bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultra-broadband metamaterial absorbers from long to very long infrared regime
Authors: Zhou Yu , Qin Zheng , Liang Zhongzhu , Meng Dejia , Xu Haiyang , Smith David R. , Liu Yichun
Published: July 2021

Broadband metamaterials absorbers with high absorption, ultrathin thickness and easy configurations are in great demand for many potential applications. In this paper, we first analyse the coupling resonances in a Ti/Ge/Ti three-layer absorber, which can realise broadband absorption from 8 to 12 μm. Then we experimentally demonstrate two types of absorbers based on the Ti/Ge/Si3N4/Ti configuration. By taking advantage of coupling surface plasmon resonances and intrinsic absorption of lossy material Si3N4, the average absorptions of two types of absorbers achieve almost 95% from 8 to 14 μm (experiment result: 78% from 6.5 to 13.5 μm). In order to expand the absorption bandwidth, we further propose two Ti/Si/SiO2/Ti absorbers which can absorb 92% and 87% of ultra-broadband light in the 14–30 μm and 8–30 μm spectral range, respectively. Our findings establish general and systematic strategies for guiding the design of metamaterial absorbers with excellent broadband absorption and pave the way for enhancing the optical performance in applications of infrared thermal emitters, imaging and photodetectors.
The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives
Authors: Wang Shun , Zheng Yan , Yang Feng , Zhu Le , Zhu Xiao-Qiang , Wang Zhe-Fang , Wu Xiao-Lin , Zhou Cheng-Hui , Yan Jia-Yan , Hu Bei-Yuan , Kong Bo , Fu De-Liang , Bruns Christiane , Zhao Yue , Qin Lun-Xiu , Dong Qiong-Zhu
Published: July 2021

Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence. Furthermore, it is usually diagnosed at an advanced stage with a very dismal prognosis. Due to the high heterogeneity, metabolic reprogramming, and dense stromal environment associated with pancreatic cancer, patients benefit little from current conventional therapy. Recent insight into the biology and genetics of pancreatic cancer has supported its molecular classification, thus expanding clinical therapeutic options. In this review, we summarize how the biological features of pancreatic cancer and its metabolic reprogramming as well as the tumor microenvironment regulate its development and progression. We further discuss potential biomarkers for pancreatic cancer diagnosis, prediction, and surveillance based on novel liquid biopsies. We also outline recent advances in defining pancreatic cancer subtypes and subtype-specific therapeutic responses and current preclinical therapeutic models. Finally, we discuss prospects and challenges in the clinical development of pancreatic cancer therapeutics.
Microbially facilitated nitrogen cycling in tropical corals
Authors: Glaze Thomas D , Erler Dirk V , Siljanen Henri M P
Published: July 2021

Tropical scleractinian corals support a diverse assemblage of microbial symbionts. This ‘microbiome’ possesses the requisite functional diversity to conduct a range of nitrogen (N) transformations including denitrification, nitrification, nitrogen fixation and dissimilatory nitrate reduction to ammonium (DNRA). Very little direct evidence has been presented to date verifying that these processes are active within tropical corals. Here we use a combination of stable isotope techniques, nutrient uptake calculations and captured metagenomics to quantify rates of nitrogen cycling processes in a selection of tropical scleractinian corals. Denitrification activity was detected in all species, albeit with very low rates, signifying limited importance in holobiont N removal. Relatively greater nitrogen fixation activity confirms that corals are net N importers to reef systems. Low net nitrification activity suggests limited N regeneration capacity; however substantial gross nitrification activity may be concealed through nitrate consumption. Based on nrfA gene abundance and measured inorganic N fluxes, we calculated significant DNRA activity in the studied corals, which has important implications for coral reef N cycling and warrants more targeted investigation. Through the quantification and characterisation of all relevant N-cycling processes, this study provides clarity on the subject of tropical coral-associated biogeochemical N-cycling.
Global hypomyelination of the brain white and gray matter in schizophrenia: quantitative imaging using macromolecular proton fraction
Authors: Smirnova Liudmila P. , Yarnykh Vasily L. , Parshukova Daria A. , Kornetova Elena G. , Semke Arkadiy V. , Usova Anna V. , Pishchelko Anna O. , Khodanovich Marina Y. , Ivanova Svetlana A.
Published: July 2021

Myelin deficiency is commonly recognized as an important pathological feature of brain tissues in schizophrenia (SZ). In this pilot study, global myelin content abnormalities in white matter (WM) and gray matter (GM) of SZ patients were non-invasively investigated using a novel clinically-targeted quantitative myelin imaging technique, fast macromolecular proton fraction (MPF) mapping. MPF maps were obtained from 23 healthy subjects and 31 SZ patients using a clinical 1.5T magnetic resonance imaging (MRI) scanner. Mean MPF in WM and GM was compared between the healthy control subjects and SZ patients with positive and negative leading symptoms using the multivariate analysis of covariance. The SZ patients had significantly reduced MPF in GM (p < 0.001) and WM (p = 0.02) with the corresponding relative decrease of 5% and 3%, respectively. The effect sizes for the myelin content loss in SZ relative to the control group were 1.0 and 1.5 for WM and GM, respectively. The SZ patients with leading negative symptoms had significantly lower MPF in GM (p < 0.001) and WM (p = 0.003) as compared to the controls and showed a significant MPF decrease in WM (p = 0.03) relative to the patients with leading positive symptoms. MPF in WM significantly negatively correlated with the disease duration in SZ patients (Pearson’s r = −0.51; p = 0.004). This study demonstrates that chronic SZ is characterized by global microscopic brain hypomyelination of both WM and GM, which is associated with the disease duration and negative symptoms. Myelin deficiency in SZ can be detected and quantified by the fast MPF mapping method.
Enlightened: addressing circadian and seasonal changes in photoperiod in animal models of bipolar disorder
Authors: McCarty Richard , Josephs Travis , Kovtun Oleg , Rosenthal Sandra J.
Published: July 2021

