bluuebunny/crossref_metadata_2025 huggingface dataset:
CoViD-19 in Italy: a mathematical model to analyze the epidemic containment strategy and the economic impacts
Authors: Verachi Fabio , Trussoni Luca , Lanzi Luciano
Published: May 2020

The objective of this paper is to evaluate the potential costs deriving from the adoption of the CoViD-19 epidemic management strategy. For this purpose, we developed a specific methodology that combines an epidemiological model, known in the literature as “SIR” (Susceptible - Infected - Recovered), and a probabilistic state model, also known as “multi-state”. The model thus conceived was then parameterized using the dataset published by the Italian Government through the Civil Protection and the Istituto Superiore di Sanità. We therefore estimated the duration of the disease and the related costs, with reference to the strategy currently under discussion between government institutions and social organizations involved. Given the flexibility of the adopted approach, the tool will also be able to provide useful indications in relation to any alternative strategies that the Government could adopt in the near future, as well as being the starting point of an analysis of the epidemic indirect costs such as losses of GDP fractions.
Predicting social distancing index during COVID-19 outbreak through online search engines trends
Authors: Lins-Filho P. C. , Araújo M. M. S. , Macêdo T. S. , Ferreira A. K. A. , Melo M. C. F. , Silva E. L. M. S. , Freitas J. L. M. , Caldas A. F.
Published: May 2020

Online-available information has been considered an accessory tool to estimate epidemiology and collect data on diseases and population behavior patterns. This study aimed to explore the potential use of Google and YouTube relative search volume to predict social distancing index in Brazil during COVID-19 outbreak and verify the correlation between social distancing measures with the course of the epidemic. Data concerning the social distancing index, epidemiological data on COVID-19 in Brazil and the search engines trends for “Coronavirus” were retrieved from online databases. Multiple linear regression was performed and resulted in a statistically significant model evidencing that Google and YouTube relative search volumes are predictors of the social distancing index. The Spearman correlation test revealed a weak correlation between social distancing measures and the course of the COVID-19 epidemic. Health authorities can apply these data to define the proper timing and location for practicing appropriate risk communication strategies.
COVID-19 higher morbidity and mortality in Chinese regions with lower air quality
Authors: Pansini Riccardo , Fornacca Davide
Published: May 2020

We investigated the geographical character of the COVID-19 infection in China and correlated it with satellite- and ground-based measurements of air quality. Controlling for population size, we found more viral infections in those areas afflicted by high Carbon Monoxide, formaldehyde, PM 2.5, and Nitrogen Dioxide values. Higher mortality was also correlated with relatively poor air quality. Air pollution appears to be a risk factor for the incidence of this disease, similar to smoking. This suggests the detrimental impact of air pollution in these types of respiratory epidemics.

Short summary

There is a significant correlation between air pollution and COVID-19 spread and mortality in China.

The correlation stands at a second-order administration level, after controlling for varying population densities and removing Wuhan and Hubei from the dataset.

Living in an area with low air quality is a risk factor for becoming infected and dying from this new form of coronavirus.
Disparities in Vulnerability to Severe Complications from COVID-19 in the United States
Authors: Wiemers Emily E. , Abrahams Scott , AlFakhri Marwa , Hotz V. Joseph , Schoeni Robert F. , Seltzer Judith A.
Published: May 2020

This paper provides the first nationally representative estimates of vulnerability to severe complications from COVID-19 overall and across race-ethnicity and socioeconomic status. We use the Panel Study of Income Dynamics (PSID) to examine the prevalence of specific health conditions associated with complications from COVID-19 and to calculate, for each individual, an index of the risk of severe complications from respiratory infections developed by DeCaprio et al. (2020). We show large disparities across race-ethnicity and socioeconomic status in the prevalence of conditions which are associated with the risk of severe complications from COVID-19. Moreover, we show that these disparities emerge early in life, prior to age 65, leading to higher vulnerability to such complications. While vulnerability is highest among older adults regardless of their race-ethnicity or socioeconomic status, our results suggest particular attention should also be given to the risk of adverse outcomes in midlife for non-Hispanic Blacks, adults with a high school degree or less, and low-income Americans.
An Ontology-based Approach to Guide and Document Variable and Data Source Selection and Data Integration Process to Support Integrative Data Analysis in Cancer Outcomes Research
Authors: Zhang Hansi , Guo Yi , Bian Jiang
Published: May 2020

Background

To reduce cancer mortality and improve cancer outcomes, it is critical to understand the various cancer risk factors (RFs) across different domains (e.g., genetic, environmental, and behavioral risk factors) and levels (e.g., individual, interpersonal, and community levels). However, prior research on RFs of cancer outcomes, has primarily focused on individual level RFs due to the lack of integrated datasets that contain multi-level, multi-domain RFs. Further, the lack of a consensus and proper guidance on systematically identify RFs also increase the difficulty of RF selection from heterogenous data sources in a multi-level integrative data analysis (mIDA) study. More importantly, as mIDA studies require integrating heterogenous data sources, the data integration processes in the limited number of existing mIDA studies are inconsistently performed and poorly documented, and thus threatening transparency and reproducibility.

Methods

Informed by the National Institute on Minority Health and Health Disparities (NIMHD) research framework, we (1) reviewed existing reporting guidelines from the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) network and (2) developed a theory-driven reporting guideline to guide the RF variable selection, data source selection, and data integration process. Then, we developed an ontology to standardize the documentation of the RF selection and data integration process in mIDA studies.

