints amongst autotrophs shape the relative proportion of AAs that are available across trophic levels and that that this constrains biomass composition.
Controlled and Selective Photo-oxidation of Amyloid-β Fibrils by Oligomericp-Phenylene Ethynylenes
Authors: Fanni Adeline M. , Okoye Daniel , Monge Florencia A. , Hammond Julia , Maghsoodi Fahimeh , Martin Tye D. , Brinkley Gabriella , Phipps M. Lisa , Evans Deborah G. , Martinez Jennifer S. , Whitten David G. , Chi Eva Y. 
Published: November 2021

AbstractPhotodynamic therapy (PDT) has been explored as a therapeutic strategy to clear toxic amyloid aggregates involved in neurodegenerative disorders such as Alzheimer’s disease. A major limitation of PDT is off-target oxidation, which can be lethal for the surrounding cells. We have shown that a novel class of oligo-p-phenylene ethynylene-based compounds (OPEs) exhibit selective binding and fluorescence turn-on in the presence of pre-fibrillar and fibrillar aggregates of disease-relevant proteins such as amyloid-β (Aβ) and α-synuclein. Concomitant with fluorescence turn-on, OPE also photosensitizes singlet oxygen under illumination through the generation of a triplet state, pointing to the potential application of OPEs as photosensitizers in PDT. Herein, we investigated the photosensitizing activity of an anionic OPE for the photo-oxidation of toxic Aβ aggregates and compared its efficacy to the well-known but non-selective photosensitizer methylene blue (MB). Our results show that while MB photo-oxidized both monomeric and fibrillar conformers of Aβ40, OPE oxidized only Aβ40 fibrils, targeting two histidine residues on the fibril surface and a methionine residue located in the fibril core. Oxidized fibrils were shorter and more dispersed, but retained the characteristic β-sheet rich fibrillar structure and the ability to seed further fibril growth. Importantly, the oxidized fibrils displayed low toxicity. We have thus discovered a class of novel theranostics for the simultaneous detection and oxidization of amyloid aggregates. Importantly, the selectivity of OPE’s photosensitizing activity overcomes the limitation of off-target oxidation of currently available photosensitizers, and represents a significant advancement of PDT as a viable strategy to treat neurodegenerative disorders.
Towards routine employment of computational tools for antimicrobial resistance determination via high-throughput sequencing
Authors: Marini Simone , Mora Rodrigo A. , Boucher Christina , Noyes Noelle , Prosperi Mattia 
Published: November 2021

AbstractAntimicrobial resistance (AMR) is a growing threat to public health and farming at large. In clinical and veterinary practice, timely characterization of the antibiotic susceptibility profile of bacterial infections is a crucial step in optimizing treatment. High-throughput sequencing is a promising option for clinical point-of-care and ecological surveillance, opening the opportunity to develop genotyping-based AMR determination as a possibly faster alternative to phenotypic testing. In the present work, we compare the performance of state-of-the-art methods for detection of AMR using high-throughput sequencing data from clinical settings. We consider five computational approaches based on alignment (AMRPlusPlus), deep learning (DeepARG), k-mer genomic signatures (KARGA, ResFinder) or hidden Markov models (Meta-MARC). We use an extensive collection of 585 isolates with available AMR resistance profiles determined by phenotypic tests across nine antibiotic classes. We show how the prediction landscape of AMR classifiers is highly heterogeneous, with balanced accuracy varying from 0.40 to 0.92. Although some algorithms—ResFinder, KARGA, and AMRPlusPlus– exhibit overall better balanced accuracy than others, the high per-AMR-class variance and related findings suggest that: (1) all algorithms might be subject to sampling bias present both in data repositories used for training and experimental/clinical settings; and (2) a portion of clinical samples might contain uncharacterized AMR genes that the algorithms—mostly trained on known AMR genes—fail to generalize upon. These results lead us to formulate practical advice for software configuration and application, and give suggestions for future study designs to further develop AMR prediction tools from proof-of-concept to bedside.
Synergy of color and motion vision for detecting approaching objects inDrosophila
Authors: Longden Kit D. , Rogers Edward M. , Nern Aljoscha , Dionne Heather , Reiser Michael B. 
Published: November 2021

