bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Anxiolytic Potential of Niranthin: In-vivo and Computational Investigations
Authors: Chopade Atul R. , Somade Prakash M. , Somade Pratik P. , Mali Suraj N.
Published: November 2020

Anxiety is an unpleasant state, which can critically decrease the quality of life is often accompanied by nervous behaviour and rumination. Niranthin is a lignan isolated from various Phyllanthus sources. The literature survey on niranthin highlights wide ranges of the therapeutic potentials. In a present study, based on our previous investigations, we evaluated pure, isolated and characterized niranthin as an anxiolytic agent. The niranthin [6-[(2R,3R)-3-[(3,4-dimethoxyphenyl)methyl]-4-methoxy-2-(methoxymethyl)butyl]-4-methoxy-1,3-benzodioxole] was purchased from commercial source and further subjected for assessment of its anxiolytic potentials using popular animal models including Elevated plus-maze model/test (EPM) and Light & Dark Exploration test (L&D). GABA-A receptor mediation was evaluated by pretreating the mice with the GABA-A receptor antagonist Flumazenil before the EPM task. Molecular docking simulation studies (pdb id: 4COF) carried out by Vlife QSAR software showed that niranthin (docking score: − 62.1714 kcal/mol) have shown comparatively best docking score compared to the standard drug Diazepam (docking score: − 63.1568 kcal/mol). To conclude, Niranthin has probable potential in the management of anxiety disorder. Our in-silico and in-vivo analysis (indirectly) indicated the plausible role of GABA mediation for anxiolytic activity. Although, these studies are preliminary, future in depth experimental explorations will be required to use Niranthin as anti-anxiety drug in near future.

Graphic Abstract
Microstructure and mechanical properties of Ti3(Al,Ga)C2/Al2O3 composites prepared by in situ reactive hot pressing
Authors: Fang Yuan , Liu Xiaohua , Feng Yuxia , Zhu Jianfeng , Jiang Wei
Published: November 2020

In this study, Ti3(Al,Ga)C2/Al2O3 composites were successfully synthesized by in situ hot pressing at 1350 °C for 2 h using Ti, Al, TiC, and Ga2O3 as raw materials. X-ray diffraction and scanning electron microscopy were used for characterizing the phase identities and microstructures of the sintered composites. The dependence of the Vickers hardness and flexural strength on the Al2O3 content was found to be in single-peak type. Ti3(Al0.6,Ga0.4)C2/10.3vol%Al2O3 composite exhibited significantly improved mechanical properties. Vickers hardness and flexural strength of the composite reached 6.58 GPa and 527.11 MPa, which were 40% and 74% higher than those of Ti3AlC2, respectively. Formation of solid solution and incorporation of second phase of Al2O3 resulted in the opposite influence on the fracture toughness. Finally, the hardening and strengthening mechanisms were discussed in detail.
On-Orbit Observations of Conjuncting Space Objects Prior to the Time of Closest Approach
Authors: Scott Robert Lauchie , Thorsteinson Stefan , Abbasi Viqar
Published: November 2020

Conjunction assessment of space objects in Low Earth Orbit (LEO) generally uses information collected by ground-based space surveillance sensors. These sensors track both the primary object (normally an active satellite) and the secondary object (typically space debris). The tracking data is used to update both objects’ orbits for collision risk assessment. The primary satellite’s involvement in this process is that of a satellite in jeopardy - the primary satellite does not usually contribute tracking data on the secondary as they are typically unequipped to do so. In this paper, an examination how an at-risk LEO primary satellite could obtain optical tracking data on a secondary object prior to the Time of Closest Approach (TCA) and assess its own collision risk without the need for additional ground-based space surveillance data is performed. This analysis was made possible by using in-situ optical measurements of space objects conjuncting with the Canadian NEOSSat Space Situational Awareness R&D microsatellite. By taking advantage of the near “constant-bearing, decreasing range” observing geometry formed during a LEO conjunction, NEOSSat can collect astrometric and photometric measurements of the secondary object in the time prior to TCA, or in the multiple half-orbits preceding TCA. This paper begins by describing the in-situ phenomenology of optically observed conjunctions in terms of the observing approach, geometry and detected astrometric and photometric characteristics. It was found that conjuncting objects are detectable to magnitude 16 and astrometric observations can be used for position covariances in the computation of probability of collision. Illustrative examples are provided. In orbits prior to TCA, in-track positioning error is improved by a factor of two or more by processing space-based observations on a filtered position estimate of the secondary. However, cross-track positioning knowledge is negligibly improved due to the inherent astrometric measurement precision of the NEOSSat sensor and the oblique observing geometry during conjunction observations. A short analysis of object detectability where star trackers could be used to perform similar observations finds that larger payload-sized objects would generally be detectable. However, smaller debris objects would require higher sensitivity from the star tracker if employed for optical conjunction derisk observations.
MOFs-Based Nitric Oxide Therapy for Tendon Regeneration
Authors: Chen Jun , Sheng Dandan , Ying Ting , Zhao Haojun , Zhang Jian , Li Yunxia , Xu He , Chen Shiyi
Published: November 2020

