bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor suppressor p53 regulates intestinal type 2 immunity
Authors: Chang Chun-Yuan , Wang Jianming , Zhao Yuhan , Liu Juan , Yang Xue , Yue Xuetian , Wang Huaying , Zhou Fan , Inclan-Rico Juan M. , Ponessa John J. , Xie Ping , Zhang Lanjing , Siracusa Mark C. , Feng Zhaohui , Hu Wenwei
Published: June 2021

The role of p53 in tumor suppression has been extensively studied and well-established. However, the role of p53 in parasitic infections and the intestinal type 2 immunity is unclear. Here, we report that p53 is crucial for intestinal type 2 immunity in response to the infection of parasites, such asTritrichomonas murisandNippostrongylus brasiliensis. Mechanistically, p53 plays a critical role in the activation of the tuft cell-IL-25-type 2 innate lymphoid cell circuit, partly via transcriptional regulation of Lrmp in tuft cells. Lrmp modulates Ca2+influx and IL-25 release, which are critical triggers of type 2 innate lymphoid cell response. Our results thus reveal a previously unrecognized function of p53 in regulating intestinal type 2 immunity to protect against parasitic infections, highlighting the role of p53 as a guardian of immune integrity.
Sub-nanometer confinement enables facile condensation of gas electrolyte for low-temperature batteries
Authors: Cai Guorui , Yin Yijie , Xia Dawei , Chen Amanda A. , Holoubek John , Scharf Jonathan , Yang Yangyuchen , Koh Ki Hwan , Li Mingqian , Davies Daniel M. , Mayer Matthew , Han Tae Hee , Meng Ying Shirley , Pascal Tod A. , Chen Zheng
Published: June 2021

Confining molecules in the nanoscale environment can lead to dramatic changes of their physical and chemical properties, which opens possibilities for new applications. There is a growing interest in liquefied gas electrolytes for electrochemical devices operating at low temperatures due to their low melting point. However, their high vapor pressure still poses potential safety concerns for practical usages. Herein, we report facile capillary condensation of gas electrolyte by strong confinement in sub-nanometer pores of metal-organic framework (MOF). By designing MOF-polymer membranes (MPMs) that present dense and continuous micropore (~0.8 nm) networks, we show significant uptake of hydrofluorocarbon molecules in MOF pores at pressure lower than the bulk counterpart. This unique property enables lithium/fluorinated graphite batteries with MPM-based electrolytes to deliver a significantly higher capacity than those with commercial separator membranes (~500 mAh g−1 vs. <0.03 mAh g−1) at −40 °C under reduced pressure of the electrolyte.
MOCCASIN: a method for correcting for known and unknown confounders in RNA splicing analysis
Authors: Slaff Barry , Radens Caleb M. , Jewell Paul , Jha Anupama , Lahens Nicholas F. , Grant Gregory R. , Thomas-Tikhonenko Andrei , Lynch Kristen W. , Barash Yoseph
Published: June 2021

The effects of confounding factors on gene expression analysis have been extensively studied following the introduction of high-throughput microarrays and subsequently RNA sequencing. In contrast, there is a lack of equivalent analysis and tools for RNA splicing. Here we first assess the effect of confounders on both expression and splicing quantifications in two large public RNA-Seq datasets (TARGET, ENCODE). We show quantification of splicing variations are affected at least as much as those of gene expression, revealing unwanted sources of variations in both datasets. Next, we develop MOCCASIN, a method to correct the effect of both known and unknown confounders on RNA splicing quantification and demonstrate MOCCASIN’s effectiveness on both synthetic and real data. Code, synthetic and corrected datasets are all made available as resources.
β-Arrestin-1 is required for adaptive β-cell mass expansion during obesity
Authors: Barella Luiz F. , Rossi Mario , Pydi Sai P. , Meister Jaroslawna , Jain Shanu , Cui Yinghong , Gavrilova Oksana , Fulgenzi Gianluca , Tessarollo Lino , Wess Jürgen
Published: June 2021

Obesity is the key driver of peripheral insulin resistance, one of the key features of type 2 diabetes (T2D). In insulin-resistant individuals, the expansion of beta-cell mass is able to delay or even prevent the onset of overt T2D. Here, we report that beta-arrestin-1 (barr1), an intracellular protein known to regulate signaling through G protein-coupled receptors, is essential for beta-cell replication and function in insulin-resistant mice maintained on an obesogenic diet. Specifically, insulin-resistant beta-cell-specificbarr1knockout mice display marked reductions in beta-cell mass and the rate of beta-cell proliferation, associated with pronounced impairments in glucose homeostasis. Mechanistic studies suggest that the observed metabolic deficits are due to reduced Pdx1 expression levels caused by beta-cell barr1 deficiency. These findings indicate that strategies aimed at enhancing barr1 activity and/or expression in beta-cells may prove useful to restore proper glucose homeostasis in T2D.
Multi-target mode of action of silver against Staphylococcus aureus endows it with capability to combat antibiotic resistance
Authors: Wang Haibo , Wang Minji , Xu Xiaohan , Gao Peng , Xu Zeling , Zhang Qi , Li Hongyan , Yan Aixin , Kao Richard Yi-Tsun , Sun Hongzhe
Published: June 2021

