bluuebunny/crossref_metadata_2025 huggingface dataset:
The first three months of the COVID-19 epidemic: Epidemiological evidence for two separate strains of SARS-CoV-2 viruses spreading and implications for prevention strategies
Authors: Wittkowski Knut M.
Published: March 2020

About one month after the COVID-19 epidemic peaked in Mainland China and SARS-CoV-2 migrated to Europe and then the U.S., the epidemiological data begin to provide important insights into the risks associated with the disease and the effectiveness of intervention strategies such as travel restrictions and lockdowns (“social distancing”). Respiratory diseases, including the 2003 SARS epidemic, remain only about two months in any given population, although peak incidence and lethality can vary. The epidemiological data suggest that at least two strains of the 2020 SARS-CoV-2 virus have evolved during its migration from Mainland China to Europe. South Korea, Iran, Italy, and Italy’s neighbors were hit by the more dangerous “SKII” variant. While the epidemic in continental Asia is about to end, and in Europe about to level off, the more recent epidemic in the younger US population is still increasing, albeit not exponentially anymore. The peak level will likely depend on which of the strains has entered the U.S. first. The same models that help us to understand the epidemic also help us to choose prevention strategies. Containment of high-risk people, like the elderly, and reducing disease severity, either by vaccination or by early treatment of complications, is the best strategy against a respiratory virus disease. Lockdowns can be effective during the month following the peak incidence in infections, when the exponential increase of cases ends. Earlier containment of low-risk people merely prolongs the time the virus needs to circulate until the incidence is high enough to initiate “herd immunity”. Later containment is not helpful, unless to prevent a rebound if containment started too early.

About the Author

Dr. Wittkowski received his PhD in computer science from the University of Stuttgart and his ScD (Habilitation) in Medical Biometry from the Eberhard-Karls-University Tübingen, both Germany. He worked for 15 years with Klaus Dietz, a leading epidemiologist who coined the term “reproduction number”, on the Epidemiology of HIV before heading for 20 years the Department of Biostatistics, Epidemiology, and Research Design at The Rockefeller University, New York. Dr. Wittkowski is currently the CEO of ASDERA LLC, a company discovering novel interventions against complex (incl. coronavirus) diseases from data of genome-wide association studies.
Inhibition of mTOR during a postnatal critical sensitive window rescues deficits in GABAergic PV cell connectivity and social behavior caused by loss ofTSC1
Authors: Choudhury Mayukh , Amegandjin Clara A. , Jadhav Vidya , Carriço Josianne Nunes , Quintal Ariane , Berryer Martin , Snapyan Marina , Chattopadhyaya Bidisha , Saghatelyan Armen , Di Cristo Graziella
Published: March 2020

Mutations in regulators of the Mechanistic Target Of Rapamycin Complex 1 (mTORC1), such asTsc1/2, lead to neurodevelopmental disorders associated with autism, intellectual disabilities and epilepsy. Whereas the effects of mTORC1 signaling dysfunction within diverse cell types are likely critical for the onset of the diverse neurological symptoms associated with mutations in mTORC1 regulators, they are not well understood. In particular, the effects of mTORC1 dys-regulation in specific types of inhibitory interneurons are unclear.

Here, we showed thatTsc1haploinsufficiency in parvalbumin (PV)-positive GABAergic interneurons either in cortical organotypic cultures orin vivocaused a premature increase in their perisomatic innervations, followed by a striking loss in adult mice. This effects were accompanied by alterations of AMPK-dependent autophagy in pre-adolescent but not adult mice. PV cell-restrictedTsc1mutant mice showed deficits in social behavior. Treatment with the mTOR inhibitor Rapamycin restricted to the third postnatal week was sufficient to permanently rescue deficits in both PV cell innervation and social behavior in adult conditional haploinsufficient mice. All together, these findings identify a novel role of Tsc1-mTORC1 signaling in the regulation of the developmental time course and maintenance of cortical PV cell connectivity and provide a mechanistic basis for the targeted rescue of autism-related behaviors in disorders associated with deregulated mTORC1 signaling.
A multiplexed bioluminescent reporter for sensitive and non-invasive tracking of DNA double strand break repair dynamicsin vitroandin vivo
Authors: Chien Jasper Che-Yung , Tabet Elie , Pinkham Kelsey , da Hora Cintia Carla , Chang Jason Cheng-Yu , Lin Steven , Badr Christian Elias , Lai Charles Pin-Kuang
Published: March 2020

Tracking DNA double strand break (DSB) repair is paramount for the understanding and therapeutic development of various diseases including cancers. Herein, we describe a multiplexed bioluminescent repair reporter (BLRR) for non-invasive monitoring of DSB repair pathways in living cells and animals. The BLRR approach employs secretedGaussiaandVargulaluciferases to simultaneously detect homology-directed repair (HDR) and non-homologous end joining (NHEJ), respectively. BLRR data are consistent with next-generation sequencing results for reporting HDR (R2= 0.9722) and NHEJ (R2= 0.919) events. Moreover, BLRR analysis allows longitudinal tracking of HDR and NHEJ activities in cells, and enables detection of DSB repairs in xenografted tumoursin vivo.Using the BLRR system, we observed a significant difference in the efficiency of CRISPR/Cas9-mediated editing with guide RNAs only 1-10 bp apart. Moreover, BLRR analysis detected altered dynamics for DSB repair induced by small-molecule modulators. Finally, we discovered HDR-suppressing functions of anticancer cardiac glycosides in human glioblastomas and glioma cancer stem-like cellsviainhibition of DNA repair protein RAD51 homolog 1 (RAD51). The BLRR method provides a highly sensitive platform to simultaneously and longitudinally track HDR and NHEJ dynamics that is sufficiently versatile for elucidating the physiology and therapeutic development of DSB repair.
Occipital Alpha-TMS causally modulates Temporal Order Judgements: Evidence for discrete temporal windows in vision
Authors: Chota Samson , Marque Phillipe , VanRullen Rufin
Published: March 2020

