bluuebunny/crossref_metadata_2025 huggingface dataset:
Synaptomic analysis of dopaminergic inputs reveal hub synapses in the mouse striatum
Authors: Paget-Blanc Vincent , Pfeffer Marlene E. , Pronot Marie , Lapios Paul , Angelo Maria-Florencia , Walle Roman , Cordelières Fabrice P. , Levet Florian , Claverol Stéphane , Lacomme Sabrina , Petrel Melina , Martin Christelle , Pitard Vincent , Desmedt-Peyrusse Véronique , Biederer Thomas , Perrais David , Trifilieff Pierre , Herzog Etienne
Published: February 2020

Dopamine is a monoamine involved in reward processing and motor control. Volume transmission is thought to be the mechanism by which monoamines modulate effector systems at glutamate and GABA synapses. Hence, dopamine synapses are scarcely described. We applied fluorescence activated synaptosome sorting to explore the features of the dopaminergic synaptome. We provide the proteome of striatal dopaminergic synapses with 57 proteins specifically enriched. Beyond canonical markers of dopamine neurotransmission (Th, Slc6a3/DAT, Slc18a2/VMAT2), we validated 6 proteins belonging to pre- and postsynaptic sides (Cpne7, Apba1/Mint1, Cadps2, Cadm2/SynCAM 2, Stx4 and Mgll). Moreover, dopaminergic varicosities adhere to both a post-synapse with cognate receptors and glutamatergic, GABAergic or cholinergic synapses in structures we named dopaminergic “hub synapses”. Markers of presynaptic vesicles and active zone, post-synaptic density and spine apparatus, are significantly increased upon association with dopamine inputs in hubs. Thus neuromodulation frequently operates from hub synapses affecting associated synapses and is not solely dependent on volume transmission. Finally, FASS provides a new framework for the exploration of dopaminergic synapses and more generally for discrete synapse populations ex-vivo.

Highlights

A first proteome of dopaminergic synapses in the striatum

Striatal dopaminergic synaptosomes display post-synaptic cognate receptors

Dopaminergic projections build hub synapses with excitatory, inhibitory, and cholinergic projections.

Cortico-striatal synaptic scaffolds are strengthened upon association in hub synapses.
G protein-Coupled Receptor Distribution Impacts the Effectiveness of Signal Transmission
Authors: Zhou Ming-Yi , Hu Ya-Yu , Chuang Huai-Hu
Published: February 2020

Numbers of activated receptor dictate efficacy of neurotransmitter stimulation. Many PLC coupled receptors activated by ligands elicit canonical downstream Gq/11 pathway to induce endogenous Ca2+gated chloride channels. The coupling from receptors to effectors was analyzed inXenopusoocytes expressing genetically modified angiotensin receptor type 1 receptor (AT1R). The latency between ATII binding and Ca2+-induced Cl−current surge was inversely correlated. AT1R activation triggered a chain of chemical reactions, of which the products were playing messengers for subsequent events. Messenger accumulation must rate-limit the agonism. For accurate quantification the speed of ATII triggered theiCl−. The T-form AT1R-IRK1 fusion exhibits faster induction compared to the M-form. The latency of the recorded none vanishediCl−, marking the lowest genuine calcium activation, took place at earlier time point by the timer time. The evokediCl−however reached similar maximal amplitudes. This kinetic effect raises the possibility to use temporal coding to complement amplitude coding (analogous to FM versus AM radio transmission) for receptor-agonist pairs.
Inhibitory neurons are a Central Controlling regulator in the effective cortical microconnectome
Authors: Kajiwara Motoki , Nomura Ritsuki , Goetze Felix , Akutsu Tatsuya , Shimono Masanori
Published: February 2020

The brain is a network system in which excitatory and inhibitory neurons keep the activity balanced in the highly non-uniform connectivity pattern of the microconnectome. It is well known that the relative percentage of inhibitory neurons is much smaller than excitatory neurons. So, in general, how the inhibitory neurons can keep the balance with the surrounding excitatory neurons is an important question.

We observed effective networks, reflecting causal interactions, of ~1000 neurons in cortical acute slices. Surprisingly, we found that inhibitory neurons are not only located at more central positions than excitatory neurons but also have stronger controlling ability of other neurons than excitatory neurons. Besides, we found that the precedence in centrality and controlling ability of inhibitory neurons are well observed in deep cortical layers by comparing with distribution of neurons coloured by NeuN immunostaining data. Preceding the observation, we also found that inhibitory neurons show higher firing rate than excitatory neurons, and that their firing rate also closely obey a log-normal distribution as previously known about excitatory neurons. Additionally, their connectivity strengths also obeyed a log-normal distribution.