Tendon regeneration is still a great challenge due to its avascular structure and low self-renewal capability. The nitric oxide (NO) therapy emerges as a promising treatment for inducing the regeneration of injured tendon by angiogenesis. Here, in this study, a system that NO-loaded metal–organic frameworks (MOFs) encapsulated in polycaprolactone (PCL)/gelatin (Gel) aligned coaxial scaffolds (NMPGA) is designed and prepared for tendon repair. In this system, NO is able to be released in vitro at a slow and stable average speed of 1.67 nM h−1 as long as 15 d without a burst release stage in the initial 48 h. Furthermore, NMPGA can not only improve the tubular formation capability of endothelial cells in vitro but also obviously increase the blood perfusion near the injured tendon in vivo, leading to accelerating the maturity of collagen and recovery of biomechanical strength of the regenerated tendon tissue. As a NO-loaded MOFs therapeutic system, NMPGA can promote tendon regeneration in a shorter healing period with better biomechanical properties in comparison with control group by angiogenesis. Therefore, this study not only provides a promising scaffold for tendon regeneration, but also paves a new way to develop a NO-based therapy for biomedical application in the future.
Extending practical flow chemistry into the undergraduate curriculum via the use of a portable low-cost 3D printed continuous flow system
Authors: Penny Matthew R. , Tsui Natalie , Hilton Stephen T.
Published: November 2020

Continuous flow chemistry is undergoing rapid growth and adoption within the pharmaceutical industry due to its ability to rapidly translate chemical discoveries from medicinal chemistry laboratories into process laboratories. Its growing significance means that it is imperative that flow chemistry is taught and experienced by both undergraduate and postgraduate synthetic chemists. However, whilst flow chemistry has been incorporated by industry, there remains a distinct lack of practical training and knowledge at both undergraduate and postgraduate levels. A key challenge associated with its implementation is the high cost (>$25,000) of the system’s themselves, which is far beyond the financial reach of most universities and research groups, meaning that this key technology remains open to only a few groups and that its associated training remains a theoretical rather than a practical subject. In order to increase access to flow chemistry, we sought to design and develop a small-footprint, low-cost and portable continuous flow system that could be used to teach flow chemistry, but that could also be used by research groups looking to transition to continuous flow chemistry. A key element of its utility focusses on its 3D printed nature, as low-cost reactors could be readily incorporated and modified to suit differing needs and educational requirements. In this paper, we demonstrate the system’s flexibility using reactors and mixing chips designed and 3D printed by an undergraduate project student (N.T.) and show how the flexibility of the system allows the investigation of differing flow paths on the same continuous flow system in parallel.
“Evacuate everyone south of that line” Analyzing structural communication patterns during natural disasters
Authors: Kušen Ema , Strembeck Mark
Published: November 2020

In this paper, we analyze more than 16 million tweets that have been sent from 6.1 million Twitter accounts and are related to nine natural disasters. As part of our analysis, we identify eight basic emotions conveyed in these tweets. We found that during natural disasters, social media messages at first predominantly express fear, while sadness and positive emotions increase in the immediate aftermath of the event. In this context, positive emotions contribute to the social phenomenon of emotional bonding and are often related to compassion, gratitude, as well as donations for disaster relief. In our analysis, we found that the users’ emotional expressions directly contribute to the emergence of the underlying communication network. In particular, we identified statistically significant structural patterns that we call emotion-exchange motifs and show that: (1) the motifs 021U and 021D are common for the communication of all eight emotions considered in this study, (2) motifs which include bidirectional edges (i.e. online conversations) are generally not characteristic for the communication of surprise, sadness, and disgust, (3) the structural analysis of a set of emotions (rather than a single emotion) leads to the formation of more complex motifs representing more complex social interactions, and (4) the messaging patterns emerging from the communication of joy and sadness show the highest structural similarity, even reaching a perfect similarity score at some point during the data-extraction period.
Temporal Unfolding of Micro-valences in Facial Expression Evoked by Visual, Auditory, and Olfactory Stimuli
Authors: Gentsch Kornelia , Beermann Ursula , Wu Lingdan , Trznadel Stéphanie , Scherer Klaus R.
Published: November 2020

Appraisal theories suggest that valence appraisal should be differentiated into micro-valences, such as intrinsic pleasantness and goal-/need-related appraisals. In contrast to a macro-valence approach, this dissociation explains, among other things, the emergence of mixed or blended emotions. Here, we extend earlier research that showed that these valence types can be empirically dissociated. We examine the timing and the response patterns of these two micro-valences via measuring facial muscle activity changes (electromyography, EMG) over the brow and the cheek regions. In addition, we explore the effects of the sensory stimulus modality (vision, audition, and olfaction) on these patterns. The two micro-valences were manipulated in a social judgment task: first, intrinsic un/pleasantness (IP) was manipulated by exposing participants to appropriate stimuli presented in different sensory domains followed by a goal conduciveness/obstruction (GC) manipulation consisting of feedback on participants’ judgments that were congruent or incongruent with their task-related goal. The results show significantly different EMG responses and timing patterns for both types of micro-valence, confirming the prediction that they are independent, consecutive parts of the appraisal process. Moreover, the lack of interaction effects with the sensory stimulus modality suggests high generalizability of the underlying appraisal mechanisms across different perception channels.
Frequency of MYD88 L256P mutation and its correlation with clinico-hematological profile in mature B-cell neoplasm
Authors: Shekhar Raja , Naseem Shano , Binota Jogeshwar , Varma Neelam , Malhotra Pankaj
Published: November 2020

Objective/background:

B-cell neoplasms are clonal tumors of B cells at various stages of maturation, including diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic lymphoma (CLL), Burkitt lymphoma (BL), lymphoplasmacytic lymphoma (LPL)/Waldenström’s macroglob- ulinemia (WM), splenic marginal zone lymphoma (SMZL), nodal marginal zone lymphoma (NMZL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and hairy cell leukemia (HCL). In this study, we analyzed the frequency of MYD88 L265P mutation and its correlation with clinico-hematological profile in mature B-cell neoplasms.

