bluuebunny/crossref_metadata_2025 huggingface dataset:
Large-Scale Measurement of Aggregate Human Colocation Patterns for Epidemiological Modeling
Authors: Iyer Shankar , Karrer Brian , Citron Daniel , Kooti Farshad , Maas Paige , Wang Zeyu , Giraudy Eugenia , Medhat Ahmed , Dow P. Alex , Pompe Alex
Published: December 2020

To understand and model public health emergencies, epidemiologists need data that describes how humans are moving and interacting across physical space. Such data has traditionally been difficult for researchers to obtain with the temporal resolution and geographic breadth that is needed to study, for example, a global pandemic. This paper describes Colocation Maps, which are spatial network datasets that have been developed within Facebook’s Data For Good program. These Maps estimate how often people from different regions are colocated: in particular, for a pair of geographic regions x and y, these Maps estimate the probability that a randomly chosen person from x and a randomly chosen person from y are simultaneously located in the same place during a randomly chosen minute in a given week. These datasets are well suited to parametrize metapopulation models of disease spread or to measure temporal changes in interactions between people from different regions; indeed, they have already been used for both of these purposes during the COVID-19 pandemic. In this paper, we show how Colocation Maps differ from existing data sources, describe how the datasets are built, provide examples of their use in compartmental modeling, and summarize ideas for further development of these and related datasets. We also conduct the first large-scale analysis of human colocation patterns across the world. Among the findings of this study, we observe that a pair of regions can exhibit high colocation despite few people moving between them. We also find that although few pairs of people are colocated for many days over the course of a week, these pairs can contribute significant fractions of the total colocation time within a region or between pairs of regions.
Genomic and phylogenetic analyses of SARS-CoV-2 strains isolated in the city of Gwangju, South Korea
Authors: Lee Ji-eun , Chung Jae Keun , Kim Tae sun , Park Jungwook , Lim Mi hyeon , Hwang Da jeong , Jeong Jin , Kim Kwang gon , Yoon Ji-eun , Kee Hye young , Seo Jin jong , Kim Min Ji
Published: December 2020

Since the first identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China in late December 2019, the coronavirus disease 2019 (COVID-19) has spread fast around the world. RNA viruses, including SARS-CoV-2, have higher gene mutations than DNA viruses during virus replication. Variations in SARS-CoV-2 genome could contribute to efficiency of viral spread and severity of COVID-19. In this study, we analyzed the locations of genomic mutations to investigate the genetic diversity among isolates of SARS-CoV-2 in Gwangju. We detected non-synonymous and frameshift mutations in various parts of SARS-CoV-2 genome. The phylogenetic analysis for whole genome showed that SARS-CoV-2 genomes in Gwangju isolates are clustered within clade V and G. Our findings not only provide a glimpse into changes of prevalent virus clades in Gwangju, South Korea, but also support genomic surveillance of SARS-CoV-2 to aid in the development of efficient therapeutic antibodies and vaccines against COVID-19.
Isothermal Amplification of Nucleic Acids with Ladder-shape Melting Curve
Authors: Wang Deguo , Wang Yongzhen , Zhang Meng , Zhang Yongqing , Sun Juntao , Song Chumei , Xiao Fugang , Ping Yuan , Pan Chen , Hu Yushan , Wang Chaoqun , Liu Yanhong
Published: December 2020

A novel method termed isothermal amplification of nucleic acids withladder-shapemeltingcurve (LMCP) was developed in the study. In this method, one pair of primers or two pairs of nested primers and a thermostable DNA polymerase (large fragment) were employed to amplify theinternaltranscribedspacer (ITS) ofOryza sativawith ladder-shape melting curve. Our results demonstrated that the LMCP assay with nested primers was 50-fold more sensitive and one-hour faster than the LAMP assay with the same level of specificity. The LMCP method has the potential to be used for the prevention and control of the emerging epidemics.
Negatively charged peptide nanofibrils from immunoglobulin light chain sequester viral particles but lack cell-binding and viral transduction-enhancing properties
Authors: Schütz Desiree , Read Clarissa , Groß Rüdiger , Röcker Annika , Rode Sascha , Annamalai Karthikeyan , Fändrich Marcus , Münch Jan
Published: December 2020

Positively charged naturally occurring or engineered peptide nanofibrils (PNF) are effective enhancers of lentiviral and retroviral transduction, an often rate limiting step in gene transfer and gene therapy approaches. These polycationic PNF are thought to bridge the electrostatic repulsions between negatively charged membranes of virions and cells, thereby enhancing virion attachment to and infection of target cells. Here, we analyzed PNF which are formed by the peptide AL1, which represents a fragment of an immunoglobulin light chain that causes systemic AL amyloidosis. We found that negatively charged AL1 PNF interact with viral particles to a comparable extent as positively charged PNF. However, AL1 PNF lacked cell binding activity and consequently did not enhance retroviral infection. These findings show that virion capture and cell binding of PNF are mediated by different mechanisms, offering avenues for the design of advanced PNF with selective functions.
Theory and simulations for crowding-induced changes in stability of proteins with applications to λ repressor
Authors: Denesyuk Natalia A. , Thirumalai D.
Published: December 2020