In summary, within the network interaction of huge numbers of neurons, inhibitory neurons seem to produce a central controlling system that sustains the homeostatic behavior of the brain. A similar evaluation in different life stages and in disease statesetc.will not only provide deeper understandings in the homeostasis of the brain, but also will provide a selective and effective way to stimulate individual neurons to modulate neuropsychiatry or neurodegeneration disease states.
Cardiorespiratory fitness and mnemonic discrimination across the adult lifespan
Authors: Nauer Rachel K. , Schon Karin , Stern Chantal E.
Published: February 2020

With a rising aging population, it is important to develop behavioral tasks that assess and track cognitive decline, and to identify protective factors that promote healthy brain aging. Mnemonic discrimination tasks that rely on pattern separation mechanisms are a promising metric to detect subtle age-related memory impairments. Behavioral performance on these tasks rely on the integrity of the hippocampus and surrounding circuitry, which are brain regions known to be adversely affected in aging and neurodegenerative disorders. Aerobic exercise, which improves cardiorespiratory fitness (CRF), has been shown to counteract aging-related decreases in structural and functional brain integrity and attenuate decline of cognitive performance. Here, we tested the hypothesis that higher CRF attenuates age-related deficits in mnemonic discrimination in both a nonspatial mnemonic discrimination (Mnemonic Similarity Task) and a virtual navigation task (Route Disambiguation Task). Importantly, we included individuals across the lifespan (aged 18–83 yr), including the middle-age range, to determine mnemonic discrimination performance across adulthood. Participants completed two mnemonic discrimination tasks and a treadmill test to assess CRF. Our results demonstrate robust negative age-related effects on mnemonic discrimination performance across both the nonspatial and spatial domains. Critically, higher CRF mitigated age-related attenuation in spatial contextual discrimination task performance, but did not show an attenuation effect on performance for object-based mnemonic discrimination. These results suggest that performance on spatial mnemonic discrimination may be a useful tool to track vulnerability in older individuals at risk for cognitive decline, and that higher CRF may lead to cognitive preservation across the adult lifespan, particularly for spatial disambiguation of similar contexts.
An in situ synchrotron study of the localized B2↔B19′ phase transformation in an Ni–Ti alloy subjected to uniaxial cyclic loading–unloading with incremental strains
Authors: Bian Xiaohui , Saleh Ahmed A. , Lynch Peter A. , Davies Christopher H. J. , Gazder Azdiar A. , Pereloma Elena V.
Published: February 2020

High-resolution in situ synchrotron X-ray diffraction was applied to study a cold-drawn and solution-treated 56Ni–44Ti wt% alloy subjected to uniaxial cyclic loading–unloading with incremental strains. The micro-mechanical behaviour associated with the partial and repeated B2↔B19′ phase transformation at the centre of the sample gauge length was studied with respect to the macroscopic stress–strain response. The lattice strains of the (110)B2 and different B19′ grain families are affected by (i) the transformation strain, the load-bearing capacity of both phases and the strain continuity maintained at/near the B2–B19′ interfaces at the centre of the gauge length, and (ii) the extent of transformation along the gauge length. With cycling and incremental strains (i) the elastic lattice strain and plastic strain in the remnant (110)B2 grain family gradually saturate at early cycles, whereas the plastic strain in the B19′ phase continues to increase. This contributes to accumulation of residual strains (degradation in superelasticity), greater non-linearity and change in the shape of the macroscopic stress–strain curve from plateau type to curvilinear elastic. (ii) The initial 〈111〉B2 fibre texture transforms to [120]B19′, [130]B19′, [150]B19′ and [010]B19′ orientations. Further increase in the applied strain with cycling results in the development of [130]B19′, [102]B19′, [102]B19′, [100]B19′ and [100]B19′ orientations.
Crystal structure, characterization and Hirshfeld analysis of bis{(E)-1-[(2,4,6-tribromophenyl)diazenyl]naphthalen-2-olato}copper(II) dimethyl sulfoxide monosolvate
Authors: Chetioui Souheyla , Bougueria Hassiba , Brihi Ouarda , Boutebdja Mehdi , Bouroumane Nadia , Merazig Hocine , Touzani Rachid
Published: February 2020

In the title compound, [Cu(C16H8Br3N2O)2]·C2H6OS, the CuII atom is tetracoordinated in a square-planar coordination, being surrounded by two N atoms and two O atoms from two N,O-bidentate (E)-1-[(2,4,6-tribromophenyl)diazenyl]naphthalen-2-olate ligands. The two N atoms and two O atoms around the metal center are trans to each other, with an O—Cu—O bond angle of 177.90 (16)° and a N—Cu—N bond angle of 177.8 (2)°. The average distances between the CuII atom and the coordinated O and N atoms are 1.892 (4) and 1.976 (4) Å, respectively. In the crystal, complexes are linked by C—H...O hydrogen bonds and by π–π interactions involving adjacent naphthalene ring systems [centroid–centroid distance = 3.679 (4) Å]. The disordered DMSO molecules interact weakly with the complex molecules, being positioned in the voids left by the packing arrangement of the square-planar complexes. The DMSO solvent molecule is disordered over two positions with occupancies of 0.70 and 0.30.
Exploring the relationship between ICT, SCM practices and organizational performance in agri-food supply chain
Authors: Kumar Anil , Singh Rohit Kr , Modgil Sachin
Published: February 2020

Purpose

This paper presents the concerns in agri-food supply chain. Further the research investigates the role of information and communication technology (ICT) in agri-food supply chain and determines the impact of supply chain management (SCM) practices on firm performance.

Design/methodology/approach

The theoretical framework was proposed for the study on the basis of existing literature. Data for the study was collected with the help of structured questionnaire from 121 executives and officers of the public food distribution agency. Partial least square (PLS)–structured equation modeling was employed to test the framework and hypotheses.

