bluuebunny/crossref_metadata_2025 huggingface dataset:
MIR22HG inhibits breast cancer progression by stabilizing LATS2 tumor suppressor
Authors: Deng Xiaochong , Ye Danrong , Hua Kaiyao , Song Hongming , Luo Qifeng , Munankarmy Amik , Liu Diya , Zhou Baian , Zheng Wenfang , Zhou Xiqian , Ji Changle , Wang Xuehui , Yu Yunhe , Fang Lin
Published: August 2021

The long noncoding RNA called MIR22 host gene (MIR22HG) was previously identified as a tumor suppressor in several cancers. However, the biological function of MIR22HG in breast cancer remains unknown. In this study, we aimed to determine the function and molecular mechanism of MIR22HG in breast cancer progression using transcriptomics and biotechnological techniques. Our results showed that MIR22HG expression was lower in the cancerous tissues than in the paired adjacent normal breast tissues. Additionally, MIR22HG was found to be mainly located in the cytoplasm and acted as a miR-629-5p sponge. Notably, MIR22HG stabilized the expression of large tumor suppressor 2 (LATS2), which promoted the LATS2-dependent phosphorylation of YAP1 and suppressed the expression of its downstream target oncogenes, thereby inhibiting the proliferation and migration of breast cancer cells. Therefore, our findings reveal the MIR22HG-dependent inhibition of breast cancer cell proliferation and migration via the miR-629-5p/LATS2 pathway, providing new insights and identifying novel therapeutic targets for breast cancer treatment.
Amnion signals are essential for mesoderm formation in primates
Authors: Yang Ran , Goedel Alexander , Kang Yu , Si Chenyang , Chu Chu , Zheng Yi , Chen Zhenzhen , Gruber Peter J. , Xiao Yao , Zhou Chikai , Witman Nevin , Eroglu Elif , Leung Chuen-Yan , Chen Yongchang , Fu Jianping , Ji Weizhi , Lanner Fredrik , Niu Yuyu , Chien Kenneth R.
Published: August 2021

Embryonic development is largely conserved among mammals. However, certain genes show divergent functions. By generating a transcriptional atlas containing >30,000 cells from post-implantation non-human primate embryos, we uncover that ISL1, a gene with a well-established role in cardiogenesis, controls a gene regulatory network in primate amnion. CRISPR/Cas9-targeting of ISL1 results in non-human primate embryos which do not yield viable offspring, demonstrating that ISL1 is critically required in primate embryogenesis. On a cellular level, mutant ISL1 embryos display a failure in mesoderm formation due to reduced BMP4 signaling from the amnion. Via loss of function and rescue studies in human embryonic stem cells we confirm a similar role of ISL1 in human in vitro derived amnion. This study highlights the importance of the amnion as a signaling center during primate mesoderm formation and demonstrates the potential of in vitro primate model systems to dissect the genetics of early human embryonic development.
An integrated in vivo/in vitro framework to enhance cell-free biosynthesis with metabolically rewired yeast extracts
Authors: Rasor Blake J. , Yi Xiunan , Brown Hunter , Alper Hal S. , Jewett Michael C.
Published: August 2021

Cell-free systems using crude cell extracts present appealing opportunities for designing biosynthetic pathways and enabling sustainable chemical synthesis. However, the lack of tools to effectively manipulate the underlying host metabolism in vitro limits the potential of these systems. Here, we create an integrated framework to address this gap that leverages cell extracts from host strains genetically rewired by multiplexed CRISPR-dCas9 modulation and other metabolic engineering techniques. As a model, we explore conversion of glucose to 2,3-butanediol in extracts from flux-enhanced Saccharomyces cerevisiae strains. We show that cellular flux rewiring in several strains of S. cerevisiae combined with systematic optimization of the cell-free reaction environment significantly increases 2,3-butanediol titers and volumetric productivities, reaching productivities greater than 0.9 g/L-h. We then show the generalizability of the framework by improving cell-free itaconic acid and glycerol biosynthesis. Our coupled in vivo/in vitro metabolic engineering approach opens opportunities for synthetic biology prototyping efforts and cell-free biomanufacturing.
Bioengineered embryoids mimic post-implantation development in vitro
Authors: Girgin Mehmet U. , Broguiere Nicolas , Hoehnel Sylke , Brandenberg Nathalie , Mercier Bastien , Arias Alfonso Martinez , Lutolf Matthias P.
Published: August 2021

The difficulty of studying post-implantation development in mammals has sparked a flurry of activity to develop in vitro models, termed embryoids, based on self-organizing pluripotent stem cells. Previous approaches to derive embryoids either lack the physiological morphology and signaling interactions, or are unconducive to model post-gastrulation development. Here, we report a bioengineering-inspired approach aimed at addressing this gap. We employ a high-throughput cell aggregation approach to simultaneously coax mouse embryonic stem cells into hundreds of uniform epiblast-like aggregates in a solid matrix-free manner. When co-cultured with mouse trophoblast stem cell aggregates, the resulting hybrid structures initiate gastrulation-like events and undergo axial morphogenesis to yield structures, termed EpiTS embryoids, with a pronounced anterior development, including brain-like regions. We identify the presence of an epithelium in EPI aggregates as the major determinant for the axial morphogenesis and anterior development seen in EpiTS embryoids. Our results demonstrate the potential of EpiTS embryoids to study peri-gastrulation development in vitro.
Seasonal Arctic sea ice forecasting with probabilistic deep learning
Authors: Andersson Tom R. , Hosking J. Scott , Pérez-Ortiz María , Paige Brooks , Elliott Andrew , Russell Chris , Law Stephen , Jones Daniel C. , Wilkinson Jeremy , Phillips Tony , Byrne James , Tietsche Steffen , Sarojini Beena Balan , Blanchard-Wrigglesworth Eduardo , Aksenov Yevgeny , Downie Rod , Shuckburgh Emily
Published: August 2021