Experiments and theories have shown that when steric interactions between crowding particles and proteins are dominant, which give rise to Asakura-Oosawa depletion forces, then the stabilities of the proteins increase compared to the infinite dilution case. We show using theoretical arguments that the crowder volume fraction (ΦC) dependent increase in the melting temperature of globular proteins,, where. The effective Flory exponent,νeff, relates the radius of gyration in the unfolded state to the number of amino acid residues in the protein. We derive the bound 1.25 ≤ α ≤ 2.0. The theoretical predictions are confirmed using molecular simulations of λ repressor in the presence of spherical crowding particles. Analyses of previous simulations and experiments confirm the predicted theoretical bound for α. We show that the non-specific attractions between crowding particles and amino acid residues have to be substantial to fully negate the enhanced protein stabilities due to intra protein attractive Asakura-Oosawa (AO) depletion potential. Using the findings, we provide an alternate explanation for the very modest (often less than 0.5 Kcal/mol) destabilization in certain proteins in the cellular milieu. Cellular environment is polydisperse containing large and small crowding agents. AO arguments suggest that proteins would be localized between large (sizes exceeding that of the proteins) crowders, which are predicted to have negligible effect on stability.In vitroexperiments containing mixtures of crowding particles could validate or invalidate the predictions.
Loss of PI3-kinase activity of inositol polyphosphate multikinase impairs PDK1-mediated AKT activation, cell migration and intestinal homeostasis
Authors: Guha Prasun , Reilly Luke , Semenza Evan R. , Abramson Efrat , Mishra Subrata , Sei Yoshitasu , Wank Stephen A. , Donowitz Mark , Snyder Solomon H.
Published: December 2020

Inositol polyphosphate multikinase (IPMK) is a rate-limiting enzyme in the inositol phosphate (IP) pathway which converts IP3 to IP4 and IP5. In mammalian cells, IPMK can also act as a phosphoinositol-3-kinase (PI3-kinase). We previously found that IPMK is a critical PI3-kinase activator of AKT. Here, we show that IPMK mediates AKT activation by promoting membrane localization and activation of PDK1. The PI3-kinase activity of IPMK is dispensable for membrane localization of AKT, which is entirely controlled by classical PI3-kinase (p110α,ß, γ, δ). By contrast, we found that PDK1 membrane localization was largely independent of classical PI3-kinase. Membrane localization of PDK1 stimulates cell migration by dissociating ROCK1 from inhibitory binding to RhoE and promoting ROCK1-mediated myosin light chain (MLC) phosphorylation. Deletion of IPMK impairs cell migration associated with the abolition of PDK1-mediated ROCK1 disinhibition and subsequent MLC phosphorylation. To investigate the physiological relevance of IPMK-mediated AKT activation, we generated mice selectively lacking IPMK in epithelial cells of the intestine, where IPMK is highly expressed. Deletion of IPMK in intestinal epithelial cells markedly reduced AKT phosphorylation and diminished numbers of Paneth cells – a crypt-resident epithelial cell type that generates the physiological niche for intestinal stem cells. Ablation of IPMK impaired intestinal epithelial cell regeneration basally and after; chemotherapy-induced damage, suggesting a broad role for IPMK in the activation of AKT and intestinal tissue regeneration. In summary, the PI3-kinase activity of IPMK promotes membrane localization of PDK1, a critical kinase whereby AKT maintains intestinal homeostasis.

One Sentence Summary

PI3-kinase activity of IPMK is essential for activation of AKT.
A nucleotide-sensing endonuclease from the Gabija bacterial defense system
Authors: Cheng Rui , Huang Fengtao , Wu Hui , Lu Xuelin , Yan Yan , Yu Bingbing , Wang Xionglue , Zhu Bin
Published: December 2020

The arms race between bacteria and phages has led to the development of exquisite bacterial defense systems including a number of uncharacterized systems distinct from the well-known Restriction-Modification and CRISPR/Cas systems. Here, we report functional analyses of the GajA protein from the newly predicted Gabija system. The GajA protein is revealed as an endonuclease unique in that: 1. It may function as a restriction enzyme or a site-specific nicking enzyme, depending on the arrangement of the recognition sequences; 2. Its activity is strictly regulated by nucleotides concentration. NTP and dNTP at physiological concentrations can fully inhibited the robust DNA cleavage activity of GajA. Interestingly, the nucleotide inhibition is mediated by an ATPase-like domain, which usually hydrolyzes ATP to stimulate the DNA cleavage when associated with other nucleases. These features suggested the mechanism of the Gabija defense in which an endonuclease activity was suppressed at normal condition, while activated by the depletion of NTP and dNTP upon the replication and transcription by invaded phages. This work highlights a concise strategy to utilize a single protein for phage resistance via nucleotide regulatory.
Fast and scalable lipid nanoparticle formulation of niclosamide (nano NCM) effectively inhibits SARS-CoV-2 replication in vitro
Authors: Wang Guankui , Gaikwad Hanmant , McCarthy Mary K , Gonzalez-Juarrero Mercedes , Li Yue , Armstrong Michael , Reisdorf Nichole , Morrison Thomas E , Simberg Dmitri
Published: December 2020

As exemplified by the COVID-19 pandemic, highly infective respiratory viruses can spread rapidly in the population because of lack of effective approaches to control viral replication and spread. Niclosamide (NCM) is an old anthelminthic drug (World Health Organization essential medicine list) with pleiotropic pharmacological activities. Several recent publications demonstrated that NCM has broad antiviral activities and potently inhibits viral replication, including replication of SARS-CoV-2, SARS-CoV, and dengue viruses. Unfortunately, NCM is almost completely insoluble in water, which limits its clinical use. We developed a highly scalable and cost-effective nanoparticle formulation of NCM (nano NCM) using only FDA-approved excipient and demonstrated potency against SARS-CoV-2 infection in cells (Vero E6 and ACE2-expressing lung epithelium cells). Our ultimate goal is to develop the nano NCM formulation for treatment of COVID-19 patients.
Response and oil degradation activities of a northeast Atlantic bacterial community to biogenic and synthetic surfactants
Authors: Nikolova Christina , Ijaz Umer Zeeshan , Magill Clayton , Kleindienst Sara , Joye Samantha B. , Gutierrez Tony
Published: December 2020

