bluuebunny/crossref_metadata_2025 huggingface dataset:
Smart disclosure: promise and perils
Authors: BAR-GILL OREN
Published: August 2019

The move to smart disclosure promises to revitalize disclosure mandates and save them from a fate of ignored verbiage. But by making disclosure relevant and effective, this shift to smart disclosure also raises several concerns. Specifically, simple disclosures like genetically modified food disclosures, restaurant hygiene grades, annual percentage rate disclosures, etc., can result in market distortions and inefficiencies as: (1) consumers might draw false inferences from the disclosure; and (2) disclosing one dimension will elevate this dimension relative to other dimensions, and thus distort demand for the product and even alter the product itself. Relatedly, System 1 disclosures, like graphic cigarette labels, might influence behavior by triggering an emotional response rather than through informed deliberation, thus abandoning traditional justifications for disclosure mandates. In light of these concerns, it is more difficult to view disclosure mandates as minimally paternalistic. Government, by tweaking disclosure design, wields substantial power over markets and consumers.
Retributivism and the Use of Imprisonment as the Ultimate Back-up Sanction
Authors: Bülow William
Published: August 2019

Imprisonment is often said to be the ultimate back-up sanction for offenders who do not abide by their non-custodial sentence. From a standard consequentialist perspective this is morally justified, if it is a cost-effective means to crime prevention. In contrast, the use of imprisonment as a back-up is much harder to justify from retributivist perspectives, with their emphasis on just desert or deserved censure. The crux is this: if the reason for a non-custodial sentence is that a prison sentence risks being a disproportionate or inappropriate sanction, retributivists need to explain how a prison term can be warranted as the backup sanction for those who breach the requirements of their non-custodial sentence, even though their original crime wasn’t serious enough to warrant imprisonment in the first place. The aim in this paper is to critically assess the extent to which retributivists can justify the use of imprisonment as the ultimate back-up sanction. In doing so, I first examine two broad strategies that are discussed in the literature, and which retributivists could employ in order to respond to this problem. The first strategy stresses how desert has only a limited role in sentencing such that it demarcates a range of deserved punishment. On this view, associated with limiting retributivism, one could initially opt for a less harsh yet deserved punishment, leaving room for the imposition of back-up sanctions when needed. The second strategy focuses on how the act of breach is a reprehensible act that can allow for a penalty increase, and thereby lead to imprisonment. Although it is argued that both strategies fail, the paper proposes an alternative solution to this problem.
Promoting Integrated Mental Health Care Services in Disaster Response Programs: Lessons Learned After the Impact of Hurricane María in Puerto Rico
Authors: Jiménez Chávez Julio C. , Viruet Sánchez Esteban , Rosario Maldonado Fernando J. , Ramos Lucca Axel J. , Barros Cartagena Barbara
Published: August 2019

Meteorological and even human-made disasters are increasing every year in frequency and magnitude. The passage of a disaster affects a society without distinction, but groups with social vulnerability (low socioeconomic status, chronic medical, or psychological conditions, limited access to resources) face the most significant impact. As a result, psychological and behavioral symptoms (eg, depression and anxiety) can ensue, making the immediate response of mental health services crucial. Secondary data from a database of a temporary healthcare unit were analyzed. A total of 54 records were reviewed to collect information; univariate and bivariate analyses were done. The purpose of this article is to present our experience regarding the incorporation of a mental health services model, with its respective benefits and challenges, into a temporary healthcare unit, after Hurricane Maria in 2017.
The charmed string: self-supporting loops through air drag
Authors: Daerr Adrian , Courson Juliette , Abello Margaux , Toutain Wladimir , Andreotti Bruno
Published: August 2019

The string shooter experiment uses counter-rotating pulleys to propel a closed string forward. Its steady state exhibits a transition from a gravity-dominated regime at low velocity towards a high-velocity regime where the string takes the form of a self-supporting loop. Here we show that this loop of light string is not suspended in the air due to inertia, but through the hydrodynamic drag exerted by the surrounding fluid, namely air. We investigate this drag experimentally and theoretically for a smooth long cylinder moving along its axis. We then derive the equations describing the shape of the string loop in the limit of vanishing string radius. The solutions present a critical point, analogous to a hydraulic jump, separating a supercritical zone where the wave velocity is smaller than the rope velocity, from a subcritical zone where waves propagate faster than the rope velocity. This property could be leveraged to create a white hole analogue similar to what has been demonstrated using surface waves on a flowing fluid. Loop solutions that are regular at the critical point are derived, discussed and compared to the experiment. In the general case, however, the critical point turns out to be the locus of a sharp turn of the string, which is modelled theoretically as a discontinuity. The hydrodynamic regularisation of this geometrical singularity, which involves non-local and added mass effects, is discussed on the basis of dimensional analysis.
ISLAM IN THE INTERIOR OF PRECOLONIAL EAST AFRICA: EVIDENCE FROM LAKE TANGANYIKA
Authors: GOODING PHILIP
Published: August 2019