Results

We summarized the review results and created a reporting guideline—ATTEST—for reporting the variable selection and data source selection and integration process. We provided an ATTEST check list to help researchers to annotate and clearly document each step of their mIDA studies to ensure the transparency and reproducibility. We used the ATTEST to report two mIDA case studies and further transformed annotation results into sematic triples, so that the relationships among variables, data sources and integration processes are explicitly standardized and modeled using the classes and properties from OD-ATTEST.

Conclusion

Our ontology-based reporting guideline solves some key challenges in current mIDA studies for cancer outcomes research, through providing (1) a theory-driven guidance for multi-level and multi-domain RF variable and data source selection; and (2) a standardized documentation of the data selection and integration processes powered by an ontology, thus a way to enable sharing of mIDA study reports among researchers.
Three-dimensional understanding of the morphological complexity of the human uterine endometrium
Authors: Yamaguchi Manako , Yoshihara Kosuke , Suda Kazuaki , Nakaoka Hirofumi , Yachida Nozomi , Ueda Haruka , Sugino Kentaro , Mori Yutaro , Yamawaki Kaoru , Tamura Ryo , Ishiguro Tatsuya , Motoyama Teiichi , Watanabe Yu , Okuda Shujiro , Tainaka Kazuki , Enomoto Takayuki
Published: May 2020

The histological basis of the human uterine endometrium has been established by 2D observation. However, the fundamental morphology of endometrial glands is not sufficiently understood because these glands have complicated winding and branching patterns. To construct a big picture of endometrial gland structure, we performed tissue-clearing-based 3D imaging of human uterine endometrial tissue. Our 3D immunohistochemistry and 3D layer analyses revealed that endometrial glands formed a plexus network in the stratum basalis, similar to the rhizome of grass. We then extended our method to assess the 3D morphology of adenomyosis, a representative “endometrium-related disease”, and observed 3D morphological features including direct invasion of endometrial glands into the myometrium and an ant colony-like network of ectopic endometrial glands within the myometrium. Thus, 3D analysis of the human endometrium and endometrium-related diseases will be a promising approach to better understand the pathologic physiology of the human endometrium.
Significant functional differences despite morphological and molecular similarity in fully differentiated matched Conditionally Reprogrammed (CRC) and Feeder free dual SMAD inhibited expanded human nasal epithelial cells
Authors: Awatade Nikhil T. , Wong Sharon L. , Pandzic Elvis , Slapetova Iveta , Capraro Alexander , Zhong Ling , Turgutoglu Nihan , Fawcett Laura K. , Whan Renee M. , Jaffe Adam , Waters Shafagh A.
Published: May 2020

Background

Patient-derived airway cells differentiated at Air Liquid Interface (ALI) are valuable models for Cystic fibrosis (CF) precision therapy. Advances in culture techniques have improved expansion capacity of airway basal cells, while retaining functional airway epithelium physiology. However, considerable variation in response to CFTR modulators is observed even when using similar ALI culture techniques. We aimed to address if variation in response reflects true biological differences between patients or technical differences as a consequence of different culture expansion methods.

Methods

Nasal epithelial brushings from 14 individuals (CF=9; non-CF=5) were collected, then equally divided and expanded under conditional reprogramming culture (CRC) and feeder-serum-free “dual-SMAD inhibition” (SMADi) methods. Expanded cells from each culture were differentiated with proprietary PneumaCult™-ALI media. Morphology (Immunofluorescence), global proteomics (LC-MS/MS) and function (barrier integrity, cilia motility, and ion transport) were compared in CRCALIand SMADiALIunder basal and CFTR corrector treated (VX-809) conditions.

Results

No significant difference in the structural morphology or global proteomics profile were observed. Barrier integrity and cilia motility were significantly different, despite no difference in cell junction morphology or cilia abundance. Epithelial Sodium Channels and Calcium-activated Chloride Channel activity did not differ but CFTR mediated chloride currents were significantly reduced in SMADiALIcompare to their CRCALIcounterparts.

Conclusion

Alteration of cellular physiological functionin vitrooccurs were more prominent than structural and differentiation potential in airway ALI. Since culture conditions significantly influence CFTR activity, this could lead to false conclusions if data from different labs are compared against each other without specific reference ranges.
Core binding factor leukemia hijacks T-cell prone PU.1 antisense promoter
Authors: van der Kouwe E. , Heller G. , Czibere A. , Castilla L.H. , Delwel R. , Di Ruscio A. , Ebralidze A.K. , Forte M. , Kazianka L. , Kornauth C. , Le T. , Lind K. , Monteiro Barbosa I.A. , Pichler A. , Pulikkan J.A. , Schmolke A-S , Sill H. , Sperr W.R. , Spittler A. , Trinh B. Q. , Valent P. , Vanura K. , Welner R.S. , Zuber J. , Tenen D.G. , Staber P.B.
Published: May 2020