Methods:

A total of 110 consecutive cases of B-cell neoplasms showing peripheral blood and/or bone marrow infiltration were included. MYD88 L265P mutation was detected by polymerase chain reaction amplification of exon 5 of MYD88 gene, followed by restriction fragment length polymorphism analysis.

Results:

Among the 110 cases, the major group was of CLL (54.5%, n = 60), followed by HCL. Other cases included MCL, LPL, DLBCL, SMZL, NMZL, FL, and BL. MYD88 L265P mutation was seen in 21 (19.1%) cases of B-cell neoplasm, whereas 89 (80.9%) cases were negative for MYD88 L265P mutation. It was most commonly seen in LPL/WM cases followed by HCL, SMZL, CLL, and MCL cases. No case of DLBCL, FL, and BL showed MYD88 L265P mutation. Statistically significant difference was seen for hemoglobin level in CLL cases, with MYD88 L265P mutated cases showing higher mean hemoglobin levels than MYD88 wild-type cases (p = .001). For other parameters, no statistically significant difference was noted between mutated and unmutated cases.

Conclusion:

MYD88 L265P mutation is seen in various B-cell neoplasms; it is most commonly seen in LPL/WM cases but not specific for it.
Ecosemiotics
Authors: Maran Timo
Published: November 2020

This Element provides an accessible introduction to ecosemiotics and demonstrates its pertinence for the study of today's unstable culture-nature relations. Ecosemiotics can be defined as the study of sign processes responsible for ecological phenomena. The arguments in this Element are developed in three steps that take inspiration from both humanities and biological sciences: 1) Showing the diversity, reach and effects of sign-mediated relations in the natural environment from the level of a single individual up the functioning of the ecosystem. 2) Demonstrating numerous ways in which prelinguistic semiotic relations are part of culture and identifying detrimental environmental effects that self-contained and purely symbol-based sign systems, texts and discourses bring along. 3) Demonstrating how ecosemiotic analysis centred on models and modelling can effectively map relations between texts and the natural environment, or the lack thereof, and how this methodology can be used artistically to initiate environmentally friendly cultural forms and practices.
Complete regularity of Ellis semigroups of -actions
Authors: BARGE MARCY , KELLENDONK JOHANNES
Published: November 2020

It is shown that the Ellis semigroup of a$\mathbb Z$-action on a compact totally disconnected space is completely regular if and only if forward proximality coincides with forward asymptoticity and backward proximality coincides with backward asymptoticity. Furthermore, the Ellis semigroup of a$\mathbb Z$- or$\mathbb R$-action for which forward proximality and backward proximality are transitive relations is shown to have at most two left minimal ideals. Finally, the notion of near simplicity of the Ellis semigroup is introduced and related to the above.
Outcomes of an ambulatory care pharmacist-led antimicrobial stewardship program within a family medicine resident clinic
Authors: Westerhof Lindsey R. , Dumkow Lisa E. , Hanrahan Tarajo L. , McPharlin Samantha V. , Egwuatu Nnaemeka E.
Published: November 2020

Objective:

To determine whether an ambulatory care pharmacist (AMCP)-led intervention improved outpatient antibiotic prescribing in a family medicine residency clinic (FMRC) for upper respiratory tract infections (URIs), urinary tract infections (UTIs), and skin and soft-tissue infections (SSTIs).

Design:

Retrospective, quasi-experimental study comparing guideline-concordant antibiotic prescribing before and after an antimicrobial stewardship program (ASP) intervention.

Setting:

Family medicine residency clinic affiliated with a community teaching hospital.

Participants:

Adult and pediatric patients prescribed antibiotics for URI, UTI, or SSTI between November 1, 2017, and April 31, 2018 (pre-ASP group), or October 1, 2018, and March 31, 2019 (ASP group), were eligible for inclusion.

Methods:

The health-system ASP physician and pharmacist provided live education and pocket cards to FMRC staff with local guidelines as a quick reference. Audit with feedback was delivered every other week by the clinic’s AMCP. Guideline-concordance was determined based on the institution’s outpatient ASP guidelines.

Results:

Overall, 525 antibiotic prescriptions were audited (pre-ASP n = 90 and ASP n = 435). Total guideline-concordant antibiotic prescribing at baseline was 38.9% (URI, 53.3%; SSTI, 16.7%; UTI, 46.7%) and improved across all 3 infection types to 57.9% (URI, 61.2%; SSTI, 57.6%; UTI, 53.5%; P = .001). Significant improvements were seen in guideline-concordant antibiotic selection (68.9% vs 80.2%; P = .018), dose (76.7% vs 86.2%; P = .023), and duration of therapy (73.3% vs 86.2%; P = .02).