Findings

The results indicate that ICT and SCM practices (logistics integration and supplier relationships) have a significant relationship. Furthermore, SCM practices (information sharing, supplier relationship and logistics integration) have a significant and positive impact on performance of the organization.

Research limitations/implications

Further research could be carried out to test the moderation effect of SCM practices between ICT and organizational performance (OP). Extending the research study to the companies operating in other sectors can enhance the external validity of the study and improve the accuracy of parameters examined.

Practical implications

This study can be of interest to the agri-food industry as well as other industry practitioners interested in improving the performance of the organization from the view of supply chain.

Originality/value

The outcomes of this study have important implications that translate into a series of recommendations for the management of public food distribution as well as other agri-food-based supply chains.
A thematic analysis of the quality audit reports in developing a framework for assessing the achievement of the graduate attributes
Authors: Halibas Alrence Santiago , Mehtab Shameena , Al-Attili Alaa , Alo Benjamin , Cordova Ronald , Cruz Maria Elisa Linda Taeza
Published: February 2020

Purpose

Graduates are expected to possess the knowledge and right skillset, commonly known as graduate attributes, which they need to become employable and work-ready. This study describes the approaches that were employed by an academic institution in developing an assessment framework for measuring the student achievement of the graduate attributes and learning outcomes.

Design/methodology/approach

It used thematic analysis in analyzing the 43 audit reports of higher educational institutions (HEIs) in Oman which have undergone the regional quality audit as well as the outcomes of the institutional standards assessment.

Findings

The analysis exposed the critical issues necessary for embedding graduate attributes and learning outcomes in higher education. Likewise, the study revealed that the assessment of the graduate attributes (GAs) and learning outcomes (LOs) is the area that garnered the most number of comments from the audit panel, and 69 per cent of the HEIs are still problematic in this area. Moreover, most of the HEIs in Oman lack the mechanisms to assess student learning as evidenced in the regional accreditation outcomes. Only 43.8 per cent of the HEIs, which have undergone the institutional accreditation process, have garnered a Met Rating in the Graduate Attributes and Student Learning Outcome criterion. Hence, this study presupposes its high relevance and usefulness to the work in this area, drawing from the experience of an HEI in Oman.

Practical implications

This study will present the relevant and meaningful content, especially good practices and potential gaps that inform HEIs regarding the current trends, policies, and practices relevant to the assessment of graduate attributes and learning outcomes in higher education.

Originality/value

This study extends the limited literature on the assessment of graduate attributes and learning outcomes, especially among the HEIs in Oman.
An exploration of sensory processing patterns and their association with demographic factors in healthy adults
Authors: Machingura Tawanda , Kaur Gurjeet , Lloyd Chris , Mickan Sharon , Shum David , Rathbone Evelyne , Green Heather
Published: February 2020

Purpose

Previous research has provided limited evidence on whether and how demographic factors associate with sensory processing patterns (SPP) in adults. This paper aims to examine relationships between SPPs and sociodemographic factors of age, sex, education and ethnicity in healthy adults.

Design/methodology/approach

A cross-sectional study design was used. A total of 71 adult participants was recruited from the community, using convenience sampling. Each participant completed the Adolescent/Adult Sensory Profile (AASP) and the Depression Anxiety Stress Scales – short version (DASS-21). Demographic information on age, sex, education and ethnicity was collected. Results were analysed using descriptive statistics and multivariate analyses of covariance (MANCOVA).

Findings

SPPs, as measured by the AASP, were significantly correlated to demographic factors of age and education after controlling for emotional distress using the DASS-21. A statistically significant multivariate effect was found across the four dependent variables (low registration, seeking, sensitivity and avoiding) for the age category, F = 6.922, p = 0.009,

ηp2 = 0.145, in the presence of a covariate DASS. The education category showed significance only in the seeking domain (p = 0.008,

ηp2 = 0.10) after controlling for DASS. There was no significant correlation between SPPs and gender or ethnicity. Results also indicated that mean scores of participants in this study were “similar to most people” as standardised in the AASP.

Research limitations/implications

This was a cross-sectional study with limitations including that the study used a relatively small sample and was based on self-reported healthy participants.

Practical implications

SPPs may correlate with healthy adults’ age and to a lesser extent education. This suggests that it might be helpful to consider such demographic factors when interpreting SPPs in clinical populations, although further research in larger samples is needed to reach firmer conclusions about possible implications of demographic variables.

Originality/value

The findings in this paper add to the growing evidence that suggest that SPPs vary with sociodemographic factors.
The red thread of information
Authors: Hartel Jenna
Published: February 2020

Purpose

In The Invisible Substrate of Information Science, a landmark article about the discipline of information science, Marcia J. Bates wrote that “…we are always looking for the red thread of information in the social texture of people's lives” (1999a, p. 1048). To sharpen our understanding of information science and to elaborate Bates' idea, the work at hand answers the question: Just what does the red thread of information entail?

Design/methodology/approach

Through a close reading of Bates' oeuvre and by applying concepts from the reference literature of information science, nine composite entities that qualify as the red thread of information are identified, elaborated, and related to existing concepts in the information science literature. In the spirit of a scientist–poet (White, 1999), several playful metaphors related to the color red are employed.

Findings

Bates' red thread of information entails: terms, genres, literatures, classification systems, scholarly communication, information retrieval, information experience, information institutions, and information policy. This same constellation of phenomena can be found in resonant visions of information science, namely, domain analysis (Hjørland, 2002), ethnography of infrastructure (Star, 1999), and social epistemology (Shera, 1968).

