bluuebunny/crossref_metadata_2025 huggingface dataset:
Morphological Alterations of CAD Cells Overexpressing AKT1
Authors: Wachira James
Published: July 2020

CAD cells are neuronal cells used in studies of cell differentiation and in cellular models of neuropathology. When cultured in differentiation medium, CAD cells exhibit characteristics of mature neurons including the generation of action potential. In addition to being a central signaling kinase in cell survival, AKT1 plays important roles in the nervous system including neuroplasticity and this study examined the localization of exogenous AKT1 in CAD cells. Neuropeptides modulate many signal transduction pathways and melacortins are implicated in regulating growth factor signal transduction pathways, including the PI3K/AKT pathway. AKT1-DsReD was transfected into CAD cells that were stably expressing melanocortin 3-receptor-GFP (MC3R-GFP), a G-protein coupled receptor. The cells were imaged with confocal microscopy to determine the fluorescent protein localization patterns. AKT1-DsRed was predominantly localized in the cytoplasm and the nucleus. Further, expression of exogenous AKT1 in these cell lines led to morphological changes reminiscent of apoptosis. As expected, MC3R-GFP localized to the plasma membrane but it internalized upon cell stimulation with the cognate ligand. In limited areas of the plasma membrane, AKT1-DsRed and MC3R-GFP were colocalized. In conclusion, quantitative studies to understand the role of relative levels of AKT1 in determining cell survival are needed.
The development of a nomogram to determine the frequency of elevated risk for non-medical opioid use in cancer patients
Authors: Yennurajalingam Sriram , Edwards Tonya , Arthur Joseph , Lu Zhanni , Erdogan Elif , Malik Jimi S. , Naqvi Syed Mujtaba Ali , Wu Jimin , Liu Diane D. , Williams Janet L. , Hui David , Reddy Suresh K. , Bruera Eduardo
Published: July 2020

Objective

Non-medical opioid use (NMOU) is a growing crisis. Cancer patients at elevated risk of NMOU (+risk) are frequently underdiagnosed. The aim of this paper was to develop a nomogram to predict the probability of +risk among cancer patients receiving outpatient supportive care consultation at a comprehensive cancer center.

Method

3,588 consecutive patients referred to a supportive care clinic were reviewed. All patients had a diagnosis of cancer and were on opioids for pain. All patients were assessed using the Edmonton Symptom Assessment Scale (ESAS), Screener and Opioid Assessment for Patients with Pain (SOAPP-14), and CAGE-AID (Cut Down-Annoyed-Guilty-Eye Opener) questionnaires. “+risk” was defined as an SOAPP-14 score of ≥7. A nomogram was devised based on the risk factors determined by the multivariate logistic regression model to estimate the probability of +risk.

Results

731/3,588 consults were +risk. +risk was significantly associated with gender, race, marital status, smoking status, depression, anxiety, financial distress, MEDD (morphine equivalent daily dose), and CAGE-AID score. TheC-index was 0.8. A nomogram was developed and can be accessed athttps://is.gd/soappnomogram. For example, for a male Hispanic patient, married, never smoked, with ESAS scores for depression = 3, anxiety = 3, financial distress = 7, a CAGE score of 0, and an MEDD score of 20, the total score is 9 + 9+0 + 0+6 + 10 + 23 + 0+1 = 58. A nomogram score of 58 indicates the probability of +risk of 0.1.

Significance of results

We established a practical nomogram to assess the +risk. The application of a nomogram based on routinely collected clinical data can help clinicians establish patients with +risk and positively impact care planning.
The Fate of International Monetary Systems: How and Why They Fall Apart
Authors: Seddon Jack
Published: July 2020

The collapses of the interwar and Bretton Woods monetary regimes have been understood as evidence that international monetary regimes fail when sudden economic shocks destabilize the political coalitions or shared ideas underpinning them. But while these histories are important, other monetary regimes, such as the Sterling Area and Latin Union, disintegrated over long periods of time. If exogenous shocks do not account for varied patterns of destabilization, what does? Using the tools of comparative-historical analysis, I argue that these patterns are the result of strategic choices made by hegemonic powers, choices that are in turn governed by the historical-structural foundations of regimes. From these foundations emerge alternative leadership strategies and membership behaviors responsible for endogenous macro-institutional effects that drive the observed regime trajectories. Regime leaders may establish visibly unequal collective arrangements that maintain their positions but leave a system vulnerable to overt internal resistance and sudden breakdown. Or leaders may reject collective arrangements in order to secretly discriminate among members, slowly building dysfunction into a system, driving its gradual abandonment by members and institutional decline. The analysis both suggests that more equal state power may improve long-run regime performance, and also locates structural vulnerabilities in contemporary regimes.
The Forward Testing Effect is Immune to Acute Psychosocial Encoding/Retrieval Stress
Authors: Pastötter Bernhard , von Dawans Bernadette , Domes Gregor , Frings Christian
Published: July 2020