Bipolar disorders (BDs) exhibit high heritability and symptoms typically first occur during late adolescence or early adulthood. Affected individuals may experience alternating bouts of mania/hypomania and depression, with euthymic periods of varying lengths interspersed between these extremes of mood. Clinical research studies have consistently demonstrated that BD patients have disturbances in circadian and seasonal rhythms, even when they are free of symptoms. In addition, some BD patients display seasonal patterns in the occurrence of manic/hypomanic and depressive episodes as well as the time of year when symptoms initially occur. Finally, the age of onset of BD symptoms is strongly influenced by the distance one lives from the equator. With few exceptions, animal models useful in the study of BD have not capitalized on these clinical findings regarding seasonal patterns in BD to explore molecular mechanisms associated with the expression of mania- and depression-like behaviors in laboratory animals. In particular, animal models would be especially useful in studying how rates of change in photoperiod that occur during early spring and fall interact with risk genes to increase the occurrence of mania- and depression-like phenotypes, respectively. Another unanswered question relates to the ways in which seasonally relevant changes in photoperiod affect responses to acute and chronic stressors in animal models. Going forward, we suggest ways in which translational research with animal models of BD could be strengthened through carefully controlled manipulations of photoperiod to enhance our understanding of mechanisms underlying seasonal patterns of BD symptoms in humans. In addition, we emphasize the value of incorporating diurnal rodent species as more appropriate animal models to study the effects of seasonal changes in light on symptoms of depression and mania that are characteristic of BD in humans.
Identification of inflammatory subgroups of schizophrenia and bipolar disorder patients with HERV-W ENV antigenemia by unsupervised cluster analysis
Authors: Tamouza Ryad , Meyer Urs , Foiselle Marianne , Richard Jean-Romain , Wu Ching-Lien , Boukouaci Wahid , Le Corvoisier Philippe , Barrau Caroline , Lucas Alexandre , Perron Hervé , Leboyer Marion
Published: July 2021

Human endogenous retroviruses (HERVs) are remnants of infections that took place several million years ago and represent around 8% of the human genome. Despite evidence implicating increased expression of HERV type W envelope (HERV-W ENV) in schizophrenia and bipolar disorder, it remains unknown whether such expression is associated with distinct clinical or biological characteristics and symptoms. Accordingly, we performed unsupervised two-step clustering of a multivariate data set that included HERV-W ENV protein antigenemia, serum cytokine levels, childhood trauma scores, and clinical data of cohorts of patients with schizophrenia (n = 29), bipolar disorder (n = 43) and healthy controls (n = 32). We found that subsets of patients with schizophrenia (~41%) and bipolar disorder (~28%) show positive antigenemia for HERV-W ENV protein, whereas the large majority (96%) of controls was found to be negative for ENV protein. Unsupervised cluster analysis identified the presence of two main clusters of patients, which were best predicted by the presence or absence of HERV-W ENV protein. HERV-W expression was associated with increased serum levels of inflammatory cytokines and higher childhood maltreatment scores. Furthermore, patients with schizophrenia who were positive for HERV-W ENV protein showed more manic symptoms and higher daily chlorpromazine (CPZ) equivalents, whereas HERV-W ENV positive patients with bipolar disorder were found to have an earlier disease onset than those who were negative for HERV-W ENV protein. Taken together, our study suggest that HERV-W ENV protein antigenemia and cytokines can be used to stratify patients with major mood and psychotic disorders into subgroups with differing inflammatory and clinical profiles.
Comparable level of aggression between patients with behavioural addiction and healthy subjects
Authors: Asaoka Yui , Won Moojun , Morita Tomonari , Ishikawa Emi , Goto Yukiori
Published: July 2021

Heightened aggression is identified in several psychiatric disorders, including addiction. In this preliminary study with a relatively small number of samples, aggression in subjects diagnosed with behavioural addiction (BA) was implicitly assessed using the point subtraction aggression paradigm (PSAP) test along with measurements of oxy- and deoxyhaemoglobin dynamics in the prefrontal cortex (PFC) during the test using functional near-infrared spectroscopy. Aggression in BA patients was no higher than that of healthy control (CT) subjects in the PSAP test. Although no apparent increase or decrease in haemoglobin concentrations was observed in the PFC of either BA patients or CT subjects, abnormal correlations within the PFC network were present in BA patients. Consistent with comparable aggression between the groups, blood concentrations of the sex hormone testosterone, which has been shown to be associated with aggressiveness, was even lower in BA patients than in CT subjects. In contrast, when a set of questionnaire surveys for the assessment of aggression were administered, BA patients rated themselves as more aggressive than non-BA subjects. Collectively, these results suggest that aggression may not be heightened in BA, but BA patients may overestimate their aggressiveness, raising concerns about the use of questionnaire surveys for assessments of affective traits such as aggression in behavioural addiction.
Overexpression of Lrp5 enhanced the anti-breast cancer effects of osteocytes in bone
Authors: Liu Shengzhi , Wu Di , Sun Xun , Fan Yao , Zha Rongrong , Jalali Aydin , Feng Yan , Li Kexin , Sano Tomohiko , Vike Nicole , Li Fangjia , Rispoli Joseph , Sudo Akihiro , Liu Jing , Robling Alexander , Nakshatri Harikrishna , Li Bai-Yan , Yokota Hiroki
Published: July 2021