Recent advances in neuroscience have challenged the view of conscious visual perception as a continuous process. Behavioral performance, reaction times and some visual illusions all undergo periodic fluctuations that can be traced back to oscillatory activity in the brain. These findings have given rise to the idea of a discrete sampling mechanism in the visual system. In this study we seek to investigate the causal relationship between occipital alpha oscillations and Temporal Order Judgements using neural entrainment via rhythmic TMS. We find that certain phases of the entrained oscillation facilitate temporal order perception of two visual stimuli, whereas others hinder it. Our findings support the idea that the visual system periodically compresses information into discrete packages within which temporal order information is lost.

Significance Statement

Correlational evidence for a relationship between brain states and perception is abundant. However, in order to truly understand the causal relationship between the two, we need to be able to manipulate one and observe changes in the other. Neural entrainment via TMS serves as a valuable tool to interfere with cortical rhythms and observe changes in perception. Here, using rhythmic TMS-pulses at 10 Hz, we investigate the effect of the phase of entrained oscillations on performance in a temporal order judgement (TOJ) task. We observe that the causally entrained oscillation indeed modulates time perception rhythmically. On top of previous work on discrete perception we were able to 1. causally influence brain rhythms in a far more direct fashion using TMS, and 2. show that previous work on discrete perception cannot simply be explained by rhythmic fluctuations in visibility. In conclusion our findings support the long discussed idea that the temporal organization of visual processing is discrete rather than continuous, and is causally modulated by cortical rhythms. To our knowledge, this is the first study providing causal evidence via TMS for an endogenous periodic modulation of time perception.
Mapping the forest disturbance regimes of Europe
Authors: Senf Cornelius , Seidl Rupert
Published: March 2020

Forest disturbances shape ecosystem composition and structure, and changes in disturbance regimes can have strong consequences for forest ecosystem services. Yet we currently lack consistent quantitative data on Europe’s forest disturbance regimes and their changes over time. Here we used satellite data to map three decades (1986-2016) of forest disturbances across continental Europe, covering 35 countries and a forest area of 210 million ha at a spatial grain of 30 m, and analyzed the patterns and trends in disturbance size, frequency and severity. Between 1986 and 2016, 17% of Europe’s forest area was disturbed by anthropogenic and/or natural causes. The 25 million individual disturbance patches had a mean patch size of 1.09 ha (range between 1stand 99thpercentile 0.18 – 10.10 ha). On average 0.52 (0.02 – 3.01) disturbances occurred per km2every year, removing 77% (22 – 100%) of the canopy. While trends in disturbance size were highly variable, disturbance frequency increased and disturbance severity decreased since 1986. Changes in disturbance rates observed for Europe’s forests are thus primarily driven by changes in disturbance frequency (i.e., more disturbances), and only to a lesser extent by increasing disturbance size. We here present the first continental-scale characterization of Europe’s forest disturbance regimes and their changes over time, providing spatially explicit information that is critical for understanding the ongoing changes in forest ecosystems across Europe.
Biochemical profile and bioactive potential of wild folk medicinal plants of Zygophyllaceae from Balochistan, Pakistan
Authors: Ahmed Alia , Hameed Amjad , Saeed Shazia
Published: March 2020