Anthropogenic warming has led to an unprecedented year-round reduction in Arctic sea ice extent. This has far-reaching consequences for indigenous and local communities, polar ecosystems, and global climate, motivating the need for accurate seasonal sea ice forecasts. While physics-based dynamical models can successfully forecast sea ice concentration several weeks ahead, they struggle to outperform simple statistical benchmarks at longer lead times. We present a probabilistic, deep learning sea ice forecasting system, IceNet. The system has been trained on climate simulations and observational data to forecast the next 6 months of monthly-averaged sea ice concentration maps. We show that IceNet advances the range of accurate sea ice forecasts, outperforming a state-of-the-art dynamical model in seasonal forecasts of summer sea ice, particularly for extreme sea ice events. This step-change in sea ice forecasting ability brings us closer to conservation tools that mitigate risks associated with rapid sea ice loss.
Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease
Authors: Lewis-Israeli Yonatan R. , Wasserman Aaron H. , Gabalski Mitchell A. , Volmert Brett D. , Ming Yixuan , Ball Kristen A. , Yang Weiyang , Zou Jinyun , Ni Guangming , Pajares Natalia , Chatzistavrou Xanthippi , Li Wen , Zhou Chao , Aguirre Aitor
Published: August 2021

Congenital heart defects constitute the most common human birth defect, however understanding of how these disorders originate is limited by our ability to model the human heart accurately in vitro. Here we report a method to generate developmentally relevant human heart organoids by self-assembly using human pluripotent stem cells. Our procedure is fully defined, efficient, reproducible, and compatible with high-content approaches. Organoids are generated through a three-step Wnt signaling modulation strategy using chemical inhibitors and growth factors. Heart organoids are comparable to age-matched human fetal cardiac tissues at the transcriptomic, structural, and cellular level. They develop sophisticated internal chambers with well-organized multi-lineage cardiac cell types, recapitulate heart field formation and atrioventricular specification, develop a complex vasculature, and exhibit robust functional activity. We also show that our organoid platform can recreate complex metabolic disorders associated with congenital heart defects, as demonstrated by an in vitro model of pregestational diabetes-induced congenital heart defects.
Oral immune dysfunction is associated with the expansion of FOXP3+PD-1+Amphiregulin+ T cells during HIV infection
Authors: Bhaskaran N. , Schneider E. , Faddoul F. , Paes da Silva A. , Asaad R. , Talla A. , Greenspan N. , Levine A. D. , McDonald D. , Karn J. , Lederman M. M. , Pandiyan P.
Published: August 2021

Residual systemic inflammation and mucosal immune dysfunction persist in people living with HIV, despite treatment with combined anti-retroviral therapy, but the underlying immune mechanisms are poorly understood. Here we report that the altered immune landscape of the oral mucosa of HIV-positive patients on therapy involves increased TLR and inflammasome signaling, localized CD4+ T cell hyperactivation, and, counterintuitively, enrichment of FOXP3+ T cells. HIV infection of oral tonsil cultures in vitro causes an increase in FOXP3+ T cells expressing PD-1, IFN-γ, Amphiregulin and IL-10. These cells persist even in the presence of anti-retroviral drugs, and further expand when stimulated by TLR2 ligands and IL-1β. Mechanistically, IL-1β upregulates PD-1 expression via AKT signaling, and PD-1 stabilizes FOXP3 and Amphiregulin through a mechanism involving asparaginyl endopeptidase, resulting in FOXP3+ cells that are incapable of suppressing CD4+ T cells in vitro. The FOXP3+ T cells that are abundant in HIV-positive patients are phenotypically similar to the in vitro cultured, HIV-responsive FOXP3+ T cells, and their presence strongly correlates with CD4+ T cell hyper-activation. This suggests that FOXP3+ T cell dysregulation might play a role in the mucosal immune dysfunction of HIV patients on therapy.
A guanidine-degrading enzyme controls genomic stability of ethylene-producing cyanobacteria
Authors: Wang Bo , Xu Yao , Wang Xin , Yuan Joshua S. , Johnson Carl H. , Young Jamey D. , Yu Jianping
Published: August 2021

Recent studies have revealed the prevalence and biological significance of guanidine metabolism in nature. However, the metabolic pathways used by microbes to degrade guanidine or mitigate its toxicity have not been widely studied. Here, via comparative proteomics and subsequent experimental validation, we demonstrate that Sll1077, previously annotated as an agmatinase enzyme in the model cyanobacterium Synechocystis sp. PCC 6803, is more likely a guanidinase as it can break down guanidine rather than agmatine into urea and ammonium. The model cyanobacterium Synechococcus elongatus PCC 7942 strain engineered to express the bacterial ethylene-forming enzyme (EFE) exhibits unstable ethylene production due to toxicity and genomic instability induced by accumulation of the EFE-byproduct guanidine. Co-expression of EFE and Sll1077 significantly enhances genomic stability and enables the resulting strain to achieve sustained high-level ethylene production. These findings expand our knowledge of natural guanidine degradation pathways and demonstrate their biotechnological application to support ethylene bioproduction.
Implantable optical fibers for immunotherapeutics delivery and tumor impedance measurement
Authors: Chin Ai Lin , Jiang Shan , Jang Eungyo , Niu Liqian , Li Liwu , Jia Xiaoting , Tong Rong
Published: August 2021