Osteocytes are the most abundant cells in bone, which is a frequent site of breast cancer metastasis. Here, we focused on Wnt signaling and evaluated tumor-osteocyte interactions. In animal experiments, mammary tumor cells were inoculated into the mammary fat pad and tibia. The role of Lrp5-mediated Wnt signaling was examined by overexpressing and silencing Lrp5 in osteocytes and establishing a conditional knockout mouse model. The results revealed that administration of osteocytes or their conditioned medium (CM) inhibited tumor progression and osteolysis. Osteocytes overexpressing Lrp5 or β-catenin displayed strikingly elevated tumor-suppressive activity, accompanied by downregulation of tumor-promoting chemokines and upregulation of apoptosis-inducing and tumor-suppressing proteins such as p53. The antitumor effect was also observed with osteocyte-derived CM that was pretreated with a Wnt-activating compound. Notably, silencing Lrp5 in tumors inhibited tumor progression, while silencing Lrp5 in osteocytes in conditional knockout mice promoted tumor progression. Osteocytes exhibited elevated Lrp5 expression in response to tumor cells, implying that osteocytes protect bone through canonical Wnt signaling. Thus, our results suggest that the Lrp5/β-catenin axis activates tumor-promoting signaling in tumor cells but tumor-suppressive signaling in osteocytes. We envision that osteocytes with Wnt activation potentially offer a novel cell-based therapy for breast cancer and osteolytic bone metastasis.
An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression
Authors: Nguyen Thao Thi Thanh , Shingyoji Masato , Hanazono Michiko , Zhong Boya , Morinaga Takao , Tada Yuji , Shimada Hideaki , Hiroshima Kenzo , Tagawa Masatoshi
Published: July 2021

A majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma.
Determination of the dynamic cellular transcriptional profiles during kidney development from birth to maturity in rats by single-cell RNA sequencing
Authors: Ding Fangrui , Tian Xiuying , Mo Jiali , Wang Botao , Zheng Jun
Published: July 2021

Recent single-cell RNA sequencing (scRNA-seq) analyses have offered much insight into the gene expression profiles in early-stage kidney development. However, comprehensive gene expression profiles from mid- and late-stage kidney development are lacking. In the present study, by using the scRNA-seq technique, we analyzed 54,704 rat kidney cells from just after birth to adulthood (six time points: postnatal days 0, 2, 5, 10, 20, and 56) including the mid and late stages of kidney development. Twenty-five original clusters and 13 different cell types were identified during these stages. Gene expression in these 13 cell types was mapped, and single cell atlas of the rat kidney from birth to maturity (http://youngbearlab.com) was built to enable users to search for a gene of interest and to evaluate its expression in different cells. The variation trend of six major types of kidney cells—intercalated cells of the collecting duct (CD-ICs), principal cells of the collecting duct (CD-PCs), cells of the distal convoluted tubules (DCTs), cells of the loop of Henle (LOH), podocytes (PDs), and cells of the proximal tubules (PTs)—during six postnatal time points was demonstrated. The trajectory of rat kidney development and the order of induction of the six major types of kidney cells from just after birth to maturity were determined. In addition, features of the dynamically changing genes as well as transcription factors during postnatal rat kidney development were identified. The present study provides a resource for achieving a deep understanding of the molecular basis of and regulatory events in the mid and late stages of kidney development.
Endothelial-specific insulin receptor substrate-1 overexpression worsens neonatal hypoxic-ischemic brain injury via mTOR-mediated tight junction disassembly
Authors: Tu Yi-Fang , Jiang Si-Tse , Chiang Chi-Wu , Chen Li-Ching , Huang Chao-Ching
Published: July 2021

Hypoxic-ischemic (HI) encephalopathy is the major cause of mortality and disability in newborns. The neurovascular unit is a major target of acute and chronic brain injury, and therapies that protect simultaneously both neurons and vascular endothelial cells from neonatal HI injury are in demand. Insulin receptors and its key downstream molecule-insulin receptor substrate −1 (IRS-1) are potential neuroprotective targets and expressed both in neuron and endothelial cells. To investigate whether IRS-1 can act similarly in neurons and vascular endothelial cells in protecting neurovascular units and brain form HI injury, we found that neuron-specific IRS-1 transgenic rats showed reduced neurovascular injury and infarct volumes, whereas endothelial-specific IRS-1 transgenic rats showed increased blood-brain barrier (BBB) disruption and exaggerated neurovascular injury after neonatal HI brain injury. Endothelial-specific IRS-1 overexpression increased vascular permeability and disassembled the tight junction protein (zonula occludens-1) complex. Inhibition of mammalian target of rapamycin (mTOR) by rapamycin preserved tight junction proteins and attenuated BBB leakage and neuronal apoptosis after HI in the endothelial-specific IRS-1 transgenic pups. Together, our findings suggested that neuronal and endothelial IRS-1 had opposite effects on the neurovascular integrity and damage after neonatal HI brain injury and that endothelial IRS-1 worsens neurovascular integrity after HI via mTOR-mediated tight junction protein disassembly.
Implication of ferroptosis in aging
Authors: Mazhar Maryam , Din Ahmad Ud , Ali Hamid , Yang Guoqiang , Ren Wei , Wang Li , Fan Xiaohui , Yang Sijin
Published: July 2021