Background

Although synthetic dispersants are effective in dispersing crude oil, they can alter the natural microbial response to oil and potentially hinder its biodegradation. Biosurfactants, however, are naturally derived products that play a similar role to synthetic dispersants in oil spill response but are easily biodegradable and less toxic. This study investigated the microbial community dynamics, ecological drivers, functional diversity, and oil biodegradation potential of a northeast Atlantic marine microbial community to crude oil when exposed to rhamnolipid or synthetic dispersant Finasol OSR52.

Results

We found the microbial community composition and diversity were markedly different in the rhamnolipid-amended treatment compared to that with Finasol, with key aromatic hydrocarbon-degrading bacteria likeCycloclasticusbeing suppressed in the Finasol treatment but not in oil-only and rhamnolipid-amended treatments. PsychrophilicColwelliaandOleispiradominated the community in both the rhamnolipid and Finasol OSR52 treatments initially but later community structure across treatments diverged significantly:RhodobacteraceaeandVibriodominated the Finasol-amended treatment andColwellia, Oleispira, and laterCycloclasticusandAlcanivorax, dominated the rhamnolipid-amended treatment.Vibrioabundance increased substantially in treatments receiving Finasol, suggesting a potentially important role for these organisms in degrading dispersant components. In fact, Finasol was linked with a negative impact on alpha diversity. Deterministic environmental filtering played a dominant role in regulating the community assembly in all treatments but was strongest in the dispersant-amended treatments. Rhamnolipid-amended and oil-only treatments had the highest functional diversity, however, the overall oil biodegradation was greater in the Finasol treatment, but aromatic biodegradation was highest in the rhamnolipid treatment.

Conclusion

Overall, the natural marine microbial community in the northeast Atlantic responded differently to crude oil dispersed with either synthetic or biogenic surfactants over time, but oil degradation was more enhanced by the synthetic dispersant. Collectively, our results advance the understanding of how rhamnolipid biosurfactants affect the natural marine microbial community, supporting their potential application in oil spills.
Connexin-36-expressing Gap Junctions in VTA GABA Neurons Sustain Opiate Dependence
Authors: Maal-Bared Geith , Yee Mandy , Harding Erika K. , Ghebreselassie Martha , Bergamini Michael , Choy Roxanne , Kim Ethan , Di Vito Stephanie , Patel Maryam , Amirzadeh Mohammadreza , Grieder Taryn E. , Nagy James I. , Bonin Robert P. , van der Kooy Derek
Published: December 2020

Drug dependence is characterized by a switch in motivation wherein a positively reinforcing substance becomes negatively reinforcing. Ventral tegmental area (VTA) GABA neurons form a point of divergence between two double dissociable pathways responsible for these respective motivational states. Here we show that this switch from drug-naïve to opiate-dependent and withdrawn (ODW) motivation is contingent upon the gap junction-forming protein, connexin-36 (Cx36), in VTA GABA neurons. Intra-VTA infusions of the Cx36 blocker, mefloquine, in ODW rats resulted in a reversion to a drug-naïve motivational state and a loss of opiate withdrawal aversions. Consistent with these data, conditional knockout mice lacking Cx36 in GABA neurons (GAD65-Cre;Cx36fl(CFP)/fl(CFP)) were perpetually drug-naïve and never experienced opiate withdrawal aversions. Further, viral-mediated rescue of Cx36 in VTA GABA neurons was sufficient to restore their susceptibility to ODW motivation. Our findings reveal a functional role for VTA gap junctions that has eluded prevailing circuit models of addiction.

Significance

The motivation to seek drugs can vary depending on prior exposure. For instance, recreational and habitual drug use can stem from a desire to experience the pleasurable or relieving properties of the substance, respectively. Here we identify a subpopulation of midbrain neurons that dictate opiate-seeking motivation via expression of the gap junction protein, connexin-36. We show that connexin-36 expression increases upon opiate dependence and withdrawal. We then demonstrate that this is not merely a correlation, as pharmacological or genetic manipulations that interfere with connexin-36 function prevent the development of opiate dependence in rats and mice. Our results identify gap junctions as a critical node in the pathogenesis of opiate addiction, and a potential new target for substance use disorder pharmacotherapies.
Low force unfolding of a single-domain protein by parallel pathways
Authors: Zhuravlev Pavel I. , Hinczewski Michael , Thirumalai D.
Published: December 2020

Deviations from linearity in the dependence of the logarithm of protein unfolding rates, logku(f), as a function of mechanical force,f, measurable in single molecule experiments, can arise for many reasons. In particular, upward curvature in logku(f) as a function of f implies that the underlying energy landscape must be multidimensional with the possibility that unfolding ensues by parallel pathways. Here, simulations using the SOP-SC model of a wild typeβ-sandwich protein and several mutants, with immunoglobulin folds, show upward curvature in the unfolding kinetics. There are substantial changes in the structures of the transition state ensembles as force is increased, signaling a switch in the unfolding pathways. Our results, when combined with previous theoretical and experimental studies, show that parallel unfolding of structurally unrelated single domain proteins can be determined from the dependence of logku(f) as a function of force (or logku[C] where [C] is the denaturant concentration).
Isoform-level transcriptome Atlas of Macrophage Activation
Authors: Vollmers Apple Cortez , Mekonen Honey E. , Campos Sophia , Carpenter Susan , Vollmers Christopher
Published: December 2020