Immune checkpoint blockade antibodies have promising clinical applications but suffer from disadvantages such as severe toxicities and moderate patient–response rates. None of the current delivery strategies, including local administration aiming to avoid systemic toxicities, can sustainably supply drugs over the course of weeks; adjustment of drug dose, either to lower systemic toxicities or to augment therapeutic response, is not possible. Herein, we develop an implantable miniaturized device using electrode-embedded optical fibers with both local delivery and measurement capabilities over the course of a few weeks. The combination of local immune checkpoint blockade antibodies delivery via this device with photodynamic therapy elicits a sustained anti-tumor immunity in multiple tumor models. Our device uses tumor impedance measurement for timely presentation of treatment outcomes, and allows modifications to the delivered drugs and their concentrations, rendering this device potentially useful for on-demand delivery of potent immunotherapeutics without exacerbating toxicities.
Tumour-targeted interleukin-12 and entinostat combination therapy improves cancer survival by reprogramming the tumour immune cell landscape
Authors: Hicks Kristin C. , Chariou Paul L. , Ozawa Yohei , Minnar Christine M. , Knudson Karin M. , Meyer Thomas J. , Bian Jing , Cam Margaret , Schlom Jeffrey , Gameiro Sofia R.
Published: August 2021

Poorly inflamed carcinomas do not respond well to immune checkpoint blockade. Converting the tumour microenvironment into a functionally inflamed immune hub would extend the clinical benefit of immune therapy to a larger proportion of cancer patients. Here we show, by using comprehensive single-cell transcriptome, proteome, and immune cell analysis, that Entinostat, a class I histone deacetylase inhibitor, facilitates accumulation of the necrosis-targeted recombinant murine immune-cytokine, NHS-rmIL12, in experimental mouse colon carcinomas and poorly immunogenic breast tumours. This combination therapy reprograms the tumour innate and adaptive immune milieu to an inflamed landscape, where the concerted action of highly functional CD8+T cells and activated neutrophils drive macrophage M1-like polarization, leading to complete tumour eradication in 41.7%-100% of cases. Biomarker signature of favourable overall survival in multiple human tumor types shows close resemblance to the immune pattern generated by Entinostat/NHS-rmIL12 combination therapy. Collectively, these findings provide a rationale for combining NHS-IL12 with Entinostat in the clinical setting.
AHR signaling is induced by infection with coronaviruses
Authors: Giovannoni Federico , Li Zhaorong , Remes-Lenicov Federico , Dávola María E. , Elizalde Mercedes , Paletta Ana , Ashkar Ali A. , Mossman Karen L. , Dugour Andrea V. , Figueroa Juan M. , Barquero Andrea A. , Ceballos Ana , Garcia Cybele C. , Quintana Francisco J.
Published: August 2021

Coronavirus infection in humans is usually associated to respiratory tract illnesses, ranging in severity from mild to life-threatening respiratory failure. The aryl hydrocarbon receptor (AHR) was recently identified as a host factor for Zika and dengue viruses; AHR antagonists boost antiviral immunity, decrease viral titers and ameliorate Zika-induced pathology in vivo. Here we report that AHR is activated by infection with different coronaviruses, potentially impacting antiviral immunity and lung epithelial cells. Indeed, the analysis of single-cell RNA-seq from lung tissue detected increased expression of AHR and AHR transcriptional targets, suggesting AHR signaling activation in SARS-CoV-2-infected epithelial cells from COVID-19 patients. Moreover, we detected an association between AHR expression and viral load in SARS-CoV-2 infected patients. Finally, we found that the pharmacological inhibition of AHR suppressed the replication in vitro of one of the causative agents of the common cold, HCoV-229E, and the causative agent of the COVID-19 pandemic, SARS-CoV-2. Taken together, these findings suggest that AHR activation is a common strategy used by coronaviruses to evade antiviral immunity and promote viral replication, which may also contribute to lung pathology. Future studies should further evaluate the potential of AHR as a target for host-directed antiviral therapy.
Controllable CO2 electrocatalytic reduction via ferroelectric switching on single atom anchored In2Se3 monolayer
Authors: Ju Lin , Tan Xin , Mao Xin , Gu Yuantong , Smith Sean , Du Aijun , Chen Zhongfang , Chen Changfeng , Kou Liangzhi
Published: August 2021

Efficient and selective CO2 electroreduction into chemical fuels promises to alleviate environmental pollution and energy crisis, but it relies on catalysts with controllable product selectivity and reaction path. Here, by means of first-principles calculations, we identify six ferroelectric catalysts comprising transition-metal atoms anchored on In2Se3 monolayer, whose catalytic performance can be controlled by ferroelectric switching based on adjusted d-band center and occupation of supported metal atoms. The polarization dependent activation allows effective control of the limiting potential of CO2 reduction on TM@In2Se3 (TM = Ni, Pd, Rh, Nb, and Re) as well as the reaction paths and final products on Nb@In2Se3 and Re@In2Se3. Interestingly, the ferroelectric switching can even reactivate the stuck catalytic CO2 reduction on Zr@In2Se3. The fairly low limiting potential and the unique ferroelectric controllable CO2 catalytic performance on atomically dispersed transition-metals on In2Se3 clearly distinguish them from traditional single atom catalysts, and open an avenue toward improving catalytic activity and selectivity for efficient and controllable electrochemical CO2 reduction reaction.
Fire-derived phosphorus fertilization of African tropical forests
Authors: Bauters Marijn , Drake Travis W. , Wagner Sasha , Baumgartner Simon , Makelele Isaac A. , Bodé Samuel , Verheyen Kris , Verbeeck Hans , Ewango Corneille , Cizungu Landry , Van Oost Kristof , Boeckx Pascal
Published: August 2021