Recent focus is on analysis of biological activities of extracts from plant species. Zygophyllaceae is exceedingly important angiosperm family with many taxa being used in folk medicines widely dispersed in arid and semi-arid zones of Balochistan, Pakistan. Only a small proportion of them have been scientifically analyzed and many species are nearly facing extinction. Therefore present investigation explores the biochemical and bioactive potential of fourteen folk medicinal plants usually used for treatments of different ailments. Fresh aerial parts of nine taxa and two fruit samples were collected from plants growing in arid and semi-arid zones of Balochistan and analyzed for enzymatic, non-enzymatic and other biochemical activities. Higher phytochemical activities were detected in the aerial parts. Superoxide dismutase was detected maximum inFagonia indica, (184.7±5.17 units/g), ascorbate peroxidase inTribulus longipetalussubsp.longipetalus(947.5±12.5 Units/g), catalase and peroxidase was higher inPeganum harmala(555.0±5.0 and 2597.8±0.4 units/g respectively). Maximum esterase and alpha amylase activity was found inZygophyllum fabago(14.3±0.44 and 140±18.8 mg/g respectively). Flavonoid content was high inT. longipetalussubsp.longipetalus(666.1±49 μg/ml). The highest total phenolic content and tannin was revealed inF. olivieri(72125±425 and 37050±1900 μM/g. respectively). Highest value of ascorbic acid was depicted inF. bruguierivar.rechingeri(448±1.5 μg/g). Total soluble Proteins and reducing sugars were detected higher inP. harmala(372.3±54 and 5.9±0.1 mg/g respectively). Maximum total antioxidant capacity (TAC) was depicted in Z. simplex(16.9±0.01 μM/g). Pigment analysis exhibited the high value of lycopene and total carotenoids inT. terrestris(7.44±0.2 and 35.5±0.0 mg/g respectively). Chlorophyll a, b and total chlorophyll content was found maximum inT. longipetalussubsp.pterophorus(549.1±9.9, 154.3±10 and 703.4±20.2 ug/g respectively). All taxa exhibited anti-inflammatory activity as well as anti-diabetic inhibitory potential. Seed extracts ofZygophyllum eurypterum(96%) exhibited highest inhibitory potential, along with twelve other taxa of Zygophyllaceae indicated (96-76%) activity when compared with the standard drug diclofenac sodium (79%). Seeds ofT. longipetalussubsp.longipetalus(85%) exhibited the highest anti-diabetic activity; other eleven taxa also exhibited inhibitory activity of α-amylase ranging from (85-69%) compared with Metformin (67%) standard drug. Phytochemical screening revealed that selected taxa proved to be the potential source of natural antioxidants and could further be explored for in-vivo studies and utilized in pharmaceutical industries as potent therapeutic agents validating their ethno-pharmacological uses.
In silicoanalysis of DNA re-replication across a complete genome reveals cell-to-cell heterogeneity and genome plasticity
Authors: Rapsomaniki Maria Anna , Maxouri Stella , Garrastacho Manuel Ramirez , Nathanailidou Patroula , Giakoumakis Nickolaos Nikiforos , Taraviras Stavros , Lygeros John , Lygerou Zoi
Published: March 2020

DNA replication is a complex and remarkably robust process: despite its inherent uncertainty, manifested through stochastic replication timing at a single-cell level, multiple control mechanisms ensure its accurate and timely completion across a population. Disruptions in these mechanisms lead to DNA re-replication, closely connected to genomic instability and oncogenesis. We present a stochastic hybrid model of DNA re-replication that accurately portrays the interplay between discrete dynamics, continuous dynamics, and uncertainty. Using experimental data on the fission yeast genome, model simulations show how different regions respond to re-replication, and permit insight into the key mechanisms affecting re-replication dynamics. Simulated and experimental population-level profiles exhibit good correlation along the genome, which is robust to model parameters, validating our approach. At a single-cell level, copy numbers of individual loci are affected by intrinsic properties of each locus,in ciseffects from adjoining loci andin transeffects from distant loci.In silicoanalysis and single-cell imaging reveal that cell-to-cell heterogeneity is inherent in re-replication and can lead to a plethora of genotypic variations. Our thoroughin silicoanalysis of DNA re-replication across a complete genome reveals that heterogeneity at the single cell level and robustness at the population level are emerging and co-existing principles of DNA re-replication. Our results indicate that re-replication can promote genome plasticity by generating many diverse genotypes within a population, potentially offering an evolutionary advantage in cells with aberrations in replication control mechanisms.
Association of Dental Scaling with Lower Risk of Spontaneous Intracranial Haemorrhage: a Cohort Study in Taiwan
Authors: Pan Jin-Shui , Hong Mei-Zhu , Shia Ben-Chang , Ye Linglong , Qin Lei , Si Li-Juan
Published: March 2020

The authors have withdrawn this manuscript because several modifications are needed for study design and results. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Analysis of antecedent factors in academic achievement and student retention
Authors: Setiawan Rony , Aprillia Ariesya , Magdalena Nonie
Published: March 2020

Purpose

Student achievement and retention are two important components that indicate the quality of a university. This is in line with one of the standards of university accreditations regarding the quality of students and graduates, which are set by BAN-PT, an institution that guarantees the quality of National Education Service delivery at every university in Indonesia. The purpose of this paper is analyzing the internal and external factors that contribute to academic achievement and student retention.

Design/methodology/approach

This paper is a causal explanatory-based study, using multiple regression analysis among five independent variables and two dependent variables separately. Several sequential tests are conducted to maintain the proper research results, such as reliability, normality, multi-collinearity and heteroscedasticity.

Findings

This paper provides empirical facts that student motivation has a significant positive impact on the level of student academic achievement, and the quality of lecturers has a significant positive impact both on student academic achievement and retention rates.

Research limitations/implications

This study is conducted within the context of a university. The generalization in the study is low. Researchers are encouraged to explore further.

Practical implications

This paper is expected to provide constructive feedback to university management in setting policies that are oriented toward strategic actions to optimize academic achievement and maintain their students.

Originality/value

This paper provides insights of good university governance concerning in higher education management.
Exploring potentials of digital nudging for business processes
Authors: Bammert Sandra , König Ulrich Matthias , Roeglinger Maximilian , Wruck Tabitha
Published: March 2020

Purpose

Business process improvement is vital for organizations as business environments are becoming ever more volatile, uncertain, complex and ambiguous. Process improvement methods help organizations sustain competitiveness. Many existing methods, however, do not fit emerging business environments as they entail initiatives with long implementation times, high investments and limited involvement of process participants. What is needed are agile process improvement approaches. The purpose of this paper is to explore the potential of digital nudging – a concept offering tools that lead individuals to better decisions – to improve business processes.

