bluuebunny/crossref_metadata_2025 huggingface dataset:
Neural Stem Cell Extracellular Vesicles Disrupt Midline Shift Predictive Outcomes in Porcine Ischemic Stroke Model
Authors: Spellicy Samantha E. , Kaiser Erin E. , Bowler Michael M. , Jurgielewicz Brian J. , Webb Robin L. , West Franklin D. , Stice Steven L.
Published: December 2019

Magnetic resonance imaging (MRI) is a clinically relevant non-invasive imaging tool commonly utilized to assess stroke progression in real time. This study investigated the utility of MRI as a predictive measure of clinical and functional outcomes when a stroke intervention is withheld or provided, in order to identify biomarkers for stroke functional outcome under these conditions. Fifteen MRI and ninety functional parameters were measured in a middle cerebral artery occlusion (MCAO) porcine ischemic stroke model. Multiparametric analysis of correlations between MRI measurements and functional outcome was conducted. Acute axial and coronal midline shift (MLS) at 24 h post-stroke were associated with decreased survival and recovery measured by modified Rankin scale (mRS) and were significantly correlated with 52 measured acute (day 1 post) and chronic (day 84 post) gait and behavior impairments in non-treated stroked animals. These results suggest that MLS may be an important non-invasive biomarker that can be used to predict patient outcomes and prognosis as well as guide therapeutic intervention and rehabilitation in non-treated animals and potentially human patients that do not receive interventional treatments. Neural stem cell–derived extracellular vesicle (NSC EV) was a disruptive therapy because NSC EV administration post-stroke disrupted MLS correlations observed in non-treated stroked animals. MLS was not associated with survival and functional outcomes in NSC EV–treated animals. In contrast to untreated animals, NSC EVs improved stroked animal outcomes regardless of MLS severity.
State Uncertainty Normality Detection
Authors: Flegel Sven K. , Bennett James C.
Published: December 2019

Two fundamentally different approaches of determining normality of the probability density function of the state estimation error are compared by application to a range of test cases. The first method is the Henze-Zirkler test, which operates on a random particle sample. The variability of its result is quantified. Using this method, departure from normality has been found to occur in three stages which are detailed. The second test compares the offset in whitened space of the predicted state to the predicted covariance mean obtained from the unscented transform. This test is much more efficient than the random particle based approach and can be applied using any perturbations model. The comparison is performed on the state estimation error in Cartesian space and using two-body motion without process noise. The more efficient, unscented transform based approach shows excellent agreement with the Henze-Zirkler test for constructed test cases. Application to orbit determination results from passive optical observations assessed with a Batch-Least-Squares orbit determination however reveals some discrepancies which have yet to be understood and underline the importance of rigorous testing.
Epigenetics of aging and disease: a brief overview
Authors: Pagiatakis Christina , Musolino Elettra , Gornati Rosalba , Bernardini Giovanni , Papait Roberto
Published: December 2019

Aging is an important risk factor for several human diseases such as cancer, cardiovascular disease and neurodegenerative disorders, resulting from a combination of genetic and environmental factors (e.g., diet, smoking, obesity and stress), which, at molecular level, cause changes in gene expression underlying the decline of physiological function. Epigenetics, which include mechanisms regulating gene expression independently of changes to DNA sequence, regulate gene expression by modulating the structure of chromatin or by regulating the binding of transcriptional machinery to DNA. Several studies showed that an impairment of epigenetic mechanisms promotes alteration of gene expression underlying several aging-related diseases. Alteration of these mechanisms is also linked with changes of gene expression that occurs during aging processes of different tissues. In this review, we will outline the potential role of epigenetics in the onset of two age-related pathologies, cancer and cardiovascular diseases.
Zwei Arten von Selbstbindungen
Authors: Hallich Oliver
Published: December 2019

Unter „Selbstbindungen“ versteht man in medizinethischen Kontexten vorwegnehmende Bitten von Patienten an ihre Ärzte, eigene spätere Behandlungspräferenzen nicht zu befolgen. In diesem Beitrag werden zwei Arten von Selbstbindungen voneinander unterschieden. Wird nach einer Phase des Kompetenzverlustes, für die ein Handeln gegen den Patientenwillen vorausschauend autorisiert wird, die Kompetenz wiedererlangt, handelt es sich um eine Odysseus-Anweisung. Wird aber, wie insbesondere im Falle von Anweisungen für das Spätstadium der Demenz, die Kompetenz nach der Behandlungssituation nicht wiedererlangt, liegt eine Selbstbindung vor, die jedoch keine Odysseus-Anweisung ist. In Bezug auf die erste Art von Selbstbindungen kommt die erwartete spätere Zustimmung des Patienten als Rechtfertigungskriterium für ein Handeln gegen den Patienwillen in Betracht. In Bezug auf die zweite Art von Selbstbindungen ist hingegen zu fragen, ob der Wille des Patienten in der Behandlungssituation als Widerruf des früheren Willens der kompetenten Person gelten kann. Ist dies der Fall, ist der zum früheren Zeitpunkt geäußerte Wunsch nicht mehr als derjenige einschlägig, der festlegt, was der Patient in der Behandlungssituation will.
Forms of Bullying and Associations Between School Perceptions and Being Bullied Among Finnish Secondary School Students Aged 13 and 15
Authors: Markkanen Ilona , Välimaa Raili , Kannas Lasse
Published: December 2019