RNA-seq is routinely used to measure gene expression changes in response to cell perturbation. Genes that are up or down-regulated following perturbation in RNA-seq studies are designated as target genes for follow-up. However, RNA-seq is limited in its ability to capture the complexity of gene isoforms, defined by the exact composition of exons and transcription start sites (TSS) and poly(A) sites they contain, as well as the expression of these isoforms. Without knowing the composition of the most dominant isoform(s) of a target gene, a minority or non-existent isoform could be selected for follow-up solely based on available annotations for that target gene from databases that are incomplete, or by their nature not tissue specific, or do not provide key information on expression levels. In all, this can lead to loss in valuable resources and time. As the vast majority of genes in the human genome express more than one isoform, there is a great need to identify the complete range of isoforms present for each gene along with their corresponding levels of expression.

Here, using the long-read nanopore-based R2C2 method, we generated an Isoform-level transcriptome Atlas of Macrophage Activation (IAMA) that identifies full-length isoforms in primary human monocyte-derived macrophages (MDMs). Macrophages are critical innate immune cells important for recognizing pathogens through use of Toll-like receptors (TLRs), culminating in the initiation of host defense pathways. We characterized isoforms for most moderate to highly expressed genes in resting and TLR-activated MDMs and generated a user-friendly portal built into the UCSC Genome Browser to explore the data (https://genome.ucsc.edu/s/vollmers/IAMA). Our atlas represents a valuable resource for innate immune research as it provides unprecedented isoform information for primary human macrophages.
ADe Novoregulation design shows an effectiveness in altering plant secondary metabolism
Authors: Li Mingzhuo , He Xianzhi , La Hovary Christophe , Zhu Yue , Dong Yilun , Liu Shibiao , Xing Hucheng , Liu Yajun , Jie Yucheng , Ma Dongming , Yuzuak Seyit , Xie De-Yu
Published: December 2020

Introduction

Transcription factors (TFs) and cis-regulatory elements (CREs) control gene transcripts involved in various biological processes. We hypothesize that TFs and CREs can be effective molecular tools forDe Novoregulation designs to engineer plants.

Objectives

We selected two Arabidopsis TF types and two tobacco CRE types to design aDe Novoregulation and evaluated its effectiveness in plant engineering.

Methods

G-box and MYB recognition elements (MREs) were identified in fourNicotiana tabacum JAZs(NtJAZs) promoters. MRE-like and G-box like elements were identified in one nicotine pathway gene promoter. TF screening led to select Arabidopsis Production of Anthocyanin Pigment 1 (PAP1/MYB) and Transparent Testa 8 (TT8/bHLH). TwoNtJAZand two nicotine pathway gene promoters were cloned from commercial Narrow Leaf Madole (NL) and KY171 (KY) tobacco cultivars. Electrophoretic mobility shift assay (EMSA), cross-linked chromatin immunoprecipitation (ChIP), and dual luciferase assays were performed to test the promoter binding and activation by PAP1 (P), TT8 (T), PAP1/TT8 together, and the PAP1/TT8/Transparent Testa Glabra 1 (TTG1) complex. A DNA cassette was designed and then synthesized for stacking and expressing PAP1 and TT8 together. Three years of field trials were performed by following industrial and GMO protocols. Gene expression and metabolic profiling were completed to characterize plant secondary metabolism.

Results

PAP1, TT8, PAP1/TT8, and the PAP1/TT8/TTG1 complex bound to and activatedNtJAZpromoters but did not bind to nicotine pathway gene promoters. The engineered red P+T plants significantly upregulated fourNtJAZsbut downregulated the tobacco alkaloid biosynthesis. Field trials showed significant reduction of five tobacco alkaloids and four carcinogenic tobacco specific nitrosamines in most or all cured leaves of engineered P+T and PAP1 genotypes.

Conclusion

G-boxes, MREs, and two TF types are appropriate molecular tools for aDe Novoregulation design to create a novel distant-pathway cross regulation for altering plant secondary metabolism.
Identification of Aorta-Specific DNA Methylation Patterns in Cell-Free DNA from Patients with Bicuspid Aortic Valve-Associated Aortopathy and Correlation with Aortic Wall Cell Death
Authors: Maredia Ashna , Guzzardi David , Aleinati Mohammad , Iqbal Fatima , Madhu Aiswarya , Wang Xuemei , Barker Alex J. , McCarthy Patrick M. , Fedak Paul W. M. , Greenway Steven C.
Published: December 2020

Objective

In a proof-of-concept study we sought to identify aorta-specific differentially methylated regions (DMRs) detectable in plasma cell-free DNA (cfDNA) obtained from patients with bicuspid aortic valve (BAV)-associated aortopathy.

Methods

We used bioinformatics and publicly-available human methylomes to identify aorta-specific DMRs. We used data from 4D-flow cardiac magnetic resonance imaging to identify regions of elevated aortic wall shear stress (WSS) in patients with BAV-associated aortopathy undergoing surgery and correlated WSS regions with aortic tissue cell death assessed using TUNEL staining. Cell-free DNA was isolated from patient plasma and levels of candidate DMRs were correlated with aortic diameter and aortic wall cell death.

Results

Aortic wall cell death was not associated with maximal aortic diameter but was significantly associated with elevated WSS. We identified 24 candidate aorta-specific DMRs and selected 4 for further study. A DMR on chromosome 11 showed acceptable specificity for the aorta and correlated significantly with aortic wall cell death. Plasma levels of total and aorta-specific cfDNA did not correlate with aortic diameter.