Design/methodology/approach

Using process deviance as theoretical lens, an online experiment with 473 participants is conducted. Within the experiment, business processes and digital nudges are implemented to examine whether digital nudging can mitigate the weaknesses of existing process improvement methods.

Findings

Digital nudging can influence the decisions of process participants and entail positive process deviance that leads to process improvement opportunities. Further, the research gives a first hint on the effectiveness of different digital nudges and lays the foundation for future research.

Research limitations/implications

Since exploring a completely new field of research and conducting the experiment in a synthetic environment, the paper serves as a first step toward the combination of digital nudging, business process improvements and positive process deviance.

Originality/value

The major achievement reported in this paper is the exploration of a new field of research. Thus, digital nudging shapes up as a promising foundation for agile process improvement, a discovery calling for future research at the intersection of digital nudging and business process management.
Adoption of blockchain in supply chain: an analysis of influencing factors
Authors: Ghode Dnyaneshwar , Yadav Vinod , Jain Rakesh , Soni Gunjan
Published: March 2020

Purpose

Blockchain technology (BT) is setting world-shattering standard in all type of transactions in business. BT has the prospective to drastically transform supply chain (SC). The main challenge is to enhance trust among the SC stakeholders. This paper aims to identify and prioritize the factors and its challenges that influence the adoptability of BT in SC. The prioritization of these factors will be helpful to the practitioners to decide the strategy of implementing the BT in SC.

Design/methodology/approach

The factors influencing adoption of BT are identified from the review of literature and expert opinion is used to rank the factors influencing the adoptability of BT in SC using grey relational analysis (GRA).

Findings

We identified and prioritized key factors: inter-organizational trust and relational governance as organizational challenge, data transparency and data immutability as technological challenge, interoperability and product type as operational challenge and social influence and behavioral intention as social challenge that influences adoptability of BT in SC.

Originality/value

The priority of these factors will guide future researchers and industry practitioners to plan rational and financial strategy for implementing BT in SC.
Offense is the best defense: the impact of workplace bullying on knowledge hiding
Authors: Yao Zhu , Zhang Xianchun , Luo Jinlian , Huang Hui
Published: March 2020

Purpose

Workplace bullying is a common negative event suffered by employees in the workplace. The harm it brings to the organization has become the focus of the field of organizational behavior. The purpose of this study was to explore whether workplace bullying has an impact on employee knowledge hiding and to discover the underlying mechanism between the two.

Design/methodology/approach

Based on the conservation of resource theory and the cognitive-affective personality system theory, this paper surveys 327R&D employees of Chinese technological corporations at two time points and explores the relationship between workplace bullying and knowledge hiding as well as the underlying mechanism. This study used confirmatory factor analysis, bootstrapping method and structural equation model to validate the research hypothesis.

Findings

The results show that workplace bullying positively correlates with knowledge hiding; emotional exhaustion and organizational identification play a mediation role between workplace bullying and knowledge hiding, and both variables play a chain mediation role in that relationship; and forgiveness climate moderates the positive impact of workplace bullying on emotional exhaustion, further moderating the chain mediation role of emotional exhaustion and organizational identification.

Originality/value

The findings of this study can not only complement the existing researches on the influence of negative workplace events on employees’ knowledge hiding behaviors but also strengthen scholars’ attention and understanding of the internal mechanism between workplace bullying and knowledge hiding.
The impact of servant leadership and transformational leadership on learning organization: a comparative analysis
Authors: Xie Lei
Published: March 2020

Purpose

Leadership has a powerful influence on learning and development in today's organizations. Various types of leadership have been found to be conducive to building a learning organization. This empirical study compared the effect of transformational and servant leadership on a learning organization (an organization that constantly transforms itself using learning and development techniques) in the context of Chinese small- and medium-sized enterprises (SMEs).

Design/methodology/approach

Four proposed hypotheses were tested using structural equation modeling.

Findings

The results show that servant leadership has no significant relationship to learning organization, whereas transformational leadership is a strong predictor.

Originality/value

This research compares two different leadership styles and presents theoretical and practical implications for scholars and practitioners. In particular, this study advances our understanding of how and which leadership style relates to learning organization by examining a structural model with three latent variables: servant leadership, transformational leadership, and learning organization.
Demystifying organisational embeddedness of leadership – a multi-method approach to validate a new construct
Authors: Busse Ronald , Winnen Lothar , Wilms Rafael , Lanwehr Ralf
Published: March 2020

Purpose

Since the dawn of leadership research, generations of scholars have looked at the topic through the lenses of leader personalities and traits, their behaviour, the situation they are in and their relations with co-workers. Same as with ideology waves in managerial discourse and though sailing under different flags, many of the above “classical” foci reverberate in “modern” organisational literature. The authors argue, however, that relatively little effort has been put into what we label as “organisational embeddedness of leadership” (OEL). The authors here focus on the role of institutionalising leadership within the setting of “poly-contextual” organisational frameworks.

Design/methodology/approach

Addressing the ambiguity of previous OEL research with fresh primary data from Germany, the authors present a clear-cut five-dimensional, 15-items construct. The authors’ empirical validation rests on (1) two independent qualitative studies and (2) three independent quantitative investigations computing exploratory (N = 61) and confirmatory (N = 172) factor analysis as well as a regression analysis (N = 131).

Findings

Structural equation modelling results indicate a single-factor model with five sub-dimensions consisting of leadership training and career development, leadership alignment, evaluation and feedback, implementation of employee interviews and supporting resources for leadership.