The rapid emergence of drug resistant Staphylococcus aureus (S. aureus) poses a serious threat to public health globally. Silver (Ag)-based antimicrobials are promising to combat antibiotic resistant S. aureus, yet their molecular targets are largely elusive. Herein, we separate and identify 38 authentic Ag+-binding proteins in S. aureus at the whole-cell scale. We then capture the molecular snapshot on the dynamic action of Ag+ against S. aureus and further validate that Ag+ could inhibit a key target 6-phosphogluconate dehydrogenase through binding to catalytic His185 by X-ray crystallography. Significantly, the multi-target mode of action of Ag+ (and nanosilver) endows its sustainable antimicrobial efficacy, leading to enhanced efficacy of conventional antibiotics and resensitization of MRSA to antibiotics. Our study resolves the long-standing question of the molecular targets of silver in S. aureus and offers insights into the sustainable bacterial susceptibility of silver, providing a potential approach for combating antimicrobial resistance.
Genetic variation associated with thyroid autoimmunity shapes the systemic immune response to PD-1 checkpoint blockade
Authors: Khan Zia , Hammer Christian , Carroll Jonathan , Di Nucci Flavia , Acosta Sergio Ley , Maiya Vidya , Bhangale Tushar , Hunkapiller Julie , Mellman Ira , Albert Matthew L. , McCarthy Mark I. , Chandler G. Scott
Published: June 2021

Activation of systemic immune responses using PD-1 checkpoint inhibitors is an essential approach to cancer therapy. Yet, the extent of benefit relative to risk of immune related adverse events (irAE) varies widely among patients. Here, we study endocrine irAE from 7 clinical trials across 6 cancers where atezolizumab (anti-PD-L1) was combined with chemotherapies and compared to standard of care. We show that atezolizumab-induced thyroid dysfunction is associated with longer survival. We construct a polygenic risk score (PRS) for lifetime risk of hypothyroidism using a GWAS from the UK Biobank and apply this PRS to genetic data collected from 2,616 patients of European ancestry from these trials. Patients with high PRS are at increased risk of atezolizumab-induced thyroid dysfunction and lower risk of death in triple negative breast cancer. Our results indicate that genetic variation associated with thyroid autoimmunity interacts with biological pathways driving the systemic immune response to PD-1 blockade.
Reinforcing one-carbon metabolism via folic acid/Folr1 promotes β-cell differentiation
Authors: Karampelias Christos , Rezanejad Habib , Rosko Mandy , Duan Likun , Lu Jing , Pazzagli Laura , Bertolino Philippe , Cesta Carolyn E. , Liu Xiaojing , Korbutt Gregory S. , Andersson Olov
Published: June 2021

Diabetes can be caused by an insufficiency in β-cell mass. Here, we performed a genetic screen in a zebrafish model of β-cell loss to identify pathways promoting β-cell regeneration. We found that both folate receptor 1 (folr1) overexpression and treatment with folinic acid, stimulated β-cell differentiation in zebrafish. Treatment with folinic acid also stimulated β-cell differentiation in cultures of neonatal pig islets, showing that the effect could be translated to a mammalian system. In both zebrafish and neonatal pig islets, the increased β-cell differentiation originated from ductal cells. Mechanistically, comparative metabolomic analysis of zebrafish with/without β-cell ablation and with/without folinic acid treatment indicated β-cell regeneration could be attributed to changes in the pyrimidine, carnitine, and serine pathways. Overall, our results suggest evolutionarily conserved and previously unknown roles for folic acid and one-carbon metabolism in the generation of β-cells.
The regulatory landscape of Arabidopsis thaliana roots at single-cell resolution
Authors: Dorrity Michael W. , Alexandre Cristina M. , Hamm Morgan O. , Vigil Anna-Lena , Fields Stanley , Queitsch Christine , Cuperus Josh T.
Published: June 2021

The scarcity of accessible sites that are dynamic or cell type-specific in plants may be due in part to tissue heterogeneity in bulk studies. To assess the effects of tissue heterogeneity, we apply single-cell ATAC-seq to Arabidopsis thaliana roots and identify thousands of differentially accessible sites, sufficient to resolve all major cell types of the root. We find that the entirety of a cell’s regulatory landscape and its transcriptome independently capture cell type identity. We leverage this shared information on cell identity to integrate accessibility and transcriptome data to characterize developmental progression, endoreduplication and cell division. We further use the combined data to characterize cell type-specific motif enrichments of transcription factor families and link the expression of family members to changing accessibility at specific loci, resolving direct and indirect effects that shape expression. Our approach provides an analytical framework to infer the gene regulatory networks that execute plant development.
Nutrients cause consolidation of soil carbon flux to small proportion of bacterial community
Authors: Stone Bram W. , Li Junhui , Koch Benjamin J. , Blazewicz Steven J. , Dijkstra Paul , Hayer Michaela , Hofmockel Kirsten S. , Liu Xiao-Jun Allen , Mau Rebecca L. , Morrissey Ember M. , Pett-Ridge Jennifer , Schwartz Egbert , Hungate Bruce A.
Published: June 2021