Conclusions

Elevated WSS created by abnormal flow hemodynamics is associated with increased aortic wall cell death which supports the use of aorta-specific cfDNA as a potential tool to identify aortopathy and stratify patient risk.

Date and Number of Institutional Review Board Approval

REB17-0207
Grey and White Matter Pathways Underlying the Relationship Between Aerobically Active Lifestyle, Cardiorespiratory Function, and Episodic Memory in the Aging Human Brain
Authors: Eisenstein Tamir , Giladi Nir , Havakuk Ofer , Lerner Yulia
Published: December 2020

Aging is associated with structural alterations of the hippocampus, a key region in episodic memory processes. Aerobic activity and maximal aerobic capacity (MAC), a key measure of cardiorespiratory function and a physiological adaptation of aerobic exercise, have been associated with biological and cognitive resilience of the brain. However, investigations of their relationship with the hippocampus in humans had resulted with inconsistent findings. This study aimed to investigate the relationship between lifestyle’s aerobic activity and MAC and hippocampal grey and white matter structure, as well as episodic memory performance in cognitively healthy older adults. In addition, we examined the relationship between aerobic activity and MAC, and cerebrovascular pathology expressed as white matter lesions (WML). Next, we used a regression-based mediation analysis to examine possible biological pathways which may underlie the relationship between MAC and hippocampal volume, which was demonstrated in previous works, and was confirmed in the current study. Fifty cognitively healthy older adults (70.92 ± 3.9 years) were divided into aerobically active (n=27) and non-active (n=23) groups, and performed structural and diffusion MRI. Forty-two participants were also evaluated for MAC. Aerobically active lifestyle and higher MAC were associated with increased hippocampal volume and microstructural integrity, as well as increased fornix microstructural integrity, and lower WML burden (p<.05). In addition, both factors were correlated with increased episodic memory performance (p<.05). Mediation analysis revealed two pathways potentially mediating the relationship between MAC, hippocampal volume, and episodic memory – a white matter pathway consisted of WML and fornix microstructure, and grey matter pathway including hippocampal microstructure. These findings shed light on possible neurobiological mechanisms that could potentially underlie the neuroprotective effect of cardiorespiratory function and aerobic physical activity on hippocampal macrostructure and memory function in the aging human brain.
Rapid Detection of SARS-CoV-2 Antigen from Serum in a Hospitalized Population
Authors: McAulay K , Kaleta EJ , Grys TE
Published: December 2020

SARS-CoV-2 viremia has been demonstrated in some patients using molecular assays. Here we demonstrate detection of SARS-CoV-2 antigen in a cohort of hospitalized patients using a rapid diagnostic test from Anhui Deepblue Medical Technology Co., Ltd. We detected antigen in serum from 11 of 13 patients at time points ranging from three to eighteen days from symptom onset and observed that the disappearance of an antigen signal was associated with seroconversion. These results demonstrate proof of principle use of a rapid antigen test with serum samples in a format compatible with point of care testing.
PKA drives paracrine crisis and WNT4-dependent testis tumor in Carney complex
Authors: Djari C. , Sahut-Barnola I. , Septier A. , Plotton I. , Montanier N. , Dufour D. , Levasseur A. , Wilmouth J. , Pointud JC. , Faucz FR. , Kamilaris C. , Lopez AG. , Guillou F. , Swain A. , Vainio S. , Tauveron I. , Val P. , Lefebvre H. , Stratakis CA. , Martinez A. , Lefrançois-Martinez AM.
Published: December 2020

Large Cell Calcifying Sertoli Cell Tumors (LCCSCTs) are among the most frequent lesions occurring in Carney complex (CNC) male patients. Although they constitute a key diagnostic criterion for this rare multiple neoplasia syndrome resulting from inactivating mutations of the tumor suppressorPRKAR1Aleading to unrepressed PKA activity, the LCCSCT pathogenesis and origin remain elusive. Mouse models targetingPrkar1ainactivation in all somatic populations or separately in each cell type were generated to decipher the molecular and paracrine networks involved in the CNC testis lesion induction. We demonstrate thatPrkar1amutation is required in both stromal and Sertoli cells for the occurrence of LCCSCT. Integrative analyses comparing transcriptomic, immunohistological data and phenotype of mutant mouse combinations led to understand the human LCCSCT pathogenesis and demonstrated unprecedented PKA-induced paracrine molecular circuits in which the aberrant WNT4 signal production is a limiting step in shaping intratubular lesions and tumor expansion both in mouse model and human CNC testes.
Efficient target cleavage by Type V Cas12a effector programmed with split CRISPR RNA
Authors: Tkach Regina , Nikitchina Natalia , Shebanov Nikita , Mekler Vladimir , Ulashchik Egor , Sharko Olga , Shmanai Vadim , Tarassov Ivan , Severinov Konstantin , Entelis Nina , Mazunin Ilya
Published: December 2020