Most histories of East Africa's precolonial interior only give cursory attention to Islam, especially in histories of present-day west-central Tanzania and the eastern Democratic Republic of Congo. Most converts to Islam in this context are usually viewed as ‘nominal’ Muslims. This article, by contrast, builds on recent scholarship on other regions and time periods that questions the conceptual validity of the ‘nominal’ Muslim. New converts necessarily questioned their social relationships, ways of living, and ritual practices through the act of conversion. On the shores of Lake Tanganyika, new converts were observable through the act of circumcision, dietary restrictions, abidance by some of Islam's core tenets, and the adoption and adaptation of certain phenomena from East Africa's Indian Ocean coast and islands. Interior populations’ conversion to Islam was bound up with broader coast-interior material, cultural, and religious exchanges.
Narrating atrocity: Genocide memorials, dark tourism, and the politics of memory
Authors: Lischer Sarah Kenyon
Published: August 2019

After a genocide, leaders compete to fill the postwar power vacuum and establish their preferred story of the past. Memorialisation, including through building memorials, provides a cornerstone of political power. The dominant public narrative determines the plotline; it labels victims and perpetrators, interprets history, assigns meaning to suffering, and sets the post-atrocity political agenda. Therefore, ownership of the past, in terms of the public account, is deeply contested. Although many factors affect the emergence of a dominant atrocity narrative, this article highlights the role of international interactions with genocide memorials, particularly how Western visitors, funders, and consultants influence the government's narrative. Western consumption of memorials often reinforces aspects of dark tourism that dehumanise victims and discourage adequate context for the uninformed visitor. Funding and consultation provided by Western states and organisations – while offering distinct benefits – tends to encourage a homogenised atrocity narrative, which reflects the values of the global human rights regime and existing standards of memorial design rather than privileging the local particularities of the atrocity experience. As shown in the cases of Rwanda, Cambodia, and Bosnia, Western involvement in public memory projects often strengthens the power of government narratives, which control the present by controlling the past.
M-embedded symmetric operator spaces and the derivation problem
Authors: HUANG JINGHAO , LEVITINA GALINA , SUKOCHEV FEDOR
Published: August 2019

Let ℳ be a semifinite von Neumann algebra with a faithful semifinite normal trace τ. Assume that E(0, ∞) is an M-embedded fully symmetric function space having order continuous norm and is not a superset of the set of all bounded vanishing functions on (0, ∞). In this paper, we prove that the corresponding operator space E(ℳ, τ) is also M-embedded. It extends earlier results by Werner [48, Proposition 4∙1] from the particular case of symmetric ideals of bounded operators on a separable Hilbert space to the case of symmetric spaces (consisting of possibly unbounded operators) on an arbitrary semifinite von Neumann algebra. Several applications are given, e.g., the derivation problem for noncommutative Lorentz spaces ℒp,1(ℳ, τ), 1 < p < ∞, has a positive answer.
Eritrea’s New Heritage Law: Drafting and Implementation Issues
Authors: Andemariam Senai W.
Published: August 2019

On 30 September 2015, the government of Eritrea issued Proclamation no. 177/2015, the Cultural and Natural Heritage Proclamation of Eritrea, to govern the country’s cultural and natural heritage. Instrumental in the inscription of the nation’s capital, Asmara, in the United Nations Educational, Scientific and Cultural Organization’s World Heritage List, the Proclamation simultaneously governs cultural (tangible and intangible) and natural heritage. The author, the main drafter of the Proclamation, discusses issues and alternatives that were debated during the drafting process, lists the key issues in relation to implementation of the Proclamation, and suggests recommendations on the way forward.
Perceptions of social, emotional, and functional values in patients with type 2 diabetes mellitus and their satisfaction with primary health care services
Authors: Budrevičiūtė Aida , Kalėdienė Ramunė , Bagdonienė Liudmila , Paukštaitienė Renata , Valius Leonas
Published: August 2019

Aim:

To explore the relationships between social, emotional, and functional values, and satisfaction of patients with type 2 diabetes mellitus (T2DM) with an emphasis on Lithuanian primary health care services providers.

Background:

Academics and practitioners are encouraging more research on service value conceptually and empirically. Primary health care settings (PHCS) use modern management of value creation for patients with chronic diseases to increase the satisfaction of patients. Satisfaction of patients is the most important factor of competitive advantage for the PHCS. In this study, perceived value concept is dealt with in a multidimensional way. The fact that the perceived value in health sector has not previously been examined as multidimentionally has increased the importance of this research.

Methods:

The study strategy is based on focus group discussions of executives and survey of patients with T2DM in the primary health care sector. The target of focus group discussions is to gain knowledge about factors developing the competitive advantage of PHCS. The survey of patients with T2DM is the background to test the conceptual model of perceived value importance on satisfaction. The study uses coefficients of correlation, exploratory factor analysis, and linear regression.

Findings:

The results of focus groups revealed the factors of competitive advantage related to perspectives of health policy, organization, human resources, and patients. The results of the survey established statistically significant links between social value and satisfaction, and functional value and satisfaction. Emotional value decreased satisfaction of patients with T2DM.
Emergence timing affects growth and reproduction of goosegrass (Eleusine indica)
Authors: Ma Xiaoyan , Ma Yajie , Wu Hanwen , Ren Xiangliang , Jiang Weili , Ma Yan
Published: August 2019