The study aimed to examine the extent to which Finnish secondary school students experience bullying, how they are bullied, and whether being bullied is associated with school perceptions. The analyses were based on data from the Finnish part of the internationalHealth Behaviour in School-aged Children(HBSC) study, and were obtained from 4262 students aged 13 and 15. The sample was nationally representative. Logistic regression analysis was performed to identify the associations between school perceptions and being bullied. Younger students reported being bullied more often than older students. Among younger students, boys were more often bullied than girls of the same age. There was no significant difference between the genders among the older students. The most common form of being bullied was verbal teasing. Boys tended to be bullied in physical ways, while girls were bullied in more indirect ways. Students with low levels of school engagement, students with poor relations with peers, and students who reported better teacher-student relations were more likely to be bullied. Feelings of loneliness and lower family affluence were also associated with being bullied. Improving the perceptions of school, and of the school experience as a whole, might have an effect on bullying at school.
The contribution of school safety to weight‐related health behaviors for transgender youth
Authors: Pistella Jessica , Ioverno Salvatore , Rodgers Melissa A. , Russell Stephen T.
Published: December 2019

Introduction

The aim of the present study is to examine gender identity disparities in different kinds of weight‐related health behaviors, including physical activity, participation in physical education at school, and healthy and unhealthy eating habits, and to investigate the relationship between school safety and such behaviors in a sample of transgender and non‐transgender students.

Method

We analyzed a statewide sample of 31,609 students (Mage = 14.04, SD = 1.70; 1.1% transgender). We used multilevel regression models to examine the interactive effects of gender identity and perceptions of school safety on the 4 different outcome variables (physical activity, physical education, healthy and unhealthy eating habits). All models included student‐ and school‐level characteristics as controls.

Results

Findings indicated that transgender students, when compared to non‐transgender students, reported (a) feeling less safe at school; (b) more physical activity, but less participation in physical education at school; and (c) both more healthy as well as unhealthy eating behaviors. Adjusted regression models showed a significant interaction between gender identity and perceived school safety on healthy eating behaviors; simple slopes indicated that transgender students have healthier eating behaviors when the school context is perceived as safe compared to those who perceived the school as less safe.

Conclusions

School interventions are needed to improve school safety for transgender youth and to reduce gender identity‐related disparities in healthy eating and physical activity. Research implications and limitations are discussed.
INTERNATIONAL HUMANITARIAN LAW AND COUNTER-TERRORISM: FUNDAMENTAL VALUES, CONFLICTING OBLIGATIONS
Authors: McKeever David
Published: December 2019

The interaction of international counter-terrorism laws with IHL is an area of renewed focus, amid widespread concern that the former are being (mis)applied to criminalise the provision of humanitarian assistance envisaged under the latter. The Security Council has begun to consider this issue in resolutions adopted in March and July 2019, but difficult questions of law and fact remain. These questions have significant practical consequences—for humanitarian agencies and those they seek to assist, as well as for States that must weigh different, and possibly conflicting, legal obligations. Much of the analysis to date and the solutions proposed, pay insufficient attention to the specifics of each legal regime.
The Condemnation-Absolution Syndrome: Issues of Validity and Generality
Authors: Keohane Robert O.
Published: December 2019

In their article “Just War and Unjust Soldiers: American Public Opinion on the Moral Equality of Combatants,” Scott Sagan and Benjamin Valentino argue that the American public evaluates soldiers’ wartime actions more according to whether the war they are fighting was initiated justly, than on their actions during warfare. In this respect, their views are more similar to those of revisionist philosophers than to those of traditional just war theorists. Before leaping to broad conclusions from their survey, it should be replicated. If the findings hold in the replication, intriguing questions could be asked about comparative cross-national attitudes and about the relationship between democracy and war.
On Reciprocity and Practical Morality: A Response to Sagan and Valentino
Authors: Walzer Michael
Published: December 2019

The findings reported in the article “Just War and Unjust Soldiers: American Public Opinion on the Moral Equality of Combatants,” by Scott Sagan and Benjamin Valentino, are indeed disturbing, but I am not convinced that they tell us all we need to know about public attitudes. Different questions, those that invite respondents to reflect on the reciprocal nature of practical morality (exemplified by the golden rule: “Do unto others . . .”), might reveal very different views of justified and unjustified conduct in war. I believe that these views, regarding, for example, the treatment of prisoners of war, would probably support the idea of the moral equality of soldiers on the battlefield.
Minimax functions on Galton–Watson trees
Authors: Martin James B. , Stasiński Roman
Published: December 2019

We consider the behaviour of minimax recursions defined on random trees. Such recursions give the value of a general class of two-player combinatorial games. We examine in particular the case where the tree is given by a Galton–Watson branching process, truncated at some depth 2n, and the terminal values of the level 2n nodes are drawn independently from some common distribution. The case of a regular tree was previously considered by Pearl, who showed that as n → ∞ the value of the game converges to a constant, and by Ali Khan, Devroye and Neininger, who obtained a distributional limit under a suitable rescaling.

For a general offspring distribution, there is a surprisingly rich variety of behaviour: the (unrescaled) value of the game may converge to a constant, or to a discrete limit with several atoms, or to a continuous distribution. We also give distributional limits under suitable rescalings in various cases.

We also address questions of endogeny. Suppose the game is played on a tree with many levels, so that the terminal values are far from the root. To be confident of playing a good first move, do we need to see the whole tree and its terminal values, or can we play close to optimally by inspecting just the first few levels of the tree? The answers again depend in an interesting way on the offspring distribution.