Abstract. The forward testing effect (FTE) refers to the finding that testing of previously studied information enhances memory for subsequently studied other information. Previous research demonstrated that the FTE is a robust phenomenon that generalizes across different materials and populations. The present study examined whether the FTE is robust under acute psychosocial encoding/retrieval stress. In each of two experimental conditions, participants studied three item lists in anticipation of final cumulative recall testing. In the testing condition, participants were tested immediately on lists 1 and 2, whereas in the restudy condition, they restudied lists 1 and 2. In both conditions, participants were tested immediately on list 3. Acute psychosocial stress was induced in participants prior to the encoding of item lists using the Trier social stress test for groups protocol. No stress was induced in a control group. Salivary cortisol, alpha amylase, and subjective stress were measured repeatedly to capture the biopsychological stress response. The results showed a significant FTE on list 3 recall, that is, testing of lists 1 and 2 enhanced the recall of list 3. No significant effect of stress on the FTE was observed, suggesting that the FTE is robust under acute psychosocial encoding/retrieval stress. The discussion provides suggestions for future research directions.
Flickers of Light Help Map the Space Junkyard
Authors: Garz�n Camilo
Published: July 2020

Researchers are identifying space debris by measuring its flickering patterns of reflected light.
India’s Food Bowl Heads Toward Desertification
Authors: Singh Gurpreet
Published: July 2020

Water-guzzling rice consumes more water than Punjab can recharge. If current irrigation rates continue, the state will empty its groundwater reserves within 20 years.
Zeb1 for RCP-induced oral cancer cell invasion and its suppression by resveratrol
Authors: Kim Jin Young , Cho Kyung Hwa , Jeong Bo Young , Park Chang Gyo , Lee Hoi Young
Published: July 2020

Rab coupling protein (RCP) is upregulated in head and neck squamous cell carcinoma (HNSCC) and is correlated with the progression and survival of patients. However, the role of RCP in one of the aggressive types of HNSCC, oral squamous cell carcinoma (OSCC), remains elusive. In the present study, we identified the important role of Zeb1 in RCP-induced OSCC epithelial-to-mesenchymal transition (EMT) and invasion. RCP induces Zeb1 expression, and silencing Zeb1 expression significantly inhibits RCP-induced OSCC invasion. In addition, Zeb1 upregulates MT1-MMP expression to promote OSCC EMT and invasion. Furthermore, we observed that the β1 integrin/EGFR/β-catenin signaling cascade mediates RCP-induced Zeb1 expression to promote OSCC invasion. Notably, we provide evidence that resveratrol (REV) strongly inhibits RCP-induced Zeb1 expression through blocking β1 integrin endosome recycling and EGFR activation, leading to suppression of RCP-induced OSCC invasion, demonstrating the important role of RCP in OSCC invasion and its reversion by REV. Collectively, the present study provides evidence for the first time that RCP aggravates OSCC invasion through increasing Zeb1 expression and subsequently upregulating MT1-MMP expression and that this process is reversed by REV, providing novel biomarkers and indicating the therapeutic potential of REV in OSCC.
Modular prophage interactions driven by capsule serotype select for capsule loss under phage predation
Authors: de Sousa Jorge A M , Buffet Amandine , Haudiquet Matthieu , Rocha Eduardo P C , Rendueles Olaya
Published: July 2020

Klebsiella species are able to colonize a wide range of environments and include worrisome nosocomial pathogens. Here, we sought to determine the abundance and infectivity of prophages of Klebsiella to understand how the interactions between induced prophages and bacteria affect population dynamics and evolution. We identified many prophages in the species, placing these taxa among the top 5% of the most polylysogenic bacteria. We selected 35 representative strains of the Klebsiella pneumoniae species complex to establish a network of induced phage–bacteria interactions. This revealed that many prophages are able to enter the lytic cycle, and subsequently kill or lysogenize closely related Klebsiella strains. Although 60% of the tested strains could produce phages that infect at least one other strain, the interaction network of all pairwise cross-infections is very sparse and mostly organized in modules corresponding to the strains’ capsule serotypes. Accordingly, capsule mutants remain uninfected showing that the capsule is a key factor for successful infections. Surprisingly, experiments in which bacteria are predated by their own prophages result in accelerated loss of the capsule. Our results show that phage infectiousness defines interaction modules between small subsets of phages and bacteria in function of capsule serotype. This limits the role of prophages as competitive weapons because they can infect very few strains of the species complex. This should also restrict phage-driven gene flow across the species. Finally, the accelerated loss of the capsule in bacteria being predated by their own phages, suggests that phages drive serotype switch in nature.
Neuroinflammatory alterations in trait anxiety: modulatory effects of minocycline
Authors: Rooney Sinead , Sah Anupam , Unger Michael S. , Kharitonova Maria , Sartori Simone B. , Schwarzer Christoph , Aigner Ludwig , Kettenmann Helmut , Wolf Susanne A. , Singewald Nicolas
Published: July 2020

High trait anxiety is a substantial risk factor for developing anxiety disorders and depression. While neuroinflammation has been identified to contribute to stress-induced anxiety, little is known about potential dysregulation in the neuroinflammatory system of genetically determined pathological anxiety or high trait anxiety individuals. We report microglial alterations in various brain regions in a mouse model of high trait anxiety (HAB). In particular, the dentate gyrus (DG) of the hippocampus of HABs exhibited enhanced density and average cell area of Iba1+, and density of phagocytic (CD68+/Iba1+) microglia compared to normal anxiety (NAB) controls. Minocycline was used to assess the capacity of a putative microglia ‘inhibitor’ in modulating hyperanxiety behavior of HABs. Chronic oral minocycline indeed reduced HAB hyperanxiety, which was associated with significant decreases in Iba1+ and CD68+Iba1+ cell densities in the DG. Addressing causality, it was demonstrated that longer (10 days), but not shorter (5 days), periods of minocycline microinfusions locally into the DG of HAB reduced Iba-1+ cell density and attenuated hyperanxiety-related behavior, indicating that neuroinflammation in the DG is at least partially involved in the maintenance of pathological anxiety. The present data reveal evidence of disturbances in the microglial system of individuals with high trait anxiety. Minocycline attenuated HAB hyperanxiety, likely by modulation of microglial activity within the DG. Thus, the present data suggest that drugs with microglia-targeted anti-inflammatory properties could be promising as novel alternative or complimentary anxiolytic therapeutic approaches in specific subgroups of individuals genetically predisposed to hyperanxiety.
Modulation of inhibitory control networks relate to clinical response following ketamine therapy in major depression
Authors: Sahib Ashish K. , Loureiro Joana RA. , Vasavada Megha M. , Kubicki Antoni , Wade Benjamin , Joshi Shantanu H. , Woods Roger P. , Congdon Eliza , Espinoza Randall , Narr Katherine L.
Published: July 2020