Life is indeed continuously going through the irreversible and inevitable process of aging. The rate of aging process depends on various factors and varies individually. These factors include various environmental stimuli including exposure to toxic chemicals, psychological stress whereas suffering with various illnesses specially the chronic diseases serve as endogenous triggers. The basic underlying mechanism for all kinds of stresses is now known to be manifested as production of excessive ROS, exhaustion of ROS neutralizing antioxidant enzymes and proteins leading to imbalance in oxidation and antioxidant processes with subsequent oxidative stress induced inflammation affecting the cells, tissues, organs and the whole body. All these factors lead to conventional cell death either through necrosis, apoptosis, or autophagy. Currently, a newly identified mechanism of iron dependent regulated cell death called ferroptosis, is of special interest for its implication in pathogenesis of various diseases such as cardiovascular disease, neurological disorders, cancers, and various other age-related disorders (ARD). In ferroptosis, the cell death occur neither by conventional apoptosis, necrosis nor by autophagy, rather dysregulated iron in the cell mediates excessive lipid peroxidation of accumulated lethal lipids. It is not surprising to assume its role in aging as previous research have identified some solid cues on the subject. In this review, we will highlight the factual evidences to support the possible role and implication of ferroptosis in aging in order to declare the need to identify and explore the interventions to prevent excessive ferroptosis leading to accelerated aging and associated liabilities of aging.
Methyltransferase-like protein 7A (METTL7A) promotes cell survival and osteogenic differentiation under metabolic stress
Authors: Lee Eugene , Kim Ju-young , Kim Tae-Kyung , Park Seo-Young , Im Gun-Il
Published: July 2021

While bone has an inherent capacity to heal itself, it is very difficult to reconstitute large bone defects. Regenerative medicine, including stem cell implantation, has been studied as a novel solution to treat these conditions. However, when the local vascularity is impaired, even the transplanted cells undergo rapid necrosis before differentiating into osteoblasts and regenerating bone. Thus, to increase the effectiveness of stem cell transplantation, it is quintessential to improve the viability of the implanted stem cells. In this study, given that the regulation of glucose may hold the key to stem cell survival and osteogenic differentiation, we investigated the molecules that can replace the effect of glucose under ischemic microenvironment of stem cell transplantation in large bone defects. By analyzing differentially expressed genes under glucose-supplemented and glucose-free conditions, we explored markers such as methyltransferase-like protein 7A (METTL7A) that are potentially related to cell survival and osteogenic differentiation. Overexpression of METTL7A gene enhanced the osteogenic differentiation and viability of human bone marrow stem cells (hBMSCs) in glucose-free conditions. When the in vivo effectiveness of METTL7A-transfected cells in bone regeneration was explored in a rat model of critical-size segmental long-bone defect, METTL7A-transfected hBMSCs showed significantly better regenerative potential than the control vector-transfected hBMSCs. DNA methylation profiles showed a large difference in methylation status of genes related to osteogenesis and cell survival between hBMSCs cultured in glucose-supplemented condition and those cultured in glucose-free condition. Interestingly, METTL7A overexpression altered the methylation status of related genes to favor osteogenic differentiation and cell survival. In conclusion, it is suggested that a novel factor METTL7A enhances osteogenic differentiation and viability of hBMSCs by regulating the methylation status of genes related to osteogenesis or survival.
A chromosome-scale genome sequence of pitaya (Hylocereus undatus) provides novel insights into the genome evolution and regulation of betalain biosynthesis
Authors: Chen Jian-ye , Xie Fang-fang , Cui Yan-ze , Chen Can-bin , Lu Wang-jin , Hu Xiao-di , Hua Qing-zhu , Zhao Jing , Wu Zhi-jiang , Gao Dan , Zhang Zhi-ke , Jiang Wen-kai , Sun Qing-ming , Hu Gui-bing , Qin Yong-hua
Published: July 2021