Goosegrass is considered one of the worst agricultural weeds worldwide. Understanding its life cycle will provide useful management information. Field experiments with six emergence times (April, May, June, July, August, and September) were conducted at Anyang, China in 2015 and 2017 to clarify the growth and reproduction of goosegrass emerging at different times within a season. The result showed that plant height, dry weight, average weight per inflorescence, total inflorescence weight, average seed number per inflorescence, and total number of seeds per plant were relatively low in the April cohort, peaked with the May or June emergence cohort, and decreased thereafter. However, the earliest emergence of goosegrass in April had the highest total number of inflorescences. The plants of the May cohort produced the greatest number of seeds: 225,954 and 322,501 seeds per plant in 2015 and 2017, respectively. Delayed emergence resulted in less seed production; most plants that emerged in September did not flower or set seed. The 1,000-seed weight did not vary among the emergence cohorts. The reproductive investment was lowest for plants of the May cohort and then increased as emergence time was delayed to June, July, and August. Fresh mature seed of all emergence cohorts was extremely dormant and had low germination only up to 6% from August to November, and high germination (44% to 93%) in December. The information gained from this study indicates that weed management strategies should focus on the early-emerged seedlings such as the April and May cohorts, so as to effectively prevent goosegrass seed production, minimize the weed seed replenishment into the soil seed bank, and reduce the infestation in subsequent seasons.
Perceived Biological and Social Characteristics of a Representative	Set of German First Names
Authors: Nett Tillmann , Dorrough Angela , Jekel Marc , Glöckner Andreas
Published: August 2019

Abstract. We provide ratings for a representative set of 2,000 German first names with regard to perceived sex, foreign origin (yes/no), and familiarity. In two studies participants ( N = 736 and N = 237) estimated intelligence, education, attractiveness, religiousness, age, warmth, and competence of persons with the respective name. Descriptive results show strong stereotypes in society in that most of the top-rated names on intelligence, competence, and religiousness were male, whereas all top-rated names on attractiveness and warmth were female. The reliability of most ratings is satisfactory. We provide correlations between the rated dimensions to give an overview of the internal structure of the dataset. To enhance usage of the dataset, we provide an R-package, which allows querying subsets of names depending on experimental requirements.
Colour compound lenses for a portable fluorescence microscope
Authors: Dai Bo , Jiao Ziao , Zheng Lulu , Bachman Hunter , Fu Yongfeng , Wan Xinjun , Zhang Yule , Huang Yu , Han Xiaodian , Zhao Chenglong , Huang Tony Jun , Zhuang Songlin , Zhang Dawei
Published: August 2019

In this article, we demonstrated a handheld smartphone fluorescence microscope (HSFM) that integrates dual-functional polymer lenses with a smartphone. The HSFM consists of a smartphone, a field-portable illumination source, and a dual-functional polymer lens that performs both optical imaging and filtering. Therefore, compared with the existing smartphone fluorescence microscope, the HSFM does not need any additional optical filters. Although fluorescence imaging has traditionally played an indispensable role in biomedical and clinical applications due to its high specificity and sensitivity for detecting cells, proteins, DNAs/RNAs, etc., the bulky elements of conventional fluorescence microscopes make them inconvenient for use in point-of-care diagnosis. The HSFM demonstrated in this article solves this problem by providing a multifunctional, miniature, small-form-factor fluorescence module. This multifunctional fluorescence module can be seamlessly attached to any smartphone camera for both bright-field and fluorescence imaging at cellular-scale resolutions without the use of additional bulky lenses/filters; in fact, the HSFM achieves magnification and light filtration using a single lens. Cell and tissue observation, cell counting, plasmid transfection evaluation, and superoxide production analysis were performed using this device. Notably, this lens system has the unique capability of functioning with numerous smartphones, irrespective of the smartphone model and the camera technology housed within each device. As such, this HSFM has the potential to pave the way for real-time point-of-care diagnosis and opens up countless possibilities for personalized medicine.
HSP90/AXL/eIF4E-regulated unfolded protein response as an acquired vulnerability in drug-resistant KRAS-mutant lung cancer
Authors: Yang Haitang , Liang Shun-Qing , Xu Duo , Yang Zhang , Marti Thomas M. , Gao Yanyun , Kocher Gregor J. , Zhao Heng , Schmid Ralph A. , Peng Ren-Wang
Published: August 2019

Drug resistance and tumor heterogeneity are formidable challenges in cancer medicine, which is particularly relevant for KRAS-mutant cancers, the epitome of malignant tumors recalcitrant to targeted therapy efforts and first-line chemotherapy. In this study, we delineate that KRAS-mutant lung cancer cells resistant to pemetrexed (MTA) and anti-MEK drug trametinib acquire an exquisite dependency on endoplasmic reticulum (ER) stress signaling, rendering resistant cancer cells selectively susceptible to blockage of HSP90, the receptor tyrosine kinase AXL, the eukaryotic translation initiation factor 4E (eIF4E), and the unfolded protein response (UPR). Mechanistically, acquisition of drug resistance enables KRAS-mutant lung cancer cells to bypass canonical KRAS effectors but entail hyperactive AXL/eIF4E, increased protein turnover in the ER, and adaptive activation of an ER stress-relief UPR survival pathway whose integrity is maintained by HSP90. Notably, the unique dependency and sensitivity induced by drug resistance are applicable to KRAS-mutant lung cancer cells undergoing de novo intratumor heterogeneity. In line with these findings, HSP90 inhibitors synergistically enhance antitumor effects of MTA and trametinib, validating a rational combination strategy to treat KRAS-mutant lung cancer. Collectively, these results uncover collateral vulnerabilities co-occurring with drug resistance and tumor heterogeneity, informing novel therapeutic avenues for KRAS-mutant lung cancer.
Circadian rest-activity patterns in bipolar disorder and borderline personality disorder
Authors: McGowan Niall M. , Goodwin Guy M. , Bilderbeck Amy C. , Saunders Kate E. A.
Published: August 2019