Subanesthetic ketamine is found to induce fast-acting and pronounced antidepressant effects, even in treatment resistant depression (TRD). However, it remains unclear how ketamine modulates neural function at the brain systems-level to regulate emotion and behavior. Here, we examined treatment-related changes in the inhibitory control network after single and repeated ketamine therapy in TRD. Forty-seven TRD patients (mean age = 38, 19 women) and 32 healthy controls (mean age = 35, 18 women) performed a functional magnetic resonance imaging (fMRI) response inhibition task at baseline, and 37 patients completed the fMRI task and symptom scales again 24 h after receiving both one and four 0.5 mg/kg intravenous ketamine infusions. Analyses of fMRI data addressed effects of diagnosis, time, and differences between treatment remitters and non-remitters. Significant decreases in brain activation were observed in the inhibitory control network, including in prefrontal and parietal regions, and visual cortex following serial ketamine treatment, p < 0.05 corrected. Remitters were distinguished from non-remitters by having lower functional activation in the supplementary motor area (SMA) prior to treatment, which normalized towards controls following serial ketamine treatment. Results suggest that ketamine treatment leads to neurofunctional plasticity in executive control networks including the SMA during a response-inhibitory task. SMA changes relate to reductions in depressive symptoms, suggesting modulation of this network play an important role in therapeutic response. In addition, early changes in the SMA network during response inhibition appear predictive of overall treatment outcome, and may serve as a biomarker of treatment response.
Association between DNA methylation levels in brain tissue and late-life depression in community-based participants
Authors: Hüls Anke , Robins Chloe , Conneely Karen N. , De Jager Philip L. , Bennett David A. , Epstein Michael P. , Wingo Thomas S. , Wingo Aliza P.
Published: July 2020

Objective

Major depressive disorder (MDD) arises from a combination of genetic and environmental risk factors and DNA methylation is one of the molecular mechanisms through which these factors can manifest. However, little is known about the epigenetic signature of MDD in brain tissue. This study aimed to investigate associations between brain tissue-based DNA methylation and late-life MDD.

Methods

We performed a brain epigenome-wide association study (EWAS) of late-life MDD in 608 participants from the Religious Order Study and the Rush Memory and Aging Project (ROS/MAP) using DNA methylation profiles of the dorsal lateral prefrontal cortex generated using the Illumina HumanMethylation450 Beadchip array. We also conducted an EWAS of MDD in each sex separately.

Results

We found epigenome-wide significant associations between brain tissue-based DNA methylation and late-life MDD. The most significant and robust association was found with altered methylation levels in the YOD1 locus (cg25594636, p value = 2.55 × 10−11; cg03899372, p value = 3.12 × 10−09; cg12796440, p value = 1.51 × 10−08, cg23982678, p value = 7.94 × 10−08). Analysis of differentially methylated regions (p value = 5.06 × 10−10) further confirmed this locus. Other significant loci include UGT8 (cg18921206, p value = 1.75 × 10−08), FNDC3B (cg20367479, p value = 4.97 × 10−08) and SLIT2 (cg10946669, p value = 8.01 × 10−08). Notably, brain tissue-based methylation levels were strongly associated with late-life MDD in men more than in women.

Conclusions

We identified altered methylation in the YOD1, UGT8, FNDC3B, and SLIT2 loci as new epigenetic factors associated with late-life MDD. Furthermore, our study highlights the sex-specific molecular heterogeneity of MDD.
LEF1 mediates osteoarthritis progression through circRNF121/miR-665/MYD88 axis via NF-кB signaling pathway
Authors: Wang Tianfu , Hao Zhiyu , Liu Changcheng , Yuan Lebin , Li Li , Yin Menghong , Li Qing , Qi Zhiming , Wang Zi
Published: July 2020

Osteoarthritis (OA) is a joint disease that causes great pain to patients and imposes a tremendous burden on the world’s medical resources. Regulatory noncoding RNAs, including circular RNAs (circRNAs) and microRNAs (miRNAs), play an important role in OA progression. Here, we identified differential expression of transcription factor LEF1 that increased circRNA circRNF121 levels in normal and OA cartilage tissues. The expression of LEF1 and circRNF121 was positively associated with Mankin’s scores. Alteration of circRNF121 mediated the degradation of extracellular mechanisms (ECM), apoptosis, and proliferation of chondrocytes. MiR-665 was identified as a direct regulatory target of circRNF121 and MYD88. Functional analysis showed that circRNF121 and MYD88 modulated ECM degradation, apoptosis, and proliferation of chondrocytes, which could be reversed by miR-665. MYD88 regulated the activity of the NF-кB signaling pathway by circRNF121 via sponging miR-665. Collectively, these data indicated that LEF1 impacted OA progression by modulating the circRNF121/miR-665/MYD88 axis via NF-кB pathway. Our research proposed a new molecular mechanism for the development of OA, and provided a prospective therapeutic target for OA.
IFN-γ promoted exosomes from mesenchymal stem cells to attenuate colitis via miR-125a and miR-125b
Authors: Yang Ruili , Huang Huaming , Cui Shengjie , Zhou Yikun , Zhang Ting , Zhou Yanheng
Published: July 2020