Summary paragraph

The blood system serves as a key model for cell differentiation and cancer. It is orchestrated by precise spatiotemporal expression of the hematopoietic master regulator PU.11–4. PU.1 gene expression is regulated through enhancer-promoter interactions within a topologically associated domain (TAD)5,6. PU.1 levels increase during myeloid differentiation while failure to do so results in myeloid leukemia7. In contrast, T-cell differentiation requires PU.1 to be completely switched off8–10. Little is known about the precise mechanisms of PU.1 repression, physiological as in T-cell differentiation, or pathological as in leukemia. Here we demonstrate that the down-regulation of PU.1 mRNA is a dynamic process involving an alternative promoter11in intron 3 that is induced by RUNX transcription factors driving noncoding antisense transcription. Core binding factor (CBF) fusions, RUNX1-ETO and CBFβ-MYH11 in t(8;21) and inv(16) acute myeloid leukemia (AML)12, activate the PU.1 antisense promoter, thus shifting from sense towards antisense transcription and blocking myeloid differentiation. In patients with CBF-AML, we found that an elevated antisense/sense ratio represents a hallmark compared to normal karyotype AML or healthy CD34+ cells. Competitive interaction of the enhancer with the proximal or the antisense promoter are at the heart of differential PU.1 expression during myeloid and T-cell development. Leukemic CBF fusions thus utilize a physiologic mechanism employed by T-cells to decrease sense PU.1 transcription. Our results identify the first example of a sense/antisense promoter competition as a crucial functional switch for gene expression perturbation by oncogenes. This novel basic disease mechanism reveals a previously unknown Achilles heel for future precise therapeutic targeting of oncogene-induced chromatin remodeling.
The mutational landscape of human olfactory G protein-coupled receptors
Authors: Jimenez Ramón Cierco , Casajuana-Martin Nil , García-Recio Adrián , Alcántara Lidia , Pardo Leonardo , Campillo Mercedes , Gonzalez Angel
Published: May 2020

Olfactory receptors (ORs) constitute a large family of sensory proteins that enable us to recognize a wide range of chemical volatiles in the environment. By contrast to the extensive information about human olfactory thresholds for thousands of odorants, studies of the genetic influence on olfaction are limited to a few examples. Here, we analyzed a compendium of 118,057 natural variants in human ORs collected from the public domain. OR mutations were categorized depending on their genomic and protein contexts, as well as their frequency of occurrence in several human populations. Functional interpretation of the natural changes was estimated from the increasing knowledge of the structure and function of the G protein-coupled receptor (GPCR) family, to which ORs belong. Our analysis reveals an extraordinary diversity of natural variations in the olfactory gene repertoire between individuals and populations, with a significant number of changes occurring at structural conserved regions. A particular attention is paid to mutations in positions linked to the conserved GPCR activation mechanism that could imply phenotypic variation in the olfactory perception. An interactive web application (available athttp://lmc.uab.cat/hORMdb) was developed for the management and visualization of this mutational dataset.
From wing shape to fluid dynamics in the barn owl (Tyto alba)
Authors: Cheney Jorn A , Stevenson Jonathan PJ , Durston Nick E , Song Jialei , Maeda Masateru , Windsor Shane P , Usherwood James R , Bomphrey Richard J
Published: May 2020

Birds morph their wings and tail in order to glide under a wide range of aerodynamic conditions. Gross wing morphing has been described in a multitude of studies, but the finer details of wing morphing are still unknown. Here, we measured the changes in wing shape and pose in a barn owl,Tyto alba, when gliding across a range of fifteen self-selected speeds. We found thatT. albadoes not use fine-wing shape control to glide at slow speeds in steady conditions, with the measured wing shapes being highly consistent across all flights. Instead,T. albarelied upon wing postural control (gross pitch) and changes in both tail shape and pose to modulate aerodynamic force. A consistent wing shape provides an exceptional aerodynamic tool for understanding gliding flight in birds through postural change and tail morphing. This geometry was used as the basis for computational fluid dynamics simulations which gave very similar wake measurements and weight support to those measured in flight. This geometry is provided here to assist other researchers interested in exploring the fluid dynamics behind gliding flight in birds.
Loss of malate-aspartate shuttle component SLC25A12 induces pulmonary metastasis
Authors: Alkan H Furkan , Vesely Paul W , Hackl Hubert , Foßelteder Johannes , Vander Heiden Matthew G , Pichler Martin , Hoefler Gerald , Bogner-Strauss Juliane G
Published: May 2020

Background

Aspartate biosynthesis and its delivery to the cytosol can be crucial for tumor growthin vivo.However, the impact of aspartate synthesis on metastasis has not been studied. We previously described that loss-of-aspartate glutamate carrier 1 (SLC25A12 or AGC1), an important component of the malate-aspartate shuttle, impairs cytosolic aspartate levels, NAD+/NADH ratio, mitochondrial respiration, and tumor growth. Here, we report the impact of AGC1-knockdown on metastasis.

Results

AGC1 expression is positively correlated with worse patient prognosis in many cancers. AGC1-knockdown in mouse lung carcinoma and melanoma cell lines leads to increased pulmonary metastasis following subcutaneous or intravenous injections, respectively. On the other hand, conventionalin vitrometastasis assays show no indication of increased metastasis capacity of AGC1-knockdown cells.