Central African tropical forests face increasing anthropogenic pressures, particularly in the form of deforestation and land-use conversion to agriculture. The long-term effects of this transformation of pristine forests to fallow-based agroecosystems and secondary forests on biogeochemical cycles that drive forest functioning are poorly understood. Here, we show that biomass burning on the African continent results in high phosphorus (P) deposition on an equatorial forest via fire-derived atmospheric emissions. Furthermore, we show that deposition loads increase with forest regrowth age, likely due to increasing canopy complexity, ranging from 0.4 kg P ha−1 yr−1 on agricultural fields to 3.1 kg P ha−1 yr−1 on old secondary forests. In forest systems, canopy wash-off of dry P deposition increases with rainfall amount, highlighting how tropical forest canopies act as dynamic reservoirs for enhanced addition of this essential plant nutrient. Overall, the observed P deposition load at the study site is substantial and demonstrates the importance of canopy trapping as a pathway for nutrient input into forest ecosystems.
Pan-cancer analysis of longitudinal metastatic tumors reveals genomic alterations and immune landscape dynamics associated with pembrolizumab sensitivity
Authors: Cindy Yang S. Y. , Lien Scott C. , Wang Ben X. , Clouthier Derek L. , Hanna Youstina , Cirlan Iulia , Zhu Kelsey , Bruce Jeffrey P. , El Ghamrasni Samah , Iafolla Marco A. J. , Oliva Marc , Hansen Aaron R. , Spreafico Anna , Bedard Philippe L. , Lheureux Stephanie , Razak Albiruni , Speers Vanessa , Berman Hal K. , Aleshin Alexey , Haibe-Kains Benjamin , Brooks David G. , McGaha Tracy L. , Butler Marcus O. , Bratman Scott V. , Ohashi Pamela S. , Siu Lillian L. , Pugh Trevor J.
Published: August 2021

Serial circulating tumor DNA (ctDNA) monitoring is emerging as a non-invasive strategy to predict and monitor immune checkpoint blockade (ICB) therapeutic efficacy across cancer types. Yet, limited data exist to show the relationship between ctDNA dynamics and tumor genome and immune microenvironment in patients receiving ICB. Here, we present an in-depth analysis of clinical, whole-exome, transcriptome, and ctDNA profiles of 73 patients with advanced solid tumors, across 30 cancer types, from a phase II basket clinical trial of pembrolizumab (NCT02644369) and report changes in genomic and immune landscapes (primary outcomes). Patients stratified by ctDNA and tumor burden dynamics correspond with survival and clinical benefit. High mutation burden, high expression of immune signatures, and mutations inBRCA2are associated with pembrolizumab molecular sensitivity, while abundant copy-number alterations andB2Mloss-of-heterozygosity corresponded with resistance. Upon treatment, induction of genes expressed by T cell, B cell, and myeloid cell populations are consistent with sensitivity and resistance. We identified the upregulated expression ofPLA2G2D, an immune-regulating phospholipase, as a potential biomarker of adaptive resistance to ICB. Together, these findings provide insights into the diversity of immunogenomic mechanisms that underpin pembrolizumab outcomes.
Efficient and continuous microwave photoconversion in hybrid cavity-semiconductor nanowire double quantum dot diodes
Authors: Khan Waqar , Potts Patrick P. , Lehmann Sebastian , Thelander Claes , Dick Kimberly A. , Samuelsson Peter , Maisi Ville F.
Published: August 2021

Converting incoming photons to electrical current is the key operation principle of optical photodetectors and it enables a host of emerging quantum information technologies. The leading approach for continuous and efficient detection in the optical domain builds on semiconductor photodiodes. However, there is a paucity of efficient and continuous photon detectors in the microwave regime, because photon energies are four to five orders of magnitude lower therein and conventional photodiodes do not have that sensitivity. Here we tackle this gap and demonstrate how microwave photons can be efficiently and continuously converted to electrical current in a high-quality, semiconducting nanowire double quantum dot resonantly coupled to a cavity. In particular, in our photodiode device, an absorbed photon gives rise to a single electron tunneling through the double dot, with a conversion efficiency reaching 6%.
Efficient intracellular delivery of proteins by a multifunctional chimaeric peptide in vitro and in vivo
Authors: Yu Siyuan , Yang Han , Li Tingdong , Pan Haifeng , Ren Shuling , Luo Guoxing , Jiang Jinlu , Yu Linqi , Chen Binbing , Zhang Yali , Wang Shaojuan , Tian Rui , Zhang Tianying , Zhang Shiyin , Chen Yixin , Yuan Quan , Ge Shengxiang , Zhang Jun , Xia Ningshao
Published: August 2021

Protein delivery with cell-penetrating peptide is opening up the possibility of using targets inside cells for therapeutic or biological applications; however, cell-penetrating peptide-mediated protein delivery commonly suffers from ineffective endosomal escape and low tolerance in serum, thereby limiting in vivo efficacy. Here, we present an intracellular protein delivery system consisting of four modules in series: cell-penetrating peptide, pH-dependent membrane active peptide, endosome-specific protease sites and a leucine zipper. This system exhibits enhanced delivery efficiency and serum tolerance, depending on proteolytic cleavage-facilitated endosomal escape and leucine zipper-based dimerisation. Intravenous injection of protein phosphatase 1B fused with this system successfully suppresses the tumour necrosis factor-α-induced systemic inflammatory response and acetaminophen-induced acute liver failure in a mouse model. We believe that the strategy of using multifunctional chimaeric peptides is valuable for the development of cell-penetrating peptide-based protein delivery systems, and facilitate the development of biological macromolecular drugs for use against intracellular targets.
Additive manufacturing of strong silica sand structures enabled by polyethyleneimine binder
Authors: Gilmer Dustin B. , Han Lu , Lehmann Michelle L. , Siddel Derek H. , Yang Guang , Chowdhury Azhad U. , Doughty Benjamin , Elliott Amy M. , Saito Tomonori
Published: August 2021