Conclusions:

An AMCP-led outpatient ASP intervention significantly improved guideline-concordant antibiotic prescribing for common infections within a FMRC.
Nutritional implications of dietary gluten avoidance among Canadians: results from the 2015 Canadian Community Health Survey
Authors: Mudryj Adriana N. , Waugh Anne K. , Slater Joyce J. , Duerksen Donald R. , Bernstein Charles N. , Riediger Natalie D.
Published: November 2020

Adherence to a gluten-free diet (GFD) is the only available treatment for gluten-related disorders, although a GFD may also be followed for discretionary reasons. The main objectives of the present study were to (1) describe and test for differences in key nutrient intakes among Canadians who follow a GFD compared with Canadians with no dietary exclusions and (2) describe additional dietary avoidances adhered to by Canadians who avoid gluten. We conducted a secondary analysis of the cross-sectional 2015 Canadian Community Health Survey-Nutrition Survey, which included a general health survey and 24-h dietary recall (n20 487). Participants were categorised as those who avoid dietary gluten and those who reported no avoidances. Key nutrient intakes were assessed, as a percentage of Dietary Recommended Intakes, including fibre, B vitamins, vitamin D, Ca, Fe, Na and Zn, and compared between the two groups usingttests. Canadians who avoided gluten had significantly lower intakes of folate, vitamin B12, vitamin D, Fe, Na and Ca compared with those who did not avoid any food groups. However, Canadians who reported following a GFD were significantly more likely to use vitamin or mineral supplements in the past 30 d. More than 20 % of those who avoided gluten also avoided dairy products. Findings suggest that following a GFD places Canadians at risk for nutrient inadequacies, particularly folate, Ca and vitamin D. Further research is required to further examine how multiple dietary avoidances among those who avoid gluten may contribute to dietary inadequacies.
Lender Forbearance
Authors: Bird Andrew , Ertan Aytekin , Karolyi Stephen A. , Ruchti Thomas G.
Published: November 2020

We use a threshold-based design to study ex post discretion in lenders’ contractual enforcement of covenant violations. At preset thresholds, lenders enforce contractual breaches only infrequently, but this enforcement is associated with material consequences (e.g., fees and renegotiations). Enforcement varies significantly over time and peaks when credit conditions are tightest, indicating that enforcement is procyclical. Costly coordination reduces enforcement: Syndicates with ex ante restrictive voting requirements enforce at lower rates. Consistent with theories of lender competition and implicit contracting, enforcement rates are lower for borrowers with access to alternative sources of financing and well-reputed lead arrangers.
‘ACCEPTABLE TRUTHS’ DURING THE FRENCH RELIGIOUS WARS
Authors: Roberts Penny
Published: November 2020

This paper seeks to provide some historical perspective on contemporary preoccupations with competing versions of the truth. Truth has always been contested and subject to scrutiny, particularly during troubled times. It can take many forms – judicial truth, religious truth, personal truth – and is bound up with the context of time and place. This paper sets out the multidisciplinary approaches to truth and examines its role in a specific context, that of early modern Europe and, in particular, the French religious wars of the sixteenth century. Truth was a subject of intense debate among both Renaissance and Reformation scholars, it was upheld as an absolute by judges, theologians and rulers. Yet, it also needed to be concealed by those who maintained a different truth to that of the authorities. In the case of France, in order to advance their cause, the Huguenots used subterfuge of various kinds, including the illicit carrying of messages. In this instance, truth was dependent on the integrity of its carrier, whether the messenger could be trusted and, therefore, their truth accepted. Both sides also sought to defend the truth by countering what they presented as the deceit of their opponents. Then, as now, acceptance of what is true depends on which side we are on and who we are prepared to believe.
Improving sentiment analysis with multi-task learning of negation
Authors: Barnes Jeremy , Velldal Erik , Øvrelid Lilja
Published: November 2020

Sentiment analysis is directly affected by compositional phenomena in language that act on the prior polarity of the words and phrases found in the text.Negationis the most prevalent of these phenomena, and in order to correctly predict sentiment, a classifier must be able to identify negation and disentangle the effect that its scope has on the final polarity of a text. This paper proposes a multi-task approach to explicitly incorporate information about negation in sentiment analysis, which we show outperforms learning negation implicitly in an end-to-end manner. We describe our approach, a cascading and hierarchical neural architecture with selective sharing of Long Short-term Memory layers, and show that explicitly training the model with negation as an auxiliary task helps improve the main task of sentiment analysis. The effect is demonstrated across several different standard English-language data sets for both tasks, and we analyze several aspects of our system related to its performance, varying types and amounts of input data and different multi-task setups.
Executive Functions and Attention in Childhood Epilepsies: A Neuropsychological Hallmark of Dysfunction?
Authors: Cainelli Elisa , Favaro Jacopo , De Carli Pietro , Luisi Concetta , Simonelli Alessandra , Vecchi Marilena , Sartori Stefano , Boniver Clementina
Published: November 2020

Objective:

Patients with epilepsy are at risk for several lifetime problems, in which neuropsychological impairments may represent an impacting factor. We evaluated the neuropsychological functions in children suffering from three main epilepsy categories. Further, we analyzed the longitudinal evolution of the neuropsychological profile over time.