Conclusion

This study highlights that certain branches of metabolism impact tumor growth and tumor metastasis differently. In addition, it also argues that commonly known metastasis indicators, including EMT genes, cell migration, or colony formation do not always reflect the metastatic capacityin vivo.
Recombination of 2Fe-2S ferredoxins reveals differences in the inheritance of thermostability and midpoint potential
Authors: Campbell Ian J. , Kahanda Dimithree , Atkinson Joshua T. , Sparks Othneil N. , Kim Jinyoung , Tseng Chia-Ping , Verduzco Rafael , Bennett George N. , Silberg Jonathan J.
Published: May 2020

Homologous recombination can be used to create enzymes that exhibit distinct activities and stabilities from proteins in nature, allowing researchers to overcome component limitations in synthetic biology. To investigate how recombination affects the physical properties of an oxidoreductase that transfers electrons, we created ferredoxin (Fd) chimeras by recombining distantly-related cyanobacterial and cyanomyophage Fds that present similar midpoint potentials but distinct thermostabilities. Fd chimeras having a wide range of amino acid substitutions retained the ability to coordinate an iron-sulfur cluster, although their thermostabilities varied with the fraction of residues inherited from each parent. The midpoint potentials of chimeric Fds also varied. However, all of the synthetic Fds exhibited midpoint potentials outside of the parental protein range. Each of the chimeric Fds could also be used to build synthetic pathways that support electron transfer between Fd-NADP reductase and sulfite reductase inEscherichia coli, although the chimeric Fds varied in the expression required to support similar levels of cellular electron transfer. These results show how recombination can be used to rapidly diversify the physical properties of protein electron carriers and reveal differences in the inheritance of thermostability and electrochemical properties. Furthermore, they illustrate how electron transfer efficiencies of chimeric Fds can be rapidly evaluated using a synthetic electron transfer pathway.
Macrophage Inflammatory State Influences Susceptibility to Lysosomal Damage
Authors: Wong Amanda O. , Marthi Matangi , Owusu Irene A. , Wobus Christiane E. , Swanson Joel A.
Published: May 2020

Macrophages possess mechanisms for reinforcing the integrity of their endolysosomal membranes against damage. This property, termed inducible renitence, was previously reported for macrophages stimulated with LPS, peptidoglycan, IFN-γ, or TNF-α. Here, we expanded the macrophage subtypes examined to include populations with well-defined functional rolesin vivo: classically activated macrophages (CA-Mφ), alternatively activated macrophages (AA-Mφ), and regulatory macrophages (Reg-Mφ). We determined that renitence is a property of CA-Mφ and Reg-Mφ, but not of AA-Mφ. Furthermore, LPS-activated macrophages possess features of both CA-Mφ and Reg-Mφ, based on their cytokine secretion profiles. As the generation of these three classes of renitent macrophages required exposure to LPS, a Toll-like receptor (TLR) ligand, we assessed whether TLR stimulation generally induced renitence. Stimulation of TLRs 2/1, 3, and 4 induced renitence, whereas stimulation of TLRs 7/8 and 9 induced modest levels of lysosomal damage protection. Renitence induced by TLR stimulation required the signaling adaptors MyD88 and TRIF. Surprisingly, the specific signaling adaptor usage requirements for some TLRs differed from those established for canonical TLR signaling. Of note, renitence induced by LPS, a TLR4 ligand, required signaling through TRIF but not MyD88. Consistent with this pattern, the type I IFN response, which is triggered by LPS stimulation through a TRIF-dependent, MyD88-independent pathway, contributed to renitence. A biologically relevant type I IFN trigger in macrophages, murine norovirus-1 (MNV-1) infection, also induced renitence. This work establishes the concept that susceptibility to lysosomal damage within macrophages varies according to inflammatory state and depends on the type I IFN response.

Summary sentence

Macrophages of distinct polarization states exhibit varying degrees of susceptibility to lysosomal damage reflecting their functional roles in host defense and immune regulation
Physical activity is positively related to local functional connectivity in adolescents’ brains
Authors: Ruotsalainen Ilona , Glerean Enrico , Karvanen Juha , Gorbach Tetiana , Renvall Ville , Syväoja Heidi J. , Tammelin Tuija H. , Parviainen Tiina
Published: May 2020

Adolescents have experienced decreased aerobic fitness levels and insufficient physical activity levels over the past decades. While both physical activity and aerobic fitness are related to physical and mental health, little is known concerning how they manifest in the brain during this stage of development, characterized by significant physical and psychosocial changes. Previous investigations have demonstrated associations of physical activity and aerobic fitness with the brain’s functional connectivity in both children and adults. However, it is difficult to generalize these results to adolescents because the development of functional connectivity has unique features during adolescence. Here, we examined how physical activity and aerobic fitness are associated with local and interhemispheric functional connectivity of the adolescent brain, as measured with resting-state functional magnetic resonance imaging (fMRI). Physical activity was measured by hip-worn accelerometers, and aerobic fitness by a maximal 20-m shuttle run test. We found that higher levels of moderate-to-vigorous physical activity, but not aerobic fitness, were linked to increased local functional connectivity as measured by regional homogeneity in 13–16-year-old participants. However, we did not find evidence for significant associations between adolescents’ physical activity or aerobic fitness and interhemispheric connectivity, as indicated by homotopic connectivity. These results suggest that physical activity, but not aerobic fitness, is related to local functional connectivity in adolescents. Moreover, physical activity shows an association with a specific brain area involved in motor functions but did not display any widespread associations with other brain regions. These results can advance our understanding of the behavior-brain associations in adolescents.
Genus-wide characterization of bumblebee genomes reveals variation associated with key ecological and behavioral traits of pollinators
Authors: Sun Cheng , Huang Jiaxing , Wang Yun , Zhao Xiaomeng , Su Long , Thomas Gregg W.C. , Zhao Mengya , Zhang Xingtan , Jungreis Irwin , Kellis Manolis , Vicario Saverio , Sharakhov Igor V. , Bondarenko Semen M. , Hasselmann Martin , Kim Chang N , Paten Benedict , Penso-Dolfin Luca , Wang Li , Chang Yuxiao , Gao Qiang , Ma Ling , Ma Lina , Zhang Zhang , Zhang Hongbo , Zhang Huahao , Ruzzante Livio , Robertson Hugh M. , Zhu Yihui , Liu Yanjie , Yang Huipeng , Ding Lele , Wang Quangui , Xu Weilin , Liang Cheng , Itgen Michael W. , Mee Lauren , Sadd Ben M. , Cao Gang , Zhang Ze , Hahn Matthew , Schaack Sarah , Barribeau Seth M. , Williams Paul H. , Waterhouse Robert M. , Mueller Rachel Lockridge
Published: May 2020