Originality/value

This work contributes to a broader understanding of “leadership emergence and development” (LED) from an organisational perspective. The limitations of the present article call for a lively debate on OEL and may illuminate some promising future research avenues.
Marco Iansiti and Karim Lakhani: strategies for the new breed of “AI first” organizations
Authors: Leavy Brian
Published: March 2020

Purpose

This interview introduces the concept of the “AI first company”, a new breed of organization that is transforming the economy and defining the emergence of a new age.

Design/methodology/approach

An interview with Harvard digital strategy experts, Marco Iansiti and Karim Lakhani, about their new book, Competing in the Age of AI: Strategy and Leadership When Algorithms and Networks Run the World. Marco Iansiti is the David Sarnoff Professor of Business Administration at Harvard Business School (HBS) and heads the school’s Technology and Operations Management Unit and the Digital Initiative. Karim R. Lakhani is the Charles E. Wilson Professor of Business Administration at HBS, and the founder and co-director of the Laboratory for Innovation Science and co-founder of the Digital Initiative at Harvard. 10; 10;The authors were interviewed by Brian Leavy, emeritus professor of strategy at Dublin City University Business School and a Strategy & Leadership contributing editor.

Findings

Digital transformation is not about creating a digital function or spinning off a digital unit, it’s about fundamentally restructuring the core of the firm by building a data-centric operating architecture supported by an agile organization that enables on-going change.

Practical implications

Essentially, we are moving away from an era of core competencies that differ from industry to industry to an age shaped by data and analytics and powered by algorithms. The concept of network is superceding the concept of industry in defining strategic options for firms.

Originality/value

The emergence of the “Age of AI” has possibly created the greatest entrepreneurial opportunity in the history of civilization and the world is literally jammed with entrepreneurial activity. Marco Iansiti and Karim Lakhani suggest ways to maximize that opportunity.
Effect of different thermocouple constructions on heat-level vapour phase soldering profiles
Authors: Alaya Mohamed Amine , Megyeri Viktória , Bušek David , Harsányi Gábor , Geczy Attila
Published: March 2020

Purpose

To improve productivity and reach better quality in assembling, measurements and proper process controlling are a necessary factor. This study aims to focus on the monitoring heat-level-based vapour phase reflow soldering (VPS), where – as it was found – different thermocouple constructions can affect the set parameters of the oven and resulting soldering profiles significantly.

Design/methodology/approach

The study experiments showed significant alteration of the heating profiles during the process of the reflowing using different construction of k-type thermocouples. In a heat-level-based VPS oven, polytetrafluoroethylene (PTFE), perfluoroalkoxy (PFA) gas and water-resistant, fibreglass, thin PFA and ultrathin PFA-covered thermocouples were tested with ±1 °C precision. The oven parameters were swept according to the heating power; the length of the introduced thermocouple cables was also taken into account. An FR4-based sample PCB was used for monitoring the temperature.

Findings

According to the results, due to the mass and volume of the thermocouples’ wires, different transients were observed on the resulting soldering profiles on the same sample PCB. The thermocouples with lower thermal mass result in faster profiles and significantly different heating factor values compared to the thermocouples that have larger thermal mass. Consequently, the length of the thermocouple wires put in the oven has also considerable effect on the heat transfer of the PCB inside the oven as well.

Originality/value

The paper shows that the thermocouple construction must be taken into account when setting up a required soldering profile, while the thermal mass of the wires might cause a significant difference in the prediction of the actual and expected soldering temperatures.
Meritocracy, Elitism and Inequality
Authors: Mijs Jonathan J.B. , Savage Mike
Published: March 2020

The appeal of meritocracy is plain to see, because it appears to promote equality of opportunity. However, in this paper we argue that meritocracy is also a deeply elitist project. Firstly, we place Michael Young in context to show how his critique of meritocracy should be understood as a socialist vision to ameliorate class divides. Secondly, we show how economic inequality in the UK has not generated systematic resistance: in fact, inequality and belief in meritocracy have gone hand in hand. Thirdly, we argue that people see their own lives as meritocratic rather than ascribed, and that such values are deeply embedded in popular life. We offer two explanations for how such views have come about, and show how they have helped construct a more unequal society.
DMHF (2,5‐dimethyl‐4‐hydroxy‐3(2H)‐furanone), a volatile food component generated by the Maillard reaction, promotes appetite and changes gene expression in the rat brain through inhalation
Authors: Yokoyama Issei , Nakai Yuji , Suzuki Yoshihiro , Ohata Motoko , Komiya Yusuke , Nagasao Jun , Arihara Keizo
Published: March 2020

Inhalation of odors can affect physiological parameter and change gene expression‐related specific function. 2,5‐Dimethyl‐4‐hydroxy‐3(2H)‐furanone (DMHF) is one of the major odor compounds generated by the Maillard reaction. We previously reported that the inhalation of DMHF decreased systolic blood pressure via the autonomic nervous system in rats. The autonomic nervous system is also closely related to appetite regulation. The present study investigated the effects of DMHF on dietary intake and gene expression. The inhalation of DMHF increased the dietary intake of rats during the feeding period. However, body weight did not change after 6 weeks feeding. A DNA microarray analysis showed that DMHF altered gene expression associated with feeding behavior and neurotransmission in the rat brain. DMHF inhalation promotes appetite and changes gene expression in rats. Furthermore, phenotypic changes may regulate neurotransmission and appetite at the mRNA level in addition to controlling the autonomic nervous system.