We also mention several open questions.
Temporal Trends and Future Predictions of Regional EMS System Utilization Using Statistical Modeling
Authors: Carr Michael J. , Bauter Robert , Shepherd Philip , Robbins Vincent , McKechnie A.J. , Cappuccia Beatrice , Merlin Mark A.
Published: December 2019

Introduction:

Trends in utilization of Emergency Medical Services (EMS) systems can be used to extrapolate future use of an EMS system, which will be valuable for the budgeting and planning of finances and resources. The best model for incorporation of seasonal and regional fluctuations in utilization to predict future utilization is unknown.

Problem:

Authors aimed to trend patterns of utilization in a regional EMS system to identify the needs of a growing population and to allow for a better understanding of how the EMS system is used on a basis of call volume and frequency of EMS transportation. The authors then used a best-fitting prediction model approach to show how the studied EMS system will be used in future years.

Methods:

Systems data were retrospectively extracted by using the electronic medical records of the studied EMS system and its computer-assisted dispatch (CAD) database from 2010 through 2017. All EMS dispatches entering the system’s 9-1-1 public service access point were captured. Annual utilization data were available from 2010 through 2017, while quarterly data were available only from 2013 through 2017. The 9-1-1 utilization per capita, Advanced Life Support (ALS) utilization per capita, and ALS cancel rates were calculated and trended over the study period. The methods of prediction were assessed through a best-fitting model approach, which statistically suggested that Additive Winter’s approach (SAS) was the best fit to determine future utilization and ALS cancel rates.

Results:

Total 9-1-1 call volume per capita increased by 32.46% between 2010 and 2017, with an average quarterly increase of 0.78% between 2013 and 2017. Total ALS call volume per capita increased by 1.93% between 2010 and 2017. Percent ALS cancellations (cancelled en route to scene) increased by eight percent between 2010 and 2017, with an average quarterly increase of 0.42% (2013–2017). Predictions to end of 2019 using Additive Winter’s approach demonstrated increasing trends in 9-1-1 call volume per capita (R2 = 0.47), increasing trends of ALS utilization per capita (R2 = 0.71), and increasing percent ALS cancellation (R2 = 0.93). Each prediction showed increasing future trends with a 95% confidence interval.

Conclusions:

The authors demonstrate paramount per capita increases of 9-1-1 call volume in the studied ALS system. There are concomitant increases of ALS cancellations prior to arrival, which suggests a potential burden on this regional ALS response system.
Rationale for Military Involvement in Humanitarian Assistance and Disaster Relief
Authors: Canyon Deon V. , Ryan Benjamin J. , Burkle Frederick M.
Published: December 2019

Good relations and trust are the foundation of soft power diplomacy and are essential for the accomplishment of domestic interventions and any bilateral or multilateral endeavor. Military use for assistance and relief is not a novel concept, but it has increased since the early 1990s with many governments choosing to provide greater numbers of forces and assets to assist domestically and internationally. The increase is due to the growing lack of capacity in global humanitarian networks and increasingly inadequate resources available to undertake United Nations humanitarian assistance and disaster relief (HADR) missions. In response, the military has been more proactive in pursuing the improvement of military-to-military and military-to-civilian integration. This trend reflects a move towards more advanced and comprehensive approaches to security cooperation and requires increased support from the civilian humanitarian sector to help meet the needs of the most vulnerable. Military assistance is progressing beyond traditional methods to place a higher value on issues relating to civil cooperation, restoring public health infrastructure, protection, and human rights, all of which are ensuring a permanent diplomatic role for this soft power approach.
Chilblains
Authors: Nyssen Astrid , Benhadou Farida , Magnée Marc , André Josette , Koopmansch Caroline , Wautrecht Jean-Claude
Published: December 2019

Summary: Idiopathic chilblain is a relatively common yet poorly recognized acrosyndrome. This literature review aims to better understand and draw attention to this disorder. Chilblain is a localized inflammation of the skin that occurs on exposure to cold but non-freezing wet weather. It usually resolves spontaneously. The etiology is uncertain, but vasospasm seems to play a role in this abnormal reaction to cold. Diagnosis is most often based on clinical presentation, but a skin biopsy can be useful in dubious cases. In histology, dermal edema and an inflammatory infiltrate are usually present. A distribution of the infiltrate particularly around the eccrine gland is typical. Systemic symptoms and underlying autoimmune disease should be screened. Avoiding cold and keeping extremities warm is the first recommendation for management, as well as smoking cessation. Calcium channel blockers (in particular nifedipine) seems to be the treatment that has been most evaluated in chilblains. However, their effectiveness is not confirmed by all studies. Topical betamethasone is often used but its effect has not been confirmed by randomized clinical trials. Other treatments, such as pentoxifylline, hydrochloroquine and topical nitroglycerin have shown positive effects only in a reduced number of patients. Acupuncture seems to bring a benefit.
An Existential Threat Model of Conspiracy Theories
Authors: van Prooijen Jan-Willem
Published: December 2019