Bumblebees are a diverse group of globally important pollinators in natural ecosystems and for agricultural food production. With both eusocial and solitary lifecycle phases, and some social parasite species, they are especially interesting models to understand social evolution, behavior, and ecology. Reports of many species in decline point to pathogen transmission, habitat loss, pesticide usage, and global climate change, as interconnected causes. These threats to bumblebee diversity make our reliance on a handful of well-studied species for agricultural pollination particularly precarious. To broadly sample bumblebee genomic and phenotypic diversity, wede novosequenced and assembled the genomes of 17 species, representing all 15 subgenera, producing the first genus-wide quantification of genetic and genomic variation potentially underlying key ecological and behavioral traits. The species phylogeny resolves subgenera relationships while incomplete lineage sorting likely drives high levels of gene tree discordance. Five chromosome-level assemblies show a stable 18-chromosome karyotype, with major rearrangements creating 25 chromosomes in social parasites. Differential transposable element activity drives changes in genome sizes, with putative domestications of repetitive sequences influencing gene coding and regulatory potential. Dynamically evolving gene families and signatures of positive selection point to genus-wide variation in processes linked to foraging, diet and metabolism, immunity and detoxification, as well as adaptations for life at high altitudes. These high-quality genomic resources capture natural genetic and phenotypic variation across bumblebees, offering new opportunities to advance our understanding of their remarkable ecological success and to identify and manage current and future threats.
Female rat sexual behavior is unaffected by perinatal fluoxetine exposure
Authors: Hegstad Jan , Huijgens Patty T. , Houwing Danielle J. , Olivier Jocelien D.A. , Heijkoop Roy , Snoeren Eelke M.S.
Published: May 2020

Serotonin plays an important role in adult female sexual behavior, however little is known about the influence of serotonin during early development on sexual functioning in adulthood. During early development, serotonin acts as neurotrophic factor, while it functions as a modulatory neurotransmitter in adulthood. The occurrence of serotonin release, could thus have different effects on behavioral outcomes, depending on the developmental period in which serotonin is released. Because serotonin is involved in the development of the HPG axis which is required for puberty establishment, serotonin could also alter expression patterns of for instance the estrogen receptor α (ERα).

The aim of our study was to investigate the effects of increased serotonin levels during early development on adult female rat sexual behavior during the full behavioral estrus in a seminatural environment. To do so, rats were perinatally exposed with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (10 mg/kg FLX) and sexual performance was tested during adulthood. All facets of female sexual behavior between the first and last lordosis (behavioral estrus), and within each copulation bout of the behavioral estrus were analyzed. Besides the length and onset of the behavioral estrus and the sexual behaviors patterns, other social and conflict behavior were also investigated. In addition, we studied the effects of perinatal FLX exposure on ERα expression patterns in the medial preoptic nucleus, ventromedial nucleus of the hypothalamus, medial amygdala, bed nucleus of the stria terminalis, and the dorsal raphé nucleus.

The results showed that perinatal fluoxetine exposure has no effect on adult female sexual behavior. The behavioral estrus of FLX-females had the same length and pattern as CTR-females. In addition, FLX- and CTR-females showed the same amount of paracopulatory behavior and lordosis, both during the full behavioral estrus and the “most active bout”. Furthermore, no differences were found in the display of social and conflict behaviors, nor in ERα expression patterns in the brain. We conclude that increases in serotonin levels during early development do not have long-term consequences for female sexual behavior in adulthood.
Implantable Electrical Connector for Reconnecting Injured Neurons, Approach and Design
Authors: Hashemi Soheil , Abdolali Ali
Published: May 2020

Abstract

In contrast to normal injuries, damages of the nervous system are very difficult to repair. In this paper, a connector is designed to reconnect injured nerve to healthy cells. This cord was designed and tested by the full wave and three dimensional electromagnetic modeling. The connector is comprised of three parts, including the conductor, dielectric coating, and second coating with high conductivity. Electromagnetic characteristics need to be unique to work fine, each part is obtained with regard to the distance between two neurons. The combination of materials with conductivity lower than 100 S/m and relative permittivity lower than 8 creates the connection of two neurons up to 35 cm. The connector is realizable by biocompatible polymers.
Divergent cancer etiologies drive distinct B cell signatures and tertiary lymphoid structures
Authors: Ruffin Ayana T , Cillo Anthony R , Tabib Tracy , Liu Angen , Onkar Sayali , Kunning Sheryl , Lampenfeld Caleb , Abecassis Irina , Qi Zengbiao , Soose Ryan , Duvvuri Umamaheswar , Kim Seungwon , Oesterrich Steffi , Lafyatis Robert , Ferris Robert L , Vignali Dario AA , Bruno Tullia C
Published: May 2020