Nutrient amendment diminished bacterial functional diversity, consolidating carbon flow through fewer bacterial taxa. Here, we show strong differences in the bacterial taxa responsible for respiration from four ecosystems, indicating the potential for taxon-specific control over soil carbon cycling. Trends in functional diversity, defined as the richness of bacteria contributing to carbon flux and their equitability of carbon use, paralleled trends in taxonomic diversity although functional diversity was lower overall. Among genera common to all ecosystems, Bradyrhizobium, the Acidobacteria genus RB41, and Streptomyces together composed 45–57% of carbon flow through bacterial productivity and respiration. Bacteria that utilized the most carbon amendment (glucose) were also those that utilized the most native soil carbon, suggesting that the behavior of key soil taxa may influence carbon balance. Mapping carbon flow through different microbial taxa as demonstrated here is crucial in developing taxon-sensitive soil carbon models that may reduce the uncertainty in climate change projections.
Cryo-EM structure of TFIIH/Rad4–Rad23–Rad33 in damaged DNA opening in nucleotide excision repair
Authors: van Eeuwen Trevor , Shim Yoonjung , Kim Hee Jong , Zhao Tingting , Basu Shrabani , Garcia Benjamin A. , Kaplan Craig D. , Min Jung-Hyun , Murakami Kenji
Published: June 2021

The versatile nucleotide excision repair (NER) pathway initiates as the XPC–RAD23B–CETN2 complex first recognizes DNA lesions from the genomic DNA and recruits the general transcription factor complex, TFIIH, for subsequent lesion verification. Here, we present a cryo-EM structure of an NER initiation complex containing Rad4–Rad23-Rad33 (yeast homologue of XPC–RAD23B–CETN2) and 7-subunit coreTFIIH assembled on a carcinogen-DNA adduct lesion at 3.9–9.2 Å resolution. A ~30-bp DNA duplex could be mapped as it straddles between Rad4 and the Ssl2 (XPB) subunit of TFIIH on the 3' and 5' side of the lesion, respectively. The simultaneous binding with Rad4 and TFIIH was permitted by an unwinding of DNA at the lesion. Translocation coupled with torque generation by Ssl2 and Rad4 would extend the DNA unwinding at the lesion and deliver the damaged strand to Rad3 (XPD) in an open form suitable for subsequent lesion scanning and verification.
An in-memory computing architecture based on two-dimensional semiconductors for multiply-accumulate operations
Authors: Wang Yin , Tang Hongwei , Xie Yufeng , Chen Xinyu , Ma Shunli , Sun Zhengzong , Sun Qingqing , Chen Lin , Zhu Hao , Wan Jing , Xu Zihan , Zhang David Wei , Zhou Peng , Bao Wenzhong
Published: June 2021

In-memory computing may enable multiply-accumulate (MAC) operations, which are the primary calculations used in artificial intelligence (AI). Performing MAC operations with high capacity in a small area with high energy efficiency remains a challenge. In this work, we propose a circuit architecture that integrates monolayer MoS2 transistors in a two-transistor–one-capacitor (2T-1C) configuration. In this structure, the memory portion is similar to a 1T-1C Dynamic Random Access Memory (DRAM) so that theoretically the cycling endurance and erase/write speed inherit the merits of DRAM. Besides, the ultralow leakage current of the MoS2 transistor enables the storage of multi-level voltages on the capacitor with a long retention time. The electrical characteristics of a single MoS2 transistor also allow analog computation by multiplying the drain voltage by the stored voltage on the capacitor. The sum-of-product is then obtained by converging the currents from multiple 2T-1C units. Based on our experiment results, a neural network is ex-situ trained for image recognition with 90.3% accuracy. In the future, such 2T-1C units can potentially be integrated into three-dimensional (3D) circuits with dense logic and memory layers for low power in-situ training of neural networks in hardware.
Light regulates stomatal development by modulating paracrine signaling from inner tissues
Authors: Wang Shenqi , Zhou Zimin , Rahiman Rini , Lee Grace Sheen Yee , Yeo Yuan Kai , Yang Xin , Lau On Sun
Published: June 2021

Developmental outcomes are shaped by the interplay between intrinsic and external factors. The production of stomata—essential pores for gas exchange in plants—is extremely plastic and offers an excellent system to study this interplay at the cell lineage level. For plants, light is a key external cue, and it promotes stomatal development and the accumulation of the master stomatal regulator SPEECHLESS (SPCH). However, how light signals are relayed to influence SPCH remains unknown. Here, we show that the light-regulated transcription factor ELONGATED HYPOCOTYL 5 (HY5), a critical regulator for photomorphogenic growth, is present in inner mesophyll cells and directly binds and activates STOMAGEN. STOMAGEN, the mesophyll-derived secreted peptide, in turn stabilizes SPCH in the epidermis, leading to enhanced stomatal production. Our work identifies a molecular link between light signaling and stomatal development that spans two tissue layers and highlights how an environmental signaling factor may coordinate growth across tissue types.
Transforming absolute value to categorical choice in primate superior colliculus during value-based decision making
Authors: Zhang Beizhen , Kan Janis Ying Ying , Yang Mingpo , Wang Xiaochun , Tu Jiahao , Dorris Michael Christopher
Published: June 2021

Value-based decision making involves choosing from multiple options with different values. Despite extensive studies on value representation in various brain regions, the neural mechanism for how multiple value options are converted to motor actions remains unclear. To study this, we developed a multi-value foraging task with varying menu of items in non-human primates using eye movements that dissociates value and choice, and conducted electrophysiological recording in the midbrain superior colliculus (SC). SC neurons encoded “absolute” value, independent of available options, during late fixation. In addition, SC neurons also represent value threshold, modulated by available options, different from conventional motor threshold. Electrical stimulation of SC neurons biased choices in a manner predicted by the difference between the value representation and the value threshold. These results reveal a neural mechanism directly transforming absolute values to categorical choices within SC, supporting highly efficient value-based decision making critical for real-world economic behaviors.
Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer’s disease
Authors: Fitz Nicholas F. , Nam Kyong Nyon , Wolfe Cody M. , Letronne Florent , Playso Brittany E. , Iordanova Bistra E. , Kozai Takashi D. Y. , Biedrzycki Richard J. , Kagan Valerian E. , Tyurina Yulia Y. , Han Xianlin , Lefterov Iliya , Koldamova Radosveta
Published: June 2021