Pitaya (Hylocereus) is the most economically important fleshy-fruited tree of the Cactaceae family that is grown worldwide, and it has attracted significant attention because of its betalain-abundant fruits. Nonetheless, the lack of a pitaya reference genome significantly hinders studies focused on its evolution, as well as the potential for genetic improvement of this crop. Herein, we employed various sequencing approaches, namely, PacBio-SMRT, Illumina HiSeq paired-end, 10× Genomics, and Hi-C (high-throughput chromosome conformation capture) to provide a chromosome-level genomic assembly of ‘GHB’ pitaya (H. undatus, 2n = 2x = 22 chromosomes). The size of the assembled pitaya genome was 1.41 Gb, with a scaffold N50 of ~127.15 Mb. In total, 27,753 protein-coding genes and 896.31 Mb of repetitive sequences in the H. undatus genome were annotated. Pitaya has undergone a WGT (whole-genome triplication), and a recent WGD (whole-genome duplication) occurred after the gamma event, which is common to the other species in Cactaceae. A total of 29,328 intact LTR-RTs (~696.45 Mb) were obtained in H. undatus, of which two significantly expanded lineages, Ty1/copia and Ty3/gypsy, were the main drivers of the expanded genome. A high-density genetic map of F1 hybrid populations of ‘GHB’ × ‘Dahong’ pitayas (H. monacanthus) and their parents were constructed, and a total of 20,872 bin markers were identified (56,380 SNPs) for 11 linkage groups. More importantly, through transcriptomic and WGCNA (weighted gene coexpression network analysis), a global view of the gene regulatory network, including structural genes and the transcription factors involved in pitaya fruit betalain biosynthesis, was presented. Our data present a valuable resource for facilitating molecular breeding programs of pitaya and shed novel light on its genomic evolution, as well as the modulation of betalain biosynthesis in edible fruits.
Anthropogenic influence on extreme precipitation over global land areas seen in multiple observational datasets
Authors: Madakumbura Gavin D. , Thackeray Chad W. , Norris Jesse , Goldenson Naomi , Hall Alex
Published: July 2021

Abstract

The intensification of extreme precipitation under anthropogenic forcing is robustly projected by global climate models, but highly challenging to detect in the observational record. Large internal variability distorts this anthropogenic signal. Models produce diverse magnitudes of precipitation response to anthropogenic forcing, largely due to differing schemes for parameterizing subgrid-scale processes. Meanwhile, multiple global observational datasets of daily precipitation exist, developed using varying techniques and inhomogeneously sampled data in space and time. Previous attempts to detect human influence on extreme precipitation have not incorporated model uncertainty, and have been limited to specific regions and observational datasets. Using machine learning methods that can account for these uncertainties and capable of identifying the time evolution of the spatial patterns, we find a physically interpretable anthropogenic signal that is detectable in all global observational datasets. Machine learning efficiently generates multiple lines of evidence supporting detection of an anthropogenic signal in global extreme precipitation.
Reward biases spontaneous neural reactivation during sleep
Authors: Sterpenich Virginie , van Schie Mojca K. M. , Catsiyannis Maximilien , Ramyead Avinash , Perrig Stephen , Yang Hee-Deok , Van De Ville Dimitri , Schwartz Sophie
Published: July 2021

Sleep favors the reactivation and consolidation of newly acquired memories. Yet, how our brain selects the noteworthy information to be reprocessed during sleep remains largely unknown. From an evolutionary perspective, individuals must retain information that promotes survival, such as avoiding dangers, finding food, or obtaining praise or money. Here, we test whether neural representations of rewarded (compared to non-rewarded) events have priority for reactivation during sleep. Using functional MRI and a brain decoding approach, we show that patterns of brain activity observed during waking behavior spontaneously reemerge during slow-wave sleep. Critically, we report a privileged reactivation of neural patterns previously associated with a rewarded task (i.e., winning at a complex game). Moreover, during sleep, activity in task-related brain regions correlates with better subsequent memory performance. Our study uncovers a neural mechanism whereby rewarded life experiences are preferentially replayed and consolidated while we sleep.
Large-scale characterization of sex pheromone communication systems in Drosophila
Authors: Khallaf Mohammed A. , Cui Rongfeng , Weißflog Jerrit , Erdogmus Maide , Svatoš Aleš , Dweck Hany K. M. , Valenzano Dario Riccardo , Hansson Bill S. , Knaden Markus
Published: July 2021

Insects use sex pheromones as a reproductive isolating mechanism to attract conspecifics and repel heterospecifics. Despite the profound knowledge of sex pheromones, little is known about the coevolutionary mechanisms and constraints on their production and detection. Using whole-genome sequences to infer the kinship among 99 drosophilids, we investigate how phylogenetic and chemical traits have interacted at a wide evolutionary timescale. Through a series of chemical syntheses and electrophysiological recordings, we identify 52 sex-specific compounds, many of which are detected via olfaction. Behavioral analyses reveal that many of the 43 male-specific compounds are transferred to the female during copulation and mediate female receptivity and/or male courtship inhibition. Measurement of phylogenetic signals demonstrates that sex pheromones and their cognate olfactory channels evolve rapidly and independently over evolutionary time to guarantee efficient intra- and inter-specific communication systems. Our results show how sexual isolation barriers between species can be reinforced by species-specific olfactory signals.
Piezoacoustics for precision control of electrons floating on helium
Authors: Byeon H. , Nasyedkin K. , Lane J. R. , Beysengulov N. R. , Zhang L. , Loloee R. , Pollanen J.
Published: July 2021