Binder Jet Additive Manufacturing (BJAM) is a versatile AM technique that can form parts from a variety of powdered materials including metals, ceramics, and polymers. BJAM utilizes inkjet printing to selectively bind these powder particles together to form complex geometries. Adoption of BJAM has been limited due to its inability to form strong green parts using conventional binders. We report the discovery of a versatile polyethyleneimine (PEI) binder for silica sand that doubled the flexural strength of parts to 6.28 MPa compared with that of the conventional binder, making it stronger than unreinforced concrete (~4.5 MPa) in flexural loading. Furthermore, we demonstrate that PEI in the printed parts can be reacted with ethyl cyanoacrylate through a secondary infiltration, resulting in an increase in flexural strength to 52.7 MPa. The strong printed parts coupled with the ability for sacrificial washout presents potential to revolutionize AM in various applications including construction and tooling.
Epigenetic inactivation of the autophagy–lysosomal system in appendix in Parkinson’s disease
Authors: Gordevicius Juozas , Li Peipei , Marshall Lee L. , Killinger Bryan A. , Lang Sean , Ensink Elizabeth , Kuhn Nathan C. , Cui Wei , Maroof Nazia , Lauria Roberta , Rueb Christina , Siebourg-Polster Juliane , Maliver Pierre , Lamp Jared , Vega Irving , Manfredsson Fredric P. , Britschgi Markus , Labrie Viviane
Published: August 2021

The gastrointestinal tract may be a site of origin for α-synuclein pathology in idiopathic Parkinson’s disease (PD). Disruption of the autophagy-lysosome pathway (ALP) may contribute to α-synuclein aggregation. Here we examined epigenetic alterations in the ALP in the appendix by deep sequencing DNA methylation at 521 ALP genes. We identified aberrant methylation at 928 cytosines affecting 326 ALP genes in the appendix of individuals with PD and widespread hypermethylation that is also seen in the brain of individuals with PD. In mice, we find that DNA methylation changes at ALP genes induced by chronic gut inflammation are greatly exacerbated by α-synuclein pathology. DNA methylation changes at ALP genes induced by synucleinopathy are associated with the ALP abnormalities observed in the appendix of individuals with PD specifically involving lysosomal genes. Our work identifies epigenetic dysregulation of the ALP which may suggest a potential mechanism for accumulation of α-synuclein pathology in idiopathic PD.
Global phylogenomic analyses of Mycobacterium abscessus provide context for non cystic fibrosis infections and the evolution of antibiotic resistance
Authors: Bronson Ryan A. , Gupta Chhavi , Manson Abigail L. , Nguyen Jan A. , Bahadirli-Talbott Asli , Parrish Nicole M. , Earl Ashlee M. , Cohen Keira A.
Published: August 2021

Mycobacterium abscessus (MAB) is an emerging pathogen that leads to chronic lung infections. To date, the global population structure of non-cystic fibrosis (CF) MAB and evolutionary patterns of drug resistance emergence have not been investigated. Here we construct a global dataset of 1,279 MAB whole genomes from CF or non-CF patients. We utilize whole genome analysis to assess relatedness, phylogeography, and drug resistance evolution. MAB isolates from CF and non-CF hosts are interspersed throughout the phylogeny, such that the majority of dominant circulating clones include isolates from both populations, indicating that global spread of MAB clones is not sequestered to CF contexts. We identify a large clade of M. abscessus harboring the erm(41) T28C mutation, predicted to confer macrolide susceptibility in this otherwise macrolide-resistant species. Identification of multiple evolutionary events within this clade, consistent with regain of wild type, intrinsic macrolide resistance, underscores the critical importance of macrolides in MAB.
SnapHiC: a computational pipeline to identify chromatin loops from single-cell Hi-C data
Authors: Yu Miao , Abnousi Armen , Zhang Yanxiao , Li Guoqiang , Lee Lindsay , Chen Ziyin , Fang Rongxin , Lagler Taylor M. , Yang Yuchen , Wen Jia , Sun Quan , Li Yun , Ren Bing , Hu Ming
Published: August 2021

Single-cell Hi-C (scHi-C) analysis has been increasingly used to map chromatin architecture in diverse tissue contexts, but computational tools to define chromatin loops at high resolution from scHi-C data are still lacking. Here, we describe Single-Nucleus Analysis Pipeline for Hi-C (SnapHiC), a method that can identify chromatin loops at high resolution and accuracy from scHi-C data. Using scHi-C data from 742 mouse embryonic stem cells, we benchmark SnapHiC against a number of computational tools developed for mapping chromatin loops and interactions from bulk Hi-C. We further demonstrate its use by analyzing single-nucleus methyl-3C-seq data from 2,869 human prefrontal cortical cells, which uncovers cell type-specific chromatin loops and predicts putative target genes for noncoding sequence variants associated with neuropsychiatric disorders. Our results indicate that SnapHiC could facilitate the analysis of cell type-specific chromatin architecture and gene regulatory programs in complex tissues.
Novel and disappearing climates in the global surface ocean from 1800 to 2100
Authors: Lotterhos Katie E. , Láruson Áki J. , Jiang Li-Qing
Published: August 2021