Methods:

Patients undergoing neuropsychological evaluation at our Department from 2012 to 2018 were identified retrospectively. We selected patients aged 6–16 years and with at least two evaluations. Three epilepsy categories were considered: focal/structural, focal self-limited, and idiopathic generalized. Each evaluation included the same structured assessment of main neuropsychological domains. The effect of the epilepsy category, illness duration, seizure status, and medication was computed in multilevel models.

Results:

We identified 103 patients (focal self-limited = 27; focal/structural = 51; and idiopathic generalized = 25), for 233 evaluations. The majority of deficits were reported in attention and executive functions (>30% of patients); the results were dichotomized to obtain global indexes. Multilevel models showed a trend toward statistical significance of category of epilepsy on the global executive index and of illness duration on global attention index. Illness duration predicted the scores of executive and attention tasks, while category and medication predicted executive task performance. Focal/structural epilepsies mostly affected the executive domain, with deficits persisting over time. By contrast, an ameliorative effect of illness duration for attention was documented in all epilepsies.

Conclusions:

This study offers lacking information about the evolution of deficits in time, the role of epilepsy category, and possible psychological implications for high-order cognitive skills, central in several social and academic problems.
Body phenotypes and sexual maturation in Brazilian and US adolescents: evidence for a change in BMI category
Authors: Cumpian Silva Jéssica , Rinaldi Ana Elisa Madalena , Guedes Vasconcelos Francisco de Assis , Assis Maria Alice Altenburg , Mazzeti Camila Medeiros , de Oliveira Mariane Helen , Conde Wolney Lisboa
Published: November 2020

Objective:

Our study aimed to describe body phenotypes (BP) estimated by multivariate analysis and their association with body mass.

Design:

BP were defined based on demographic variables, anthropometric data (body mass, height, skinfolds and circumferences), body composition (phase angle measured by bioelectrical impedance analysis), biochemical parameters (TAG, glucose, total cholesterol ratio/LDL, Hb and sexual maturation (pubic hair and breasts or gonads). ANOVA was performed to verify the differences between skin colour and the stages of pubertal development, BP, body composition, anthropometric and biochemical variables.

Setting:

Cities of São Paulo-SP, Piracicaba-SP and Florianópolis-SC from Brazil and the United States.

Participants:

9269 adolescents aged between 10 and 15 years old.

Results:

The composition of BP was similar in all surveys, which are: BP1 was composed by skinfolds, body mass and circumferences variables; BP2 by pubic hair, breast in girls or gonad in boys, height and age; BP3 by cholesterol, TAG and glucose; and BP4 by phase angle, Hb and glucose (negative loading). There was a strong correlation (r = 0·9, P < 0·001) between BP1 and BMI.

Conclusion:

We highlighted independence observed between biochemical parameters, anthropometry, body composition and sexual maturation. BP may support the calculation of scores for diagnosis of obesity based on anthropometric variables and overcome ambiguity in the isolated use of BMI.
Miranda in the Balkans: decadent despotism, consulship, and the making of a south-eastern revolutionary in the Age of Revolution
Authors: Simeonov Simeon
Published: November 2020

In 1786 Francisco de Miranda, the revolutionary ‘Precursor’ of Latin American independence, toured the Ottoman empire. Focused on the Atlantic dimensions of Miranda’s activism, historians have marginalized his experiences in the Balkans. This article argues that Miranda’s Balkan explorations represented a major inflection point in his revolutionary career. By expanding his experience with consular networks, the Balkans allowed him to develop new revolutionary strategies for channelling his discontent with imperial rule. Rather than resorting to print, consulates enabled Miranda to build secret coalitions in his increasingly public confrontation with what he called imperial ‘despotism’, a type of imperial rule featuring burdensome impositions, limitations on freedom of movement, and ethnic or religious discrimination. By excavating the first Latin American revolutionary encounter with the Balkans and stressing the common forms of anti-imperial mobilization, the article charts a more expansive and inclusive ‘south-eastern’ framework for rethinking the global Age of Revolution.
Reframing the Language of Retreat
Authors: Maldonado Julie , Marino Elizabeth , Iaukea Lesley
Published: November 2020

With so many communities facing relocation from a changing climate, reframing “managed retreat” is needed to respect people's self-determination.
Updated risk-oriented strategy for acute lymphoblastic leukemia in adult patients 18–65 years: NILG ALL 10/07
Authors: Bassan Renato , Pavoni Chiara , Intermesoli Tamara , Spinelli Orietta , Tosi Manuela , Audisio Ernesta , Marmont Filippo , Cattaneo Chiara , Borlenghi Erika , Cortelazzo Sergio , Cavattoni Irene , Fumagalli Monica , Mattei Daniele , Romani Claudio , Cortelezzi Agostino , Fracchiolla Nicola , Ciceri Fabio , Bernardi Massimo , Scattolin Anna Maria , Depaoli Lorella , Masciulli Arianna , Oldani Elena , Rambaldi Alessandro
Published: November 2020