Bipolar disorder (BD) and borderline personality disorder (BPD) are two psychiatric disorders with overlapping features that can be challenging to separate diagnostically. Growing evidence suggests that circadian rhythm disturbances are associated with psychiatric illness, however circadian patterns of behaviour have not been elucidated in BPD or differentiated from BD. This study compared the circadian structure and timing of rest-activity patterns in BPD with BD and healthy volunteers. Participants with BD (N = 31) and BPD (N = 21) and healthy controls (HC, N = 35) wore an actigraph on their non-dominant wrist for 28 day periods as part of the Automated Monitoring of Symptom Severity (AMoSS) study. Non-parametric circadian rhythm analysis of rest-activity patterns and cosinor analysis of distal temperature rhythms were conducted to elucidate circadian function between groups. Covariates controlled for included employment status, BMI and gender. Compared with HC and BD, individuals with BPD showed significantly delayed phase of night-time rest patterns (“L5 onset”) (mean difference = 1:47 h, P < 0.001; mean difference = 1:38 h, P = 0.009, respectively), and relative to HC showed delayed daytime activity onset (“M10 onset”) (mean difference = 2:13 h, P = 0.048) and delayed temperature phase (mean difference = 1:22 h, P = 0.034). These findings suggest that delayed circadian function may be a clinically important phenotype in individuals with BPD. Future work should interrogate the causality of this association and examine interventions which target delayed circadian function in the treatment of BPD.
Involvement of inflammatory gene expression pathways in depressed patients with hyperphagia
Authors: de Kluiver Hilde , Jansen Rick , Milaneschi Yuri , Penninx Brenda W. J. H.
Published: August 2019

The pathophysiology of major depressive disorder (MDD) is highly heterogeneous. Previous evidence at the DNA level as well as on the serum protein level suggests that the role of inflammation in MDD pathology is stronger in patients with hyperphagia during an active episode. Which inflammatory pathways differ in MDD patients with hyperphagia inflammatory pathways in terms of gene expression is unknown. We analyzed whole-blood gene expression profiles of 881 current MDD cases and 331 controls from the Netherlands Study of Depression and Anxiety (NESDA). The MDD patients were stratified according to patients with hyperphagia (characterized by increased appetite and/or weight,N = 246) or hypophagia (characterized by decreased appetite and/or weight,N = 342). Using results of differential gene expression analysis between controls and the MDD subgroups, enrichment of curated inflammatory pathways was estimated. The majority of the pathways were significantly (FDR < 0.1) enriched in the expression profiles of MDD cases with hyperphagia, including top pathways related to factors responsible for the onset of inflammatory response (‘caspase’, ‘GATA3’, ‘NFAT’, and ‘inflammasomes’ pathways). Only two pathways (‘adaptive immune system’ and ‘IL-8- and CXCR2-mediated signaling’) were enriched in the MDD with hypophagia subgroup, these were also enriched in the total current MDD group and the group with hyperphagia. This confirms the importance of inflammation in MDD pathology of patients with hyperphagia, and suggests that distinguishing more uniform MDD phenotypes can help in finding their pathophysiological basis.
Hippocampal volume change following ECT is mediated by rs699947 in the promotor region of VEGF
Authors: Van Den Bossche Maarten J. A. , Emsell Louise , Dols Annemiek , Vansteelandt Kristof , De Winter François-Laurent , Van den Stock Jan , Sienaert Pascal , Stek Max L. , Bouckaert Filip , Vandenbulcke Mathieu
Published: August 2019

Several studies have shown that electroconvulsive therapy (ECT) results in increased hippocampal volume. It is likely that a multitude of mechanisms including neurogenesis, gliogenesis, synaptogenesis, angiogenesis, and vasculogenesis contribute to this volume increase. Neurotrophins, like vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) seem to play a crucial mediating role in several of these mechanisms. We hypothesized that two regulatory SNPs in the VEGF and BDNF gene influence the changes in hippocampal volume following ECT. We combined genotyping and brain MRI assessment in a sample of older adults suffering from major depressive disorder to test this hypothesis. Our results show an effect of rs699947 (in the promotor region of VEGF) on hippocampal volume changes following ECT. However, we did not find a clear effect of rs6265 (in BDNF). To the best of our knowledge, this is the first study investigating possible genetic mechanisms involved in hippocampal volume change during ECT treatment.
Evidence for cerebello-thalamo-cortical hyperconnectivity as a heritable trait for schizophrenia
Authors: Cao Hengyi , Ingvar Martin , Hultman Christina M. , Cannon Tyrone
Published: August 2019