Research limitations/implications

With the vital vermilion filament in clear view, newcomers can more easily engage the material, conceptual, and social machinery of information science, and specialists are reminded of what constitutes information science as a whole. Future researchers and scientist–poets may wish to supplement the nine composite entities with additional, emergent information phenomena.

Originality/value

Though the explication of information science that follows is relatively orthodox and time-bound, the paper offers an imaginative, accessible, yet technically precise way of understanding the field.
Information encountering re-encountered
Authors: Erdelez Sanda , Makri Stephann
Published: February 2020

Purpose

In order to understand the totality, diversity and richness of human information behavior, increasing research attention has been paid to examining serendipity in the context of information acquisition. However, several issues have arisen as this research subfield has tried to find its feet; we have used different, inconsistent terminology to define this phenomenon (e.g. information encountering, accidental information discovery, incidental information acquisition), the scope of the phenomenon has not been clearly defined and its nature was not fully understood or fleshed-out.

Design/methodology/approach

In this paper, information encountering (IE) was proposed as the preferred term for serendipity in the context of information acquisition.

Findings

A reconceptualized definition and scope of IE was presented, a temporal model of IE and a refined model of IE that integrates the IE process with contextual factors and extends previous models of IE to include additional information acquisition activities pre- and postencounter.

Originality/value

By providing a more precise definition, clearer scope and richer theoretical description of the nature of IE, there was hope to make the phenomenon of serendipity in the context of information acquisition more accessible, encouraging future research consistency and thereby promoting deeper, more unified theoretical development.
Uncomfortable in my own skin – emerging, early-stage identity-related information needs of transgender people
Authors: Huttunen Aira , Hirvonen Noora , Kähkönen Lotta
Published: February 2020

Purpose

This study aims to increase the understanding of the early-stage identity-related information needs of transgender people.

Design/methodology/approach

This study draws on social constructivism, queer theory and information practice research. In accordance with the queer phenomenological approach which emphasises lived experiences, data was collected by interviewing 25 individuals who identified as transgender. The data was analysed with a focus on how early-stage information needs are formed into conscious information needs.

Findings

The formation of early-stage information needs were conceptualised as a chain including a trigger for information seeking, finding the right words and understanding the experience. Especially the bodily changes starting at puberty were strong causes of discomfort causing friction between the subjects' own gendered body and their gender experience, even leading to gender dysphoria. Finding words to describe the experience played an important role in the process of identity formation. In many cases this was difficult because of the lack of accurate and relevant information.

Social implications

Providing information especially of varying transgender experiences is vital for individuals trying to understand and verbalise their gender identity.

Originality/value

This study provides an understanding of the early-stage information needs described by transgender people and the process of building identities through disorientation. This study suggests that early-stage information needs are a valid concept to help understand how embodied experiences and the friction between the lived experience and the social world can lead to information seeking.
The impact of labor market freedom on state-level in-migration in the US
Authors: Cebula Richard J. , Duquette Christopher M. , Jolley G. Jason
Published: February 2020

Purpose

Influences on the pattern of internal migration in the US, including economic factors, quality-of-life factors and public policy variables have been extensively studied by regional scientists since the early 1970s. Interestingly, a small number of studies also address the effects of economic freedom on migration. The purpose of this paper is to add to the migration literature by examining the impact of labor market freedom on both gross and net state in-migration over the study period 2008–2016.

Design/methodology/approach

This study uses dynamic panel data analysis to investigate the impact of labor market freedom on both gross and net state in-migration over the study period 2008–2016.

Findings

The panel generalized method of moments analysis reveals that overall labor market freedom exercised a positive and statistically significant impact on both measures of state in-migration over the study period. The study finds a 1 percentage point increase in the overall labor market freedom index results in a 2.8 percent increase in the gross in-migration rate.

Research limitations/implications

The findings imply states interested in attracting migrants and stimulating economic growth should pursue policies consistent with increased labor freedom.

Originality/value

The emphasis in the present study is on the impact of labor market freedom on state-level in-migration patterns, both gross and net, over a contemporary time period that includes both the Great Recession and subsequent recovering.
Yoga for anxiety and depression – a literature review
Authors: Nanthakumar Chandra
Published: February 2020

Purpose

The purpose of this paper is to investigate the effectiveness of classical yoga not only as a complementary therapy but also as a viable option in the management of anxiety and depression.

Design/methodology/approach

Papers were retrieved using a combination of databases including PubMed/MEDLINE and PsycINFO.

Findings

The findings revealed that the practice of yoga as complementary therapy and also as a stand-alone therapy is effective in managing and reducing anxiety and depression.

Research limitations/implications

All the studies reviewed in this paper were methodologically limited in terms of sample size, sample heterogeneity, yoga intervention styles, duration of practice and teaching methods. Further research is needed to address key areas such as how much yoga is needed per week, duration of each class and specifically the types of asanas and pranayama to practise to bring about change in the anxiety and depressive states.

Practical implications

This review has provided substantial insight to yoga as a complementary and/or stand-alone therapy for anxiety and depression which is much needed in this contemporary society. The Malaysian community especially teenagers and adults, should consider incorporating yoga as part of their daily routine to experience and reap its benefits. It is suggested that yoga be included as part of the physical education curriculum in learning institutions and as a recreational activity for staff in public and private organisations.