An updated strategy combining pediatric-based chemotherapy with risk-oriented allogeneic hematopoietic cell transplantation (HCT) was evaluated in Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph− ALL) and compared with a published control series. Following induction–consolidation chemotherapy, responsive patients were assigned to receive maintenance chemotherapy or undergo early HCT according to the risk stratification criteria and minimal residual disease (MRD) status. Of the 203 study patients (median age 41 years, range 17–67), 140/161 with Ph− ALL achieved complete remission (86.9%; 91.6% ≤55 years,P = 0.0002), with complete MRD clearing in 68/109; 55 patients were assigned to maintenance chemotherapy, and 85 to HCT due to very high-risk characteristics (hyperleukocytosis, adverse genetics, early/mature T-precursor ALL, and MRD persistence). The 5-year relapse incidence was 36%, and the treatment-related mortality rate was 18%. Median overall and relapse-free survival were 7.4 and 6.2 years, with rates of 54 and 53% at 5 years, respectively, which were significantly better than those obtained with the historical protocol (P = 0.001 andP = 0.005, respectively), without significant differences between maintenance and HCT cohorts. In prognostic analysis, MRD negativity and age ≤55 years were the most favorable independent prognostic factors. A reduction in treatment toxicity and further improvements in the risk definitions and risk-oriented design are the focuses of this ongoing research.
Themis regulates metabolic signaling and effector functions in CD4+ T cells by controlling NFAT nuclear translocation
Authors: Prasad Mukul , Brzostek Joanna , Gautam Namrata , Balyan Renu , Rybakin Vasily , Gascoigne Nicholas R. J.
Published: November 2020

Themis is a T cell lineage-specific molecule that is involved in TCR signal transduction. The effects of germline Themis deletion on peripheral CD4+ T cell function have not been described before. In this study, we found that Themis-deficient CD4+ T cells had poor proliferative responses, reduced cytokine production in vitro and weaker inflammatory potential, as measured by their ability to cause colitis in vivo. Resting T cells are quiescent, whereas activated T cells have high metabolic demands. Fulfillment of these metabolic demands depends upon nutrient availability and upregulation of nutrient intake channels after efficient TCR signal transduction, which leads to metabolic reprogramming in T cells. We tested whether defects in effector functions were caused by impaired metabolic shifts in Themis-deficient CD4+ T cells due to inefficient TCR signal transduction, in turn caused by the lack of Themis. We found that upon TCR stimulation, Themis-deficient CD4+ T cells were unable to upregulate the expression of insulin receptor (IR), glucose transporter (GLUT1), the neutral amino acid transporter CD98 and the mTOR pathway, as measured by c-Myc and pS6 expression. Mitochondrial analysis of activated Themis-deficient CD4+ T cells showed more oxidative phosphorylation (OXPHOS) than aerobic glycolysis, indicating defective metabolic reprogramming. Furthermore, we found reduced NFAT translocation in Themis-deficient CD4+ T cells upon TCR stimulation. Using previously reported ChIP-seq and RNA-seq data, we found that NFAT nuclear translocation controls IR gene expression. Together, our results describe an internal circuit between TCR signal transduction, NFAT nuclear translocation, and metabolic signaling in CD4+ T cells.
Genetic-optimised aperiodic code for distributed optical fibre sensors
Authors: Sun Xizi , Yang Zhisheng , Hong Xiaobin , Zaslawski Simon , Wang Sheng , Soto Marcelo A. , Gao Xia , Wu Jian , Thévenaz Luc
Published: November 2020

Distributed optical fibre sensors deliver a map of a physical quantity along an optical fibre, providing a unique solution for health monitoring of targeted structures. Considerable developments over recent years have pushed conventional distributed sensors towards their ultimate performance, while any significant improvement demands a substantial hardware overhead. Here, a technique is proposed, encoding the interrogating light signal by a single-sequence aperiodic code and spatially resolving the fibre information through a fast post-processing. The code sequence is once forever computed by a specifically developed genetic algorithm, enabling a performance enhancement using an unmodified conventional configuration for the sensor. The proposed approach is experimentally demonstrated in Brillouin and Raman based sensors, both outperforming the state-of-the-art. This methodological breakthrough can be readily implemented in existing instruments by only modifying the software, offering a simple and cost-effective upgrade towards higher performance for distributed fibre sensing.
Modelling transmission and control of the COVID-19 pandemic in Australia
Authors: Chang Sheryl L. , Harding Nathan , Zachreson Cameron , Cliff Oliver M. , Prokopenko Mikhail
Published: November 2020

There is a continuing debate on relative benefits of various mitigation and suppression strategies aimed to control the spread of COVID-19. Here we report the results of agent-based modelling using a fine-grained computational simulation of the ongoing COVID-19 pandemic in Australia. This model is calibrated to match key characteristics of COVID-19 transmission. An important calibration outcome is the age-dependent fraction of symptomatic cases, with this fraction for children found to be one-fifth of such fraction for adults. We apply the model to compare several intervention strategies, including restrictions on international air travel, case isolation, home quarantine, social distancing with varying levels of compliance, and school closures. School closures are not found to bring decisive benefits unless coupled with high level of social distancing compliance. We report several trade-offs, and an important transition across the levels of social distancing compliance, in the range between 70% and 80% levels, with compliance at the 90% level found to control the disease within 13–14 weeks, when coupled with effective case isolation and international travel restrictions.
A steric gate controls P/E hybrid-state formation of tRNA on the ribosome
Authors: Levi Mariana , Walak Kelsey , Wang Ailun , Mohanty Udayan , Whitford Paul C.
Published: November 2020