Abstract. People endorse conspiracy theories particularly when they experience existential threat, that is, feelings of anxiety or uncertainty often because of distressing societal events. At the same time, such feelings also often lead people to support groups frequently implicated in conspiracy theories (e.g., the government). The present contribution aims to resolve this paradox by proposing an Existential Threat Model of Conspiracy Theories, which stipulates under what conditions existential threat does versus does not stimulate conspiracy theories. The model specifically illuminates that feelings of existential threat increase epistemic sense-making processes, which in turn stimulate conspiracy theories only when antagonistic outgroups are salient. Moreover, once formed conspiracy theories are not functional to reduce feelings of existential threat; instead, conspiracy theories can be a source of existential threat in itself, stimulating further conspiracy theorizing and contributing to a generalized conspiracist mindset. In the discussion, I discuss implications of the model, and illuminate how one may base interventions on the model to breaks this cyclical process and reduce conspiracy beliefs.
AGU’s Bridge Program Creates Opportunities for Underrepresented Students
Authors: McEntee Chris
Published: December 2019

In its first year, 20% of the 250 active Earth and space science graduate programs in the United States applied for partnership with the program.
Dark carbon fixation in the Arabian Sea oxygen minimum zone contributes to sedimentary organic carbon (SOM)
Authors: Lengger Sabine K. , Rush Darci , Mayser Jan Peter , Blewett Jerome , Schwartz‐Narbonne Rachel , Talbot Helen M. , Middelburg Jack J. , Jetten Mike S.M. , Schouten Stefan , Sinninghe Damsté Jaap S. , Pancost Richard D.
Published: December 2019

In response to rising CO2 concentrations and increasing global sea surface temperatures, oxygen minimum zones (OMZ), or “dead zones”, are expected to expand. OMZs are fueled by high primary productivity, resulting in enhanced biological oxygen demand at depth, subsequent oxygen depletion, and attenuation of remineralization. This results in the deposition of organic carbon‐rich sediments. Carbon drawdown is estimated by biogeochemical models; however, a major process is ignored: carbon fixation in the mid‐ and lower water column. Here, we show that chemoautotrophic carbon fixation is important in the Arabian Sea OMZ; and manifests in a 13C‐depleted signature of sedimentary organic carbon. We determined the δ13C values of Corg deposited in close spatial proximity but over a steep bottom‐water oxygen gradient, and the δ13C composition of biomarkers of chemoautotrophic bacteria capable of anaerobic ammonia oxidation (anammox). Isotope mixing models show that detritus from anammox bacteria or other chemoautotrophs likely forms a substantial part of the organic matter deposited within the Arabian Sea OMZ (~17%), implying that the contribution of chemoautotrophs to settling organic matter is exported to the sediment. This has implications for the evaluation of past, and future, OMZs: biogeochemical models that operate on the assumption that all sinking organic matter is photosynthetically derived, without new addition of carbon, could significantly underestimate the extent of remineralization. Oxygen demand in oxygen minimum zones could thus be higher than projections suggest, leading to a more intense expansion of OMZs than expected.
MKP-1 reduces Aβ generation and alleviates cognitive impairments in Alzheimer’s disease models
Authors: Du Yehong , Du Yexiang , Zhang Yun , Huang Zhilin , Fu Min , Li Junjie , Pang Yayan , Lei Peng , Wang Yu Tian , Song Weihong , He Guiqiong , Dong Zhifang
Published: December 2019

Mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) is an essential negative regulator of MAPKs by dephosphorylating MAPKs at both tyrosine and threonine residues. Dysregulation of the MAPK signaling pathway has been associated with Alzheimer’s disease (AD). However, the role of MKP-1 in AD pathogenesis remains elusive. Here, we report that MKP-1 levels were decreased in the brain tissues of patients with AD and an AD mouse model. The reduction in MKP-1 gene expression appeared to be a result of transcriptional inhibition via transcription factor specificity protein 1 (Sp1) cis-acting binding elements in the MKP-1 gene promoter. Amyloid-β (Aβ)-induced Sp1 activation decreased MKP-1 expression. However, upregulation of MKP-1 inhibited the expression of both Aβ precursor protein (APP) and β-site APP-cleaving enzyme 1 by inactivating the extracellular signal-regulated kinase 1/2 (ERK)/MAPK signaling pathway. Furthermore, upregulation of MKP-1 reduced Aβ production and plaque formation and improved hippocampal long-term potentiation (LTP) and cognitive deficits in APP/PS1 transgenic mice. Our results demonstrate that MKP-1 impairment facilitates the pathogenesis of AD, whereas upregulation of MKP-1 plays a neuroprotective role to reduce Alzheimer-related phenotypes. Thus, this study suggests that MKP-1 is a novel molecule for AD treatment.
DNA-PKcs promotes alcohol-related liver disease by activating Drp1-related mitochondrial fission and repressing FUNDC1-required mitophagy
Authors: Zhou Hao , Zhu Pingjun , Wang Jin , Toan Sam , Ren Jun
Published: December 2019