Originality/value

The findings of this review provide an avenue for victims to cope with and manage anxiety and depression through the practice of yoga.
Experiments and evaluation of public policies: Methods, implementation, and challenges
Authors: Jensen Paul H.
Published: February 2020

Evidence‐based policymaking is all about developing and implementing better public policies. Although the logic underpinning this philosophy is simple, the practicalities of demonstrating causal effects of a public policy are much more complex. In recent years, there has been a wave of optimism about the usefulness of experimental approaches to public policy evaluation which mimics the clean, causal inferences observed in clinical trials. Although these methods, such as randomised controlled trials, have been widely advocated and implemented, they are not without their potential problems. In this paper, we consider the strengths, weaknesses, and challenges posed by the revolution in policy evaluation brought about by embracing experimental methods.
Financing Local Police Spending in England and Wales: Fiscal Federalism in Practice
Authors: Crawford Rowena , Disney Richard , Simpson Polly
Published: February 2020

Since 1995, police forces in England and Wales have been able to raise revenues locally to supplement grants from central government. We analyse the variation across police force areas in locally raised police revenues over the 2000s, and we find that three‐quarters of the temporal and spatial variation in local revenues per head can be explained by differences in incomes, prices and local preferences. A particularly robust parameter is the effective local community tax price associated with raising revenue. We discuss the police funding model in the wider context of fiscal federalism, and we point to alternative funding structures that could be adopted.
Effects of adding solid and molten chocolate on the physicochemical, antioxidant, microbiological, and sensory properties of ewe's milk cheese
Authors: Ashkezary Mansour Rabie , Bonanno Adriana , Todaro Massimo , Settanni Luca , Gaglio Raimondo , Todaro Aldo , Alabiso Marco , Maniaci Giuseppe , Mazza Francesca , Grigoli Antonino Di
Published: February 2020

A novel dairy product, namely “chocolate cheese”, was produced with two typical Sicilian food products: Pecorino cheese, processed from ewe's milk, and Modica chocolate. The cheese, manufactured with 0%, 5%, 10%, and 15% (w/w) solid or molten chocolate, was evaluated after 0, 2, 4, and 6 weeks of vacuum storage for its nutritional and health properties. The addition of chocolate reduced the pH, protein, fat, and ash; the addition of 5% or 10% molten chocolate reduced hardness (N/mm2). The addition of either solid or molten chocolate resulted in a slight increase (P < 0.1038) in the total polyphenol content, a higher oleic acid content, and less oxidative stability. The microbiological profile showed that the total mesophilic count and the number of mesophilic coccus lactic acid bacteria (LAB) were approximately equal (about 108 CFU/g) in all cheese. The survival of the microorganisms was affected by both the chocolate added and the storage time. Chocolate cheese stored for 6 weeks had less Enterobacteriaceae than control cheese, whereas yeasts were detected at higher cell densities in the former cheese. Filamentous fungi were undetectable in some cheese. Differences were also observed in the number of mesophilic rod LAB, which increased progressively over time in all cheese, and in Enterobacteriaceae, yeasts, and filamentous fungi, which decreased during storage. Descriptive and hedonic sensory tests and principal component analysis showed that fresh cheese and cheese stored for 2 weeks, including 5% molten chocolate, were the most preferred by evaluators. Based on these results, chocolate cheese has the potential to be appreciated in the market for its nutritional, health, and sensory properties.

Practical Application

Chocolate cheese, made by combining two typical Sicilian foods, Pecorino cheese and Modica chocolate, is proposed as a novel dairy product. The highest sensory acceptance was obtained with the addition of 5% molten chocolate and storage for 2 weeks. Given its improved antioxidant properties, healthier fat, and sensory properties, chocolate cheese has the potential to be appreciated in the market, especially by young consumers.
Different administration routes of recombinant human endostatin combined with concurrent chemoradiotherapy might lead to different efficacy and safety profile in unresectable stage III non‐small cell lung cancer: Updated follow‐up results from two phase II trials
Authors: Honglian Ma , Zhouguang Hui , Fang PENG , Lujun Zhao , Dongming Li , Yujin Xu , Yong Bao , Liming Xu , Yirui Zhai , Xiao Hu , Jin Wang , Yue Kong , Lvhua Wang , Ming Chen
Published: February 2020

Background

There are two main choices of administration route of recombinant human endostatin (Endostar) available and the treatment options of concurrent chemoradiotherapy (CCRT) have changed over time. The aim of this study was to observe the long‐term efficacy and safety of different administration routes of Endostar combined with CCRT.

Methods

Patients with unresectable stage III non‐small cell lung cancer (NSCLC) from two phase II trials were included as two cohorts. Both were treated with Endostar combined with CCRT. Endostar was administrated by intravenous injection (7.5 mg/m2/day, seven days) in the IV arm and by continuous intravenous pumping (7.5 mg/m2/24 hours, 120 hours) in the CIV arm.