Piezoelectric surface acoustic waves (SAWs) are powerful for investigating and controlling elementary and collective excitations in condensed matter. In semiconductor two-dimensional electron systems SAWs have been used to reveal the spatial and temporal structure of electronic states, produce quantized charge pumping, and transfer quantum information. In contrast to semiconductors, electrons trapped above the surface of superfluid helium form an ultra-high mobility, two-dimensional electron system home to strongly-interacting Coulomb liquid and solid states, which exhibit non-trivial spatial structure and temporal dynamics prime for SAW-based experiments. Here we report on the coupling of electrons on helium to an evanescent piezoelectric SAW. We demonstrate precision acoustoelectric transport of as little as ~0.01% of the electrons, opening the door to future quantized charge pumping experiments. We also show SAWs are a route to investigating the high-frequency dynamical response, and relaxational processes, of collective excitations of the electronic liquid and solid phases of electrons on helium.
A microbiota–root–shoot circuit favours Arabidopsis growth over defence under suboptimal light
Authors: Hou Shiji , Thiergart Thorsten , Vannier Nathan , Mesny Fantin , Ziegler Jörg , Pickel Brigitte , Hacquard Stéphane
Published: July 2021

Bidirectional root–shoot signalling is probably key in orchestrating stress responses and ensuring plant survival. Here, we show that Arabidopsis thaliana responses to microbial root commensals and light are interconnected along a microbiota–root–shoot axis. Microbiota and light manipulation experiments in a gnotobiotic plant system reveal that low photosynthetically active radiation perceived by leaves induces long-distance modulation of root bacterial communities but not fungal or oomycete communities. Reciprocally, microbial commensals alleviate plant growth deficiency under low photosynthetically active radiation. This growth rescue was associated with reduced microbiota-induced aboveground defence responses and altered resistance to foliar pathogens compared with the control light condition. Inspection of a set of A. thaliana mutants reveals that this microbiota- and light-dependent growth–defence trade-off is directly explained by belowground bacterial community composition and requires the host transcriptional regulator MYC2. Our work indicates that aboveground stress responses in plants can be modulated by signals from microbial root commensals.
Systemic immune reaction in axillary lymph nodes adds to tumor-infiltrating lymphocytes in triple-negative breast cancer prognostication
Authors: Liu Fangfang , Hardiman Thomas , Wu Kailiang , Quist Jelmar , Gazinska Patrycja , Ng Tony , Purushotham Arnie , Salgado Roberto , Guo Xiaojing , Pinder Sarah E. , Grigoriadis Anita
Published: July 2021

The level of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative (TNBC) and HER2-positive breast cancers convey prognostic information. The importance of systemic immunity to local immunity is unknown in breast cancer. We previously demonstrated that histological alterations in axillary lymph nodes (LNs) carry clinical relevance. Here, we capture local immune responses by scoring TILs at the primary tumor and systemic immune responses by recording the formation of secondary follicles, also known as germinal centers, in 2,857 cancer-free and involved axillary LNs on haematoxylin and eosin (H&E) stained sections from a retrospective cohort of 161 LN-positive triple-negative and HER2-positive breast cancer patients. Our data demonstrate that the number of germinal center formations across all cancer-free LNs, similar to high levels of TILs, is associated with a good prognosis in low TILs TNBC. This highlights the importance of assessing both primary and LN immune responses for prognostication and for future breast cancer research.
Evaluation of overall survival and barriers to surgery for patients with breast cancer treated without surgery: a National Cancer Database analysis
Authors: Boyce-Fappiano D. , Bedrosian I. , Shen Y. , Lin H. , Gjyshi O. , Yoder A. , Shaitelman S. F. , Woodward W. A.
Published: July 2021

Surgery remains the foundation of curative therapy for non-metastatic breast cancer, but many patients do not undergo surgery. Evidence is limited regarding this population. We sought to assess factors associated with lack of surgery and overall survival (OS) in patients not receiving breast cancer surgery. Retrospective cohort study of patients in the US National Cancer Database treated in 2004–2016. The dataset comprised 2,696,734 patients; excluding patients with unknown surgical status or stage IV, cT0, cTx, or pIS, metastatic or recurrent disease resulted in 1,192,294 patients for analysis. Chi-square and Wilcoxon rank-sum tests were used to assess differences between groups. OS was analyzed using the Kaplan–Meier method with a Cox proportional hazards model performed to assess associated factors. In total 50,626 (4.3%) did not undergo surgery. Black race, age >50 years, lower income, uninsured or public insurance, and lower education were more prevalent in the non-surgical cohort; this group was also more likely to have more comorbidities, higher disease stage, and more aggressive disease biology. Only 3,689 non-surgical patients (7.3%) received radiation therapy (RT). Median OS time for the non-surgical patients was 58 months (3-year and 5-year OS rates 63% and 49%). Median OS times were longer for patients who received chemotherapy (80 vs 50 (no-chemo) months) and RT (85 vs 56 (no-RT) months). On multivariate analysis, age, race, income, insurance status, comorbidity score, disease stage, tumor subtype, treatment facility type and location, and receipt of RT were associated with OS. On subgroup analysis, receipt of chemotherapy improved OS for patients with triple negative (HR 0.66, 95% CI 0.59–0.75, P < 0.001) and HER2+ (HR 0.74, 95% CI 0.65–0.84, P < 0.001) subgroups while RT improved OS for ER+ (HR 0.72, 95% CI 0.64–0.82, P < 0.001) and favorable-disease (ER+, early-stage, age >60) (HR 0.61, 95% CI 0.45–0.83, P = 0.002) subgroups. Approximately 4% of women with breast cancer do not undergo surgery, particularly those with more aggressive disease and lower socioeconomic status. Despite its benefits, RT was underutilized. This study provides a benchmark of survival outcomes for patients who do not undergo surgery and highlights a potential role for use of RT.
Accurate long-range forecasting of COVID-19 mortality in the USA
Authors: Ramazi Pouria , Haratian Arezoo , Meghdadi Maryam , Mari Oriyad Arash , Lewis Mark A. , Maleki Zeinab , Vega Roberto , Wang Hao , Wishart David S. , Greiner Russell
Published: July 2021

