bluuebunny/crossref_metadata_2025 huggingface dataset:
4035 Astrocyte LDLR-Related Protein 1 Increases Cytokine Sensitivity – The Role of Glia in Recovery after Brain Damage
Authors: Ahmad Sadiya , Reed Pamela , Sprauge Shane , Sayre Naomi
Published: July 2020

OBJECTIVES/GOALS: The limited treatment options for ischemic stroke patients have resulted in stroke being a leading cause of death and the primary cause of long-term disability in the U.S. Finding effective treatment options requires a better fundamental understanding of the ongoing processes that contribute to poor long-term outcome. METHODS/STUDY POPULATION: Expression of Apolipoprotein E4 predisposes stroke patients to poor long-term outcome. This study aims to test one possible mechanism by which ApoE4 contributes to cognitive decline after stroke. Here, we examine the effect of a major ApoE4 receptor, low-density lipoprotein receptor related protein 1 (LRP1) on sensitivity to stress in astrocytes. LRP1 binds and moves extracellular ligands and plasma membrane proteins into the endocytic system. Others have shown that LRP1 regulates cell-surface TNF receptor (TNFR1) in non-astrocytic cells. We propose That LRP1 similarly regulates TNFR1 in the central nervous system to attenuate inflammatory response after stroke. Studies have shown that ApoE4 slows the recycling of endocytic LDL receptors. We hypothesize that ApoE4 inhibits the ability of LRP1 to remove TNFR1 from the plasma membrane. This is expected to increase cytokine sensitivity, resulting in worse outcome after stroke. We investigated the effect of LRP1 on astrocyte TNFα signaling and response in immortalized ApoE null mouse astrocytes subjected to lentiviral-mediated knockdown of LRP1. The astrocyte response to TNFα stimulation was tested in a time dependent manner using Western blotting of NFkB pathway components, which are the downstream mediators of TNFα signaling. We also tested astrocyte viability after prolonged TNFα stimulation using Alamar Blue reagent. We found that LRP1 deficient cells have increased phosphorylation of NFkB upon TNFα stimulation, and that loss of LRP1 resulted in significant loss of astrocyte viability after prolonged stimulation. RESULTS/ANTICIPATED RESULTS: Altogether, our results indicate that loss of LRP1 renders astrocytes more sensitive to TNFα. Future experiments will focus on testing the influence of LRP1 on recovery after middle cerebral artery occlusion in mice. DISCUSSION/SIGNIFICANCE OF IMPACT: These studies will elucidate how astrocyte-LRP1 contributes to outcome after stroke, and helps us to understand one potential way that ApoE4 exerts pathological effects. A better understanding of the long-term processes after stroke will allow identification of therapies which improve the morbidity and mortality associated with stroke. CONFLICT OF INTEREST DESCRIPTION: NA.
4535 Development of a Mouse Model to study interactions between parental history of alcohol use and early life adversity on behavioral and neurobiological development of offspring
Authors: Porter Grace , Morales Juan , Valdespino Roslyn , Acheson Ashley , O’Connor Jason
Published: July 2020