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a novel housekeeper of hepatic mitochondrial homeostasis outside the DNA repair process. In this study, DNA-PKcs was upregulated in the livers of mice that were exposed to alcohol; the expression of DNA-PKcs positively correlated with hepatic steatosis, fibrosis, apoptosis, and mitochondrial damage. Functional studies revealed that liver-specific DNA-PKcs knockout (DNA-PKcsLKO) mice were protected from chronic ethanol-induced liver injury and mitochondrial damage. Mechanistic investigations established that DNA-PKcs promoted p53 activation, which elevated dynamin-related protein 1 (Drp1)-related mitochondrial fission but repressed FUN14 domain containing 1 (FUNDC1)-required mitophagy. Excessive fission and defective mitophagy triggered mtDNA damage, mitochondrial respiratory inhibition, mROS overproduction, cardiolipin oxidation, redox imbalance, calcium overload, and hepatic mitochondrial apoptosis. In contrast, the deletion of DNA-PKcs rescued these phenotypic alterations, which alleviated the susceptibility of hepatocytes to alcohol-induced cytotoxicity. Additionally, we also showed that orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) was the upstream signal for DNA-PKcs activation and that the genetic ablation of NR4A1 ameliorated the progression of alcohol-related liver disease (ARLD); these results were similar to those obtained in DNA-PKcs knockout mice. Collectively, our results identified the NR4A1/DNA-PKcs/p53 axis as a novel signaling pathway responsible for ARLD pathogenesis that acts by activating Drp1-related mitochondrial fission and restricting FUNDC1-required mitophagy. The findings have potential implications for new approaches for ARLD therapy.
Stem-cell-ubiquitous genes spatiotemporally coordinate division through regulation of stem-cell-specific gene networks
Authors: Clark Natalie M. , Buckner Eli , Fisher Adam P. , Nelson Emily C. , Nguyen Thomas T. , Simmons Abigail R. , de Luis Balaguer Maria A. , Butler-Smith Tiara , Sheldon Parnell J. , Bergmann Dominique C. , Williams Cranos M. , Sozzani Rossangela
Published: December 2019

Stem cells are responsible for generating all of the differentiated cells, tissues, and organs in a multicellular organism and, thus, play a crucial role in cell renewal, regeneration, and organization. A number of stem cell type-specific genes have a known role in stem cell maintenance, identity, and/or division. Yet, how genes expressed across different stem cell types, referred to here as stem-cell-ubiquitous genes, contribute to stem cell regulation is less understood. Here, we find that, in the Arabidopsis root, a stem-cell-ubiquitous gene, TESMIN-LIKE CXC2 (TCX2), controls stem cell division by regulating stem cell-type specific networks. Development of a mathematical model of TCX2 expression allows us to show that TCX2 orchestrates the coordinated division of different stem cell types. Our results highlight that genes expressed across different stem cell types ensure cross-communication among cells, allowing them to divide and develop harmonically together.
CSB promoter downregulation via histone H3 hypoacetylation is an early determinant of replicative senescence
Authors: Crochemore Clément , Fernández-Molina Cristina , Montagne Benjamin , Salles Audrey , Ricchetti Miria
Published: December 2019

Cellular senescence has causative links with ageing and age-related diseases, however, it remains unclear if progeroid factors cause senescence in normal cells. Here, we show that depletion of CSB, a protein mutated in progeroid Cockayne syndrome (CS), is the earliest known trigger of p21-dependent replicative senescence. CSB depletion promotes overexpression of the HTRA3 protease resulting in mitochondrial impairments, which are causally linked to CS pathological phenotypes. The CSB promoter is downregulated by histone H3 hypoacetylation during DNA damage-response. Mechanistically, CSB binds to the p21 promoter thereby downregulating its transcription and blocking replicative senescence in a p53-independent manner. This activity of CSB is independent of its role in the repair of UV-induced DNA damage. HTRA3 accumulation and senescence are partially rescued upon reduction of oxidative/nitrosative stress. These findings establish a CSB/p21 axis that acts as a barrier to replicative senescence, and link a progeroid factor with the process of regular ageing in human.
LinkedSV for detection of mosaic structural variants from linked-read exome and genome sequencing data
Authors: Fang Li , Kao Charlly , Gonzalez Michael V. , Mafra Fernanda A. , Pellegrino da Silva Renata , Li Mingyao , Wenzel Sören-Sebastian , Wimmer Katharina , Hakonarson Hakon , Wang Kai
Published: December 2019

Linked-read sequencing provides long-range information on short-read sequencing data by barcoding reads originating from the same DNA molecule, and can improve detection and breakpoint identification for structural variants (SVs). Here we present LinkedSV for SV detection on linked-read sequencing data. LinkedSV considers barcode overlapping and enriched fragment endpoints as signals to detect large SVs, while it leverages read depth, paired-end signals and local assembly to detect small SVs. Benchmarking studies demonstrate that LinkedSV outperforms existing tools, especially on exome data and on somatic SVs with low variant allele frequencies. We demonstrate clinical cases where LinkedSV identifies disease-causal SVs from linked-read exome sequencing data missed by conventional exome sequencing, and show examples where LinkedSV identifies SVs missed by high-coverage long-read sequencing. In summary, LinkedSV can detect SVs missed by conventional short-read and long-read sequencing approaches, and may resolve negative cases from clinical genome/exome sequencing studies.
Quantum engineered Kondo lattices
Authors: Figgins Jeremy , Mattos Laila S. , Mar Warren , Chen Yi-Ting , Manoharan Hari C. , Morr Dirk K.
Published: December 2019