The need for improved models that can accurately predict COVID-19 dynamics is vital to managing the pandemic and its consequences. We use machine learning techniques to design an adaptive learner that, based on epidemiological data available at any given time, produces a model that accurately forecasts the number of reported COVID-19 deaths and cases in the United States, up to 10 weeks into the future with a mean absolute percentage error of 9%. In addition to being the most accurate long-range COVID predictor so far developed, it captures the observed periodicity in daily reported numbers. Its effectiveness is based on three design features: (1) producing different model parameters to predict the number of COVID deaths (and cases) from each time and for a given number of weeks into the future, (2) systematically searching over the available covariates and their historical values to find an effective combination, and (3) training the model using “last-fold partitioning”, where each proposed model is validated on only the last instance of the training dataset, rather than being cross-validated. Assessments against many other published COVID predictors show that this predictor is 19–48% more accurate.
A scaffolded approach to unearth potential antibacterial components from epicarp of Malaysian Nephelium lappaceum L.
Authors: Asghar Ali , Tan Yong Chiang , Zahoor Mohammad , Zainal Abidin Syafiq Asnawi , Yow Yoon-Yen , Khan Ezzat , Lahiri Chandrajit
Published: July 2021

The emergence and spread of antimicrobial resistance have been of serious concern to human health and the management of bacterial infectious diseases. Effective treatment of these diseases requires the development of novel therapeutics, preferably free of side effects. In this regard, natural products are frequently conceived to be potential alternative sources for novel antibacterial compounds. Herein, we have evaluated the antibacterial activity of the epicarp extracts of the Malaysian cultivar of yellow rambutan fruit (Nephelium lappaceum L.) against six pathogens namely, Bacillus subtilis, methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pyogenes, Pseudomonas aeruginosa, Klebsiella pneumoniae and Salmonella enterica. Among a series of solvent extracts, fractions of ethyl acetate and acetone have revealed significant activity towards all tested strains. Chemical profiling of these fractions, via HPLC, LC–MS and GC–MS, has generated a library of potentially bioactive compounds. Downstream virtual screening, pharmacological prediction, and receptor-ligand molecular dynamics simulation have eventually unveiled novel potential antibacterial compounds, which can be extracted for medicinal use. We report compounds like catechin, eplerenone and oritin-4-beta-ol to be computationally inhibiting the ATP-binding domain of the chaperone, DnaK of P. aeruginosa and MRSA. Thus, our work follows the objective to propose new antimicrobials capable of perforating the barrier of resistance posed by both the gram positives and the negatives.
Association between thyroid cysts and hypertension by atherosclerosis status: a cross-sectional study
Authors: Shimizu Yuji , Kawashiri Shin-Ya , Noguchi Yuko , Nagata Yasuhiro , Maeda Takahiro , Hayashida Naomi
Published: July 2021

Our recent studies indicate that thyroid cysts have clinical implications. Thyroid cysts could have a positive effect on the supply of thyroid hormones. Both hyperthyroidism and hypothyroidism cause hypertension. Hypothyroidism, but not hyperthyroidism, is a risk factor for atherosclerosis. Therefore, thyroid cysts could be associated with hypertension, and atherosclerosis might influence the association between thyroid cysts and hypertension. To evaluate the clinical significance of thyroid cysts, a cross-sectional study was conducted with 1801 Japanese aged 40–74 years. Thyroid cysts were significantly positively associated with hypertension in participants without atherosclerosis. However, there was a significant inverse association in those with atherosclerosis. The potential confounding factor adjusted odd ratios and 95% confidence intervals (95% CIs) were 1.49 (95% CI 1.17–1.90) for participants without atherosclerosis and 0.49 (95% CI 0.24–0.98) for those with atherosclerosis. The present study demonstrates that thyroid cysts have clinical implications because thyroid cysts support thyroid hormone activity. Our findings provide sufficient evidence to develop a risk assessment for hypertension for the general population, even though further research is required.
Secret messaging with endogenous chemistry
Authors: Kennedy Eamonn , Geiser Joseph , Arcadia Christopher E. , Weber Peter M. , Rose Christopher , Rubenstein Brenda M. , Rosenstein Jacob K.
Published: July 2021

Data encoded in molecules offers opportunities for secret messaging and extreme information density. Here, we explore how the same chemical and physical dimensions used to encode molecular information can expose molecular messages to detection and manipulation. To address these vulnerabilities, we write data using an object’s pre-existing surface chemistry in ways that are indistinguishable from the original substrate. While it is simple to embed chemical information onto common objects (covers) using routine steganographic permutation, chemically embedded covers are found to be resistant to detection by sophisticated analytical tools. Using Turbo codes for efficient digital error correction, we demonstrate recovery of secret keys hidden in the pre-existing chemistry of American one dollar bills. These demonstrations highlight ways to improve security in other molecular domains, and show how the chemical fingerprints of common objects can be harnessed for data storage and communication.
Genome-wide CRISPR/Cas9 screening in human iPS derived cardiomyocytes uncovers novel mediators of doxorubicin cardiotoxicity
Authors: Sapp Valerie , Aguirre Aitor , Mainkar Gayatri , Ding Jeffrey , Adler Eric , Liao Ronglih , Sharma Sonia , Jain Mohit
Published: July 2021