AbstractColor and motion are used by many species to identify salient moving objects. They are processed largely independently, but color contributes to motion processing in humans, for example, enabling moving colored objects to be detected when their luminance matches the background. Here, we demonstrate an unexpected, additional contribution of color to motion vision inDrosophila. We show that behavioral ON-motion responses are more sensitive to UV than for OFF-motion, and we identify cellular pathways connecting UV-sensitive R7 photoreceptors to ON and OFF-motion-sensitive T4 and T5 cells, using neurogenetics and calcium imaging. Remarkably, the synergy of color and motion vision enhances the detection of approaching UV discs, but not green discs with the same chromatic contrast, and we show how this generalizes for visual systems with ON and OFF pathways. Our results provide a computational and circuit basis for how color enhances motion vision to favor the detection of saliently colored objects.
Chigno/CG11180 and SUMO are Chinmo-Interacting Proteins with a Role in Drosophila Testes Stem Cells
Authors: Rinehart Leanna , Stewart Wendy E. , Luffman Natalie , Wawersik Matthew , Kerscher Oliver 
Published: November 2021

ABSTRACTMaintenance of sexual identity on the cellular level ensures the proper function of sexually dimorphic genes expressed in the brain and gonads. Disruption of genes that regulate sex maintenance alters the cellular structure of these tissues and leads to infertility and diseases, such as diabetes, obesity, and gonadal cancers. Sex maintenance in the testis of Drosophila melanogaster depends on the previously identified gene chinmo (Chronologically inappropriate morphogenesis). Chinmo’s effect on testis differentiation has been investigated in detail, but there is still much to be elucidated about its structure, function, and interactions with other proteins. Using a two-hybrid screen, we find that Chinmo interacts with itself, the small ubiquitin-like modifier SUMO, the novel protein CG11180, and four other proteins (CG4318, Ova (Ovaries absent), Taf3 (TBP-associated factor 3), and CG18269). Since both Chinmo and CG11180 contain sumoylation sites and SUMO-interacting motifs (SIMs), we analyzed their interaction in more detail. Using site-directed mutagenesis of a unique SIM in CG11180, we demonstrate that Chinmo’s interaction with CG11180 is SUMOdependent. Furthermore, to assess the functional relevance of both SUMO and CG11180, we performed RNAi-mediated knockdown of both proteins in somatic cells of the Drosophila testis. Using this approach, we find that CG11180 and SUMO are required in somatic cells of adult testes, and that reduction of either protein causes formation of germ cell tumors. Overall, our work indicates that SUMO functionally links Chinmo and CG11180 in somatic cells of the adult Drosophila testis. Consistent with the CG11180 knockdown phenotype in male testes, and to underscore its connection to Chinmo, we propose the name Childless Gambino (Chigno) for CG11180.
Sulcal depth in prefrontal cortex: A novel predictor of working memory performance
Authors: Yao Jewelia K. , Voorhies Willa I. , Miller Jacob A. , Bunge Silvia A. , Weiner Kevin S. 
Published: November 2021

AbstractThe neuroanatomical changes that underpin cognitive development is of major interest in neuroscience. Of the many aspects of neuroanatomy to consider, tertiary sulci are particularly appealing as they emerge last in gestation, show a protracted development after birth, and are either human- or hominoid-specific. Thus, they are ideal targets for exploring morphological-cognitive relationships with cognitive skills, such as verbal working memory (WM), that also show protracted development. Yet, the relationship between sulcal morphology and verbal WM is unknown, either in development or more generally. To fill this gap, we adopted a data-driven approach with cross-validation to examine the relationship between sulcal depth in lateral prefrontal cortex (LPFC) and verbal WM in 60 participants ages 6-18. These analyses identified nine left, but not right, LPFC sulci (of which six were tertiary) whose depth predicted verbal WM performance. Most of these sulci are located within and around contours of functionally defined parcellations of LPFC proposed previously. This sulcal depth model out-performed models with age or cortical thickness. Taken together, these findings contribute to building empirical support for a classic theory that tertiary sulci serve as landmarks in association cortices that contribute to aspects of human behavior that show a protracted development.
MTG16 (CBFA2T3) regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors
Authors: Brown Rachel E. , Jacobse Justin , Anant Shruti A. , Blunt Koral M. , Chen Bob , Vega Paige N. , Jones Chase T. , Pilat Jennifer M. , Revetta Frank , Gorby Aidan H. , Stengel Kristy R. , Choksi Yash A. , Palin Kimmo , Piazuelo M. Blanca , Washington M. Kay , Lau Ken S. , Goettel Jeremy A. , Hiebert Scott W. , Short Sarah P. , Williams Christopher S. 
Published: November 2021