OBJECTIVES/GOALS: Individuals with a family history of alcoholism (FH+) are more likely to develop an alcohol use disorder than those with no such history. Early life adversity has a high coincidence with FH+ making pathogenic studies difficult in clinical studies. Here, we developed a mouse model to study pathogenic mechanisms underlying these risk factors. METHODS/STUDY POPULATION: Male and female C57BL6/J mice were exposed to increasing concentrations of ethanol (3-21%) or water for 15 days prior to breeding. Ethanol was not present during gestation. Offspring were either removed from the home cage and isolated for 3 hours or left undisturbed from postnatal days 1-21. Beginning on PND 56 offspring mice were assessed for clinically relevant behavioral disruptions in social behavior, cognitive working memory, locomotor activity, anxiety-like phenotypes, ethanol preference and binge drinking behavior. In a separate experiment, brains of Cx3cr2+/GFPxCcr2+/RFP mice from ELA or control conditions were collected every 7 days after birth for assessment of neuroinflammation and central immune cell morphology and density. RESULTS/ANTICIPATED RESULTS: Mice with a family history of ethanol exposure and ELA are predicted to exhibit behavioral changes (impaired working memory, reduced social behavior, increased anxiety-like behaviors, increased ethanol consumption) to a greater extent than mice with a family history of ethanol exposure or ELA alone. We expect markers of neuroinflammation (cytokine expression, immune cell activation) to predict the behavioral changes in these mice. DISCUSSION/SIGNIFICANCE OF IMPACT: Alcohol consumption and stressful life events are known environmental precipitants to neuroinflammation, which in turns may predispose individuals to anti-social and risky behavior. A mouse model of these early postnatal conditions will allow basic scientists to unravel the biological underpinnings of the behaviors driven by these factors.
4579 Distinct clinical and immunological responses to αPD-1, kαPD-L1 and αPD-L2 immunotherapy in B16 melanoma in aged versus young hosts includes T-cell stem cell effects and PD-L2 expression differences
Authors: Garcia Myrna G , Padron Alvaro , Deng Yilun , Gupta Harshita , Kancharla Aravind , Reyes Ryan , Curiel Tyler
Published: July 2020

OBJECTIVES/GOALS: Aging is the biggest risk factor for cancer, yet little is known about cancer immunotherapy effects. Here we investigate melanoma response to αPD-1, αPD-L1 and αPD-L2 in young vs. aged hosts. We look at different immune outcomes as possible mechanism. METHODS/STUDY POPULATION: We tested αPD-1 (100 μg/mouse), αPD-L1 (100 μg/mouse) or αPD-L2 (200 μg/mouse) in aged (18-24 months) and young (3-8 months) mice challenged orthotopically with B16. Tumors and draining lymph nodes (TDLN) were analyzed by flow. Bone marrow-derived DC were generated with GM-CSF. RESULTS/ANTICIPATED RESULTS: We reported that αPD-1 treats young and aged with B16 and αPD-L1 only treats young. aPD-L2 treated B16 in aged but, remarkably, not young, the first anti-cancer single agent immunotherapy exhibiting this property. Efficacy in young (aPD-1, aPD-L1) and aged (aPD-1, aPD-L2) correlated with increased T cell stem cells (TCSC) and total tumor-infiltrating lymphocytes (TIL), but TCSC differed by age and treatment (e.g., distinct CCR2, CXCR5, CXCR3, PD-1 and TIM- expression). Aged expressed significantly more T-cell PD-1 and up to 40-fold more PD-L2 versus young in myeloid and NK cells, and TCSC. Bone marrow-derived DC experiments suggest aged DC are destined for high PD-L2 versus young. DISCUSSION/SIGNIFICANCE OF IMPACT: Treatment differences in aged vs. young could depend on immune checkpoint or TCSC differences. We are now identifying mechanisms for increased PD-L2 and contributions to aPD-L2 efficacy in aged, and testing TCSC effects. Our work can improve cancer immunotherapy in aged hosts and further provide important insights even in young hosts.
4165 Mechanisms of Prophage-Mediated Virulence Driving Community-Acquired MRSA Contagion
Authors: Ulrich Robert James , Irnov Irnov , Sause William , Podkowik Magdelena , Torres Victor , Shopsin Bo
Published: July 2020