CRISPR RNAs (crRNAs) directing target DNA cleavage by type V-A Cas12a nucleases consist of repeat-derived 5’-scaffold moiety and 3’-spacer moiety. We demonstrate that removal of most of the 20-nucleotide scaffold has only a slight effect onin vitrotarget DNA cleavage by Cas12a ortholog from Acidaminococcus sp (AsCas12a). In fact, residual cleavage was observed even in the presence of a 20-nucleotide crRNA spacer part only, while crRNAs split into two individual moieties (scaffold and spacer RNAs) catalyzed highly specific and efficient cleavage of target DNA. Our data also indicate that AsCas12a combined with split crRNA forms a stable complex with the target. These observations were also confirmed in lysates of human cells expressing AsCas12a. The ability of the AsCas12a nuclease to be programmed with split crRNAs opens new lines of inquiry into the mechanisms of target recognition and cleavage and will further facilitate genome editing techniques based on Cas12a nucleases.
Binding strength and hydrogen bond numbers between Covid-19 RBD and HVR of antibody
Authors: Wang Ryan Taoran , Xu Alex Fan , Zhou Qi , Song Tinglu , Xu Kelvin J. , Xu Gu
Published: December 2020

The global battle against the Covid-19 pandemic relies strongly on the human defence of antibody, which is assumed to bind the antigen’s Receptor Binding Domain with its Hypervariable Region. Due to the similarity to other viruses such as SARS, however, our understanding of the antibody-virus interaction has been largely limited to the genomic sequencing, which poses serious challenges to the containment, vaccine exploration and rapid serum testing. Based on the physical/chemical nature of the interaction, infrared spectroscopy was employed to reveal the binding disparity, when unusual temperature dependence was discovered from the 1550cm-1absorption band, attributed to the hydrogen bonds by carboxyl/amino groups, binding the SARS-CoV-2 spike protein and closely resembled SARS-CoV-2 or SARS-CoV-1 antibodies. The infrared absorption intensity, associated with the number of hydrogen bonds, was found to increase sharply between 27°C and 31°C, with the relative absorbance matches at 37°C the hydrogen bonding numbers of the two antibody types (19 vs 12). Meanwhile the ratio of bonds at 27°C, calculated by thermodynamic exponentials rather than by the layman’s guess, produces at least 5% inaccuracy. As a result, the specificity of the SARS-CoV-2 antibody will be more conclusive beyond 31°C, instead of at the usual room temperature of 20°C - 25°C, when the vaccine research and antibody diagnosis would likely be undermined. Beyond genomic sequencing, the temperature dependence, as well as the bond number match at 37°C between relative absorbance and the hydrogen bonding numbers of the two antibody types, are not only of clinical significance in particular, but also of a sample for the physical/chemical understanding of the vaccine-antibody interactions in general.
Methane emission of humans is explained by dietary habits, host genetics, local formate availability and a uniform archaeome
Authors: Kumpitsch Christina , Fischmeister Florian , Mahnert Alexander , Lackner Sonja , Wilding Marilena , Sturm Corina , Springer Anna , Madl Tobias , Holasek Sandra , Hoegenauer Christoph , Berg Ivan , Schoepf Veronika , Moissl-Eichinger Christine
Published: December 2020

Archaea are responsible for methane production in the human gastrointestinal tract. Twenty percent of the Western populations exhale substantial amounts of this gas. The underlying principle determining high or low methane emission and its effect on human health was still not sufficiently understood. In this study, we analysed the gastrointestinal microbiome, archaeome, metagenome, metabolome, and eating behaviour of 100 healthy young adults. We correlated high levels of human methane emission (5-75 ppm) with a 1000-fold increase in Methanobrevibacter smithii. This archaeon co-occurred with a bacterial community specialised on dietary fibre degradation, which included members of the Ruminococcaceae and Christensenellaceae. Methane production was negatively affected by high vitamin B12 and fat intake of the subjects, and was positively associated with increased formate concentrations in the gut. Overall, methane emission is explained by dietary habits, host genetics, local metabolite availability and microbiome/archaeome composition, emphasizing the unique biology of high methane-emitters which has potentially positive impact on human health.
Microbial regulation of hexokinase 2 links mitochondrial metabolism and cell death in colitis
Authors: Hamm Jacob , Hinrichsen Finn , Schröder Lena , Mishra Neha , Shima Kensuke , Walker Alesia , Sommer Nina , Klischies Kenneth , Prasse Daniela , Zimmermann Johannes , Kaiser Sina , Bordoni Dora , Fazio Antonella , Laue Georg , Tremaroli Valentina , Basic Marijana , Häsler Robert , Schmitz Ruth A. , Krautwald Stefan , Wolf Andrea , Stecher Bärbel , Schmitt-Kopplin Philippe , Kaleta Christoph , Rupp Jan , Bäckhed Fredrik , Rosenstiel Philip , Sommer Felix
Published: December 2020

Hexokinases (HK) catalyze the first step of glycolysis and thereby limit its pace. HK2 is highly expressed in the gut epithelium, plays a role in immune responses and is upregulated in inflammation and ulcerative colitis1–3. Here, we examined the microbial regulation of HK2 and its impact on intestinal inflammation by generating mice lacking HK2 specifically in intestinal epithelial cells (Hk2ΔIEC).Hk2ΔIECmice were less susceptible to acute intestinal inflammation upon challenge with dextran sodium sulfate (DSS). Analyzing the epithelial transcriptome fromHk2ΔIECmice during acute colitis revealed downregulation of cell death signaling and mitochondrial dysfunction dependent on loss of HK2. Using intestinal organoids derived fromHk2ΔIECmice and Caco-2 cells lacking HK2, we identified peptidyl-prolyl cis-trans isomerase (PPIF) as a key target of HK2-mediated regulation of mitochondrial permeability and repression of cell-death during intestinal inflammation. The microbiota strongly regulated HK2 expression and activity. The microbially-derived short-chain fatty acid (SCFA) butyrate repressed HK2 expression and oral supplementation protected wildtype but notHk2ΔIECmice from DSS colitis. Our findings define a novel mechanism how butyrate may act as a protective factor for intestinal barrier homeostasis and suggest targeted HK2 inhibition as a promising therapeutic avenue in intestinal inflammation.
Microbially induced chromium isotope fractionation and trace elements behavior in lower Cambrian microbialites from the Jaíba Member, Bambuí Basin, Brazil
Authors: Uhlein Gabriel J. , Caxito Fabrício A. , Frei Robert , Uhlein Alexandre , Sial Alcides N. , Dantas Elton L.
Published: December 2020