AbstractAberrant epithelial differentiation and regeneration contribute to colon pathologies including inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). MTG16 (CBFA2T3) is a transcriptional corepressor expressed in the colonic epithelium. MTG16 deficiency in mice exacerbates colitis and increases tumor burden in CAC, though the underlying mechanisms remain unclear. Here, we identified MTG16 as a central mediator of epithelial differentiation, promoting goblet and restraining enteroendocrine cell development in homeostasis and enabling regeneration following dextran sulfate sodium (DSS)-induced colitis. Transcriptomic analyses implicated increased E box-binding transcription factor (E protein) activity in MTG16-deficient colon crypts. Using a novel mouse model with a point mutation that disrupts MTG16:E protein complex formation (Mtg16P209T), we established that MTG16 exerts control over colonic epithelial differentiation and regeneration by repressing E protein-mediated transcription. Mimicking murine colitis,MTG16expression was increased in biopsies from patients with active IBD compared to unaffected controls. Finally, uncoupling MTG16:E protein interactions only partially phenocopied the enhanced tumorigenicity ofMtg16-/-colon in the azoxymethane(AOM)/DSS-induced model of CAC, indicating that MTG16 protects from tumorigenesis through additional mechanisms. Collectively, our results demonstrate that MTG16, via its repression of E protein targets, is a key regulator of cell fate decisions during colon homeostasis, colitis, and cancer.Graphical Abstract
Identification of key interactions of benzimidazole resistance-associated amino acid mutations inAscarisβ-tubulins by molecular docking simulations
Authors: Jones Ben P. , van Vliet Arnoud H.M. , LaCourse E. James , Betson Martha 
Published: November 2021

AbstractAscarisspecies are soil-transmitted helminths that infect humans and livestock mainly in low and middle-income countries. Benzimidazole (BZ) class drugs have predominated for many years in the treatment ofAscarisinfections, but persistent use of BZs has already led to widespread resistance in other nematodes, and treatment failure is emerging forAscaris. Benzimidazoles act by binding to β-tubulin proteins and destabilising microtubules. Three mutations in the β-tubulin protein family are associated with BZ resistance. Seven shared β-tubulin isotypes were identified inAscaris lumbricoidesandA. suumgenomes. Benzimidazoles were predicted to bind to all β-tubulin isotypes usingin silicodocking, demonstrating that the selectivity of BZs to interact with one or two β-tubulin isotypes is likely the result of isotype expression levels affecting the frequency of interaction.Ascarisβ-tubulin isotype A clusters with helminth β-tubulins previously shown to interact with BZ. Molecular dynamics simulations using β-tubulin isotype A highlighted the key role of amino acid E198 in BZ-β-tubulin interactions. Simulations indicated that mutations at amino acids E198A and F200Y alter binding of BZ, whereas there was no obvious effect of the F167Y mutation. In conclusion, the key interactions vital for BZ binding with β-tubulins have been identified and show how mutations can lead to resistance in nematodes.
Semi-quantitative detection of pseudouridine modifications and type I/II hypermodifications in human mRNAs using direct and long-read sequencing
Authors: Tavakoli Sepideh , Nabizadehmashhadtoroghi Mohammad , Makhamreh Amr , Gamper Howard , McCormick Caroline A. , Rezapour Neda K. , Hou Ya-Ming , Wanunu Meni , Rouhanifard Sara H. 
Published: November 2021

AbstractWe developed and applied a semi-quantitative method for high-confidence identification of pseudouridylated sites on mammalian mRNAs via direct long-read nanopore sequencing. A comparative analysis of a modification-free transcriptome reveals that the depth of coverage and specific k-mer sequences are critical parameters for accurate basecalling. By adjusting these parameters for high-confidence U-to-C basecalling errors, we identified many known sites of pseudouridylation and uncovered new uridine-modified sites, many of which fall in k-mers that are known targets of pseudouridine synthases. Identified sites were validated using 1,000-mer synthetic RNA controls bearing a single pseudouridine in the center position which demonstrate systematical under-calling using our approach. We identify mRNAs with up to 7 unique modification sites. Our pipeline allows direct detection of low-, medium-, and high-occupancy pseudouridine modifications on native RNA molecules from nanopore sequencing data as well as multiple modifications on the same strand.