APOE and Trem2 are major genetic risk factors for Alzheimer’s disease (AD), but how they affect microglia response to Aβ remains unclear. Here we report an APOE isoform-specific phospholipid signature with correlation between human APOEε3/3 and APOEε4/4 AD brain and lipoproteins from astrocyte conditioned media of APOE3 and APOE4 mice. Using preclinical AD mouse models, we show that APOE3 lipoproteins, unlike APOE4, induce faster microglial migration towards injected Aβ, facilitate Aβ uptake, and ameliorate Aβ effects on cognition. Bulk and single-cell RNA-seq demonstrate that, compared to APOE4, cortical infusion of APOE3 lipoproteins upregulates a higher proportion of genes linked to an activated microglia response, and this trend is augmented by TREM2 deficiency. In vitro, lack of TREM2 decreases Aβ uptake by APOE4-treated microglia only, suggesting TREM2-APOE interaction. Our study elucidates phenotypic and transcriptional differences in microglial response to Aβ mediated by APOE3 or APOE4 lipoproteins in preclinical models of AD.
Hippocampal place cell sequences differ during correct and error trials in a spatial memory task
Authors: Zheng Chenguang , Hwaun Ernie , Loza Carlos A. , Colgin Laura Lee
Published: June 2021

Theta rhythms temporally coordinate sequences of hippocampal place cell ensembles during active behaviors, while sharp wave-ripples coordinate place cell sequences during rest. We investigated whether such coordination of hippocampal place cell sequences is disrupted during error trials in a delayed match-to-place task. As a reward location was learned across trials, place cell sequences developed that represented temporally compressed paths to the reward location during the approach to the reward location. Less compressed paths were represented on error trials as an incorrect stop location was approached. During rest periods of correct but not error trials, place cell sequences developed a bias to replay representations of paths ending at the correct reward location. These results support the hypothesis that coordination of place cell sequences by theta rhythms and sharp wave-ripples develops as a reward location is learned and may be important for the successful performance of a spatial memory task.
Vapor-phased fabrication and modulation of cell-laden scaffolding materials
Authors: Wu Chih-Yu , Wu Ting-Ying , Guan Zhen-Yu , Wang Peng-Yuan , Yang Yen-Ching , Huang Chao-Wei , Lin Tzu-Hung , Chen Hsien-Yeh
Published: June 2021

Bottom–up approaches using building blocks of modules to fabricate scaffolds for tissue engineering applications have enabled the fabrication of structurally complex and multifunctional materials allowing for physical and chemical flexibility to better mimic the native extracellular matrix. Here we report a vapor-phased fabrication process for constructing three-dimensional modulated scaffold materials via simple steps based on controlling mass transport of vapor sublimation and deposition. We demonstrate the fabrication of scaffolds comprised of multiple biomolecules and living cells with built-in boundaries separating the distinct compartments containing defined biological configurations and functions. We show that the fabricated scaffolds have mass production potential. We demonstrate overall >80% cell viability of encapsulated cells and that modulated scaffolds exhibit enhanced cell proliferation, osteogenesis, and neurogenesis, which can be assembled into various geometric configurations. We perform cell co-culture experiments to show independent osteogenesis and angiogenesis activities from separate compartments in one scaffold construct.
OPG/TRAIL ratio as a predictive biomarker of mortality in patients with type A acute aortic dissection
Authors: Lu Jie , Li Ping , Ma Ke , Li Yang , Yuan Hui , Zhu Junming , Duan Weixun , Ou Jingsong , Huang Yonghong , Wu Long , Pan Xueliang , Zhang Hui , Du Jie , Li Yulin
Published: June 2021

Following hospital discharge, patients with type A acute aortic dissection (TA-AAD) may present an increase in mortality risk. However, little is known about specific biomarkers associated with post-discharge survival, and there is a paucity of prognostic markers associated with TA-AAD. Here, we identify nine candidate proteins specific for patietns with TA-AAD in a cross-sectional dataset by unbiased protein screening and in-depth bioinformatic analyses. In addition, we explore their association with short-term and long-term mortality in a derivation cohort of patients with TA-AAD, including an internal (n = 300) and external (n = 236) dataset. An elevated osteoprotegerin (OPG)/tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) ratio was the strongest predictor of overall, 30-day, post-30-day mortality in both datasets and was confirmed to be a strong predictor of mortality in an independent validation cohort (n = 400). Based on OPG/TRAIL ratio-guided risk stratification, patients at high risk (>33) had a higher 1-year mortality (55.6% vs. 4.3%; 68.2% vs. 2.6%) than patients at low risk (<4) in both cohorts. In Conclusion, we show that an elevated OPG/TRAIL ratio is associated with a significant increase in short-term and long-term mortality in patients with TA-AAD.
Visceral obesity and insulin resistance associate with CD36 deletion in lymphatic endothelial cells
Authors: Cifarelli Vincenza , Appak-Baskoy Sila , Peche Vivek S. , Kluzak Andrew , Shew Trevor , Narendran Ramkumar , Pietka Kathryn M. , Cella Marina , Walls Curtis W. , Czepielewski Rafael , Ivanov Stoyan , Randolph Gwendalyn J. , Augustin Hellmut G. , Abumrad Nada A.
Published: June 2021