Bone marrow mesenchymal stem cells (MSCs) have demonstrated therapeutic effects for colitis through immunomodulation and anti-inflammation. However, whether MSC-derived exosomes possessed the similar function remains unclear. In present study, exosomes were isolated from control and IFN-γ-primed MSCs and was verified by transmission electron microscope (TEM) and immunofluorescence staining. Administration of exosomes to mice significantly improved the disease activity index and histological score of colitis, and decreased the ratio of Th17 cells with elevated Treg cells ratio in mice colitis model. Exosomes from IFN-γ-primed MSCs showed superior therapeutic effects to colitis. Exosomes treatment inhibited Th17 differentiation in vitro, and exosomes from IFN-γ-primed MSCs showed higher inhibition efficacy. Mechanistically, exosomes treatment significantly decreased the expression of Stat3 and p-Stat3 to inhibit Th17 cells differentiation. IFN-γ pretreatment increased the level of miR-125a and miR-125b of exosomes, which directly targeted on Stat3, to repress Th17 cell differentiation. Moreover, combination of miR-125a and miR-125b agmior infusion also showed therapeutic effects for colitis, accompanied by decreased Th17 cell ratio. Collectively, this study demonstrates that IFN-γ treatment promoted exosomes from MSCs to attenuate colitis through increasing the level of miR-125a and miR-125b, which binding on 3′-UTR of Stat3 to repress Th17 cell differentiation. This study provides a new approach of exocytosis on the treatment of colitis.
CircularRNA-9119 protects hepatocellular carcinoma cells from apoptosis by intercepting miR-26a/JAK1/STAT3 signaling
Authors: Yang Lixue , Xue Hui , Sun Yanfu , Zhang Lei , Xue Feng , Ge Ruiliang
Published: July 2020

Hepatocellular carcinoma (HCC) is a more common malignancy than the majority of cancers and ranks second in the world’s top causes of cancer-related mortality. The objective of the study was to investigate and explain how circularRNA-9119 (circ9119) regulated the properties of HCC cell lines. Cancer cells isolated from HCC patients and HCC cell lines showed clearly upregulated expression of circ9119 and Janus kinase 1 (JAK1) with decreased levels of miR-26a compared to healthy controls and normal hepatic cells. To determine the function of circ9119, circ9119 was silenced in HCC cells, resulting in significantly less proliferation of HCC cells and increasing apoptosis. Circ9119 silencing also resulted in the upregulation of miR-26a. Bioinformatics prediction and dual-luciferase reporter assays showed that circ9119 targeted miR-26a. Further studies revealed that miR-26a had the opposite effect on circ9119; the inhibition of miR-26a antagonized circ9119 silencing, leading to reduced cell proliferation and increased apoptosis, while the ectopic overexpression of miR-26a impaired cell growth. Additionally, we found that the JAK1 3′-UTR was targeted by miR-26a; a decrease in the levels of JAK1 protein and mRNA followed transfection of a miR-26a mimic. Administration of the JAK1 inhibitor, baricitinib, caused the activation of signal transducer and activator of transcription 3 (STAT3) and revealed an effect similar to that of circ9119 silencing on cell proliferation and apoptosis. These results showed that circ9119 could modulate apoptosis, and broadly, cell proliferation by competitively binding miR-26a, which targeted JAK1-STAT3, in HCC cell lines. This study is a novel description of circ9119 regulation of HCC.
Extracellular vesicles in cardiovascular diseases
Authors: Fu Shihui , Zhang Yujie , Li Yulong , Luo Leiming , Zhao Yali , Yao Yao
Published: July 2020

Due to the continued high incidence and mortality rate worldwide, there is still a need to develop new strategies for the prevention, diagnosis and treatment of cardiovascular diseases (CVDs). Proper cardiovascular function depends on the coordinated interplay and communication between cardiomyocytes and noncardiomyocytes. Extracellular vesicles (EVs) are enclosed in a lipid bilayer and represent a significant mechanism for intracellular communication. By containing and transporting various bioactive molecules, such as micro-ribonucleic acids (miRs) and proteins, to target cells, EVs impart favourable, neutral or detrimental effects on recipient cells, such as modulating gene expression, influencing cell phenotype, affecting molecular pathways and mediating biological behaviours. EVs can be released by cardiovascular system-related cells, such as cardiomyocytes, endotheliocytes, fibroblasts, platelets, smooth muscle cells, leucocytes, monocytes and macrophages. EVs containing miRs and proteins regulate a multitude of diverse functions in target cells, maintaining cardiovascular balance and health or inducing pathological changes in CVDs. On the one hand, miRs and proteins transferred by EVs play biological roles in maintaining normal cardiac structure and function under physiological conditions. On the other hand, EVs change the composition of their miR and protein cargoes under pathological conditions, which gives rise to the development of CVDs. Therefore, EVs hold tremendous potential to prevent, diagnose and treat CVDs. The current article reviews the specific functions of EVs in different CVDs.
A molecular map of murine lymph node blood vascular endothelium at single cell resolution
Authors: Brulois Kevin , Rajaraman Anusha , Szade Agata , Nordling Sofia , Bogoslowski Ania , Dermadi Denis , Rahman Milladur , Kiefel Helena , O’Hara Edward , Koning Jasper J. , Kawashima Hiroto , Zhou Bin , Vestweber Dietmar , Red-Horse Kristy , Mebius Reina E. , Adams Ralf H. , Kubes Paul , Pan Junliang , Butcher Eugene C.
Published: July 2020