Our recent study has demonstrated that increased connectivity in the cerebello-thalamo-cortical (CTC) circuitry is a state-independent neural trait that can potentially predict the onset of psychosis. One possible cause of such “trait” abnormality would be genetic predisposition. Here, we tested this hypothesis using multi-paradigm functional magnetic resonance imaging (fMRI) data from two independent twin cohorts. In a sample of 85 monozygotic (MZ) and 52 dizygotic (DZ) healthy twin pairs acquired from the Human Connectome Project, we showed that the connectivity pattern of the identified CTC circuitry was more similar in the MZ twins (r = 0.54) compared with that in the DZ twins (r = 0.22). The structural equation modeling analysis revealed a heritability estimate of 0.52 for the CTC connectivity, suggesting a moderately strong genetic effect. Moreover, using an independent schizophrenia cotwin sample (10 discordant MZ cotwins, 30 discordant DZ cotwins, and 32 control cotwins), we observed a significant linear relationship between genetic distance to schizophrenia and the connectivity strength in the CTC circuitry (i.e., schizophrenia MZ cotwins > schizophrenia DZ cotwins > control twins, P = 0.045). The present data provide converging evidence that increased connectivity in the CTC circuitry is likely to be a heritable trait that is associated with the genetic risk of schizophrenia.
A multimodal MRI study of the neural mechanisms of emotion regulation impairment in women with obesity
Authors: Steward Trevor , Picó-Pérez Maria , Mestre-Bach Gemma , Martínez-Zalacaín Ignacio , Suñol Maria , Jiménez-Murcia Susana , Fernández-Formoso Jose A. , Vilarrasa Nuria , García-Ruiz-de-Gordejuela Amador , Veciana de las Heras Misericordia , Custal Nuria , Virgili Nuria , Lopez-Urdiales Rafael , Menchón José M. , Granero Roser , Soriano-Mas Carles , Fernandez-Aranda Fernando
Published: August 2019

Maladaptive emotion regulation contributes to overeating and impedes weight loss. Our study aimed to compare the voluntary downregulation of negative emotions by means of cognitive reappraisal in adult women with obesity (OB) and female healthy controls (HC) using a data-driven, multimodal magnetic resonance imaging (MRI) approach. Women with OB (n = 24) and HC (n = 25) carried out an emotion regulation task during functional MRI scanning. Seed-to-voxel resting-state connectivity patterns derived from activation peaks identified by this task were compared between groups. Diffusion tensor imaging (DTI) was used to examine white matter microstructure integrity between regions exhibiting group differences in resting-state functional connectivity. Participants in the OB group presented reduced activation in the ventromedial prefrontal (vmPFC) cortex in comparison to the HC group when downregulating negative emotions, along with heightened activation in the extrastriate visual cortex (p < 0.05, AlphaSim-corrected). Moreover, vmPFC peak activity levels during cognitive reappraisal were negatively correlated with self-reported difficulties in emotion regulation. OB patients exhibited decreased functional connectivity between the vmPFC and the temporal pole during rest (peak-pFWE = 0.039). Decreased fractional white-matter track volume in the uncinate fasciculus, which links these two regions, was also found in participants with OB. Taken together, our findings are indicative of emotion regulation deficits in OB being underpinned by dysfunctional hypoactivity in the vmPFC and hyperactivity in the extrastriate visual cortex. Our results provide a potential target circuit for neuromodulatory interventions to improve emotion regulation skills and weight-loss intervention outcomes.
Temporal dynamics of miRNAs in human DLPFC and its association with miRNA dysregulation in schizophrenia
Authors: Hu Zhonghua , Gao Shouguo , Lindberg Daniel , Panja Debabrata , Wakabayashi Yoshi , Li Keshen , Kleinman Joel E. , Zhu Jun , Li Zheng
Published: August 2019

Brain development is dependent on programmed gene expression, which is both genetically and epigenetically regulated. Post-transcriptional regulation of gene expression by microRNAs (miRNAs) is essential for brain development. As abnormal brain development is hypothesized to be associated with schizophrenia, miRNAs are an intriguing target for this disorder. The aims of this study were to determine the temporal dynamics of miRNA expression in the human dorsolateral prefrontal cortex (DLPFC), and the relationship between miRNA’s temporal expression pattern and dysregulation in schizophrenia. This study used next-generation sequencing to characterize the temporal dynamics of miRNA expression in the DLPFC of 109 normal subjects (second trimester–74 years of age) and miRNA expression changes in 34 schizophrenia patients. Unlike mRNAs, the majority of which exhibits a wave of change in fetuses, most miRNAs are preferentially expressed during a certain period before puberty. It is noted that in schizophrenia patients, miRNAs normally enriched in infants tend to be upregulated, while those normally enriched in prepuberty tend to be downregulated, and the targets of these miRNAs are enriched for genes encoding synaptic proteins and those associated with schizophrenia. In addition, miR-936 and miR-3162 were found to be increased in the DLPFC of patients with schizophrenia. These findings reveal the temporal dynamics of miRNAs in the human DLPFC, implicate the importance of miRNAs in DLPFC development, and suggest a possible link between schizophrenia and dysregulation of miRNAs enriched in infancy and prepuberty.
Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids
Authors: Alcala N. , Leblay N. , Gabriel A. A. G. , Mangiante L. , Hervas D. , Giffon T. , Sertier A. S. , Ferrari A. , Derks J. , Ghantous A. , Delhomme T. M. , Chabrier A. , Cuenin C. , Abedi-Ardekani B. , Boland A. , Olaso R. , Meyer V. , Altmuller J. , Le Calvez-Kelm F. , Durand G. , Voegele C. , Boyault S. , Moonen L. , Lemaitre N. , Lorimier P. , Toffart A. C. , Soltermann A. , Clement J. H. , Saenger J. , Field J. K. , Brevet M. , Blanc-Fournier C. , Galateau-Salle F. , Le Stang N. , Russell P. A. , Wright G. , Sozzi G. , Pastorino U. , Lacomme S. , Vignaud J. M. , Hofman V. , Hofman P. , Brustugun O. T. , Lund-Iversen M. , Thomas de Montpreville V. , Muscarella L. A. , Graziano P. , Popper H. , Stojsic J. , Deleuze J. F. , Herceg Z. , Viari A. , Nuernberg P. , Pelosi G. , Dingemans A. M. C. , Milione M. , Roz L. , Brcic L. , Volante M. , Papotti M. G. , Caux C. , Sandoval J. , Hernandez-Vargas H. , Brambilla E. , Speel E. J. M. , Girard N. , Lantuejoul S. , McKay J. D. , Foll M. , Fernandez-Cuesta L.
Published: August 2019