Disruption of lymphatic lipid transport is linked to obesity and type 2 diabetes (T2D), but regulation of lymphatic vessel function and its link to disease remain unclear. Here we show that intestinal lymphatic endothelial cells (LECs) have an increasing CD36 expression from lymphatic capillaries (lacteals) to collecting vessels, and that LEC CD36 regulates lymphatic integrity and optimizes lipid transport. Inducible deletion of CD36 in LECs in adult mice (Cd36ΔLEC) increases discontinuity of LEC VE-cadherin junctions in lacteals and collecting vessels. Cd36ΔLEC mice display slower transport of absorbed lipid, more permeable mesenteric lymphatics, accumulation of inflamed visceral fat and impaired glucose disposal. CD36 silencing in cultured LECs suppresses cell respiration, reduces VEGF-C-mediated VEGFR2/AKT phosphorylation and destabilizes VE-cadherin junctions. Thus, LEC CD36 optimizes lymphatic junctions and integrity of lymphatic lipid transport, and its loss in mice causes lymph leakage, visceral adiposity and glucose intolerance, phenotypes that increase risk of T2D.
Spatio-temporal mRNA tracking in the early zebrafish embryo
Authors: Holler Karoline , Neuschulz Anika , Drewe-Boß Philipp , Mintcheva Janita , Spanjaard Bastiaan , Arsiè Roberto , Ohler Uwe , Landthaler Markus , Junker Jan Philipp
Published: June 2021

Early stages of embryogenesis depend on subcellular localization and transport of maternal mRNA. However, systematic analysis of these processes is hindered by a lack of spatio-temporal information in single-cell RNA sequencing. Here, we combine spatially-resolved transcriptomics and single-cell RNA labeling to perform a spatio-temporal analysis of the transcriptome during early zebrafish development. We measure spatial localization of mRNA molecules within the one-cell stage embryo, which allows us to identify a class of mRNAs that are specifically localized at an extraembryonic position, the vegetal pole. Furthermore, we establish a method for high-throughput single-cell RNA labeling in early zebrafish embryos, which enables us to follow the fate of individual maternal transcripts until gastrulation. This approach reveals that many localized transcripts are specifically transported to the primordial germ cells. Finally, we acquire spatial transcriptomes of two xenopus species and compare evolutionary conservation of localized genes as well as enriched sequence motifs.
The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers
Authors: De Mattos-Arruda Leticia , Cortes Javier , Blanco-Heredia Juan , Tiezzi Daniel G. , Villacampa Guillermo , Gonçalves-Ribeiro Samuel , Paré Laia , Souza Carla Anjos , Ortega Vanesa , Sammut Stephen-John , Cusco Pol , Fasani Roberta , Chin Suet-Feung , Perez-Garcia Jose , Dienstmann Rodrigo , Nuciforo Paolo , Villagrasa Patricia , Rubio Isabel T. , Prat Aleix , Caldas Carlos
Published: June 2021

The biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN-NCT01669252). Whole-exome data (N = 88 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples). Tumour mutation burden varied across patients at baseline but not across the sampling timepoints for each patient. Mutational signatures were not always conserved across tumours. There was a trend towards higher odds of response and less hazard to relapse when the percentage of subclonal mutations was low, suggesting that more homogenous tumours might have better responses to neoadjuvant therapy. Few driver mutations (5.1%) generated putative neoantigens. Mutation and neoantigen load were positively correlated (R2 = 0.94, p = <0.001); neoantigen load was weakly correlated with stromal TILs (R2 = 0.16, p = 0.02). An enrichment in pathways linked to immune infiltration and reduced programmed cell death expression were seen after 12 weeks of eribulin in good responders. VEGF was downregulated over time in the good responder group and FABP5, an inductor of epithelial mesenchymal transition (EMT), was upregulated in cases that recurred (p < 0.05). Mutational heterogeneity, subclonal architecture and the improvement of immune microenvironment along with remodelling of hypoxia and EMT may influence the response to neoadjuvant treatment.
Climate change drives widespread shifts in lake thermal habitat
Authors: Kraemer Benjamin M. , Pilla Rachel M. , Woolway R. Iestyn , Anneville Orlane , Ban Syuhei , Colom-Montero William , Devlin Shawn P. , Dokulil Martin T. , Gaiser Evelyn E. , Hambright K. David , Hessen Dag O. , Higgins Scott N. , Jöhnk Klaus D. , Keller Wendel , Knoll Lesley B. , Leavitt Peter R. , Lepori Fabio , Luger Martin S. , Maberly Stephen C. , Müller-Navarra Dörthe C. , Paterson Andrew M. , Pierson Donald C. , Richardson David C. , Rogora Michela , Rusak James A. , Sadro Steven , Salmaso Nico , Schmid Martin , Silow Eugene A. , Sommaruga Ruben , Stelzer Julio A. A. , Straile Dietmar , Thiery Wim , Timofeyev Maxim A. , Verburg Piet , Weyhenmeyer Gesa A. , Adrian Rita
Published: June 2021