Practical Application

DMHF is an important flavor component in the food industry. In this study, we first observed that the inhalation of DMHF promotes appetite. This finding is directly connected with the industrial application.
Galacto‐conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity
Authors: González‐Gualda Estela , Pàez‐Ribes Marta , Lozano‐Torres Beatriz , Macias David , Wilson Joseph R. , González‐López Cristina , Ou Hui‐Ling , Mirón‐Barroso Sofía , Zhang Zhenguang , Lérida‐Viso Araceli , Blandez Juan F. , Bernardos Andrea , Sancenón Félix , Rovira Miguel , Fruk Ljiljana , Martins Carla P. , Serrano Manuel , Doherty Gary J. , Martínez‐Máñez Ramón , Muñoz‐Espín Daniel
Published: March 2020

Pharmacologically active compounds with preferential cytotoxic activity for senescent cells, known as senolytics, can ameliorate or even revert pathological manifestations of senescence in numerous preclinical mouse disease models, including cancer models. However, translation of senolytic therapies to human disease is hampered by their suboptimal specificity for senescent cells and important toxicities that narrow their therapeutic windows. We have previously shown that the high levels of senescence‐associated lysosomal β‐galactosidase (SA‐β‐gal) found within senescent cells can be exploited to specifically release tracers and cytotoxic cargoes from galactose‐encapsulated nanoparticles within these cells. Here, we show that galacto‐conjugation of the BCL‐2 family inhibitor Navitoclax results in a potent senolytic prodrug (Nav‐Gal), that can be preferentially activated by SA‐β‐gal activity in a wide range of cell types. Nav‐Gal selectively induces senescent cell apoptosis and has a higher senolytic index than Navitoclax (through reduced activation in nonsenescent cells). Nav‐Gal enhances the cytotoxicity of standard senescence‐inducing chemotherapy (cisplatin) in human A549 lung cancer cells. Concomitant treatment with cisplatin and Nav‐Gal in vivo results in the eradication of senescent lung cancer cells and significantly reduces tumour growth. Importantly, galacto‐conjugation reduces Navitoclax‐induced platelet apoptosis in human and murine blood samples treated ex vivo, and thrombocytopenia at therapeutically effective concentrations in murine lung cancer models. Taken together, we provide a potentially versatile strategy for generating effective senolytic prodrugs with reduced toxicities.
Measurement concerns and agreement of environmental social governance ratings
Authors: Widyawati Luluk
Published: March 2020

Measurement quality of environmental, social, and governance (ESG) rating is important, considering the increasing interest in socially responsible investment. This paper examines the measurement quality of four ESG ratings. Comprehensive analysis of the ratings, including its dimensionality, reliability, and validity suggests that they have significantly different measurement construct and measurement concerns, despite some commonalities. This study also presents a novel approach to examine the convergence of ESG ratings by assessing the level of agreement. The results of interrater reliability analysis suggest that while the agreement between ESG scores is low, there is evidence of a low to moderate agreement of ESG rankings.
A life‐time of hazardous drinking and harm to health among older adults: findings from the Whitehall II prospective cohort study
Authors: Ng Fat Linda , Bell Steven , Britton Annie
Published: March 2020

Aims

To investigate associations of life‐time hazardous and binge drinking with biomarkers of cardiometabolic health, liver function, cardiovascular disease (CVD) and mortality.

Design

Prospective cohort study with median follow‐up time to CVD incidence of 4.5 years.

Setting

London, UK: civil servants within the Whitehall II Study.

Participants

A total of 4820 drinkers aged 59–83 years with biological measurements during the 2011–12 survey.

Measurements

Hazardous drinking was defined as having an AUDIT‐C score ≥ 5 calculated at each decade of life, forming the following groups: never hazardous drinker, former early (stopping before age 50), former later (stopping after age 50), current hazardous drinker and consistent hazardous drinker (hazardous drinker at each decade of life).

Findings

More than half the sample had been hazardous drinkers at some point during their life‐time, comprising former early (< age 50) (19%), former later (≥ age 50) (11%), current (21%) and consistent hazardous drinker (AUDIT‐C ≥ 5 across life (5%). After adjusting for covariates, waist circumference was larger with more persistent hazardous drinking (e.g. compared with never hazardous drinkers, former early had increased waist circumference by 1.17 cm [95% confidence interval (CI) = 0.25‐2.08]; former later by 1.88 cm (CI = 0.77–2.98); current by 2.44 cm (CI = 1.50–3.34) and consistent hazardous drinker by 3.85 cm (CI = 2.23–5.47). Current hazardous drinkers had higher systolic blood pressure (2.44 mmHg, CI = 1.19–3.68) and fatty liver index scores (4.05 mmHg, CI = 2.92–5.18) than never hazardous drinkers. Current hazardous drinkers [hazard ratio (HR) = 2.75, CI = 1.44–5.22) had an elevated risk of stroke, and former later hazardous drinkers had an elevated risk of non‐CVD mortality (HR = 1.93, CI = 1.19–3.14) than never hazardous drinkers. Life‐time binge drinking was associated with larger waist circumferences and poorer liver function compared with never binge drinkers.