Blood vascular endothelial cells (BECs) control the immune response by regulating blood flow and immune cell recruitment in lymphoid tissues. However, the diversity of BEC and their origins during immune angiogenesis remain unclear. Here we profile transcriptomes of BEC from peripheral lymph nodes and map phenotypes to the vasculature. We identify multiple subsets, including a medullary venous population whose gene signature predicts a selective role in myeloid cell (vs lymphocyte) recruitment to the medulla, confirmed by videomicroscopy. We define five capillary subsets, including a capillary resident precursor (CRP) that displays stem cell and migratory gene signatures, and contributes to homeostatic BEC turnover and to neogenesis of high endothelium after immunization. Cell alignments show retention of developmental programs along trajectories from CRP to mature venous and arterial populations. Our single cell atlas provides a molecular roadmap of the lymph node blood vasculature and defines subset specialization for leukocyte recruitment and vascular homeostasis.
Autophagy deficiency promotes triple-negative breast cancer resistance to T cell-mediated cytotoxicity by blocking tenascin-C degradation
Authors: Li Zhi-Ling , Zhang Hai-Liang , Huang Yun , Huang Jun-Hao , Sun Peng , Zhou Ning-Ning , Chen Yu-Hong , Mai Jia , Wang Yan , Yu Yan , Zhou Li-Huan , Li Xuan , Yang Dong , Peng Xiao-Dan , Feng Gong-Kan , Tang Jun , Zhu Xiao-Feng , Deng Rong
Published: July 2020

Most triple-negative breast cancer (TNBC) patients fail to respond to T cell-mediated immunotherapies. Unfortunately, the molecular determinants are still poorly understood. Breast cancer is the disease genetically linked to a deficiency in autophagy. Here, we show that autophagy defects in TNBC cells inhibit T cell-mediated tumour killing in vitro and in vivo. Mechanistically, we identify Tenascin-C as a candidate for autophagy deficiency-mediated immunosuppression, in which Tenascin-C is Lys63-ubiquitinated by Skp2, particularly at Lys942 and Lys1882, thus promoting its recognition by p62 and leading to its selective autophagic degradation. High Tenascin-C expression is associated with poor prognosis and inversely correlated with LC3B expression and CD8+T cells in TNBC patients. More importantly, inhibition of Tenascin-C in autophagy-impaired TNBC cells sensitizes T cell-mediated tumour killing and improves antitumour effects of single anti-PD1/PDL1 therapy. Our results provide a potential strategy for targeting TNBC with the combination of Tenascin-C blockade and immune checkpoint inhibitors.
Multiparameter squeezing for optimal quantum enhancements in sensor networks
Authors: Gessner Manuel , Smerzi Augusto , Pezzè Luca
Published: July 2020

Squeezing currently represents the leading strategy for quantum enhanced precision measurements of a single parameter in a variety of continuous- and discrete-variable settings and technological applications. However, many important physical problems including imaging and field sensing require the simultaneous measurement of multiple unknown parameters. The development of multiparameter quantum metrology is yet hindered by the intrinsic difficulty in finding saturable sensitivity bounds and feasible estimation strategies. Here, we derive the general operational concept of multiparameter squeezing, identifying metrologically useful states and optimal estimation strategies. When applied to spin- or continuous-variable systems, our results generalize widely-used spin- or quadrature-squeezing parameters. Multiparameter squeezing provides a practical and versatile concept that paves the way to the development of quantum-enhanced estimation of multiple phases, gradients, and fields, and for the efficient characterization of multimode quantum states in atomic and optical sensor networks.
Contacting domains segregate a lipid transporter from a solute transporter in the malarial host–parasite interface
Authors: Garten Matthias , Beck Josh R. , Roth Robyn , Tenkova-Heuser Tatyana , Heuser John , Istvan Eva S. , Bleck Christopher K. E. , Goldberg Daniel E. , Zimmerberg Joshua
Published: July 2020

The malaria parasite interfaces with its host erythrocyte (RBC) using a unique organelle, the parasitophorous vacuole (PV). The mechanism(s) are obscure by which its limiting membrane, the parasitophorous vacuolar membrane (PVM), collaborates with the parasite plasma membrane (PPM) to support the transport of proteins, lipids, nutrients, and metabolites between the cytoplasm of the parasite and the cytoplasm of the RBC. Here, we demonstrate that the PV has structure characterized by micrometer-sized regions of especially close apposition between the PVM and the PPM. To determine if these contact sites are involved in any sort of transport, we localize the PVM nutrient-permeable and protein export channel EXP2, as well as the PPM lipid transporter PfNCR1. We find that EXP2 is excluded from, but PfNCR1 is included within these regions of close apposition. We conclude that the host-parasite interface is structured to segregate those transporters of hydrophilic and hydrophobic substrates.
Modelling the incremental benefit of introducing malaria screening strategies to antenatal care in Africa
Authors: Walker Patrick G. T. , Cairns Matt , Slater Hannah , Gutman Julie , Kayentao Kassoum , Williams John E. , Coulibaly Sheick O. , Khairallah Carole , Taylor Steve , Meshnick Steven R. , Hill Jenny , Mwapasa Victor , Kalilani-Phiri Linda , Bojang Kalifa , Kariuki Simon , Tagbor Harry , Griffin Jamie T. , Madanitsa Mwayi , Ghani Azra C. H. , Desai Meghna , ter Kuile Feiko O.
Published: July 2020