Lake surfaces are warming worldwide, raising concerns about lake organism responses to thermal habitat changes. Species may cope with temperature increases by shifting their seasonality or their depth to track suitable thermal habitats, but these responses may be constrained by ecological interactions, life histories or limiting resources. Here we use 32 million temperature measurements from 139 lakes to quantify thermal habitat change (percentage of non-overlap) and assess how this change is exacerbated by potential habitat constraints. Long-term temperature change resulted in an average 6.2% non-overlap between thermal habitats in baseline (1978–1995) and recent (1996–2013) time periods, with non-overlap increasing to 19.4% on average when habitats were restricted by season and depth. Tropical lakes exhibited substantially higher thermal non-overlap compared with lakes at other latitudes. Lakes with high thermal habitat change coincided with those having numerous endemic species, suggesting that conservation actions should consider thermal habitat change to preserve lake biodiversity.
Dose–response effects of light therapy on sleepiness and circadian phase shift in shift workers: a meta-analysis and moderator analysis
Authors: Lam Calvin , Chung Min-Huey
Published: June 2021

Light therapy has been considered to be effective in mitigating sleepiness and regulating circadian phase shift in shift workers. However, the effective treatment dose of light therapy remains undetermined. We performed a meta-analysis of randomized experimental studies to determine the effect of light therapy doses on sleepiness and circadian phase shift in shift workers. An article search was performed in 10 electronic databases from inception to June 2020. Two raters independently screened and extracted data and reached consensus. Twenty-one eligible studies were included. Analyses were performed using random-effects models. Light therapy exerted significantly small to medium effects on sleepiness and large treatment effects on circadian phase shift. Moderator analyses performed with subgroup and metaregression analyses revealed that medium-intensity light therapy for a shorter duration more effectively reduced sleepiness at night, whereas higher-intensity light therapy more effectively induced phase shifting, but the required treatment duration remained inconclusive. This study provides evidence regarding the effect of light therapy in reducing sleepiness and shifting circadian phase in shift workers. Exposure to medium-intensity light for a short duration at night reduced sleepiness, whereas exposure to high-intensity light improved sleep by shifting their circadian phase.
Age-sex population adjusted analysis of disease severity in epidemics as a tool to devise public health policies for COVID-19
Authors: Cannistraci Carlo Vittorio , Valsecchi Maria Grazia , Capua Ilaria
Published: June 2021

Governments continue to update social intervention strategies to contain COVID-19 infections. However, investigation of COVID-19 severity indicators across the population might help to design more precise strategies, balancing the need to keep people safe and to reduce the socio-economic burden of generalized restriction precedures. Here, we propose a method for age-sex population-adjusted analysis of disease severity in epidemics that has the advantage to use simple and repeatable variables, which are daily or weekly available. This allows to monitor the effect of public health policies in short term, and to repeat these calculations over time to surveille epidemic dynamics and impact. Our method can help to define a risk-categorization of likeliness to develop a severe COVID-19 disease which requires intensive care or is indicative of a higher risk of dying. Indeed, analysis of suitable open-access COVID-19 data in three European countries indicates that individuals in the 0–40 age interval and females under 60 are significantly less likely to develop a severe condition and die, whereas males equal or above 60 are more likely at risk of severe disease and death. Hence, a combination of age-adaptive and sex-balanced guidelines for social interventions could represent key public health management tools for policymakers.
Human immune system adaptations to simulated microgravity revealed by single-cell mass cytometry
Authors: Spatz J. M. , Fulford M. Hughes , Tsai A. , Gaudilliere D. , Hedou J. , Ganio E. , Angst M. , Aghaeepour N. , Gaudilliere Brice
Published: June 2021

Exposure to microgravity (µG) during space flights produces a state of immunosuppression, leading to increased viral shedding, which could interfere with long term missions. However, the cellular mechanisms that underlie the immunosuppressive effects of µG are ill-defined. A deep understanding of human immune adaptations to µG is a necessary first step to design data-driven interventions aimed at preserving astronauts’ immune defense during short- and long-term spaceflights. We employed a high-dimensional mass cytometry approach to characterize over 250 cell-specific functional responses in 18 innate and adaptive immune cell subsets exposed to 1G or simulated (s)µG using the Rotating Wall Vessel. A statistically stringent elastic net method produced a multivariate model that accurately stratified immune responses observed in 1G and sµG (p value 2E−4, cross-validation). Aspects of our analysis resonated with prior knowledge of human immune adaptations to µG, including the dampening of Natural Killer, CD4+ and CD8+ T cell responses. Remarkably, we found that sµG enhanced STAT5 signaling responses of immunosuppressive Tregs. Our results suggest µG exerts a dual effect on the human immune system, simultaneously dampening cytotoxic responses while enhancing Treg function. Our study provides a single-cell readout of sµG-induced immune dysfunctions and an analytical framework for future studies of human immune adaptations to human long-term spaceflights.
An easy-to-use function to assess deep space radiation in human brains
Authors: Khaksarighiri Salman , Guo Jingnan , Wimmer-Schweingruber Robert , Narici Livio
Published: June 2021

Health risks from radiation exposure in space are an important factor for astronauts’ safety as they venture on long-duration missions to the Moon or Mars. It is important to assess the radiation level inside the human brain to evaluate the possible hazardous effects on the central nervous system especially during solar energetic particle (SEP) events. We use a realistic model of the head/brain structure and calculate the radiation deposit therein by realistic SEP events, also under various shielding scenarios. We then determine the relation between the radiation dose deposited in different parts of the brain and the properties of the SEP events and obtain some simple and ready-to-use functions which can be used to quickly and reliably forecast the event dose in the brain. Such a novel tool can be used from fast nowcasting of the consequences of SEP events to optimization of shielding systems and other mitigation strategies of astronauts in space.
Evolution of social relationships between first-year students at middle school: from cliques to circles
Authors: Escribano Diego , Doldán-Martelli Victoria , Lapuente Francisco J. , Cuesta José A. , Sánchez Angel
Published: June 2021