Marine ecosystems are experiencing unprecedented warming and acidification caused by anthropogenic carbon dioxide. For the global sea surface, we quantified the degree that present climates are disappearing and novel climates (without recent analogs) are emerging, spanning from 1800 through different emission scenarios to 2100. We quantified the sea surface environment based on model estimates of carbonate chemistry and temperature. Between 1800 and 2000, no gridpoints on the ocean surface were estimated to have experienced an extreme degree of global disappearance or novelty. In other words, the majority of environmental shifts since 1800 were not novel, which is consistent with evidence that marine species have been able to track shifting environments via dispersal. However, between 2000 and 2100 under Representative Concentrations Pathway (RCP) 4.5 and 8.5 projections, 10–82% of the surface ocean is estimated to experience an extreme degree of global novelty. Additionally, 35–95% of the surface ocean is estimated to experience an extreme degree of global disappearance. These upward estimates of climate novelty and disappearance are larger than those predicted for terrestrial systems. Without mitigation, many species will face rapidly disappearing or novel climates that cannot be outpaced by dispersal and may require evolutionary adaptation to keep pace.
Changes in copeptin levels before and 3 months after transsphenoidal surgery according to the presence of postoperative central diabetes insipidus
Authors: Kim Yoo Hyung , Kim Yong Hwy , Je Young Soo , Lee Kyoung Ryul , Lim Hwan Sub , Kim Jung Hee
Published: August 2021

Copeptin levels reflect arginine vasopressin (AVP) release from the hypothalamus. Pituitary surgery often impairs AVP release and results in central diabetes insipidus (CDI). Here, we aimed to investigate how serum copeptin level changes 3 months after pituitary surgery and whether it has a diagnostic value for postoperative permanent CDI. Consecutive patients who underwent endoscopic transsphenoidal surgery at a single tertiary hospital were recruited. Serum copeptin levels were measured preoperatively and 3 months postoperatively. Among 88 patients, transient and permanent CDI occurred in 17 (19.3%) and 23 (26.1%), respectively. Three-month postoperative copeptin levels significantly declined from preoperative levels in permanent CDI group (P < 0.001, percentage difference =  − 42.2%) and also in the transient CDI group (P = 0.002, − 27.2%). Three months postoperative copeptin level < 1.9 pmol/L under normal serum sodium levels was the optimal cutoff value for diagnosing permanent CDI with an accuracy of 81.8%, while 3-month postoperative copeptin level ≥ 3.5 pmol/L excluded the CDI with a negative predictive value of 100%. Conclusively, 3 months postoperative copeptin levels significantly decreased from preoperative levels in the transient CDI group as well as the permanent CDI group. Three-month postoperative copeptin levels ≥ 3.5 pmol/L under normal serum sodium levels may be diagnostic for excluding postoperative CDI.
A prospective cohort study on longitudinal trajectories of cognitive function after stroke
Authors: Buvarp Dongni , Rafsten Lena , Abzhandadze Tamar , Sunnerhagen Katharina S.
Published: August 2021

The study aimed to determine longitudinal trajectories of cognitive function during the first year after stroke. The Montreal Cognitive Assessment (MoCA) was used to screen cognitive function at 36–48 h, 3-months, and 12-months post-stroke. Individuals who shared similar trajectories were classified by applying the group-based trajectory models. Data from 94 patients were included in the analysis. Three cognitive functioning groups were identified by the trajectory models: high [14 patients (15%)], medium [58 (62%)] and low [22 (23%)]. For the high and medium groups, cognitive function improved at 12 months, but this did not occur in the low group. After age, sex and education matching to the normative MoCA from the Swedish population, 52 patients (55%) were found to be cognitively impaired at baseline, and few patients had recovered at 12 months. The impact on memory differs between cognitive functioning groups, whereas the impact on activities of daily living was not different. Patients with the poorest cognitive function did not improve at one-year poststroke and were prone to severe memory problems. These findings may help to increase focus on long-term rehabilitation plans for those patients, and more accurately assess their needs and difficulties experienced in daily living.
Phytochemistry reflects different evolutionary history in traditional classes versus specialized structural motifs
Authors: Uckele Kathryn A. , Jahner Joshua P. , Tepe Eric J. , Richards Lora A. , Dyer Lee A. , Ochsenrider Kaitlin M. , Philbin Casey S. , Kato Massuo J. , Yamaguchi Lydia F. , Forister Matthew L. , Smilanich Angela M. , Dodson Craig D. , Jeffrey Christopher S. , Parchman Thomas L.
Published: August 2021

Foundational hypotheses addressing plant–insect codiversification and plant defense theory typically assume a macroevolutionary pattern whereby closely related plants have similar chemical profiles. However, numerous studies have documented variation in the degree of phytochemical trait lability, raising the possibility that phytochemical evolution is more nuanced than initially assumed. We utilize proton nuclear magnetic resonance (1H NMR) data, chemical classification, and double digest restriction-site associated DNA sequencing (ddRADseq) to resolve evolutionary relationships and characterize the evolution of secondary chemistry in the Neotropical plant clade Radula (Piper; Piperaceae). Sequencing data substantially improved phylogenetic resolution relative to past studies, and spectroscopic characterization revealed the presence of 35 metabolite classes. Metabolite classes displayed phylogenetic signal, whereas the crude 1H NMR spectra featured little evidence of phylogenetic signal in multivariate tests of chemical resonances. Evolutionary correlations were detected in two pairs of compound classes (flavonoids with chalcones; p-alkenyl phenols with kavalactones), where the gain or loss of a class was dependent on the other’s state. Overall, the evolution of secondary chemistry in Radula is characterized by strong phylogenetic signal of traditional compound classes and weak phylogenetic signal of specialized chemical motifs, consistent with both classic evolutionary hypotheses and recent examinations of phytochemical evolution in young lineages.
Location of the radial nerve along the humeral shaft between the prone and lateral decubitus positions at different elbow positions
Authors: Suwannaphisit Sitthiphong , Aonsong Wachirakorn , Suwanno Porames , Chuaychoosakoon Chaiwat
Published: August 2021