Atomic manipulation techniques have provided a bottom-up approach to investigating the unconventional properties and complex phases of strongly correlated electron materials. By engineering artificial systems containing tens to thousands of atoms with tailored electronic or magnetic properties, it has become possible to explore how quantum many-body effects emerge as the size of a system is increased from the nanoscale to the mesoscale. Here we investigate both theoretically and experimentally the quantum engineering of nanoscale Kondo lattices – Kondo droplets – exemplifying nanoscopic replicas of heavy-fermion materials. We demonstrate that by changing a droplet’s real-space geometry, we can not only create coherently coupled Kondo droplets whose properties asymptotically approach those of a quantum-coherent Kondo lattice, but also markedly increase or decrease the droplet’s Kondo temperature. Furthermore we report on the discovery of a new quantum phenomenon – the Kondo echo – a signature of droplets containing Kondo holes functioning as direct probes of spatially extended, quantum-coherent Kondo cloud correlations.
Short-term availability of adult-born neurons for memory encoding
Authors: Forest Jérémy , Moreno Mélissa , Cavelius Matthias , Chalençon Laura , Ziessel Anne , Sacquet Joëlle , Richard Marion , Didier Anne , Mandairon Nathalie
Published: December 2019

Adult olfactory neurogenesis provides waves of new neurons involved in memory encoding. However, how the olfactory bulb deals with neuronal renewal to ensure the persistence of pertinent memories and the flexibility to integrate new events remains unanswered. To address this issue, mice performed two successive olfactory discrimination learning tasks with varying times between tasks. We show that with a short time between tasks, adult-born neurons supporting the first learning task appear to be highly sensitive to interference. Furthermore, targeting these neurons using selective light-induced inhibition altered memory of this first task without affecting that of the second, suggesting that neurons in their critical period of integration may only support one memory trace. A longer period between the two tasks allowed for an increased resilience to interference. Hence, newly formed adult-born neurons regulate the transience or persistence of a memory as a function of information relevance and retrograde interference.
High-resolution label-free 3D mapping of extracellular pH of single living cells
Authors: Zhang Yanjun , Takahashi Yasufumi , Hong Sung Pil , Liu Fengjie , Bednarska Joanna , Goff Philip S. , Novak Pavel , Shevchuk Andrew , Gopal Sahana , Barozzi Iros , Magnani Luca , Sakai Hideki , Suguru Yoshimoto , Fujii Takuto , Erofeev Alexander , Gorelkin Peter , Majouga Alexander , Weiss Dominik J. , Edwards Christopher , Ivanov Aleksandar P. , Klenerman David , Sviderskaya Elena V. , Edel Joshua B. , Korchev Yuri
Published: December 2019

Dynamic mapping of extracellular pH (pHe) at the single-cell level is critical for understanding the role of H+ in cellular and subcellular processes, with particular importance in cancer. While several pHe sensing techniques have been developed, accessing this information at the single-cell level requires improvement in sensitivity, spatial and temporal resolution. We report on a zwitterionic label-free pH nanoprobe that addresses these long-standing challenges. The probe has a sensitivity > 0.01 units, 2 ms response time, and 50 nm spatial resolution. The platform was integrated into a double-barrel nanoprobe combining pH sensing with feedback-controlled distance dependance via Scanning Ion Conductance Microscopy. This allows for the simultaneous 3D topographical imaging and pHe monitoring of living cancer cells. These classes of nanoprobes were used for real-time high spatiotemporal resolution pHe mapping at the subcellular level and revealed tumour heterogeneity of the peri-cellular environments of melanoma and breast cancer cells.
Programmable and robust static topological solitons in mechanical metamaterials
Authors: Zhang Yafei , Li Bo , Zheng Q. S. , Genin Guy M. , Chen C. Q.
Published: December 2019

Solitary, persistent wave packets called solitons hold potential to transfer information and energy across a wide range of spatial and temporal scales in physical, chemical, and biological systems. Mechanical solitons characteristically emerge either as a single wave packet or uncorrelated propagating topological entities through space and/or time, but these are notoriously difficult to control. Here, we report a theoretical framework for programming static periodic topological solitons into a metamaterial, and demonstrate its implementation in real metamaterials computationally and experimentally. The solitons are excited by deformation localizations under quasi-static compression, and arise from buckling-induced kink-antikink bands that provide domain separation barriers. The soliton number and wavelength demonstrate a previously unreported size-dependence, due to intrinsic length scales. We identify that these unanticipated solitons stem from displacive phase transitions with periodic topological excitations captured by the well-known $${\varphi }^{4}$$

φ

4

theory. Results reveal pathways for robust regularizations of stochastic responses of metamaterials.
NAIL-MS reveals the repair of 2-methylthiocytidine by AlkB in E. coli
Authors: Reichle Valentin F. , Petrov Dimitar P. , Weber Verena , Jung Kirsten , Kellner Stefanie
Published: December 2019

RNAs contain post-transcriptional modifications, which fulfill a variety of functions in translation, secondary structure stabilization and cellular stress survival. Here, 2-methylthiocytidine (ms2C) is identified in tRNA of E. coli and P. aeruginosa using NAIL-MS (nucleic acid isotope labeling coupled mass spectrometry) in combination with genetic screening experiments. ms2C is only found in 2-thiocytidine (s2C) containing tRNAs, namely tRNAArgCCG, tRNAArgICG, tRNAArgUCU and tRNASerGCU at low abundances. ms2C is not formed by commonly known tRNA methyltransferases. Instead, we observe its formation in vitro and in vivo during exposure to methylating agents. More than half of the s2C containing tRNA can be methylated to carry ms2C. With a pulse-chase NAIL-MS experiment, the repair mechanism by AlkB dependent sulfur demethylation is demonstrated in vivo. Overall, we describe ms2C as a bacterial tRNA modification and damage product. Its repair by AlkB and other pathways is demonstrated in vivo by our powerful NAIL-MS approach.
Chromosome-associated RNA–protein complexes promote pairing of homologous chromosomes during meiosis in Schizosaccharomyces pombe
Authors: Ding Da-Qiao , Okamasa Kasumi , Katou Yuki , Oya Eriko , Nakayama Jun-ichi , Chikashige Yuji , Shirahige Katsuhiko , Haraguchi Tokuko , Hiraoka Yasushi
Published: December 2019