Plasmodium falciparum in pregnancy is a major cause of adverse pregnancy outcomes. We combine performance estimates of standard rapid diagnostic tests (RDT) from trials of intermittent screening and treatment in pregnancy (ISTp) with modelling to assess whether screening at antenatal visits improves upon current intermittent preventative therapy with sulphadoxine-pyrimethamine (IPTp-SP). We estimate that RDTs in primigravidae at first antenatal visit are substantially more sensitive than in non-pregnant adults (OR = 17.2, 95% Cr.I. 13.8-21.6), and that sensitivity declines in subsequent visits and with gravidity, likely driven by declining susceptibility to placental infection. Monthly ISTp with standard RDTs, even with highly effective drugs, is not superior to monthly IPTp-SP. However, a hybrid strategy, recently adopted in Tanzania, combining testing and treatment at first visit with IPTp-SP may offer benefit, especially in areas with high-grade SP resistance. Screening and treatment in the first trimester, when IPTp-SP is contraindicated, could substantially improve pregnancy outcomes.
Paraventricular hypothalamus mediates diurnal rhythm of metabolism
Authors: Kim Eun Ran , Xu Yuanzhong , Cassidy Ryan M. , Lu Yungang , Yang Yongjie , Tian Jinbin , Li De-Pei , Van Drunen Rachel , Ribas-Latre Aleix , Cai Zhao-Lin , Xue Mingshan , Arenkiel Benjamin R. , Eckel-Mahan Kristin , Xu Yong , Tong Qingchun
Published: July 2020

Defective rhythmic metabolism is associated with high-fat high-caloric diet (HFD) feeding, ageing and obesity; however, the neural basis underlying HFD effects on diurnal metabolism remains elusive. Here we show that deletion of BMAL1, a core clock gene, in paraventricular hypothalamic (PVH) neurons reduces diurnal rhythmicity in metabolism, causes obesity and diminishes PVH neuron activation in response to fast-refeeding. Animal models mimicking deficiency in PVH neuron responsiveness, achieved through clamping PVH neuron activity at high or low levels, both show obesity and reduced diurnal rhythmicity in metabolism. Interestingly, the PVH exhibits BMAL1-controlled rhythmic expression of GABA-A receptor γ2 subunit, and dampening rhythmicity of GABAergic input to the PVH reduces diurnal rhythmicity in metabolism and causes obesity. Finally, BMAL1 deletion blunts PVH neuron responses to external stressors, an effect mimicked by HFD feeding. Thus, BMAL1-driven PVH neuron responsiveness in dynamic activity changes involving rhythmic GABAergic neurotransmission mediates diurnal rhythmicity in metabolism and is implicated in diet-induced obesity.
Nested whole-genome duplications coincide with diversification and high morphological disparity in Brassicaceae
Authors: Walden Nora , German Dmitry A. , Wolf Eva M. , Kiefer Markus , Rigault Philippe , Huang Xiao-Chen , Kiefer Christiane , Schmickl Roswitha , Franzke Andreas , Neuffer Barbara , Mummenhoff Klaus , Koch Marcus A.
Published: July 2020

Angiosperms have become the dominant terrestrial plant group by diversifying for ~145 million years into a broad range of environments. During the course of evolution, numerous morphological innovations arose, often preceded by whole genome duplications (WGD). The mustard family (Brassicaceae), a successful angiosperm clade with ~4000 species, has been diversifying into many evolutionary lineages for more than 30 million years. Here we develop a species inventory, analyze morphological variation, and present a maternal, plastome-based genus-level phylogeny. We show that increased morphological disparity, despite an apparent absence of clade-specific morphological innovations, is found in tribes with WGDs or diversification rate shifts. Both are important processes in Brassicaceae, resulting in an overall high net diversification rate. Character states show frequent and independent gain and loss, and form varying combinations. Therefore, Brassicaceae pave the way to concepts of phylogenetic genome-wide association studies to analyze the evolution of morphological form and function.
Post-replicative pairing of sister ter regions in Escherichia coli involves multiple activities of MatP
Authors: Crozat Estelle , Tardin Catherine , Salhi Maya , Rousseau Philippe , Lablaine Armand , Bertoni Tommaso , Holcman David , Sclavi Bianca , Cicuta Pietro , Cornet François
Published: July 2020

The ter region of the bacterial chromosome, where replication terminates, is the last to be segregated before cell division in Escherichia coli. Delayed segregation is controlled by the MatP protein, which binds to specific sites (matS) within ter, and interacts with other proteins such as ZapB. Here, we investigate the role of MatP by combining short-time mobility analyses of the ter locus with biochemical approaches. We find that ter mobility is similar to that of a non ter locus, except when sister ter loci are paired after replication. This effect depends on MatP, the persistence of catenanes, and ZapB. We characterise MatP/DNA complexes and conclude that MatP binds DNA as a tetramer, but bridging matS sites in a DNA-rich environment remains infrequent. We propose that tetramerisation of MatP links matS sites with ZapB and/or with non-specific DNA to promote optimal pairing of sister ter regions until cell division.
Ultra-conformal drawn-on-skin electronics for multifunctional motion artifact-free sensing and point-of-care treatment
Authors: Ershad Faheem , Thukral Anish , Yue Jiping , Comeaux Phillip , Lu Yuntao , Shim Hyunseok , Sim Kyoseung , Kim Nam-In , Rao Zhoulyu , Guevara Ross , Contreras Luis , Pan Fengjiao , Zhang Yongcao , Guan Ying-Shi , Yang Pinyi , Wang Xu , Wang Peng , Wu Xiaoyang , Yu Cunjiang
Published: July 2020