Human induced pluripotent stem (iPS) cell technologies coupled with genetic engineering now facilitate the study of the molecular underpinnings of disease in relevant human cell types. Application of CRISPR/Cas9-based approaches for genome-scale functional screening in iPS-derived cells, however, has been limited by technical constraints, including inefficient transduction in pooled format, loss of library representation, and poor cellular differentiation. Herein, we present optimized approaches for whole-genome CRISPR/Cas9 based screening in human iPS derived cardiomyocytes with near genome-wide representation at both the iPS and differentiated cell stages. As proof-of-concept, we perform a screen to investigate mechanisms underlying doxorubicin mediated cell death in iPS derived cardiomyocytes. We identified two poorly characterized, human-specific transporters (SLCO1A2, SLCO1B3) whose loss of function protects against doxorubicin-cardiotoxicity, but does not affect cell death in cancer cells. This study provides a technical framework for genome-wide functional screening in iPS derived cells and identifies new targets to mitigate doxorubicin-cardiotoxicity in humans.
Assessing the post-treatment therapeutic effect of pinaverium in irritable bowel syndrome: a randomized controlled trial
Authors: Zheng Liang , Lu Weimin , Xiao Qi , Lai Yaoliang , Fan Heng , Sun Yuling , Huang Dawei , Wang Yuanyuan , Li Zhen , Jiang Zhengyan , Liu Xingxing , Zhang Lijuan , Zuo Dongmei , Shou Zhexing , Tang Qing , Huang Huisuo , Yang Yongqiang , Tang Zongxiang , Xiao Jun
Published: July 2021

Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder significantly decreasing patients’ lives of quality and placing huge economic burden on our society. Existing studies indicated that the therapeutic effects maintained for a period of time after the treatments were discontinued. It is clinically important to assess these post-treatment therapeutic effects (PTTE), which prevent IBS from relapsing. To assess the PTTE in pinaverium treatment and obtain high-quality evidence to justify the use of PTTE for long-term IBS management, we performed this controlled, double blind study on patients with IBS who were randomized to pinaverium 50 mg (n = 132) or placebo (n = 132), three times daily, for 4 weeks, and were followed up for 57 weeks after the treatments. The primary endpoints were abdominal pain and stool consistency. The secondary endpoints were pain frequency and stool frequency. The tertiary endpoints were global overall symptom and adverse events. Three days after pinaverium was discontinued, endpoints rebounded only 23.2–42.8% (P < 0.015 cf. placebo). The PTTE (P < 0.05 cf. placebo) lasted 9–17 weeks, which is similar to other antispasmodics with a 15-week treatment in striking contrast to ≥ 1 year PTTE in cognitive behavior therapy and < 1 week PTTE in serotonin antagonist treatment indicating that PTTE length markedly depends on the medication class used for the treatment and less depends on treatment length. After 17 weeks, the stage could be considered as an IBS natural history [no significant differences between pinaverium and placebo (all endpoints’ P’s > 0.05)], during which an average of 51.5–56.4% of patients (pool pinaverium and placebo data together) had IBS symptoms. These results provide clinical insights into efficient and cost-effective management of refractory IBS, and lend support to the IBS management that the selection of a therapy should consider both its effectiveness during treatment and its PTTE after the treatment.

Trial registration number: NCT02330029 (16/08/2016).
A bacteriocin-based treatment option for Staphylococcus haemolyticus biofilms
Authors: Kranjec Christian , Kristensen Sofie S. , Bartkiewicz Karolina T. , Brønner Mikkel , Cavanagh Jorunn P. , Srikantam Aparna , Mathiesen Geir , Diep Dzung B.
Published: July 2021

Bacteriocins are ribosomally-synthesized antimicrobial peptides, showing great potential as novel treatment options for multidrug-resistant pathogens. In this study, we designed a novel hybrid bacteriocin, Hybrid 1 (H1), by combing the N-terminal part and the C-terminal part of the related bacteriocins enterocin K1 (K1) and enterocin EJ97 (EJ97), respectively. Like the parental bacteriocins, H1 used the membrane-bound protease RseP as receptor, however, it differed from the others in the inhibition spectrum. Most notably, H1 showed a superior antimicrobial effect towards Staphylococcus haemolyticus—an important nosocomial pathogen. To avoid strain-dependency, we further evaluated H1 against 27 clinical and commensal S. haemolyticus strains, with H1 indeed showing high activity towards all strains. To curtail the rise of resistant mutants and further explore the potential of H1 as a therapeutic agent, we designed a bacteriocin-based formulation where H1 was used in combination with the broad-spectrum bacteriocins micrococcin P1 and garvicin KS. Unlike the individual bacteriocins, the three-component combination was highly effective against planktonic cells and completely eradicated biofilm-associated S. haemolyticus cells in vitro. Most importantly, the formulation efficiently prevented development of resistant mutants as well. These findings indicate the potential of a bacteriocins-based formulation as a treatment option for S. haemolyticus.