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value ofOTPexpression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.
Ancient DNA from the skeletons of Roopkund Lake reveals Mediterranean migrants in India
Authors: Harney Éadaoin , Nayak Ayushi , Patterson Nick , Joglekar Pramod , Mushrif-Tripathy Veena , Mallick Swapan , Rohland Nadin , Sedig Jakob , Adamski Nicole , Bernardos Rebecca , Broomandkhoshbacht Nasreen , Culleton Brendan J. , Ferry Matthew , Harper Thomas K. , Michel Megan , Oppenheimer Jonas , Stewardson Kristin , Zhang Zhao , Harashawaradhana  , Bartwal Maanwendra Singh , Kumar Sachin , Diyundi Subhash Chandra , Roberts Patrick , Boivin Nicole , Kennett Douglas J. , Thangaraj Kumarasamy , Reich David , Rai Niraj
Published: August 2019

Situated at over 5,000 meters above sea level in the Himalayan Mountains, Roopkund Lake is home to the scattered skeletal remains of several hundred individuals of unknown origin. We report genome-wide ancient DNA for 38 skeletons from Roopkund Lake, and find that they cluster into three distinct groups. A group of 23 individuals have ancestry that falls within the range of variation of present-day South Asians. A further 14 have ancestry typical of the eastern Mediterranean. We also identify one individual with Southeast Asian-related ancestry. Radiocarbon dating indicates that these remains were not deposited simultaneously. Instead, all of the individuals with South Asian-related ancestry date to ~800 CE (but with evidence of being deposited in more than one event), while all other individuals date to ~1800 CE. These differences are also reflected in stable isotope measurements, which reveal a distinct dietary profile for the two main groups.
Syringeable immunotherapeutic nanogel reshapes tumor microenvironment and prevents tumor metastasis and recurrence
Authors: Song Chanyoung , Phuengkham Hathaichanok , Kim Young Seob , Dinh Van Vuong , Lee Inho , Shin Il Woo , Shin Hong Sik , Jin Seung Mo , Um Soong Ho , Lee Hyunseung , Hong Kwan Soo , Jin Seon-Mi , Lee Eunji , Kang Tae Heung , Park Yeong-Min , Lim Yong Taik
Published: August 2019

The low response rate of current cancer immunotherapy suggests the presence of few antigen-specific T cells and a high number of immunosuppressive factors in tumor microenvironment (TME). Here, we develop a syringeable immunomodulatory multidomain nanogel (iGel) that overcomes the limitation by reprogramming of the pro-tumoral TME to antitumoral immune niches. Local and extended release of immunomodulatory drugs from iGel deplete immunosuppressive cells, while inducing immunogenic cell death and increased immunogenicity. When iGel is applied as a local postsurgical treatment, both systemic antitumor immunity and a memory T cell response are generated, and the recurrence and metastasis of tumors to lungs and other organs are significantly inhibited. Reshaping of the TME using iGel also reverts non-responding groups to checkpoint blockade therapies into responding groups. The iGel is expected as an immunotherapeutic platform that can reshape immunosuppressive TMEs and synergize cancer immunotherapy with checkpoint therapies, with minimized systemic toxicity.
Visualizing structural transitions of ligand-dependent gating of the TRPM2 channel
Authors: Yin Ying , Wu Mengyu , Hsu Allen L. , Borschel William F. , Borgnia Mario J. , Lander Gabriel C. , Lee Seok-Yong
Published: August 2019

The transient receptor potential melastatin 2 (TRPM2) channel plays a key role in redox sensation in many cell types. Channel activation requires binding of both ADP-ribose (ADPR) and Ca2+. The recently published TRPM2 structures from Danio rerio in the ligand-free and the ADPR/Ca2+-bound conditions represent the channel in closed and open states, which uncovered substantial tertiary and quaternary conformational rearrangements. However, it is unclear how these rearrangements are achieved within the tetrameric channel during channel gating. Here we report the cryo-electron microscopy structures of Danio rerio TRPM2 in the absence of ligands, in complex with Ca2+ alone, and with both ADPR and Ca2+, resolved to ~4.3 Å, ~3.8 Å, and ~4.2 Å, respectively. In contrast to the published results, our studies capture ligand-bound TRPM2 structures in two-fold symmetric intermediate states, offering a glimpse of the structural transitions that bridge the closed and open conformations.
Changes in Neuroimmune and Neuronal Death Markers after Adolescent Alcohol Exposure in Rats are Reversed by Donepezil
Authors: Swartzwelder H. S. , Healey Kati L. , Liu Wen , Dubester Kira , Miller Kelsey M. , Crews Fulton T.
Published: August 2019