The ribosome is a biomolecular machine that undergoes multiple large-scale structural rearrangements during protein elongation. Here, we focus on a conformational rearrangement during translocation, known as P/E hybrid-state formation. Using a model that explicitly represents all non-hydrogen atoms, we simulated more than 120 spontaneous transitions, where the tRNA molecule is displaced between the P and E sites of the large subunit. In addition to predicting a free-energy landscape that is consistent with previous experimental observations, the simulations reveal how a six-residue gate-like region can limit P/E formation, where sub-angstrom structural perturbations lead to an order-of-magnitude change in kinetics. Thus, this precisely defined set of residues represents a novel target that may be used to control functional dynamics in bacterial ribosomes. This theoretical analysis establishes a direct relationship between ribosome structure and large-scale dynamics, and it suggests how next-generation experiments may precisely dissect the energetics of hybrid formation on the ribosome.
Particle-size dependent structural transformation of skyrmion lattice
Authors: Takagi R. , Yamasaki Y. , Yokouchi T. , Ukleev V. , Yokoyama Y. , Nakao H. , Arima T. , Tokura Y. , Seki S.
Published: November 2020

Magnetic skyrmion is a topologically protected particle-like object in magnetic materials, appearing as a nanometric swirling spin texture. The size and shape of skyrmion particles can be flexibly controlled by external stimuli, which suggests unique features of their crystallization and lattice transformation process. Here, we investigated the detailed mechanism of structural transition of skyrmion lattice (SkL) in a prototype chiral cubic magnet Cu2OSeO3, by combining resonant soft X-ray scattering (RSXS) experiment and micromagnetic simulation. This compound is found to undergo a triangular-to-square lattice transformation of metastable skyrmions by sweeping magnetic field (B). Our simulation suggests that the symmetry change of metastable SkL is mainly triggered by the B-induced modification of skyrmion core diameter and associated energy cost at the skyrmion-skyrmion interface region. Such internal deformation of skyrmion particle has further been confirmed by probing the higher harmonics in the RSXS pattern. These results demonstrate that the size/shape degree of freedom of skyrmion particle is an important factor to determine their stable lattice form, revealing the exotic manner of phase transition process for topological soliton ensembles in the non-equilibrium condition.
Vascular surveillance by haptotactic blood platelets in inflammation and infection
Authors: Nicolai Leo , Schiefelbein Karin , Lipsky Silvia , Leunig Alexander , Hoffknecht Marie , Pekayvaz Kami , Raude Ben , Marx Charlotte , Ehrlich Andreas , Pircher Joachim , Zhang Zhe , Saleh Inas , Marel Anna-Kristina , Löf Achim , Petzold Tobias , Lorenz Michael , Stark Konstantin , Pick Robert , Rosenberger Gerhild , Weckbach Ludwig , Uhl Bernd , Xia Sheng , Reichel Christoph Andreas , Walzog Barbara , Schulz Christian , Zheden Vanessa , Bender Markus , Li Rong , Massberg Steffen , Gaertner Florian
Published: November 2020

Breakdown of vascular barriers is a major complication of inflammatory diseases. Anucleate platelets form blood-clots during thrombosis, but also play a crucial role in inflammation. While spatio-temporal dynamics of clot formation are well characterized, the cell-biological mechanisms of platelet recruitment to inflammatory micro-environments remain incompletely understood. Here we identify Arp2/3-dependent lamellipodia formation as a prominent morphological feature of immune-responsive platelets. Platelets use lamellipodia to scan for fibrin(ogen) deposited on the inflamed vasculature and to directionally spread, to polarize and to govern haptotactic migration along gradients of the adhesive ligand. Platelet-specific abrogation of Arp2/3 interferes with haptotactic repositioning of platelets to microlesions, thus impairing vascular sealing and provoking inflammatory microbleeding. During infection, haptotaxis promotes capture of bacteria and prevents hematogenic dissemination, rendering platelets gate-keepers of the inflamed microvasculature. Consequently, these findings identify haptotaxis as a key effector function of immune-responsive platelets.
Free-space optical delay line using space-time wave packets
Authors: Yessenov Murat , Bhaduri Basanta , Delfyett Peter J. , Abouraddy Ayman F.
Published: November 2020

An optical buffer featuring a large delay-bandwidth-product—a critical component for future all-optical communications networks—remains elusive. Central to its realization is a controllable inline optical delay line, previously accomplished via engineered dispersion in optical materials or photonic structures constrained by a low delay-bandwidth product. Here we show that space-time wave packets whose group velocity is continuously tunable in free space provide a versatile platform for constructing inline optical delay lines. By spatio-temporal spectral-phase-modulation, wave packets in the same or in different spectral windows that initially overlap in space and time subsequently separate by multiple pulse widths upon free propagation by virtue of their different group velocities. Delay-bandwidth products of  ~100 for pulses of width  ~1 ps are observed, with no fundamental limit on the system bandwidth.
Insights into interfacial effect and local lithium-ion transport in polycrystalline cathodes of solid-state batteries
Authors: Lou Shuaifeng , Liu Qianwen , Zhang Fang , Liu Qingsong , Yu Zhenjiang , Mu Tiansheng , Zhao Yang , Borovilas James , Chen Yijun , Ge Mingyuan , Xiao Xianghui , Lee Wah-Keat , Yin Geping , Yang Yuan , Sun Xueliang , Wang Jiajun
Published: November 2020