In east‐central Brazil, the Ediacaran‐Cambrian Bambuí Basin has the potential to provide a record of unique geochemical responses of Earth's ocean and atmosphere evolution during this key time interval. From this perspective, we studied an interval of the upper Bambuí Basin using sedimentologic, stratigraphic, and chemostratigraphic tools. The lower Cambrian Jaíba Member of the uppermost Serra da Saudade Formation is an interval of up to 60 m‐thick of carbonate rocks disposed into two shallowing upward trends. Inner to outer ramp and high‐energy shoal deposits are described, in which laminated microbialites are the prevailing sedimentary facies. REE + Y data suggest contamination by iron (oxy)hydroxides that are dissociated from the riverine detritic flux. Sedimentary iron enrichment may be related to the settling of iron nanoparticles in coastal environments, diagenetic iron mobilization, or both. MREE enrichment is caused by microbial degradation of organic matter in the iron reduction zone during the anoxic early‐diagenetic stage. Chromium isotopes yielded negatively fractionated values (δ53Cr = −0.69 to −0.27‰), probably resulting from biotic and abiotic reduction of dissolved Cr(VI) to light and less toxic Cr(III) within pores of microbial mats. The δ53Cr data of the Jaíba microbialite are thus a product of metabolic reactions in microbial mats and do not reflect seawater signal. The isotopic offset from seawater is feasible from molecular diffusion of Cr into pore water and reduction reactions occurring deep inside the mat, although the exact mechanism and consequences are not yet fully understood due to the poor preservation of metabolic reactions in the geological record. Our study suggests that Cr isotopes can be used to reconstruct Cr and other metals cycling within ancient microbial mats, and that caution should be taken when using past microbialites to infer seawater Cr records and redox state of the atmosphere and ocean.
Whither the State? The Oslo Peace Process and Neoliberal Configurations of Palestine
Authors: Morrison Suzanne
Published: December 2020

Objective

This article considers the raison d'être of international institutions in the occupied Palestinian territories during the Oslo period (1993–2000) and discusses how these institutions have shaped the notion of a future Palestinian state through their policy recommendations and development projects.

Methods

Drawing on neo‐Gramscian concepts of hegemony and internationalization of the state this project analyzes the Oslo peace process through primary source data and information in the Oslo Accords as well as the official reports and publications of the major international development and financial organizations involved in the Palestinian territories.

Results

Through policy recommendations, development projects, and donor funding and aid coordination, international institutions set in motion the neoliberal conceptualization and configuration of Palestine during the Oslo process.

Conclusion

I conclude with a review of the findings, as illustrated throughout the article, and emphasize that Palestine's conceptualization will continue to be rooted in the development of the neoliberal condition as long as a political process that would lead to Palestinian self‐determination and an end the conflict is not pursued.
Evolución de la política de cambio climático en Colombia
Authors: Guardela Contreras Luis Magin
Published: December 2020

El presente artículo, es resultado del avance de la investigación doctoral denominada: “Sostenibilidad ambiental urbana en el Caribe Colombiano: análisis jurídico-administrativo de las actuaciones realizadas por los Distritos del Caribe Colombiano para lograr la mitigación y adaptación al cambio climático”, la cual dentro de sus objetivos trazó analizar la política pública de cambio climático, acotando los avances en la consolidación de una visión y, en consecuencia, la formulación de la misma. Para lograr este objetivo se utilizó una metodología de corte jurídico, analítico y descriptivo con enfoque predominante cualitativo, cuyo insumo primario fueron las medidas jurídico-administrativas adoptadas por los estamentos políticos-administrativos en relación al objeto de estudio. Del cual se concluye que para hacer efectiva la visión preventiva (mitigación) y adaptativa para afrontar el fenómeno, se debe realizar: a) La articulación  efectiva de las entidades que integran la gestión pública del Estado Colombiano; b) la inclusión efectiva de rubros presupuestales  sobre cambio climático en las entidades públicas de todo los niveles, en razón de la transversalidad de la política pública, y; c) el reforzamiento de las apuestas en las variables de mitigación y adaptación en los instrumentos de planificación del territorio, desarrollo socioeconómico y la gestión del riesgo de desastres.
Sobre algoritmos y eficiencias: fijación de precios y empresas de redes de transporte
Authors: Arboleda Suárez Carlos Ignacio
Published: December 2020

El sector de la movilidad urbana ha sido uno de los más afectados por la creciente utilización de aplicaciones móviles. Éstas han generado una reducción de costos de entrada y de transacción tan importantes que los mercados han crecido de forma asombrosa. Sin embargo, y como suele ser el caso, las normas no han evolucionado tan rápidamente. Las plataformas digitales suponen un reto en el ordenamiento jurídico, el cual no ha sido ajeno a nuestra concepción de libre competencia. Por ello, es importante entender los impactos económicos –negativos y positivos- que traen estas tecnologías de movilidad para entender su modelo de negocio, proceso de formación de precios y transacciones y, en últimas, evitar regularlos de manera equivocada con categorías legales que ya no se acoplan a la realidad.
ToF-SIMS imaging of dual biomolecular monolayer gradients
Authors: Evenbratt Hanne , Munem Marwa , Malmberg Per
Published: December 2020