People organize their social relationships under a restriction on the number that a single individual can maintain simultaneously (the so-called Dunbar’s number, ~150). Additionally, personal networks show a characteristic layered structure where each layer corresponds to relationships of different emotional closeness. This structure, referred to as Dunbar’s circles, has mostly been considered from a static viewpoint, and their structure and evolution is largely unexplored. Here we study the issue of the evolution of the structure of positive and negative relationships in early adolescence by using data from students in their first year at middle school obtained from surveys conducted in class in two different waves separated by several months. Our results show that, initially, students have a lower number of total relationships but the majority are more intense and over time they report a higher number of total relationships, but the more intense relationships appear in a lower proportion. We have also found differences in the structure of communities at both temporal moments. While in the first instance the communities that appeared are mixed, made up of both boys and girls, in the second they changed so that they were separated primarily by gender. In addition, the size of each community was stabilized around 15 people, which coincides with the size of the second Dunbar’s circle, known as the sympathy group in social psychology. As a consequence, in groups with around 20 students of the same gender, they tend to split in two separate communities of about 10 each, below the second Dunbar’s circle threshold. On the other hand, groups with more stable community structure appear to go through the inverse process of friendship evolution, becoming more focused on their best relationships. All these results suggest how the layered structure of the personal network, as well as the community structure of the social network, emerge directly from the union of both positive and negative relationships. Thus, we provide a new perspective about its temporal evolution that may have relevant applications to improve school life and student performance.
Lost opportunities for mismatch repair (MMR) screening among minority women with endometrial cancer
Authors: Huang Marilyn , Hunter Tegan , Fein Lydia A. , Galli Johnny , George Sophia , Schlumbrecht Matthew , McCarter Kelly , Sinno Abdulrahman K. , Guido Luiz P. , Pinto Andre
Published: June 2021

Lynch Syndrome (LS) prevalence in underrepresented minorities are lacking. The objective of this study was to assess the prevalence of LS in a minority patient population. Secondary objectives included identifying factors associated with successful LS screening and to characterize clinicopathologic features. Women with endometrial cancer treated within a university system from 2014 and 2016 were included. Immunohistochemistry (IHC) results of MLH1, PMS2, MSH2 and MSH6 were obtained from medical records and clinicopathologic factors abstracted. Patients not previously screened for LS were screened. 276 patients were evaluable. More minority women were screened as part of their routine cancer care (p = 0.005). Additionally, women 50 years or younger were more likely to be screened for LS compared to women older than 51(p = 0.009) and uninsured or reliant on Medicaid patients (p = 0.011) were more likely to be screened during routine care. Six patients received confirmatory germline testing for LS (4.3%), and another 8 patients had a staining pattern suggestive of LS. In an underrepresented population, the rate of LS in endometrial cancer is similar to previous reports. LS may be under diagnosed and opportunities missed when universal screening is not applied in minority women.
Hydroxychloroquine plus standard of care compared with standard of care alone in COVID-19: a meta-analysis of randomized controlled trials
Authors: Amani Bahman , Khanijahani Ahmad , Amani Behnam
Published: June 2021

The efficacy and safety of Hydroxychloroquine (HCQ) in treating coronavirus disease (COVID-19) is disputed. This systematic review and meta-analysis aimed to examine the efficacy and safety of HCQ in addition to standard of care (SOC) in COVID-19. PubMed, the Cochrane Library, Embase, Web of sciences, and medRxiv were searched up to March 15, 2021. Clinical studies registry databases were also searched for identifying potential clinical trials. The references list of the key studies was reviewed to identify additional relevant resources. The quality of the included studies was evaluated using the Cochrane Collaboration tool and Jadad checklist. Meta-analysis was performed using RevMan software (version 5.3). Eleven randomized controlled trials with a total number of 8161 patients were identified as eligible for meta-analysis. No significant differences were observed between the two treatment groups in terms of negative rate of polymerase chain reaction (PCR) (Risk ratio [RR]: 0.99, 95% confidence interval (CI) 0.90, 1.08; P = 0.76), PCR negative conversion time (Mean difference [MD]: − 1.06, 95% CI − 3.10, 0.97; P = 0.30), all-cause mortality (RR: 1.09, 95% CI 1.00, 1.20; P = 0.06), body temperature recovery time (MD: − 0.64, 95% CI − 1.37, 0.10; P = 0.09), length of hospital stay (MD: − 0.17, 95% CI − 0.80, 0.46; P = 0.59), use of mechanical ventilation (RR: 1.12, 95% CI 0.95, 1.32; P = 0.19), and disease progression (RR = 0.82, 95% CI 0.37, 1.85; P = 0.64). However, there was a significant difference between two groups regarding adverse events (RR: 1.81, 95% CI 1.36, 2.42; P < 0.05). The findings suggest that the addition of HCQ to SOC has no benefit in the treatment of hospitalized patients with COVID-19. Additionally, it is associated with more adverse events.
Facile synthesis of PEDOT-rGO/HKUST-1 for high performance symmetrical supercapacitor device
Authors: Mohanadas Dharshini , Mohd Abdah Muhammad Amirul Aizat , Azman Nur Hawa Nabilah , Ravoof Thahira B. S. A. , Sulaiman Yusran
Published: June 2021