An accurate extraction of physiological and physical signals from human skin is crucial for health monitoring, disease prevention, and treatment. Recent advances in wearable bioelectronics directly embedded to the epidermal surface are a promising solution for future epidermal sensing. However, the existing wearable bioelectronics are susceptible to motion artifacts as they lack proper adhesion and conformal interfacing with the skin during motion. Here, we present ultra-conformal, customizable, and deformable drawn-on-skin electronics, which is robust to motion due to strong adhesion and ultra-conformality of the electronic inks drawn directly on skin. Electronic inks, including conductors, semiconductors, and dielectrics, are drawn on-demand in a freeform manner to develop devices, such as transistors, strain sensors, temperature sensors, heaters, skin hydration sensors, and electrophysiological sensors. Electrophysiological signal monitoring during motion shows drawn-on-skin electronics’ immunity to motion artifacts. Additionally, electrical stimulation based on drawn-on-skin electronics demonstrates accelerated healing of skin wounds.
Histone deacetylase 3 controls lung alveolar macrophage development and homeostasis
Authors: Yao Yi , Liu Queping , Adrianto Indra , Wu Xiaojun , Glassbrook James , Khalasawi Namir , Yin Congcong , Yi Qijun , Dong Zheng , Geissmann Frederic , Zhou Li , Mi Qing-Sheng
Published: July 2020

Alveolar macrophages (AMs) derived from embryonic precursors seed the lung before birth and self-maintain locally throughout adulthood, but are regenerated by bone marrow (BM) under stress conditions. However, the regulation of AM development and maintenance remains poorly understood. Here, we show that histone deacetylase 3 (HDAC3) is a key epigenetic factor required for AM embryonic development, postnatal homeostasis, maturation, and regeneration from BM. Loss of HDAC3 in early embryonic development affects AM development starting at E14.5, while loss of HDAC3 after birth affects AM homeostasis and maturation. Single-cell RNA sequencing analyses reveal four distinct AM sub-clusters and a dysregulated cluster-specific pathway in the HDAC3-deficient AMs. Moreover, HDAC3-deficient AMs exhibit severe mitochondrial oxidative dysfunction and deteriorative cell death. Mechanistically, HDAC3 directly binds toPpargenhancers, and HDAC3 deficiency impairsPpargexpression and its signaling pathway. Our findings identify HDAC3 as a key epigenetic regulator of lung AM development and homeostasis.
Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer
Authors: Buqué Aitziber , Bloy Norma , Perez-Lanzón Maria , Iribarren Kristina , Humeau Juliette , Pol Jonathan G. , Levesque Sarah , Mondragon Laura , Yamazaki Takahiro , Sato Ai , Aranda Fernando , Durand Sylvère , Boissonnas Alexandre , Fucikova Jitka , Senovilla Laura , Enot David , Hensler Michal , Kremer Margerie , Stoll Gautier , Hu Yang , Massa Chiara , Formenti Silvia C. , Seliger Barbara , Elemento Olivier , Spisek Radek , André Fabrice , Zitvogel Laurence , Delaloge Suzette , Kroemer Guido , Galluzzi Lorenzo
Published: July 2020

Hormone receptor (HR)+ breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR+ BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HR+HER2− BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR+ BC.
Functional 3D architecture in an intrinsically disordered E3 ligase domain facilitates ubiquitin transfer
Authors: Murphy Paul , Xu Yingqi , Rouse Sarah L. , Jaffray Ellis G. , Plechanovová Anna , Matthews Steve J. , Carlos Penedo J. , Hay Ronald T.
Published: July 2020

The human genome contains an estimated 600 ubiquitin E3 ligases, many of which are single-subunit E3s (ssE3s) that can bind to both substrate and ubiquitin-loaded E2 (E2~Ub). Within ssE3s structural disorder tends to be located in substrate binding and domain linking regions. RNF4 is a ssE3 ligase with a C-terminal RING domain and disordered N-terminal region containing SUMO Interactions Motifs (SIMs) required to bind SUMO modified substrates. Here we show that, although the N-terminal region of RNF4 bears no secondary structure, it maintains a compact global architecture primed for SUMO interaction. Segregated charged regions within the RNF4 N-terminus promote compaction, juxtaposing RING domain and SIMs to facilitate substrate ubiquitination. Mutations that induce a more extended shape reduce ubiquitination activity. Our result offer insight into a key step in substrate ubiquitination by a member of the largest ubiquitin ligase subtype and reveal how a defined architecture within a disordered region contributes to E3 ligase function.
Tensor factorization for elucidating mechanisms of piezoresponse relaxation via dynamic Piezoresponse Force Spectroscopy
Authors: Kelley Kyle P. , Li Linglong , Ren Yao , Ehara Yoshitaka , Funakubo Hiroshi , Somnath Suhas , Jesse Stephen , Cao Ye , Kannan Ramakrishnan , Vasudevan Rama K. , Kalinin Sergei V.
Published: July 2020