Adolescent intermittent ethanol (AIE) exposure diminishes neurogenesis and dendritic spine density in the dentate gyrus. The cholinesterase inhibitor, donepezil (Aricept), reverses AIE effects on dendritic spines, possibly by interacting with inflammatory and/or epigenetic mediators after AIE exposure. This study tests the hypothesis that donepezil reverses AIE-induced neuroimmune, and epigenetic changes in the adult dentate gyrus. Adolescent Sprague-Dawley male rats (PD30-43) were given 10 intermittent, intragastric doses of ethanol (5.0 g/kg) or isovolumetric water (AIW). Twenty-one days later half of the animals from each group were treated with either donepezil or isovolumetric water (i.g.) once daily for four days. Two hours after the last donepezil or water dose animals were sacrificed and brains prepared for immunohistochemical analyses. AIE reduced immunoreactivity for doublecortin (DCX) and increased immunoreactivity for activated caspase-3 and death receptor-3 in adulthood, suggesting an enduring attenuation of neurogenesis and an increase in progenitor death. These effects were reversed by donepezil treatment in adulthood. AIE also increased immunoreactivity for the inflammatory signaling molecules HMGB1 and RAGE, as well as the activated phosphorylated transcription factor pNFκB p65, and the gene silencing marker dimethylated histone H3K9. All of these AIE effects were also reversed by donepezil, with the exception of HMGB1.
Deep-sea Sediment Resuspension by Internal Solitary Waves in the Northern South China Sea
Authors: Jia Yonggang , Tian Zhuangcai , Shi Xuefa , Liu J. Paul , Chen Jiangxin , Liu Xiaolei , Ye Ruijie , Ren Ziyin , Tian Jiwei
Published: August 2019

Internal solitary waves (ISWs) can cause strong vertical and horizontal currents and turbulent mixing in the ocean. These processes affect sediment and pollutant transport, acoustic transmissions and man-made structures in the shallow and deep oceans. Previous studies of the role of ISWs in suspending seafloor sediments and forming marine nepheloid layers were mainly conducted in shallow-water environments. In summer 2017, we observed at least four thick (70–140 m) benthic nepheloid layers (BNLs) at water depths between 956 and 1545 m over continental slopes in the northern South China Sea. We found there was a good correlation between the timing of the ISW packet and variations of the deepwater suspended sediment concentration (SSC). At a depth of 956 m, when the ISW arrived, the near-bottom SSC rapidly increased by two orders of magnitude to 0.62 mg/l at 8 m above the bottom. At two much deeper stations, the ISW-induced horizontal velocity reached 59.6–79.3 cm/s, which was one order of magnitude more than the seafloor contour currents velocity. The SSC, 10 m above the sea floor, rapidly increased to 0.10 mg/l (depth of 1545 m) and 1.25 mg/l (depth of 1252 m). In this study, we found that ISWs could suspend much more sediments on deepwater areas than previously thought. Specifically, we estimated that ISWs could induce and suspend 787 Mt/yr of sediment from shelf to deep-sea areas of the northern South China Sea. The total amount of sediment resuspended by shoaling ISWs was 2.7 times that of river-derived sediment reaching the northern South China Sea. This accounted for 6.1% of the global river-discharged sediment (16.4% of that from Asian rivers) transported to the sea.
Early changes in ammonia levels and liver function in patients with advanced hepatocellular carcinoma treated by lenvatinib therapy
Authors: Ohya Kazuki , Kawaoka Tomokazu , Namba Maiko , Uchikawa Shinsuke , Kodama Kenichiro , Morio Kei , Nakahara Takashi , Murakami Eisuke , Hiramatsu Akira , Tsuge Masataka , Yamauchi Masami , Imamura Michio , Chayama Kazuaki , Aikata Hiroshi
Published: August 2019

We aimed to investigate the early changes in ammonia levels and liver function in patients with advanced hepatocellular carcinoma treated with lenvatinib. This retrospective study included 23 patients with advanced hepatocellular carcinoma who were able to receive lenvatinib continuously for at least 1 week. We compared their ammonia levels (NH3), total bilirubin (Bil), albumin, and prothrombin (PT) activity at before and after 1 week of lenvatinib administration, and additionally, compared the 2 groups which were divided based on the presence/absence of portosystemic collaterals (PSCs). Before administration of lenvatinib the patients with PSCs had significantly worse ammonia levels and liver function than the patients without PSCs (NH3: P = 0.013, Bil: P = 0.004, PT: P = 0.047, respectively). Moreover, the indices were worse in all the patients after 1 week of lenvatinib than before administration (NH3: P = 0.001, Bil: P = 0.025, PT: P < 0.001, respectively). Moreover, the changes in ammonia levels were investigated for 4 weeks. The ammonia level increased, to peak at 2 weeks, but decreased after 3 weeks. None of the patients discontinued lenvatinib therapy because of an adverse event. The ammonia levels of the study patients increased from baseline at 1 week after lenvatinib administration, but therapy could be continued for 4 weeks by appropriate management.
The cortico-rubral and cerebello-rubral pathways are topographically organized within the human red nucleus
Authors: Cacciola Alberto , Milardi Demetrio , Basile Gianpaolo Antonio , Bertino Salvatore , Calamuneri Alessandro , Chillemi Gaetana , Paladina Giuseppe , Impellizzeri Federica , Trimarchi Fabio , Anastasi Giuseppe , Bramanti Alessia , Rizzo Giuseppina
Published: August 2019