Results

A total of 48 patients were included in the IV arm and 67 patients in the CIV arm. The median progression‐free survival (PFS), overall survival (OS), local recurrence‐free survival (LRFS) and distant metastasis‐free survival (DMFS) in the IV arm and CIV arm were 9.9 months versus 15.4 months (HR = 0.751, 95% CI 0.487–1.160, P = 0.200), 24.0 months versus 38.5 months (HR = 0.746, 95% CI 0.473–1.178, P = 0.209), 32.3 months versus 27.1 months (HR = 1.193, 95% CI 0.673–2.115, P = 0.546), 20.1 months versus 49.7 months (HR = 0.603, 95% CI 0.351–1.036, P = 0.067). The one, three, five‐year PFS in the IV arm and CIV arm was 45.8% versus 52.9%, 18.3% versus 31.4%, and 18.3% versus 27.7% and the one, three, five‐year OS was 81.2% versus 82.1%, 31.1% versus 50.3%, and 31.1% versus 41%, respectively. Incidence of hematological adverse reactions were numerically lower in the CIV arm than the IV arm.

Conclusions

Endostar delivered by CIV with CCRT may be a better option than IV in terms of potential survival and safety for unresectable stage III NSCLC.

Key points

Significant findings of the study Endostar delivered by continuous intravenous pumping might achieve more favorable survival over intravenous injection and reduce adverse hematological reactions in patients with unresectable stage III NSCLC treated with Endostar combined with CCRT.What this study adds The administration route of recombinant human endostatin is also one key factor for survival and safety to consider when treating patients with unresectable stage III NSCLC.
Class A CpG oligodeoxynucleotide inhibits IFN‐γ‐induced signaling and apoptosis in lung cancer
Authors: Teranishi Shuhei , Kobayashi Nobuaki , Katakura Seigo , Kamimaki Chisato , Kubo Sousuke , Shibata Yuji , Yamamoto Masaki , Kudo Makoto , Piao Hongmei , Kaneko Takeshi
Published: February 2020

Background

Currently, anticancer immunotherapy based on PD‐1/PD‐L1 blockade with immune checkpoint inhibitors (ICIs) is being used as a standard therapy for non‐small cell lung cancer (NSCLC). However, more effective treatments are required as these tumors are often resistant and refractory. Here, we aimed to determine the effects of immunomodulatory oligodeoxynucleotides (ODNs) in terms of the presence or absence of CpG motifs and the number of consecutive guanosines.

Methods

Western blots were used to measure the molecules which regulate the expression of PD‐L1 in human lung cancer cell lines after incubation with several cytokines and ODNs. The expression of PD‐L1 and β2‐microglobulin (β2‐MG) on A549 cells, and IFN‐γ‐induced apoptosis with ODNs were examined by flow cytometry. The relationship between IFN‐γ receptor and ODN was analyzed by ELISA and immunofluorescence chemistry.

Results

Our results verified that A‐CpG ODNs suppress the upregulation of IFN‐γ‐induced PD‐L1 and β2‐MG expression. In addition, we found that ODNs with six or more consecutive guanosines (ODNs with poly‐G sequences) may competitively inhibit the IFN‐γ receptor and abolish the effect of IFN‐γ, thereby suppressing apoptosis and indoleamine 2,3‐dioxygenase 1 expression in human lung cancer cells. The tumor microenvironment regulates whether this action will promote or suppress tumor immunity. Thus, in immunotherapy with CpG ODNs, it is essential to consider the effect of ODNs with poly‐G sequences.

Conclusions

This study suggests that ODNs containing six or more consecutive guanosines may inhibit the binding of IFN‐γ to IFN‐γ receptor. However, it does not directly show that ODNs containing six or more consecutive guanosines competitively inhibit the IFN‐γ receptor, and further studies are warranted to confirm this finding.

Key points

Significant findings of the study: Oligodeoxynucleotides with a contiguous sequence of six or more guanosines may competitively inhibit the IFN‐γ receptor and abolish the action of IFN‐γ. This may suppress IFN‐γ‐induced apoptosis and indoleamine‐2,3‐dioxygenase‐1 expression in human lung cancer cells.

What this study adds: A‐CpG and poly‐G ODN may overcome tolerance if the cause of ICI tolerance is high IDO expression. However, IFN‐γ also has the effect of suppressing apoptosis of cancer cells, and it is necessary to identify the cause of resistance.
Severe hepatotoxicity due to osimertinib after nivolumab therapy in patients with non‐small cell lung cancer harboring EGFR mutation
Authors: Yamaguchi Ou , Kaira Kyoichi , Kawasaki Tomonori , Mouri Atsuto , Hashimoto Kosuke , Shiono Ayako , Shinomiya Shun , Miura Yu , Nishihara Fuyumi , Murayama Yoshitake , Kobayashi Kunihiko , Mochida Satoshi , Kagamu Hiroshi
Published: February 2020

Background

Osimertinib is the most promising treatment option for patients with epidermal growth factor receptor (EGFR) mutation‐positive non‐small cell lung cancer (NSCLC) with acquired T790M resistance. However, recent studies have suggested that osimertinib could increase the frequency of serious adverse events (AEs) if administered immediately after immune checkpoint inhibitor (ICI) treatment.

Methods

In this single‐institution retrospective study conducted from May 2016 to January 2019, osimertinib was administered to 47 patients with pretreated advanced NSCLC harboring the EGFR mutation.