Interfacial issues commonly exist in solid-state batteries, and the microstructural complexity combines with the chemical heterogeneity to govern the local interfacial chemistry. The conventional wisdom suggests that “point-to-point” ion diffusion at the interface determines the ion transport kinetics. Here, we show that solid-solid ion transport kinetics are not only impacted by the physical interfacial contact but are also closely associated with the interior local environments within polycrystalline particles. In spite of the initial discrete interfacial contact, solid-state batteries may still display homogeneous lithium-ion transportation owing to the chemical potential force to achieve an ionic-electronic equilibrium. Nevertheless, once the interior local environment within secondary particle is disrupted upon cycling, it triggers charge distribution from homogeneity to heterogeneity and leads to fast capacity fading. Our work highlights the importance of interior local environment within polycrystalline particles for electrochemical reactions in solid-state batteries and provides crucial insights into underlying mechanism in interfacial transport.
A computational method for detection of ligand-binding proteins from dose range thermal proteome profiles
Authors: Kurzawa Nils , Becher Isabelle , Sridharan Sindhuja , Franken Holger , Mateus André , Anders Simon , Bantscheff Marcus , Huber Wolfgang , Savitski Mikhail M.
Published: November 2020

Detecting ligand-protein interactions in living cells is a fundamental challenge in molecular biology and drug research. Proteome-wide profiling of thermal stability as a function of ligand concentration promises to tackle this challenge. However, current data analysis strategies use preset thresholds that can lead to suboptimal sensitivity/specificity tradeoffs and limited comparability across datasets. Here, we present a method based on statistical hypothesis testing on curves, which provides control of the false discovery rate. We apply it to several datasets probing epigenetic drugs and a metabolite. This leads us to detect off-target drug engagement, including the finding that the HDAC8 inhibitor PCI-34051 and its analog BRD-3811 bind to and inhibit leucine aminopeptidase 3. An implementation is available as an R package from Bioconductor (https://bioconductor.org/packages/TPP2D). We hope that our method will facilitate prioritizing targets from thermal profiling experiments.
Few keystone plant genera support the majority of Lepidoptera species
Authors: Narango Desiree L. , Tallamy Douglas W. , Shropshire Kimberley J.
Published: November 2020

Functional food webs are essential for the successful conservation of ecological communities, and in terrestrial systems, food webs are built on a foundation of coevolved interactions between plants and their consumers. Here, we collate published data on host plant ranges and associated host plant-Lepidoptera interactions from across the contiguous United States and demonstrate that among ecosystems, distributions of plant-herbivore interactions are consistently skewed, with a small percentage of plant genera supporting the majority of Lepidoptera. Plant identities critical for retaining interaction diversity are similar and independent of geography. Given the importance of Lepidoptera to food webs and ecosystem function, efficient and effective restoration of degraded landscapes depends on the inclusion of such ‘keystone’ plants.
Co-regulation of the transcription controlling ATF2 phosphoswitch by JNK and p38
Authors: Kirsch Klára , Zeke András , Tőke Orsolya , Sok Péter , Sethi Ashish , Sebő Anna , Kumar Ganesan Senthil , Egri Péter , Póti Ádám L. , Gooley Paul , Peti Wolfgang , Bento Isabel , Alexa Anita , Reményi Attila
Published: November 2020

Transcription factor phosphorylation at specific sites often activates gene expression, but how environmental cues quantitatively control transcription is not well-understood. Activating protein 1 transcription factors are phosphorylated by mitogen-activated protein kinases (MAPK) in their transactivation domains (TAD) at so-called phosphoswitches, which are a hallmark in response to growth factors, cytokines or stress. We show that the ATF2 TAD is controlled by functionally distinct signaling pathways (JNK and p38) through structurally different MAPK binding sites. Moreover, JNK mediated phosphorylation at an evolutionarily more recent site diminishes p38 binding and made the phosphoswitch differently sensitive to JNK and p38 in vertebrates. Structures of MAPK-TAD complexes and mechanistic modeling of ATF2 TAD phosphorylation in cells suggest that kinase binding motifs and phosphorylation sites line up to maximize MAPK based co-regulation. This study shows how the activity of an ancient transcription controlling phosphoswitch became dependent on the relative flux of upstream signals.
Two-dimensional vacancy platelets as precursors for basal dislocation loops in hexagonal zirconium
Authors: Liu Si-Mian , Beyerlein Irene J. , Han Wei-Zhong
Published: November 2020

Zirconium alloys are widely used structural materials of choice in the nuclear industry due to their exceptional radiation and corrosion resistance. However long-time exposure to irradiation eventually results in undesirable shape changes, irradiation growth, that limit the service life of the component. Crystal defects called  loops, routinely seen no smaller than 13 nm in diameter, are the source of the problem. How they form remains a matter of debate. Here, using transmission electron microscopy, we reveal the existence of a novel defect, nanoscale triangle-shaped vacancy plates. Energy considerations suggest that the collapse of the atomically thick triangle-shaped vacancy platelets can directly produce  dislocation loops. This mechanism agrees with experiment and implies a characteristic incubation period for the formation of  dislocation loops in zirconium alloys.