The Red Nucleus (RN) is a large nucleus located in the ventral midbrain: it is subdivided into a small caudal magnocellular part (mRN) and a large rostral parvocellular part (pRN). These distinct structural regions are part of functionally different networks and show distinctive connectivity features: the mRN is connected to the interposed nucleus, whilst the pRN is mainly connected to dentate nucleus, cortex and inferior olivary complex. Despite functional neuroimaging studies suggest RN involvement in complex motor and higher order functions, the pRN and mRN cannot be distinguished using conventional MRI. Herein, we employ high-quality structural and diffusion MRI data of 100 individuals from the Human Connectome Project repository and constrained spherical deconvolution tractography to perform connectivity-based segmentation of the human RN. In particular, we tracked connections of RN with the inferior olivary complex, the interposed nucleus, the dentate nucleus and the cerebral cortex. We found that the RN can be subdivided according to its connectivity into two clusters: a large ventrolateral one, mainly connected with the cerebral cortex and the inferior olivary complex, and a smaller dorsomedial one, mainly connected with the interposed nucleus. This structural topography strongly reflects the connectivity patterns of pRN and mRN respectively. Structural connectivity-based segmentation could represent a useful tool for the identification of distinct subregions of the human red nucleus on 3T MRI thus allowing a better evaluation of this subcortical structure in healthy and pathological conditions.
Sex difference in IgE sensitization associated with alcohol consumption in the general population
Authors: Roh Daeyoung , Lee Dong-Hee , Lee Sang-Kyu , Kim Soo Whan , Kim Sung Won , Cho Jin Hee , Kim Byung-Guk , Shin Ji-Hyeon
Published: August 2019

The association of alcohol consumption and immunoglobulin E (IgE) sensitization is debated. Few population-based studies have investigated whether such associations differ by sex. We explored the association of alcohol consumption with IgE sensitization in the general population, stratified by sex. We analyzed data for 1,723 adults from the 2010 Korean National Health and Nutrition Examination Survey. We divided subjects into three groups according to their self-reported alcohol consumption or serum level of gamma-glutamyltransferase (GGT), an objective marker of alcohol consumption. After adjustments, the odds ratios (ORs) of male high-risk drinkers were 2.09 (95% confidence interval [CI], 1.34–3.28) for total IgE and 1.71 (95% CI, 1.03–2.83) forDermatophagoides farinae(DF)-specific IgE compared with male low-risk drinkers. In females, the dog-specific IgE level was associated with high-risk drinking (OR, 11.74; 95% CI, 2.04–67.24). The ORs of males in the high-serum-GGT group were 2.73 (95% CI, 1.72–4.33) for total IgE and 2.17 (95% CI, 1.35–3.47) for DF-specific IgE compared with those in the low-serum-GGT group. This study suggests a possible link between alcohol consumption and IgE sensitization, moreover, the risk of IgE sensitization was significantly higher in male high-risk drinkers. Therefore, clinicians should consider the risk of IgE sensitization possibly afflicting male high-risk drinkers.
ASIC3-dependent metabolomics profiling of serum and urine in a mouse model of fibromyalgia
Authors: Hsu Wei-Hsiang , Lee Cheng-Han , Chao Yen-Ming , Kuo Ching-Hua , Ku Wei-Chi , Chen Chih-Cheng , Lin Yun-Lian
Published: August 2019

Fibromyalgia (FM) is characterized by chronic widespread pain. The pathogenesis of FM remains unclear. No specific biomarkers are available. Animal models of FM may provide an opportunity to explore potential biomarkers in a relative homogenous disease condition. Here, we probed the metabolomics profiles of serum and urine in a mouse model of FM induced by intermittent cold stress (ICS). We focused on the role of acid-sensing ion channel 3 (ASIC3) in the metabolomics profiling because ICS treatment induced chronic widespread muscle pain lasting for 1 month in wild-type (Asic3+/+) but not Asic3-knockout (Asic3−/−) mice. Serum and urine samples were collected from both genotypes at different ICS stages, including before ICS (basal level) and post-ICS at days 10 (middle phase, P10) and 40 (recovery phase, P40). Control naïve mice and ICS-induced FM mice differed in 1H-NMR- and LC-MS-based metabolomics profiling. On pathway analysis, the leading regulated pathways in Asic3+/+ mice were taurine and hypotaurine, cysteine and methionine, glycerophospholipid, and ascorbate and aldarate metabolisms, and the major pathways in Asic3−/− mice involved amino acid-related metabolism. Finally, we developed an algorithm for the impactful metabolites in the FM model including cis-aconitate, kynurenate, taurine, pyroglutamic acid, pyrrolidonecarboxylic acid, and 4-methoxyphenylacetic acid in urine as well as carnitine, deoxycholic acid, lysoPC(16:0), lysoPC(20:3), oleoyl-L-carnitine, and trimethylamine N-oxide in serum. Asic3−/− mice were impaired in only muscle allodynia development but not other pain symptoms in the ICS model, so the ASIC3-dependent metabolomics changes could be useful for developing diagnostic biomarkers specific to chronic widespread muscle pain, the core symptom of FM. Further pharmacological validations are needed to validate these metabolomics changes as potential biomarkers for FM diagnosis and/or treatment responses.