Conclusion

Hazardous drinking may increase cardiometabolic risk factors; this is made worse by persistent hazardous drinking throughout life, particularly in relation to weight gain, suggesting benefits of early intervention.
Outcomes of older patients with primary central nervous system lymphoma treated in routine clinical practice in the UK: methotrexate dose intensity correlates with response and survival
Authors: Martinez‐Calle Nicolás , Poynton Edward , Alchawaf Alia , Kassam Shireen , Horan Matthew , Rafferty Mark , Kelsey Phillipa , Scott Gemma , Culligan Dominic J. , Buckley Hannah , Lim Yeong J. , Ngu Loretta , McCulloch Rory , Rowntree Clare , Wright Josh , McKay Pamela , Fourali Samih , Eyre Toby A. , Smith Jeffrey , Osborne Wendy , Yallop Deborah , Linton Kim , Fox Christopher P. , Cwynarski Kate
Published: March 2020

Data on older patients with primary central nervous system lymphoma (PCNSL) are scarce. Comorbidities and performance status frequently compromise outcomes in this group. Medical records for consecutive patients ≥65 years (n = 244) with PCNSL diagnosed 2012–2017 from 14 UK centres were retrospectively reviewed. Of these 192 patients received methotrexate (MTX)‐based treatment. Patients were categorised based on clinician's treatment choice into ‘palliative’ (n = 52), ‘less intensive: MTX ± rituximab ± alkylators’ (n = 74) and ‘intensive: MTX/cytarabine combinations’ (n = 118) groups. Complete remission (CR) rate, two‐year progression‐free survival (PFS) and overall survival (OS) rates were 49%, 11% and 24% for the less intensive and 69%, 40% and 50% for the intensive groups. Treatment‐related mortality (TRM) was 6·8% for MTX‐treated patients. Median MTX cumulative dose was 8·8 g/m2 (range 1·5–21) over a median of three cycles. Higher relative dose intensity of MTX (MTX‐RDI) was associated with improved PFS and OS in both groups adjusting for age, Eastern cooperative oncology group (ECOG) score and baseline parameters. Two‐year PFS and OS for patients receiving four or more induction cycles followed by consolidation (n = 36) were 65% and 70% respectively. Older patients completing MTX‐based induction and consolidation had clinical outcomes similar to those in younger cohorts. These retrospective data suggest that maximising MTX‐RDI and delivering consolidation in a subgroup of older patients may improve clinical outcomes.
FNDC3B 3′‐UTR shortening escapes from microRNA‐mediated gene repression and promotes nasopharyngeal carcinoma progression
Authors: Li Ying‐Qing , Chen Yang , Xu Ya‐Fei , He Qing‐Mei , Yang Xiao‐Jing , Li Ying‐Qin , Hong Xiao‐Hong , Huang Sheng‐Yan , Tang Ling‐Long , Liu Na
Published: March 2020

Alternative polyadenylation (APA), which induces shortening of the 3′‐UTR, is emerging as an important feature in cancer development and progression. Nevertheless, the effects and mechanisms of APA‐induced 3′‐UTR shortening in nasopharyngeal carcinoma (NPC) remain largely unclear. Fibronectin type III domain containing 3B (FNDC3B) tended to use proximal polyadenylation site and produce shorter 3′‐UTR according to our previous sequencing study. Herein, we found that FNDC3B with shorter 3′‐UTR could escape from miRNA‐mediated gene repression, and caused its increased expression in NPC. Knocking down of FNDC3B inhibited NPC cell proliferation, migration, invasion, and metastasis in vitro and in vivo. Overexpression of FNDC3B, especially those with shorter 3′‐UTR, promoted NPC progression. Furthermore, the mechanism study revealed that FNDC3B could bind to and stabilize myosin heavy chain 9 (MYH9) to activate the Wnt/β‐catenin signaling pathway. In addition, MYH9 could reverse the inhibitory effects of FNDC3B knockdown in NPC. Altogether, our results suggested that the 3′‐UTR shortening of FNDC3B mRNA mediated its overexpression in NPC and promoted NPC progression by targeting MYH9. This newly identified FNDC3B‐MYH9‐Wnt/β‐catenin axis could represent potential targets for individualized treatment in NPC.
Potential new therapy of Rapalink‐1, a new generation mammalian target of rapamycin inhibitor, against sunitinib‐resistant renal cell carcinoma
Authors: Kuroshima Kazuki , Yoshino Hirofumi , Okamura Shunsuke , Tsuruda Masafumi , Osako Yoichi , Sakaguchi Takashi , Sugita Satoshi , Tatarano Shuichi , Nakagawa Masayuki , Enokida Hideki
Published: March 2020