OBJECTIVES/GOALS: We recently identified a CA-MRSA strain in Brooklyn, New York (USA300-BKV) causing an outbreak of severe skin infections in predominantly healthy children. The evolution of USA300-BKV included acquisition of a novel prophage, and our objective is to identify the prophage-encoded gene(s) and mechanism responsible for increased bacterial virulence. METHODS/STUDY POPULATION: We deleted candidate genes from a novel mosaic block of phage-encoded genes in USA300-BKV that have been shown to enhance virulence in a murine skin infection model. Deletion mutants and complemented clones will be evaluated in vivo to identify culprit genes and determine the effect of lineage-specific genetic variation on the phenotype. Complementary studies include a comprehensive characterization of phage and bacterial genes expressed during lysogeny in vitro using RNA sequencing (RNA-Seq), and in vivo using a targeted approach focusing on known bacterial virulence and phage lytic pathways as well as candidate genes identified by in vitro studies. RESULTS/ANTICIPATED RESULTS: Comparison of otherwise isogenic lab strains showed that the mosaic block of phage genes present in USA300-BKV enhance skin abscess size in mice, confirming previous results. As this region of the phage, named mΦ11, does not contain known toxin genes, we hypothesize that mΦ11 modulates expression of bacterial host genes to enhance virulence. Thus, transcriptional profiles of CA-MRSA containing mΦ11 and selected deletion mutants are expected to reveal changes in known or novel virulence factors compared to controls. Candidate regulators specific to the mosaic block include an adenine methyltransferase linked to changes in global gene expression of other bacterial species. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results will broaden scientific understanding of phage-bacterial interactions and determine the mechanisms by which phage impact virulence independent from toxin gene carriage. Identification of phage-encoded gene(s) enhancing CA-MRSA contagion will inform surveillance efforts and identify novel therapeutic targets.
4478 Not just GLUT1: genome sequencing reveals genetic heterogeneity in Doose syndrome
Authors: Calhoun Jeffrey Dennis , Gunti Jonathan , Angione Katie , Geiger Elizabeth , Eschbach Krista , Smith Garnett , Joshi Charuta , Shaikh Tamim , Demarest Scott , Carvill Gemma
Published: July 2020

OBJECTIVES/GOALS: Epilepsy with myoclonic-atonic seizures (EMAS) is a childhood onset epilepsy disorder characterized by seizures with sudden loss of posture, or drop seizures. Our objective was to use short-read genome sequencing in 40 EMAS trios to better understand variants contributing to the development of EMAS. METHODS/STUDY POPULATION: Eligibility for the cohort included a potential diagnosis of EMAS by child neurology faculty at Children’s Hospital Colorado. Exclusion criteria included lack of drop seizures upon chart review or structural abnormality on MRI. Some individuals had prior genetic testing and priority for genome sequencing was given to individuals without clear genetic diagnosis based on previous testing. We analyzed single nucleotide variants (SNVs), small insertions and deletions (INDELs), and larger structural variants (SVs) from trio genomes and determined those that were likely contributory based on standardized American College of Medical Genetics (ACMG) criteria. RESULTS/ANTICIPATED RESULTS: Our initial analysis focused on variants in coding regions of known epilepsy-associated genes. We identified pathogenic or likely pathogenic variants in 6 different individuals involving 6 unique genes. Of these, 5 are de novo SNVs or INDELs and 1 is a de novo SV. One of these involve a de novo heterozygous variant in an X-linked gene (ARHGEF9) in a female individual. We hypothesize the skewed X-inactivation may result in primarily expression of the pathogenic variant. We anticipate identifying additional candidate variants in coding regions of genes previously not associated with EMAS or pediatric epilepsies as well as in noncoding regions of the genome. DISCUSSION/SIGNIFICANCE OF IMPACT: Despite the genetic heterogeneity of EMAS, our initial analysis identified de novo pathogenic or likely pathogenic variants in 15% (6/40) of our cohort. As the cost continues to decline, short read genome sequencing represents a promising diagnostic tool for EMAS and other pediatric onset epilepsy syndromes. CONFLICT OF INTEREST DESCRIPTION: The authors have no conflicts of interest to disclose. SD has consulted for Upsher-Smith, Biomarin and Neurogene on an unrelated subject matter. GLC holds a research collaborative grant with Stoke therapeutics on unrelated subject matter.
THE EXACT STRENGTH OF THE CLASS FORCING THEOREM
Authors: GITMAN VICTORIA , HAMKINS JOEL DAVID , HOLY PETER , SCHLICHT PHILIPP , WILLIAMS KAMERYN J.
Published: July 2020