Current immunotherapy paradigms aim to reinvigorate CD8+T cells, but the contribution of humoral immunity to antitumor immunity remains understudied1,2. Head and neck squamous cell carcinoma (HNSCC) is caused by either human papillomavirus (HPV+) or environmental carcinogens (i.e. tobacco and alcohol; HPV–)3,4. Here, we demonstrate that HPV+ HNSCC patients have transcriptional signatures of germinal center (GC) tumor infiltrating B cells (TIL-Bs) and spatial organization of immune cells consistent with GC-like tertiary lymphoid structures (TLS), both of which correlate with favorable outcomes in HNSCC patients. Further, our single-cell RNAseq data also indicate that GC TIL-Bs are characterized by distinct waves of gene expression consistent with dark zone, light zone and a transitional state of GC B cells. High-dimensional spectral flow cytometry permitted in depth characterization of activated, memory and GC TIL-Bs. Further, single cell RNAseq analysis and subsequent protein validation identified a role for semaphorin 4a (Sema4a) in the differentiation of GC TIL-Bs and indicated that expression of Sema4a was enhanced on GC TIL-Bs and within GC-like TLS in the TME. Thus, in contrast to some reports on the detrimental role of TIL-Bs in human tumors, our findings suggest that TIL-Bs play an instrumental role in antitumor immunity5,6. Novel therapeutics to enhance TIL-B responses in HNSCC should be prioritized as a compliment to current T-cell mediated immunotherapies.
Direct reprogramming of adult hepatocytes to generate LGR5+ endodermal progenitor
Authors: Chaker Diana , Desterke Christophe , Moniaux Nicolas , Ernault Tony , Oudrhiri Noufissa , Faivre Jamila , Turhan Ali G , Bennaceur-Griscelli Annelise , Griscelli Frank
Published: May 2020

We successfully converted hepatocytes isolated from adult mice into expandable and stable leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5)-positive endodermal progenitor cells (EndoPCs). This was accomplishedin vitrothrough transient exposure to four transcriptional factors (OCT3/4, SOX2, KLF4, and cMYC) and STAT3 activators. EndoPCs were generated by a process that involved an epithelial-mesenchymal transition (EMT) without the use of any components of the canonical WNT/β-catenin or LGR5/R-spondin signaling pathways. We showed that the proliferation and capacity for self-renewal of EndoPCs in 2D long-term culture were controlled by three interrelated signaling pathways: gp130/JAK/STAT3, LGR5/R-spondin, and WNT/β-catenin. After long-term maintenance in two- and three-dimensional culture systems, EndoPCs were able to differentiate into liver-restricted lineages such as hepatocyte-like cells and bile duct-like structuresin vitroandin vivo. After intra-muscular injection, EndoPCs generated macroscopically visible and well-vascularized liver-like tissue, which contained Alb+liver parenchyma-like structures and substantial, KRT7/KRT19+bile duct-like cell organizations.

Conclusion

We have developed an efficient method for producing LGR5+adult endodermal stem cells. These cells will be useful for thein vitrostudy of the molecular mechanisms of liver development and have important potential for therapeutic strategies, including approaches based on bioengineered liver tissue. These cells also open up new avenues for experiments focused on disease modeling, toxicology studies, and regenerative medicine applications.
The effect of resource limitation on the temperature-dependence of mosquito population fitness
Authors: Huxley Paul J. , Murray Kris A. , Pawar Samraat , Cator Lauren J.
Published: May 2020

Laboratory-derived temperature dependencies of life history traits are increasingly being used to make mechanistic predictions for how climatic warming will affect vector-borne disease dynamics, partially by affecting abundance dynamics of the vector population. These temperature-trait relationships are typically estimated from populations reared on optimal resource supply, even though natural populations of vectors are expected to experience variation in resource supply, including intermittent resource limitation. Using laboratory experiments on the mosquitoAedes aegypti, a principal arbovirus vector, combined with stage-structured population modelling, we show that low-resource supply significantly depresses the vector’s maximal population growth rate across the entire temperature range (22-32°C) and causes it to peak at a lower temperature than at high-resource supply. This effect is primarily driven by an increase in juvenile mortality and development time, combined with an exaggerated decrease in adult size with temperature at low-resource supply. Our study suggests that projections of vector abundance and disease transmission based on laboratory studies are likely to substantially underestimate how resource supply can modulate the temperature-dependency of population-level fitness through its influence on juvenile survival and development time. Our results provide compelling evidence for future studies to consider resource supply when predicting the effects of climate and habitat change on disease vectors and transmission.
Non-REM sleep facilitates consolidation of contextual fear memory through temporal coding among hippocampal neurons
Authors: Skilling Quinton M. , Clawson Brittany C. , Eniwaye Bolaji , Shaver James , Ognjanovski Nicolette , Aton Sara J. , Zochowski Michal
Published: May 2020