Results

Of the 47 patients, 20 (42.6%) were men and 27 (57.4%) were women. The median age was 71 years (range 37–83 years). A total of 19 patients (40.4%) had a smoking history. Furthermore, seven patients (14.9%) received osimertinib immediately after nivolumab therapy, while 40 patients (85.1%) were treated with osimertinib after treatment with drugs other than nivolumab. The frequency of grade 3 or 4 hepatotoxicity was significantly higher in patients with nivolumab prior to osimertinib (4/7; 57.1%) than in those treated with drugs other than nivolumab prior to osimertinib (2/40; 5.0%) (P = 0.0026). Liver biopsies were performed in two patients who received osimertinib immediately after nivolumab. In both patients, CD‐8‐positive T cell infiltration was predominantly observed in the liver tissues.

Conclusions

The use of osimertinib immediately after nivolumab significantly increased the frequency of grade 3 or higher hepatotoxicity in patients with advanced NSCLC harboring EGFR mutation acquired T790M resistance.
Prolonging seedling age does not reduce grain yields in machine‐transplanted early‐season rice under precision sowing
Authors: Huang Min , Fang Shengliang , Cao Fangbo , Chen Jiana , Shan Shuanglü , Liu Yu , Lei Tao , Tian Alin , Tao Zui , Zou Yingbin
Published: February 2020

High seed sowing rates have shortened seedling age in conventional machine‐transplanted rice, which has become a challenge for intensive rice production in China. This study aimed to test our hypothesis that prolonging seedling age may not lead to reduced yield in machine‐transplanted early‐season rice under precision sowing. Field experiments were conducted with two cultivars in 2 years to determine the effect of prolonging seedling age on seedling traits, grain yield, and yield attributes in machine‐transplanted early‐season rice with printed sowing (a new precision sowing method). All tested seedling traits, including height, basal width, leaf and root number, and shoot and root biomass, were significantly increased when seedling age was prolonged from 20 days (a commonly recommended seedling age for conventional machine transplanting) to 30 days. The prolonged seedling age did not significantly affect grain yield, yield components, or biomass production and translocation. These results support our hypothesis and suggest that adopting precision sowing is a feasible way to prolong seedling age of machine‐transplanted early‐season rice.
General Anesthetic Exposure During Early Adolescence Persistently Alters Ethanol Responses
Authors: Landin Justine D. , Gore‐Langton Jonathan K. , Varlinskaya Elena I. , Spear Linda P. , Werner David F.
Published: February 2020

Background

Adolescent alcohol abuse can lead to behavioral dysfunction and chronic, relapsing alcohol use disorder (AUD) in adulthood. However, not all adolescents that consume alcohol will develop an AUD; therefore, it is critical to identify neural and environmental risk factors that contribute to increases in susceptibility to AUDs following adolescent alcohol (ethanol [EtOH]) exposure. We previously found that adolescent anesthetic exposure led to strikingly similar behavioral and neural effects as adolescent alcohol exposure. Therefore, we tested the hypothesis that general anesthetic exposure during early adolescence would alter EtOH responses consistent with an exacerbation of the adolescent alcohol phenotype.

Methods

To test this hypothesis, early‐adolescent male Sprague‐Dawley rats were exposed for a short duration to the general anesthetic isoflurane and tested on multiple EtOH‐induced behaviors in mid‐late adolescence or adulthood.

Results

Adolescent rats exposed to isoflurane exhibited decreases in sensitivity to negative properties of EtOH such as its aversive, hypnotic, and socially suppressive effects, as well as increases in voluntary EtOH intake and cognitive impairment. Select behaviors were noted to persist into adulthood following adolescent isoflurane exposure. Similar exposure in adults had no effects on EtOH sensitivity.

Conclusions

This study demonstrates for the first time that early‐adolescent isoflurane exposure alters EtOH sensitivity in a manner consistent with an exacerbation of adolescent‐typical alcohol responding. These findings suggest that general anesthetic exposure during adolescence may be an environmental risk factor contributing to an enhanced susceptibility to developing AUDs in an already vulnerable population.
Can network analysis shed light on predictors of lithium response in bipolar I disorder?
Authors: Scott J. , Bellivier F. , Manchia M. , Schulze T. , Alda M. , Etain B. ,   investigators involved in the ConLiGen collaboration
Published: February 2020

Objective

To undertake a large‐scale clinical study of predictors of lithium (Li) response in bipolar I disorder (BD‐I) and apply contemporary multivariate approaches to account for inter‐relationships between putative predictors.

Methods

We used network analysis to estimate the number and strength of connections between potential predictors of good Li response (measured by a new scoring algorithm for the Retrospective Assessment of Response to Lithium Scale) in 900 individuals with BD‐I recruited to the Consortium of Lithium Genetics.

Results

After accounting for co‐associations between potential predictors, the most important factors associated with the good Li response phenotype were panic disorder, manic predominant polarity, manic first episode, age at onset between 15–32 years and family history of BD. Factors most strongly linked to poor outcome were comorbid obsessive–compulsive disorder, alcohol and/or substance misuse, and/or psychosis (symptoms or syndromes).