The class forcing theorem, which asserts that every class forcing notion
${\mathbb {P}}$
admits a forcing relation
$\Vdash _{\mathbb {P}}$
, that is, a relation satisfying the forcing relation recursion—it follows that statements true in the corresponding forcing extensions are forced and forced statements are true—is equivalent over Gödel–Bernays set theory
$\text {GBC}$
to the principle of elementary transfinite recursion
$\text {ETR}_{\text {Ord}}$
for class recursions of length
$\text {Ord}$
. It is also equivalent to the existence of truth predicates for the infinitary languages
$\mathcal {L}_{\text {Ord},\omega }(\in ,A)$
, allowing any class parameter A; to the existence of truth predicates for the language
$\mathcal {L}_{\text {Ord},\text {Ord}}(\in ,A)$
; to the existence of
$\text {Ord}$
-iterated truth predicates for first-order set theory
$\mathcal {L}_{\omega ,\omega }(\in ,A)$
; to the assertion that every separative class partial order
${\mathbb {P}}$
has a set-complete class Boolean completion; to a class-join separation principle; and to the principle of determinacy for clopen class games of rank at most
$\text {Ord}+1$
. Unlike set forcing, if every class forcing notion
${\mathbb {P}}$
has a forcing relation merely for atomic formulas, then every such
${\mathbb {P}}$
has a uniform forcing relation applicable simultaneously to all formulas. Our results situate the class forcing theorem in the rich hierarchy of theories between
$\text {GBC}$
and Kelley–Morse set theory
$\text {KM}$
.
“Real Good and Sincere Catholics”: White Catholicism and Massive Resistance to Desegregation in Chicago, 1965–1968
Authors: Cressler Matthew J.
Published: July 2020

Although the civil rights movement has long been framed as a pivotal turning point in twentieth-century U.S. religious history, comparatively little attention has been directed to the role of religion in what has been termed “the long segregation movement.” Likewise, Catholic historians tend to emphasize the exceptional few priests, sisters, and lay people committed to interracial justice over and against the majority of white Catholics who either opposed integration or objected to the means by which it would be achieved. This article argues that, in order to fully understand U.S. Catholicism in the twentieth century, scholars must reckon with the ways racial whiteness shaped the Catholicness of white Catholics. It takes as its primary source more than six hundred letters written by white Catholics outraged and disgusted over the Archdiocese of Chicago's apparent support for desegregation between 1965 and 1968. These letters not only illuminate the inseparability of religion and race, but they also reveal that white Catholicism itself operated as a religio-racial formation in the lives of white Catholics. Given the overwhelming white Catholic (and white religious) resistance to integration, this article argues that the long segregation movement and massive resistance to desegregation ought to be included as signal events in the telling of U.S. Catholic and U.S. religious history.
Antimodernism and Orthodox Judaism's Heretical Imperative: An American Religious Counterpoint
Authors: Eleff Zev , Farber Seth
Published: July 2020

This article argues that the case of religious authority within Orthodox Judaism is an important counterexample to the broader and understudied developments in American religion during the final decades of the twentieth century. Using an array of untapped primary sources and drawing on themes addressed by scholars of American religious history and modern Jewish history, this article demonstrates how Orthodox Jewish elites used “approximational heresies” to police their faith community. In so doing, Orthodox leaders furnished “indicators” of apostasy that were unknown in previous epochs and served to stand in for traditional types that proved otherwise insufficient to counteract new trends in modern life and culture. Orthodox Jewish “antimodernism” was animated by a need to demonstrate what was “in” and what was “out” of bounds as well as by the emergence of a triumphalism that was unique among American faiths. Likewise, the rank-and-file abided because they either agreed with these measures or feared becoming “outsiders.” This outlook contrasts with the attitudes of other religious groups—on the “left” and the “right”—that absorbed a spirit of “inclusiveness” and, therefore, eschewed heresy hunting and the boldness evinced by Orthodox elites during this period. The article concludes that the pervasiveness of this counterculture among the Orthodox Jewish community was so powerful that it, counterintuitively, introduced the strategies of the antimodernists to the American-acculturated, so-called Modern Orthodox community.
THE CASTLE OF ACHANDUIN, LISMORE—A POINT OF REFERENCE FOR THE RADIOCARBON ANALYSIS OF MORTAR-ENTRAPPED RELICT LIMEKILN FUELS
Authors: Thacker Mark
Published: July 2020