Identification of the radial nerve is important during the posterior approach to a humerus fracture. During this procedure, the patient can be placed in the prone or lateral decubitus position depending on the surgeon’s preference. The distance from the radial nerve to the osseous structures will be different in each position. The purpose of this study was to identify the safety zones in various patient and elbow flexion positions. The distances from the olecranon to the center of the radial groove and intermuscular septum and lateral epicondyle to the lateral intermuscular septum were measured using a digital Vernier caliper. The measurements were performed with cadavers in the lateral decubitus and prone positions at different elbow flexion angles. The distance from where the radial nerve crossed the posterior aspect of the humerus measured from the upper part of the olecranon to the center of the radial nerve in both positions at different elbow flexion angles varied from a mean maximum distance of 130.00 mm with the elbow in full extension in the prone position to a minimum distance of 121.01 mm with the elbow in flexion at 120° in the lateral decubitus position. The mean distance of the radial nerve from the upper olecranon to the lateral intermuscular septum varied from 107.13 to 102.22 mm. The distance from the lateral epicondyle to the lateral edge of the radial nerve varied from 119.92 to 125.38 mm. There was not significant contrast in the position of the radial nerve with osseous landmarks concerning different degrees of flexion, except for 120°, which is not significant, as this flexion angle is rarely used.
Role of charge accumulation in guided streamer evolution in helium DBD plasma jets
Authors: Pinchuk Mikhail , Nikiforov Anton , Snetov Vadim , Chen Zhaoquan , Leys Christophe , Stepanova Olga
Published: August 2021

Experimental data are presented on the evolution of a helium atmospheric pressure plasma jet driven by a tailored voltage waveform generated as bunches of voltage pulses consisting of a superposition of $$\approx 43$$

≈
43

 kHz bipolar square pulses and $$\approx 300$$

≈
300

 kHz oscillations. The characteristics of directed ionization waves (guided streamers) are compared for bunches with different first pulse polarities and different bunch duty cycles. The longest and brightest streamers are achieved at the voltage bunch with the first negative pulse and a minimum duty cycle. The dynamics of streamers at the voltage bunch with the first positive pulse are characterized by the shortest length and a lower brightness. The plasma jet length can be smoothly changed by varying the number of pulses in the bunch and the polarity of the first pulse. It is thus possible to precisely localize the region of a strong field in space by combining the parameters of the applied voltage (the duty cycle and polarity of the first pulse of a bunch) with a stepwise propagation mode of a guided streamer.
Diagnostic value of IMP3 and p53 immunohistochemical staining in EUS-guided fine-needle aspiration for solid pancreatic tumors
Authors: Mikata Rintaro , Yasui Shin , Kishimoto Takashi , Kouchi Yusuke , Shingyoji Ayako , Senoo Junichi , Takahashi Koji , Nagashima Hiroki , Kusakabe Yuko , Ohyama Hiroshi , Ohno Izumi , Sugiyama Harutoshi , Chiba Tetsuhiro , Kato Jun , Kato Naoya
Published: August 2021

We previously identified insulin-like growth factor-II messenger ribonucleic acid-binding protein 3 (IMP3) as a valuable marker to distinguish malignant from benign lesions in pancreatic solid masses. The aim of this prospective study was to evaluate the usefulness of IMP3 and p53 immunohistochemical staining in endoscopic ultrasound-guided fine-needle aspiration (EUS–FNA) samples for pancreatic solid masses. The study recruited 90 consecutive patients with pancreatic masses, including 62 pancreatic ductal adenocarcinomas (PDACs), 11 benign tumors, and 17 other tumors, who underwent EUS–FNA, and conducted IMP3 and p53 immunohistochemical staining. The main outcome measurement was improved diagnostic utility using IMP3 and p53 immunohistochemical staining. IMP3 and p53 expressions were detected in 60.8% and 49.4% of malignant lesions, 69.4% and 58.1% of PDACs, and 0% of benign lesions, respectively. In PDAC and benign tumors, the use of IMP3 and/or p53 immunostaining increased the sensitivity of cytohistological analysis from 88.7 to 93.5%, although the difference was not statistically significant. The sensitivity of histological analysis combined with that of IMP3 staining was 91.9%, which was significantly greater than that of histology alone (80.6%). The use of IMP3 and p53 immunohistochemical staining did not significantly improve the sensitivity of cytohistological analysis; however, IMP3 staining may be helpful for the histological analysis of malignant pancreatic tumors.
Bovine innate immune phenotyping via a standardized whole blood stimulation assay
Authors: Reid Cian , Beynon Charlotte , Kennedy Emer , O’Farrelly Cliona , Meade Kieran G.
Published: August 2021