Pairing of homologous chromosomes in meiosis is essential for sexual reproduction. We have previously demonstrated that the fission yeast sme2 RNA, a meiosis-specific long noncoding RNA (lncRNA), accumulates at the sme2 chromosomal loci and mediates their robust pairing in meiosis. However, the mechanisms underlying lncRNA-mediated homologous pairing have remained elusive. In this study, we identify conserved RNA-binding proteins that are required for robust pairing of homologous chromosomes. These proteins accumulate mainly at the sme2 and two other chromosomal loci together with meiosis-specific lncRNAs transcribed from these loci. Remarkably, the chromosomal accumulation of these lncRNA–protein complexes is required for robust pairing. Moreover, the lncRNA–protein complexes exhibit phase separation properties, since 1,6-hexanediol treatment reversibly disassembled these complexes and disrupted the pairing of associated loci. We propose that lncRNA–protein complexes assembled at specific chromosomal loci mediate recognition and subsequent pairing of homologous chromosomes.
Optimal verification of general bipartite pure states
Authors: Yu Xiao-Dong , Shang Jiangwei , Gühne Otfried
Published: December 2019

The efficient and reliable verification of quantum states plays a crucial role in various quantum information processing tasks. We consider the task of verifying entangled states using one-way and two-way classical communication and completely characterize the optimal strategies via convex optimization. We solve these optimization problems using both analytical and numerical methods, and the optimal strategies can be constructed for any bipartite pure state. Compared with the nonadaptive approach, our adaptive strategies significantly improve the efficiency of quantum state verification. Moreover, these strategies are experimentally feasible, as only few local projective measurements are required.
Mitigation of acyl-homoserine lactone (AHL) based bacterial quorum sensing, virulence functions, and biofilm formation by yttrium oxide core/shell nanospheres: Novel approach to combat drug resistance
Authors: Husain Fohad Mabood , Ansari Anees A. , Khan Aslam , Ahmad Naushad , Albadri Abdulrahman , Albalawi Thamer H.
Published: December 2019

The present study evaluated the efficacy of Y2O3:Tb (core) and Y2O3:Tb@SiO2 nanospheres (core/shell NSs) against virulence functions regulated by quorum sensing (QS) and biofilm formation in pathogenic bacteria. Scanning electron microscope (SEM) images were used to study the size, shape, and morphology. The images clearly displayed spherical shaped, mono-dispersed particles with narrow size distribution and an average grain size of 110–130 nm. The chemical composition of the samples was determined by using energy dispersive X-ray (EDX) and X-ray photoelectron spectroscopy (XPS). We determined the impact of core and core/shell NSs on QS using sensor strains of Chromobacterium violaceum CVO26 and Pseudomonas aeruginosa PAO1 in a comparative study. Sub-MICs of core and core/shell NSs substantially suppressed QS-controlled violacein production in C. violaceum. Similar concentration-dependent effect of sub-MICs of synthesized core and core/shell NSs was observed in the QS-regulated virulence functions (elastase, total protease, pyocyanin production, swarming motility, and exopolysaccharide production) in PAO1. A concentration-dependent decrease (14–60%) was recorded in the biofilm forming capability of PAO1, upon treatment with core and core/shell NSs. Moreover, core/shell NSs were more effective in inhibiting biofilm at higher tested concentrations as compared to core-NSs. The synthesized NSs demonstrated significantly impaired attachment of cells to the microtiter plate indicating that NSs target biofilm inhibition at the attachment stage. Based on these results, we predict that core and core/shell NSs may be an alternative to combat the threat of drug-resistant pathogenic bacteria.
Two-dimensional Tunable Dirac/Weyl Semimetal in Non-Abelian Gauge Field
Authors: Guo Yaowu , Lin Zhi , Zhao Jia-Qiang , Lou Jie , Chen Yan
Published: December 2019

Three-dimensional(3D) Weyl semimetal(WSM) with linear energy spectra has attracted significant interest. Especially they have been observed experimentally in several solid materials with the breaking of inversion symmetry. Here we predict a new family of particle-hole($${\mathscr{C}}$$
C
) invariant 2D WSMs in the non-Abelian gauge field, which can emerge in the low energy bands being close to Fermi energy (dubbed Weyl-I) and the high energy bands being away from Fermi energy (dubbed Weyl-II), only when the time-reversal symmetry($${\mathscr{T}}$$
T
) of the 2D Dirac semimetal is broken in the presence of in-plane Zeeman fields. Moreover, a 2D Dirac node can split into a pair of Weyl nodes showing the same Berry phase, and the 2D WSM, being protected by $${\mathscr{T}}$$
T
symmetry, exhibits four Weyl-I nodes, whose energies are invariant with the variation of the magnetic field. The corresponding Fermi velocity and Berry connection have been calculated. Based on the 2D WSMs, we also examine inhomogeneous pairings of attractive Fermi gases and find a new kind of the LO states with the beat frequency. This 2D WSM provides a realistic and promising platform for exploring and manipulating exotic Weyl physics, which may increase the experimental feasibility in the context of ultracold atoms.
Molecular Characterization of Methicillin- Resistant Staphylococcus aureus in a Tertiary Care hospital in Kuwait
Authors: Alfouzan Wadha , Udo Edet E. , Modhaffer Azizah , Alosaimi Asma’a
Published: December 2019