The results of a short program of landscape, buildings and materials analysis undertaken at Achanduin Castle, Lismore, Scotland (NM 8043 3927) are presented from the pilot phase of the Scottish Medieval Castles & Chapels C14 Project (SMCCCP). The study presents the first independent chronological evidence relating to the construction of this important medieval building, by radiocarbon analysis of a limited assemblage of Mortar-Entrapped Relict Limekiln Fuel (MERLF) fragments. Informed by a wider investigation of structural phasing and sample taphonomy, these measurements are constrained within a series of different Bayesian models, to generate a range of comparative estimates for the building’s constructional chronology. The precision with which the construction of this building can now be dated, from other evidence associated with the site, makes the Achanduin Castle study a useful point of reference for wider materials research.
Pharyngeal closure after a total laryngectomy: mechanical versus manual technique
Authors: Sansa-Perna A , Casasayas-Plass M , Rovira-Martínez C , López-Vilas M , García-Lorenzo J , Quer-Agusti M , León-Vintró X
Published: July 2020

Objective

To verify the main advantages and drawbacks of mechanical suturing for pharyngeal closure after total laryngectomy versus a manual suturing technique.

Methods

A retrospective review was carried out of 126 total laryngectomies performed between 2008 and 2018. Manual closure was performed in 80 cases (63.5 per cent) and mechanical suturing was performed in 46 cases (36.5 per cent).

Results

Mechanical suturing was used significantly more frequently in patients with: glottic tumours (p = 0.008), less local tumour extension (p = 0.017) and less pre-operative morbidity (p = 0.014). There were no significant differences in the incidence of pharyngocutaneous fistula between the manual suture group (16.3 per cent) and the mechanical suture group (13.0 per cent) (p = 0.628). None of the patients treated with mechanical suturing had positive surgical margins. Cancer-specific survival for the mechanical suture group was higher than that for the manual suture group (p = 0.009).

Conclusion

Mechanical suturing of the pharynx after total laryngectomy is an oncologically safe technique if used in suitable cases.
The epistemological shift from palace chronicles to scholarly Khmer historiography under French colonial rule
Authors: Thun Theara
Published: July 2020

Identifying the role of colonial-sponsored institutions and written texts produced by local scholars, this article argues that, although Cambodian scholars’ intellectual orientation was not necessarily restricted to French scholarship, French colonial rule had played the key role in introducing modern historiography and creating the platforms for the epistemological transition in Cambodia which underwent different categories of knowledge adoption and various projects of translation of local individuals. Capturing the dynamic of the epistemological transition allows us to highlight a broader picture of the interplay between a long-existing body of knowledge and more contemporary scholarship under Western colonisation.
Recent publications on Indonesian manuscripts
Authors: Acri Andrea
Published: July 2020

The fascinating yet still underexplored world of manuscripts hailing from Southeast Asia, including the nation-state of Indonesia, has received some impetus in recent years, thanks to the new appreciation for this written heritage by state and non-state actors both within and without the country. Traditionally perceived as a dry (and hardly scientific or ‘intellectual’) subject that was the preserve of a small circle of specialist librarians, codicology (and Asian codicology in particular) has become a vibrant discipline, with several teams of scholars and projects worldwide focusing on manuscripts as objects, as well as on ‘manuscript cultures’. These projects and approaches duly recognise the role of manuscripts (and not onlytexts) as prime carriers of cultural and civilisational values across time and space, as well as their relevance for the culture and identity of contemporary societies. This essay reviews some recent publications on Indonesian manuscripts catering to researchers as well as the wider public.
Genetic variability in thePhysconia muscigenagroup (Physciaceae, Ascomycota) in the Northern Hemisphere
Authors: Starosta Jakub , Svoboda David
Published: July 2020