Precise characterization of a monolayer of two different biomolecules in a gradient pattern on a glass surface puts high demand on the method used. Some techniques can detect protein monolayers but not on a glass surface. Others can distinguish between different proteins but not identify a gradient pattern. Here, we used ToF-SIMS to validate the complete surface composition, checking all the necessary boxes. As these types of surfaces can dictate sensitive cell behaviors, the precision on a nanolevel is crucial, and to visualize and determine the molecular distribution become essential. The dual monolayer consisted of laminin 521 and one of three other biomolecules of different sizes, epidermal growth factor, growth differentiation factor 5, or bovine serum albumin, creating opposing gradient patterns. The resulting ToF-SIMS imaging and line scan data provided detailed information on the distribution of the adsorbed proteins.
Bonobos engage in joint commitment
Authors: Heesen Raphaela , Bangerter Adrian , Zuberbühler Klaus , Rossano Federico , Iglesias Katia , Guéry Jean-Pascal , Genty Emilie
Published: December 2020

Bonobos reengage partners after interruptions of social activities, suggesting that they engage in joint commitment.
Weyl fermions, Fermi arcs, and minority-spin carriers in ferromagnetic CoS
2
Authors: Schröter Niels B. M. , Robredo Iñigo , Klemenz Sebastian , Kirby Robert J. , Krieger Jonas A. , Pei Ding , Yu Tianlun , Stolz Samuel , Schmitt Thorsten , Dudin Pavel , Kim Timur K. , Cacho Cephise , Schnyder Andreas , Bergara Aitor , Strocov Vladimir N. , de Juan Fernando , Vergniory Maia G. , Schoop Leslie M.
Published: December 2020

Pyrite CoS
2
, which was long studied as a potential half-metal, is shown to be a magnetic Weyl semimetal.
Portomesenteric thrombosis after robotic sleeve gastrectomy
Authors: Jaikaran Omkaar , Lim Derek , Binetti Brian , Meytes Vadim
Published: December 2020

Portomesenteric thrombosis is an important but rarely reported complication following bariatric surgery. It has been suggested that the incidence of portal vein thrombosis is directly related to many risk factors inherent in the bariatric population as well as factors related to local and systemic effects of laparoscopic surgery. Possible aetiologies vary from systemic inherited hypercoagulable states to a direct inflammatory reaction of portosystemic vessels. Here we present a case report of a 47-year-old obese women who underwent a robotic sleeve gastrectomy with subsequent development of a main portal vein, complete right intrahepatic portal vein and splenic vein thrombosis ultimately found to have a compound mutation of the methylenetetrahydrofolate reductase C677T and A1298C alleles.
Chronic active Epstein-Barr virus: a multidisciplinary approach
Authors: Wauchope Jessica , Dorris Colm Brendan , Smith Caroline Patricia , Hanna Brendan
Published: December 2020

A 17-year-old Caucasian male presented to ENT with angular stomatitis, oral ulceration and cervical lymphadenopathy. Over the subsequent 18 months he developed recurrent upper respiratory tract infections, pyrexia of unknown origin, oral ulceration and maxillary sinus osteomyelitis. Extensive investigation ensued from various specialties. Positive investigations included a mild but persistently elevated serum Epstein-Barr virus PCR; however, no unifying diagnosis was elicited. It is noteworthy that a significant factor contributing to a delay in his diagnosis was poor compliance with invasive investigations. Ultimately, deteriorating liver function prompted liver biopsy which confirmed a diagnosis of chronic active Epstein-Barr virus infection (CAEBV). This enabled referral for curative treatment in the form of a stem cell transplant. CAEBV is extremely rare in Western countries. Due to fatal complications early diagnosis is critical for successful treatment. Our case highlights the need for regular clinical re-evaluation and a comprehensive multispecialty approach in such cases.
Sustained clinical response to infliximab in refractory Cronkhite-Canada syndrome
Authors: Jiang Caroline Di , Myint Helen , Tie Andy , Stace Nigel H
Published: December 2020

A 59-year-old man with refractory Cronkhite-Canada syndrome (CCS) had poor clinical response to high-dose intravenous steroids, azathioprine, total parenteral nutrition and best supportive care. He remained highly symptomatic with abdominal pain, diarrhoea, recurrent sepsis and profound weight loss. Infliximab induction was given as rescue therapy, with marked clinical improvement observed within 3 weeks. This allowed steroid taper. Within 12 months of infliximab therapy, he achieved complete clinical remission and returned to his baseline weight and a full oral diet. Sequential endoscopies observed significant regression of previous marked gastrointestinal polyposis, including histological remission on colonic biopsies at 3.5 and 5 years of treatment. He currently remains in remission following 6 years of combination therapy with 5 mg/kg 8 weekly infliximab and azathioprine, and there is ongoing discussion with regard to the benefits and risks of therapy de-escalation. This case demonstrates the effectiveness of infliximab in inducing and maintaining remission in refractory CCS.
Okinawa Beyond the Hub-and-spoke Alliance System: A Reappraisal
Authors: UNTALAN Carmina Yu
Published: December 2020

Okinawa is a cornerstone of the US–Japan alliance. However, it has been marginalised in East Asian international relations whereby a state-centric view of international relations predominates. In an era of power transitions and increasing importance of non-traditional security concerns, Washington and Tokyo need to recognise Okinawa’s contribution as a non-state actor in upholding human security values for the alliance to stay attuned to shifting regional and global needs.