Cattle vary in their susceptibility to infection and immunopathology, but our ability to measure and longitudinally profile immune response variation is limited by the lack of standardized immune phenotyping assays for high-throughput analysis. Here we report longitudinal innate immune response profiles in cattle using a low-blood volume, whole blood stimulation system—the ImmunoChek (IChek) assay. By minimizing cell manipulation, our standardized system minimizes the potential for artefactual results and enables repeatable temporal comparative analysis in cattle. IChek successfully captured biological variation in innate cytokine (IL-1β and IL-6) and chemokine (IL-8) responses to 24-hr stimulation with either Gram-negative (LPS), Gram-positive (PamCSK4) bacterial or viral (R848) pathogen-associated molecular patterns (PAMPs) across a 4-month time window. Significant and repeatable patterns of inter-individual variation in cytokine and chemokine responses, as well as consistent high innate immune responder individuals were identified at both baseline and induced levels. Correlation coefficients between immune response read-outs (IL-1β, IL-6 and IL-8) varied according to PAMP. Strong significant positive correlations were observed between circulating monocytes and IL-6 levels for null and induced responses (0.49–0.61) and between neutrophils and cytokine responses to R848 (0.38–0.47). The standardized assay facilitates high-throughput bovine innate immune response profiling to identify phenotypes associated with disease susceptibility and responses to vaccination.
Resonance Raman enhancement by the intralayer and interlayer electron–phonon processes in twisted bilayer graphene
Authors: Moutinho M. V. O. , Eliel G. S. N. , Righi A. , Gontijo R. N. , Paillet M. , Michel T. , Chiu Po-Wen , Venezuela P. , Pimenta M. A.
Published: August 2021

Twisted bilayer graphene is a fascinating system due to the possibility of tuning the electronic and optical properties by controlling the twisting angle $$\theta$$
θ
between the layers. The coupling between the Dirac cones of the two graphene layers gives rise to van Hove singularities (vHs) in the density of electronic states, whose energies vary with $$\theta$$
θ
. Raman spectroscopy is a fundamental tool to study twisted bilayer graphene (TBG) systems since the Raman response is hugely enhanced when the photons are in resonance with transition between vHs and new peaks appear in the Raman spectra due to phonons within the interior of the Brillouin zone of graphene that are activated by the Moiré superlattice. It was recently shown that these new peaks can be activated by the intralayer and the interlayer electron–phonon processes. In this work we study how each one of these processes enhances the intensities of the peaks coming from the acoustic and optical phonon branches of graphene. Resonance Raman measurements, performed in many different TBG samples with $$\theta$$
θ
between $$4^{\circ }$$

4
∘

and $$16^{\circ }$$

16
∘

and using several different laser excitation energies in the near-infrared (NIR) and visible ranges (1.39–2.71 eV), reveal the distinct enhancement of the different phonons of graphene by the intralayer and interlayer processes. Experimental results are nicely explained by theoretical calculations of the double-resonance Raman intensity in graphene by imposing the momentum conservation rules for the intralayer and the interlayer electron–phonon resonant conditions in TBGs. Our results show that the resonant enhancement of the Raman response in all cases is affected by the quantum interference effect and the symmetry requirements of the double resonance Raman process in graphene.
A novel and efficient approach to high-throughput production of HLA-E/peptide monomer for T-cell epitope screening
Authors: Vaurs Juliette , Douchin Gaël , Echasserieau Klara , Oger Romain , Jouand Nicolas , Fortun Agnès , Hesnard Leslie , Croyal Mikaël , Pecorari Frédéric , Gervois Nadine , Bernardeau Karine
Published: August 2021

Over the past two decades, there has been a great interest in the study of HLA-E-restricted αβ T cells during bacterial and viral infections, including recently SARS-CoV-2 infection. Phenotyping of these specific HLA-E-restricted T cells requires new tools such as tetramers for rapid cell staining or sorting, as well as for the identification of new peptides capable to bind to the HLA-E pocket. To this aim, we have developed an optimal photosensitive peptide to generate stable HLA-E/pUV complexes allowing high-throughput production of new HLA-E/peptide complexes by peptide exchange. We characterized the UV exchange by ELISA and improved the peptide exchange readout using size exclusion chromatography. This novel approach for complex quantification is indeed very important to perform tetramerization of MHC/peptide complexes with the high quality required for detection of specific T cells. Our approach allows the rapid screening of peptides capable of binding to the non-classical human HLA-E allele, paving the way for the development of new therapeutic approaches based on the detection of HLA-E-restricted T cells.
First identification of ITM2B interactome in the human retina
Authors: Wohlschlegel J. , Argentini M. , Michiels C. , Letellier C. , Forster V. , Condroyer C. , He Z. , Thuret G. , Zeitz C. , Léger T. , Audo I.
Published: August 2021

Integral Membrane Protein 2 B (ITM2B) is a type II ubiquitous transmembrane protein which role remains unclear. ITM2B mutations have been associated with different disorders: mutations leading to longer mutant proteins have been reported in two distinct Alzheimer-like autosomal dominant disorders with early-onset progressive dementia and cerebellar ataxia. Both disorders share neurological features including severe cerebral amyloid angiopathy, non-neuritic plaques, and fibrillary tangles as in Alzheimer disease. Our group reported a missense mutation in ITM2B, in an unusual retinal dystrophy with no dementia. This finding suggests a specific role of ITM2B in the retina. As the identification of retinal-specific ITM2B partners could bring new insights into the cellular functions of ITM2B, we performed quantitative proteomics of ITM2B interactome of the human retina. Overall, 457 ITM2B partners were identified with 8 of them involved in visual transduction. In addition, bulk Gene Ontology analyses showed that many ITM2B partners are involved in several other biological functions, such as microtubule organization, protein translation and interestingly, mitochondrial homeostasis. These data represent the first report of the ITM2B interactome in the human retina and may serve as a valuable inventory of new potential ITM2B partners for future investigations of ITM2B physiological functions and dysfunctions.