Methicillin-resistant Staphylococcus aureus (MRSA) are a major cause of healthcare and community- associated infections due to their ability to express a variety of virulence factors. We investigated 209 MRSA isolates obtained from 1 January to 31 December 2016 using a combination of phenotypic and genotypic methods to understand the genetic backgrounds of MRSA strains obtained in a General hospital in Kuwait. Antibiotics susceptibility was performed with disk diffusion, and MIC was measured with Etest strips. Molecular typing was performed using SCCmec typing, spa typing, and DNA microarray for antibiotic resistance and virulence genes. The isolates were susceptible to vancomycin, teicoplanin, rifampicin, ceftaroline, and linezolid but were resistant to gentamicin, tetracycline, erythromycin, fusidic acid, chloramphenicol and ciprofloxacin. Molecular typing revealed six SCCmec types, 56 spa types and 16 clonal complexes (CC). The common SCCmec types were type IV (39.5%), type III (34.4%), type V (25.8%) and type VI (3.8%). The dominant spa types were t860 (23.9%), t945 (8.6%), t127 (6.7%), t688 (6.7%), t304 (6.2) and t044 (5.7%). The other spa types occurred sporadically. Genes for PVL was detected in 59 (28.2%) of the isolates. CC8-ST239-MRSA-III + SCCmer (23.3%) was the most prevalent clone, followed by CC6-MRSA-IV (8.3%), CC80-MRSA-IV [PVL+] (5.8%), CC5-MRSA-VI + SCCfus (5.0%), CC30-MRSA-IV[PVL+] (4.1%), CC1-MRSA-V + SCCfus [PVL+] (4.1%), CC5-MRSA-V + SCCfus (4.1%) and CC22-MRSA-IV[PVL+] (4.1%). The study revealed that despite the emergence of MRSA with diverse genetic backgrounds over the years, ST239-MRSA-III remained the dominant clone in the hospital. This warrants reassessment of infection prevention and control procedures at this hospital.
The expression pattern of OsDim1 in rice and its proposed function
Authors: Doku Henry Akrofi , Gan Shu-Xian , Zhu Qian , Nadir Sadia , Li Wei , Li Meng-Ting , Zhou Li , Li Cheng-Yun , Kang Sang-Gu , Park Eui-Ho , Chen Li-Juan , Lee Dong-Sun
Published: December 2019

Development of plant tissues is dependent on numerous factors, including hormone activity, signaling, cell division, and elongation. In plants, Defective Entry into Mitosis 1 (Dim1) homologs are recognized as pivotal in leaf senescence and progress of normal growth, but their role in rice has not been functionally characterized. The findings presented in this paper suggest that OsDim1 is important in early seedling development, pollen tube elongation, and impacts rice yield components. The gene is expressed in the scutellum, endosperm, embryonic root, shoot, pollen grains and tubes, as well as in several organs of the rice flower. According to the present study findings, RNAi mediated knockdown of OsDim1 resulted in phytohormonal imbalance, reduced amylase activity, affected differentiation of embryonic root elongation zone tissues, suppressed embryonic root and shoot growth, and impaired pollen tube elongation. In contrast, overexpression of OsDim1 showed significant growth in embryonic roots and shoots, while it increased culm length, total number of tillers per plant, seed setting rate, and total number of grains per panicle compared to its wild type line. In summary, we propose OsDim1 plays an important role in seedling growth and pollen tube elongation, and has pleiotropic effects on reproductive tissues.
Unravelling Receptor and RGD Motif Dependence of Retargeted Adenoviral Vectors using Advanced Tumor Model Systems
Authors: Chernyavska M. , Schmid M. , Freitag P. C. , Palacio-Castañeda V. , Piruska A. , Huck W. T. S. , Plückthun A. , Verdurmen W. P. R.
Published: December 2019

Recent advances in engineering adenoviruses are paving the way for new therapeutic gene delivery approaches in cancer. However, there is limited knowledge regarding the impact of adenoviral retargeting on transduction efficiency in more complex tumor architectures, and the role of the RGD loop at the penton base in retargeting is unclear. To address this gap, we used tumor models of increasing complexity to study the role of the receptor and the RGD motif. Employing tumor-fibroblast co-culture models, we demonstrate the importance of the RGD motif for efficient transduction in 2D through the epithelial cell adhesion molecule (EpCAM), but not the epidermal growth factor receptor (EGFR). Via optical clearing of co-culture spheroids, we show that the RGD motif is required for transduction via both receptors in 3D tumor architectures. We subsequently employed a custom-designed microfluidic model containing collagen-embedded tumor spheroids, mimicking the interplay between interstitial flow, extracellular matrix and adenoviral transduction. Image analysis of on-chip cleared spheroids indicated the importance of the RGD motif for on-chip adenoviral transduction. Together, our results show the interrelationship between receptor characteristics, the RGD motif, the 3D tumor architecture and retargeted adenoviral transduction efficiency. The findings are important for the rational design of next-generation therapeutic adenoviruses.