Conclusions

Network analysis can offer important additional insights to prospective studies of predictors of Li treatment outcomes. It appears to especially help in further clarifying the role of family history of BD (i.e. its direct and indirect associations) and highlighting the positive and negative associations of different subtypes of anxiety disorders with Li response, particularly the little‐known negative association between Li response and obsessive–compulsive disorder.
A meta‐analysis on association between CSN3 gene variants and milk yield and composition in cattle
Authors: Mahmoudi P. , Rostamzadeh J. , Rashidi A. , Zergani E. , Razmkabir M.
Published: February 2020

A meta‐analysis on the effects of A and B alleles, the most frequent alleles of CSN3 gene, on milk yield and composition traits was conducted by pooling a large dataset consisting of 30 471 genotyped cattle. Four genetic models, comprising dominant (AA + AB vs. BB), recessive (AA vs. AB + BB), additive (AA vs. BB) and co‐dominant (AA + BB vs. AB), were employed to analyze data. Standardized mean difference (SMD) was used to measure the size of the effects of A and B alleles of CSN3 on studied traits. Effect sizes of 0.2, 0.5 and 0.8 represent small, medium and large effects, respectively. The results indicate that B allele, in the form of BB genotype, has a significant, but medium effect on lactation yield under dominant (SMD = 0.259, P‐value = 0.006) and additive (SMD = 0.279, P‐value = 0.035) models. Moreover, a small decrease in the fat percentage occurred in cows having A allele under dominant (SMD = −0.077, P‐value = 0.006) and additive (SMD = −0.106, P‐value = 0.035) models. Furthermore, CSN3 variants significantly but slightly affect protein percentage under dominant (SMD = −0.146, P‐value = 0.000), recessive (SMD = −0.077, P‐value = 0.000) and additive (SMD = −0.219, P‐value = 0.000) models, showing the negative effect of A allele on this trait. Meta‐analysis results reveal that daily milk yield is slightly affected by CSN3 variants under recessive (SMD = 0.056, P‐value = 0.033) and additive (SMD = 0.061, P‐value = 0.013) genetic models. There is no effect of CSN3 variants on either protein or fat yield. In addition, the effects of CSN3 variants on milk‐related traits were not observed under the co‐dominant model. Sensitivity and publication bias analyses were carried out to confirm the stability of meta‐analyses results.
Association of NE, leptin, and 5‐HT with electrophysiological parameters in patients with primary premature ejaculation
Authors: Xia Jiadong , Zhang Qijie , Wang Yamin , Luan Jiaochen , Yang Jie , Cong Rong , Wang Zengjun , Song Ninghong
Published: February 2020

Objective

To investigate the possible role of serum norepinephrine (NE), leptin, and 5‐hydroxytryptamine (5‐HT) and their correlations with sympathetic skin response located in the penis (PSSR) in primary premature ejaculation (PPE).

Methods

We compared the serum level of NE, leptin, and 5‐HT, intravaginal ejaculatory latency time (IELT) and the premature ejaculation diagnostic tool (PEDT) scores between 57 PPE patients and 42 healthy control men as controls, who were recruited between September 2016 and January 2019. Additionally, the amplitude and latency of PSSR were measured and compared between the two groups.

Results

Compared with healthy men, both leptin and NE increased significantly in PPE patients (P = .003, P = .005), while serum 5‐HT remarkably decreased (P = .002). Serum leptin, NE, and 5‐HT were significantly correlated with the diagnosis of PPE, PSSR amplitude, and latency. Moreover, compared with single serum indicator, NE/5‐HT and leptin/5‐HT had a stronger correlation with both PSSR amplitude (r = .8377, P < .001; r = .9323, P < .001, respectively) and latency (r = −.8058, P < .001; r = −.8901, P < .001, respectively).

Conclusion

Significant differences in leptin, NE, and 5‐HT are observed between PPE patients and the controls, which supports the hypothesis of hyperactive sympathetic nerve system (SNS) in PPE. Additionally, leptin/5‐HT ratio may serve as an ideal indicator for reflecting SNS activity and predicting treatment response in PPE patients in the future.
Laparoscopic‐endoscopic cooperative surgery for early gastric cancer with gastroesophageal varices
Authors: Namikawa Tsutomu , Iwabu Jun , Munekage Masaya , Uemura Sunao , Maeda Hiromichi , Kitagawa Hiroyuki , Nakayama Taku , Fukuhara Hideo , Inoue Keiji , Al‐Sheikh Mariam , Jaiswal Nalin , Kobayashi Michiya , Hanazaki Kazuhiro
Published: February 2020

This report describes a patient with early gastric cancer with gastroesophageal varices who underwent laparoscopic‐endoscopic cooperative surgery. The patient, a 75‐year‐old woman, was referred to our hospital for the treatment of gastric cancer. Esophagogastroduodenoscopy revealed a superficial spreading‐type tumor on the posterior wall of the upper third of the stomach that was very close to the gastric varices. Biopsy specimens showed a moderately differentiated tubular adenocarcinoma. Abdominal contrast‐enhanced CT showed an enhanced submucosal area with noticeably dilated veins around the perigastric region and no masses in the liver. The patient underwent local resection of the stomach using laparoscopic‐endoscopic cooperative surgery; this procedure was chosen because of the patient's risk of bleeding from the gastric varices in the area adjacent to the cancer during endoscopic submucosal dissection. Macroscopic examination of the resected specimen showed a superficial spreading lesion measuring 55 × 50 mm. The pathological diagnosis was moderately differentiated tubular adenocarcinoma invading the gastric submucosal layer without lymphovascular invasion.