Sunitinib, a multitargeted receptor tyrosine kinase inhibitor including vascular endothelial growth factor, has been widely used as a first‐line treatment against metastatic renal cell carcinoma (mRCC). However, mRCC often acquires resistance to sunitinib, rendering it difficult to treat with this agent. Recently, Rapalink‐1, a drug that links rapamycin and the mTOR kinase inhibitor MLN0128, has been developed with excellent therapeutic effects against breast cancer cells carrying mTOR resistance mutations. The aim of the present study was to evaluate the in vitro and in vivo therapeutic efficacy of Rapalink‐1 against renal cell carcinoma (RCC) compared to temsirolimus, which is commonly used as a small molecule inhibitor of mTOR and is a derivative of rapamycin. In comparison with temsirolimus, Rapalink‐1 showed significantly greater effects against proliferation, migration, invasion and cFolony formation in sunitinib‐naïve RCC cells. Inhibition was achieved through suppression of the phosphorylation of substrates in the mTOR signal pathway, such as p70S6K, eukaryotic translation initiation factor 4E‐binding protein 1 (4EBP1) and AKT. In addition, Rapalink‐1 had greater tumor suppressive effects than temsirolimus against the sunitinib‐resistant 786‐o cell line (SU‐R 786‐o), which we had previously established, as well as 3 additional SU‐R cell lines established here. RNA sequencing showed that Rapalink‐1 suppressed not only the mTOR signaling pathway but also a part of the MAPK signaling pathway, the ErbB signaling pathway and ABC transporters that were associated with resistance to several drugs. Our study suggests the possibility of a new treatment option for patients with RCC that is either sunitinib‐sensitive or sunitinib‐resistant.
Reprograming the tumor immunologic microenvironment using neoadjuvant chemotherapy in osteosarcoma
Authors: Deng Chuangzhong , Xu Yanyang , Fu Jianchang , Zhu Xiaojun , Chen Hongmin , Xu Huaiyuan , Wang Gaoyuan , Song Yijiang , Song Guohui , Lu Jinchang , Liu Ranyi , Tang Qinglian , Huang Wenlin , Wang Jin
Published: March 2020

Tumor‐infiltrating immune cells play a crucial role in tumor progression and response to treatment. However, the limited studies on infiltrating immune cells have shown inconsistent and even controversial results for osteosarcoma (OS). In addition, the dynamic changes of infiltrating immune cells after neoadjuvant chemotherapy are largely unknown. We downloaded the RNA expression matrix and clinical information of 80 OS patients from the TARGET database. CIBERSORT was used to evaluate the proportion of 22 immune cell types in patients based on gene expression data. M2 macrophages were found to be the most abundant immune cell type and were associated with improved survival in OS. Another cohort of pretreated OS samples was evaluated by immunohistochemistry to validate the results from CIBERSORT analysis. Matched biopsy and surgical samples from 27 patients were collected to investigate the dynamic change of immune cells and factors before and after neoadjuvant chemotherapy. Neoadjuvant chemotherapy was associated with increased densities of CD3+ T cells, CD8+ T cells, Ki67 + CD8+ T cells and PD‐L1+ immune cells. Moreover, HLA‐DR‐CD33+ myeloid‐derived suppressive cells (MDSC) were decreased after treatment. We determined that the application of chemotherapy may activate the local immune status and convert OS into an immune “hot” tumor. These findings provide rationale for investigating the schedule of immunotherapy treatment in OS patients in future clinical trials.
Recent advances in understanding connexin gap junction pathology in demyelinating diseases
Authors: Masaki Katsuhisa
Published: March 2020

Multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) and Baló’s disease (BD) are inflammatory demyelinating diseases of the central nervous system. We previously reported that aquaporin‐4 antibody‐independent astrocytopathy can occur in heterogeneous demyelinating conditions. We focused on connexins (Cxs), which form gap junctions between astrocytes and oligodendrocytes to form the glial syncytium of the central nervous system. We investigated the pathological expression pattern of Cx43/Cx30 in astrocytes, and Cx47/Cx32 in oligodendrocytes in autopsied samples from MS, NMOSD and BD. Astrocytic Cx43 and oligodendrocytic Cx32/Cx47 were extensively diminished in both demyelinated and myelinated layers in all BD cases. Half of the NMOSD and MS cases showed preferential loss of astrocytic Cx43 in active demyelinating and chronic active lesions, where heterotypic Cx43/Cx47 astrocyte‐oligodendrocyte gap junctions were widely lost. Loss of Cx43 was frequently accompanied by distal oligodendrogliopathy, which is characterized by a preferential loss of myelin‐associated glycoprotein and apoptotic‐like oligodendrocytes. Isolated perivascular lesions in the spinal cord of NMOSD cases showed loss of aquaporin‐4 and Cx43, indicating early involvement of Cx43 in NMOSD. Neuronal and glial Cxs were affected in gray matter demyelination in MS and neurodegenerative diseases. Our findings show that Cx43 astrocytopathy and Cx47/Cx32 oligodendrogliopathy can be seen in MS, BD and NMOSD. Furthermore, the loss of astrocytic Cx43 might be associated with disease aggressiveness and distal oligodendrogliopathy in demyelinating conditions. Early disruption of glial gap junctions might disturb the glial syncytium and disrupt intercell communication, thereby inducing oligodendroglial injury and subsequent demyelination.
Beyond ‘developmentalism’: A relational and embodied approach to young children's development
Authors: Gabriel Norman
Published: March 2020

This article begins by discussing ‘developmentalism’, one of the key debates that has characterised the current theoretical impasse in the development of childhood studies. I use Norbert Elias's concept of the relation between love and learning as a foundation to develop the way in which young children's development is a non‐linear, temporal and embodied process. I argue that we need to develop a relational approach that moves beyond some of the binary divisions between ‘nature’ and ‘biology’, drawing on concepts from particular theoretical traditions that have been under‐utilised, particularly the relational school of psychoanalysis and the work of Maurice Merleau‐Ponty.