Spatially resolved time and voltage-dependent polarization dynamics in PbTiO3 thin films is explored using dynamic piezoresponse force microscopy (D-PFM) in conjunction with interferometric displacement sensing. This approach gives rise to 4D data sets containing information on bias-dependent relaxation dynamics at each spatial location without long-range electrostatic artifacts. To interpret these data sets in the absence of defined physical models, we employ a non-negative tensor factorization method which clearly presents the data as a product of simple behaviors allowing for direct physics interpretation. Correspondingly, we perform phase-field modeling finding the existence of ‘hard’ and ‘soft’ domain wall edges. This approach can be extended to other multidimensional spectroscopies for which even exploratory data analysis leads to unsatisfactory results due to many components in the decomposition.
LH supplementation of ovarian stimulation protocols influences follicular fluid steroid composition contributing to the improvement of ovarian response in poor responder women
Authors: Marchiani S. , Tamburrino L. , Benini F. , Pallecchi M. , Bignozzi C. , Conforti A. , Alviggi C. , Vignozzi L. , Danza G. , Pellegrini S. , Baldi E.
Published: July 2020

In this prospective study, we evaluated the steroid levels in 111 follicular fluids (FF) collected from 13 women stimulated with FSH monotherapy and 205 FF collected from 28 women stimulated with FSH + LH because of a previous history of hypo-responsiveness to FSH. Steroid levels were measured by HPLC/MS–MS and related to ovarian stimulation protocol, oocyte maturity, fertilization and quality of blastocysts, after individually tracking the fate of all retrieved oocytes. 17-Hydroxy-Progesterone, Androstenedione, Estradiol and Estrone were significantly higher in the FSH + LH protocol. Progesterone, 17-Hydroxy-Progesterone and Estradiol were more expressed in FF yielding a mature oocyte (p < 0.01) in the FSH + LH protocol. FF Progesterone concentration was correlated with the rate of normal fertilization in the FSH protocol. None of the FF steroids measured were associated with blastocyst quality and achievement of pregnancy. Our results indicate that LH supplementation in hypo-responsive women modifies ovarian steroid production, mimicking physiological production better and likely contributing to an improved ovarian response. Employing a correct methodological procedure to evaluate the relationship between FF steroid hormones and assisted reproduction outcomes, our study reveals that some steroids in single follicles may be helpful in predicting oocyte maturity and fertilization.
Roniciclib down-regulates stemness and inhibits cell growth by inducing nucleolar stress in neuroblastoma
Authors: Ognibene Marzia , Pezzolo Annalisa
Published: July 2020

Neuroblastoma, an embryonic tumor arising from neuronal crest progenitor cells, has been shown to contain a population of undifferentiated stem cells responsible for the malignant state and the unfavorable prognosis. Although many previous studies have analyzed neuroblastoma stem cells and their therapeutic targeting, this topic appears still open to novel investigations. Here we found that neurospheres derived from neuroblastoma stem-like cells showed a homogeneous staining for several key nucleolar proteins, such as Nucleolin, Nucleophosmin-1, Glypican-2 and PES-1. We investigated the effects of Roniciclib (BAY 1000394), an anticancer stem cells agent, on neurospheres and on an orthotopic neuroblastoma mouse model, discovering an impressive inhibition of tumor growth and indicating good chances for the use of Roniciclib in vivo. We demonstrated that Roniciclib is not only a Wnt/β-catenin signaling inhibitor, but also a nucleolar stress inducer, revealing a possible novel mechanism underlying Roniciclib-mediated repression of cell proliferation. Furthermore, we found that high expression of Nucleophosmin-1 correlates with patients’ short survival. The co-expression of several stem cell surface antigens such as CD44v6 and CD114, together with the nucleolar markers here described, extends new possibilities to isolate undifferentiated subpopulations from neuroblastoma and identify new targets for the treatment of this childhood malignancy.
Resource partitioning among stranded aquatic mammals from Amazon and Northeastern coast of Brazil revealed through Carbon and Nitrogen Stable Isotopes
Authors: Costa Alexandra F. , Botta Silvina , Siciliano Salvatore , Giarrizzo Tommaso
Published: July 2020

Aquatic mammals play an important role in community structure. The present study applied stable isotope analysis (SIA) to evidence trophic relationships and resource partitioning among aquatic mammals inhabiting different environments in the Amazon estuarine complex and adjacent coastal zone (AE) and Northeastern coast (NC) of Brazil. In addition, isotopic niche partitioning among Sotalia guianensis, Inia spp. and Trichechus inunguis within the AE was also evaluated, and ecological S. guianensis stocks were characterized. Among marine delphinids, the carbon isotopic composition in offshore species mirrored that of nearshore species, contradicting the pattern of decreasing δ13C values characteristic of many areas around the world including areas in Southeastern and Southern Brazil. Isotopic niches were highly distinct, with no overlap among the assessed species inhabiting the AE. Inia spp. and T. inunguis occupied significantly larger isotopic niche spaces, suggesting high habitat plasticity. S. guianensis inhabited two coastal regions indicating an ecological distinction. Nitrogen values were similar between S. guianensis from the NC and AE, indicating comparable trophic positions. However, NC specimens presented more variable δ13C values compared to those from AE. SIA results also allowed for insights concerning habitat use and the trophic ecology of dolphin species inhabiting different oceanographic regions off Northern/Northeast Brazil. These findings provide novel data on the stable isotope composition for cetaceans and sirenians from this region, and aid in furthering knowledge on the trophic ecology and habitat use of the investigated species.