A novel poly(3,4-ethylenedioxythiophene)-reduced graphene oxide/copper-based metal–organic framework (PrGO/HKUST-1) has been successfully fabricated by incorporating electrochemically synthesized poly(3,4-ethylenedioxythiophene)-reduced graphene oxide (PrGO) and hydrothermally synthesized copper-based metal–organic framework (HKUST-1). The field emission scanning microscopy (FESEM) and elemental mapping analysis revealed an even distribution of poly(3,4-ethylenedioxythiophene) (PEDOT), reduced graphene oxide (rGO) and HKUST-1. The crystalline structure and vibration modes of PrGO/HKUST-1 were validated utilizing X-ray diffraction (XRD) as well as Raman spectroscopy, respectively. A remarkable specific capacitance (360.5 F/g) was obtained for PrGO/HKUST-1 compared to HKUST-1 (103.1 F/g), PrGO (98.5 F/g) and PEDOT (50.8 F/g) using KCl/PVA as a gel electrolyte. Moreover, PrGO/HKUST-1 composite with the longest charge/discharge time displayed excellent specific energy (21.0 Wh/kg), specific power (479.7 W/kg) and an outstanding cycle life (95.5%) over 4000 cycles. Thus, the PrGO/HKUST-1 can be recognized as a promising energy storage material.
Measurements of the swimming speeds of motile microorganisms using object tracking and their correlation with water pollution and rheology levels
Authors: Shunmugam Ashaa Preyadharishini , Subramanian Gowtham , Fernandez Javier G.
Published: June 2021

Self-propelled microscopic organisms are ubiquitous in water. Such organisms’ motility depends on hydrodynamic and physical factors related to the rheology of the surrounding media and biological factors depending on the organisms’ state and well-being. Here we demonstrate that the swimming speed of Paramecium aurelia, a unicellular protozoan, globally found in fresh, brackish, and salt waters, can be used as a measurable frugal indicator of the presence of pollutants in water. This study establishes a significant and consistent relationship between Paramecia’s swimming speed and the presence of five different organic and inorganic contaminants at varying concentrations centered around drinking water thresholds. The large size and ubiquity of the targeted microorganism, the avoidance of reagents or specialized tools for the measurement, and the simple data collection based on an object tracking algorithm enable the automatization of the assessment and real-time results using globally available technology.
Genes encoding putative bicarbonate transporters as a missing molecular link between molt and mineralization in crustaceans
Authors: Abehsera Shai , Bentov Shmuel , Li Xuguang , Weil Simy , Manor Rivka , Sagi Shahar , Li Shihao , Li Fuhua , Khalaila Isam , Aflalo Eliahu D. , Sagi Amir
Published: June 2021

During their life, crustaceans undergo several molts, which if theoretically compared to the human body would be equivalent to replacing all bones at a single event. Such a dramatic repetitive event is coupled to unique molecular mechanisms of mineralization so far mostly unknown. Unlike human bone mineralized with calcium phosphate, the crustacean exoskeleton is mineralized mainly by calcium carbonate. Crustacean growth thus necessitates well-timed mobilization of bicarbonate to specific extracellular sites of biomineralization at distinct molt cycle stages. Here, by looking at the crayfish Cherax quadricarinatus at different molting stages, we suggest that the mechanisms of bicarbonate ion transport for mineralization in crustaceans involve the SLC4 family of transporters and that these proteins play a key role in the tight coupling between molt cycle events and mineral deposition. This discovery of putative bicarbonate transporters in a pancrustacean with functional genomic evidence from genes encoding the SLC4 family—mostly known for their role in pH control—is discussed in the context of the evolution of calcium carbonate biomineralization.
Study of deactivation in mesocellular foam carbon (MCF-C) catalyst used in gas-phase dehydrogenation of ethanol
Authors: Klinthongchai Yoottapong , Prichanont Seeroong , Praserthdam Piyasan , Jongsomjit Bunjerd
Published: June 2021

Mesocellular foam carbon (MCF-C) is one the captivating materials for using in gas phase dehydrogenation of ethanol. Extraordinary, enlarge pore size, high surface area, high acidity, and spherical shape with interconnected pore for high diffusion. In contrary, the occurrence of the coke is a majority causes for inhibiting the active sites on catalyst surface. Thus, this study aims to investigate the occurrence of the coke to optimize the higher catalytic activity, and also to avoid the coke formation. The MCF-C was synthesized and investigated using various techniques. MCF-C was spent in gas-phase dehydrogenation of ethanol under mild conditions. The deactivation of catalyst was investigated toward different conditions. Effects of reaction condition including different reaction temperatures of 300, 350, and 400 °C on the deactivation behaviors were determined. The results indicated that the operating temperature at 400 °C significantly retained the lowest change of ethanol conversion, which favored in the higher temperature. After running reaction, the physical properties as pore size, surface area, and pore volume of spent catalysts were decreased owing to the coke formation, which possibly blocked the pore that directly affected to the difficult diffusion of reactant and caused to be lower in catalytic activity. Furthermore, a slight decrease in either acidity or basicity was observed owing to consumption of reactant at surface of catalyst or chemical change on surface caused by coke formation. Therefore, it can remarkably choose the suitable operating temperature to avoid deactivation of catalyst, and then optimize the ethanol conversion or yield of acetaldehyde.