Sleep plays a critical role in memory consolidation, although the exact mechanisms mediating this process are unknown. Combining computational andin vivoexperimental approaches, we test the hypothesis that reduced cholinergic input to the hippocampus during non-rapid eye movement (NREM) sleep generates stable spike timing relationships between neurons. We find that the order of firing among neurons during a period of NREM sleep reflects their relative firing rates during prior wake, and changes as a function of prior learning. We show that learning-dependent pattern formation (e.g. “replay”) in the hippocampus during NREM, together with spike timing dependent plasticity (STDP), restructures network activity in a manner similar to that observed in brain circuits across periods of sleep. This suggests that sleep actively promotes memory consolidation by switching the network from rate-based to firing phase-based information encoding.
Mathematical modelling of megakaryopoiesis in Mpl-deficient and continuously thrombopoietin-stimulated mice points to an unknown control mechanism
Authors: Diebner Hans H. , Gottschalk Andrea , Baldow Christoph , Klose Markus , Glauche Ingmar
Published: May 2020

Thrombopoietin (TPO) is the ligand of the Mpl receptor and the key regulator of megakaryopoiesis and platelet production. A loss or gain of the TPO-receptor function affects haematopoiesis and results in severe diseases in humans. Appropriate mouse strains are available to mimic both myeloproliferative neoplasm (MPN) and congenital amegakaryocytic thrombocytopenia (CAMT) resulting from TPO overexpression or knockout of TPO receptor Mpl on megakaryocytes and platelets, respectively. However, at a quantitative level it is not understood, how the known regulations can establish the impaired but stable disease phenotypes.

Starting out from an established mathematical model for megakaryopoiesis, we aim to adapt it to both the healthy situation and to distinct diseased phenotypes mimicking MPN. We thereby identify, that some of the model parameters are invariant with respect to the mouse strain while others have to be estimated in a strain-dependent manner. A systematic process of parameter identification provides strong evidence that the well-known excess production of megakaryocytes and early progenitors in MPN is either directly contingent on Mpl expression of platelets and megakaryocytes or, alternatively, that the knockout of Mpl is not as precisely restricted to megakaryocytes and platelets but may also effect their progenitors.

In conclusion, our analysis hints towards an opaque control mechanism rendering megakaryopoiesis at a yet unknown level, and awaiting further experimental evaluation.
Integrating multimodal data through interpretable heterogeneous ensembles
Authors: Li Yan Chak , Wang Linhua , Law Jeffrey N. , Murali T. M. , Pandey Gaurav
Published: May 2020

Motivation

Integrating multimodal data represents an effective approach to predicting biomedical characteristics, such as protein functions and disease outcomes. However, existing data integration approaches do not sufficiently address the heterogeneous semantics of multimodal data. In particular, early and intermediate approaches that rely on a uniform integrated representation reinforce the consensus among the modalities, but may lose exclusive local information. The alternative late integration approach that can address this challenge has not been systematically studied for biomedical problems.

Results

We propose Ensemble Integration (EI) as a novel systematic implementation of the late integration approach. EI infers local predictive models from the individual data modalities using appropriate algorithms, and uses effective heterogeneous ensemble algorithms to integrate these local models into a global predictive model. We also propose a novel interpretation method for EI models. We tested EI on the problems of predicting protein function from multimodal STRING data, and mortality due to COVID-19 from multimodal data in electronic health records. We found that EI accomplished its goal of producing significantly more accurate predictions than each individual modality. It also performed better than several established early integration methods for each of these problems. The interpretation of a representative EI model for COVID-19 mortality prediction identified several disease-relevant features, such as laboratory test (blood urea nitrogen (BUN) and calcium) and vital sign measurements (minimum oxygen saturation) and demographics (age). These results demonstrated the effectiveness of the EI framework for biomedical data integration and predictive modeling.

Availability

Code and data are available athttps://github.com/GauravPandeyLab/ensemble_integration.

Contact

gaurav.pandey@mssm.edu
Development of a Tet-On inducible expression system for the anhydrobiotic cell line, Pv11
Authors: Tokumoto Shoko , Miyata Yugo , Usui Kengo , Deviatiiarov Ruslan , Ohkawa Takahiro , Kondratieva Sabina , Shagimardanova Elena , Gusev Oleg , Cornette Richard , Itoh Masayoshi , Hayashizaki Yoshihide , Kikawada Takahiro
Published: May 2020

The Pv11 cell line established from an African chironomid,Polypedilum vanderplanki, is the only cell line tolerant to complete desiccation. In Pv11 cells, a constitutive expression system for Pv11 cells was previously exploited and several reporter genes were successfully expressed. Here we report the identification of an effective minimal promoter for Pv11 cells and its application to the Tet-On inducible expression system. First, using a luciferase reporter assay, we showed that a 202 bp deletion fragment derived from the constitutively active 121-promoter functions in Pv11 cells as an appropriate minimal promoter with the Tet-On inducible expression system. The AcGFP1 protein was also successfully expressed in Pv11 cells using the inducible system. In addition to these reporter genes, avian myeloblastosis virus reverse transcriptase α subunit (AMV RTα), which is one of the most widely commercially available RNA-dependent DNA polymerases, was successfully expressed through the inducible expression system and its catalytic activity was verified. These results demonstrate the establishment of an inducible expression system in cells that can be preserved in the dry state and highlight a possible application to the production of large and complex proteins.

Highlights

A 202 bp-deletion fragment derived from a constitutively active promoter was identified as a minimal promoter in Pv11 cells.

A Tet-On inducible expression system was developed for Pv11 cells using the minimal promoter.

Typical reporter genes (GFP and luciferase) and an enzyme with complex structure, i.e. a viral reverse transcriptase, were successfully and inducibly expressed in Pv11 cells using the Tet-On system.
Cercosporamide inhibits bone morphogenetic protein receptor type I kinase activity in zebrafish
Authors: Hoeksma Jelmer , van der Zon Gerard C.M. , Dijke Peter ten , den Hertog Jeroen
Published: May 2020

Zebrafish models are well established tools for investigating underlying mechanisms of diseases. Here, we identified cercosporamide, a metabolite from the fungusAscochyta aquiliqiae, as a potent bone morphogenetic protein (BMP) type I receptor kinase inhibitor through a zebrafish embryo phenotypic screen. The developmental defects in zebrafish, including lack of the ventral fin induced by cercosporamide was strikingly similar as the phenotypes caused by renowned small molecule BMP type I receptor kinase inhibitors and inactivating mutations in zebrafish BMP receptors. In mammalian cell-based assays, cercosporamide blocked BMP/SMAD-dependent transcriptional reporter activity and BMP-induced SMAD1/5-phosphorylation. Biochemical assays with a panel of purified recombinant kinases demonstrated that cercosporamide directly inhibited kinase activity of BMP type I receptors (also called activin receptor-like kinases (ALKs)). In mammalian cells, cercosporamide selectively inhibited constitutively active BMP type I receptor-induced SMAD1/5 phosphorylation. Importantly, cercosporamide rescued the developmental defects caused by constitutively active Alk2 in zebrafish embryos. Taken together, we believe cercosporamide may be the first of a new class of molecules with potential to be developed further for clinical use against diseases that are causally linked to overactivation of BMP receptor signaling, including Fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma.
Multivalent lipid targeting by the calcium-independent C2A domain of Slp-4/granuphilin
Authors: Alnaas Aml A , Watson-Siriboe Abena , Tran Sherleen , Negussie Mikias , Henderson Jack A. , Osterberg J. Ryan , Chon Nara Lee , Oviedo Julianna , Lyakhova Tatyana , Michel Cole , Reisdorph Nichole , Reisdorph Richard , Shearn Colin T. , Lin Hai , Knight Jefferson D.
Published: May 2020

Synaptotagmin-like protein 4 (Slp-4), also known as granuphilin, is a Rab effector responsible for docking secretory vesicles to the plasma membrane before exocytosis. Slp-4 binds vesicular Rab proteins via an N-terminal Slp homology (SHD) domain, interacts with plasma membrane SNARE complex proteins via a central linker region, and contains tandem C-terminal C2 domains (C2A and C2B) with affinity for phosphatidylinositol-(4,5)-bisphosphate (PIP2). The Slp-4 C2A domain binds with low nanomolar apparent affinity to PIP2in lipid vesicles that also contain background anionic lipids such as phosphatidylserine (PS), but much weaker when either the background anionic lipids or PIP2are removed. Through computational and experimental approaches, we show that this high affinity membrane interaction arises from concerted interaction at multiple sites on the C2A domain. In addition to a conserved PIP2-selective lysine cluster, there exists a larger cationic surface surrounding the cluster which contributes substantially to the affinity for physiologically relevant lipid compositions. While mutations at the PIP2-selective site decrease affinity for PIP2, multiple mutations are needed to decrease binding to physiologically relevant lipid compositions. Docking and molecular dynamics simulations indicate several conformationally flexible loops that contribute to the nonspecific cationic surface. We also identify and characterize a covalently modified variant in the bacterially expressed protein, which arises through reactivity of the PIP2-binding lysine cluster with endogenous bacterial compounds and has a low membrane affinity. Overall, multivalent lipid binding by the Slp-4 C2A domain provides selective recognition and high affinity docking of large dense-core secretory vesicles to the plasma membrane.
Role of matrix metalloproteinase-9 in neurodevelopmental disorders and experience-dependent plasticity in Xenopus tadpoles
Authors: Gore Sayali , James Eric J. , Huang Lin-Chien , Park Jenn J. , Berghella Andrea , Thompson Adrian , Cline Hollis T. , Aizenman Carlos D.
Published: May 2020

Matrix metalloproteinase-9 (MMP-9) is a secreted endopeptidase targeting extracellular matrix proteins, creating permissive environments for neuronal development and plasticity. Developmental dysregulation of MMP-9 is also associated with neurodevelopmental disorders (ND). Here we test the hypothesis that chronically elevated MMP-9 activity during early neurodevelopment is responsible for neural circuit hyperconnectivity observed after early exposure to valproic acid (VPA), a known teratogen associated with autism spectrum disorder in humans. InXenopustadpoles, VPA exposure results in excess local synaptic connectivity, disrupted social behavior and increased seizure susceptibility. We found that overexpressing MMP-9 in the brain copies effects of VPA on synaptic connectivity, and blocking MMP-9 activity pharmacologically or genetically reverses effects of VPA on physiology and behavior. We further show that during normal neurodevelopment MMP-9 levels are tightly regulated by neuronal activity and required for structural plasticity. These studies show a critical role for MMP-9 in both normal and abnormal development.