The principal goal of our study was to test whether ecologically and chemically different populations of lichens in thePhysconia muscigenagroup belong to a single, or multiple, species. We used sequence data from three markers (ITS rDNA, mtSSU rDNA and TEF1-α) for the reconstruction of phylogenetic trees based on a sampling of mostly European and Canadian populations ofP. muscigena(Ach.) Poelt,P. muscigenavar.bayeri(Nádv.) Poelt andP. isidiomuscigenaEssl. In addition, we sought any possible geographical or ecological trends among chemotypes and haplotypes. Results show that: 1) sequence data of ITS rDNA and TEF1-α show large genetic variation in thePhysconia muscigenagroup, which does not correlate with geographical distribution or thallus chemistry; 2)Physconia muscigenavar.bayeriandP. isidiomuscigenaappear undifferentiated withP. muscigenain our phylogenetic trees, and the three species cannot be distinguished on the basis of ITS rDNA, mtSSU rDNA and TEF1-α sequences. We therefore synonymizedPhysconia muscigenavar.bayeriwithP. muscigenaand we recombineP. isidiomuscigenaas a variety ofP. muscigena.
Contributions to the lichen genus Cresponea (Roccellaceae)
Authors: Kantvilas Gintaras
Published: July 2020

Two Tasmanian species of the genus Cresponea are treated: C. graemeannae Kantvilas sp. nov., characterized by a very thin, saxicolous thallus, apothecia with a thick, radially fissured margin, thinly pruinose disc, hypothecium inspersed with oil droplets, and 5–9-septate ascospores, 25–40 × 6–8 μm; and C. subpremnea (Kantvilas & Vĕzda) Kantvilas comb. nov. The latter has ascospores 30–58 × 4.5–7 μm, which distinguish it from the related C. plurilocularis (Nyl.) Egea & Torrente (ascospores 27–45 × 6–8 μm). The taxa are illustrated, discussed and compared. Cresponea litoralis Elix, based on an Australian type, is considered a synonym of Bactrospora myriadea (Fée) Egea & Torrente. A key to the species of Cresponea reported from Australia is presented.
A new species of Synarthonia from Luxembourg, and a new combination in the genus Reichlingia (Arthoniaceae)
Authors: Ertz Damien , Aptroot André , Sanderson Neil , Coppins Brian , Van den Broeck Dries , Diederich Paul
Published: July 2020

A new species of Synarthonia, S. leproidica, is described from Luxembourg. Phylogenetic analyses of mtSSU and RPB2 sequences were used to determine the generic affiliation of this sterile species. Synarthonia leproidica differs from all other species of the genus by the combination of a leproid thallus and the production of psoromic acid. It is the sister species to S. muriformis in our phylogenetic analyses. The discovery of the new species suggests that other strictly sorediate lichen species might have been overlooked in Europe, even in intensely explored countries such as Luxembourg. Phylogenetic analyses further confirm the placement of Reichlingia anombrophila in the genus Reichlingia and of Synarthonia astroidestera in the genus Synarthonia. Arthonia atlantica is transferred to the genus Reichlingia as R. dendritica.
Integrative omics analysis identifies differential biological pathways that are associated with regional grey matter volume changes in major depressive disorder
Authors: Sha Zhiqiang , Banihashemi Layla
Published: July 2020

Background

Major depressive disorder (MDD) is accompanied by alterations in grey matter volume. However, the biological processes associated with regional structural perturbations remain elusive.

Methods

We applied integrative omics analysis to investigate specialized transcriptome signatures and translational determinants associated with regional grey matter variations in 2737 MDD patients relative to 3098 controls by summarizing the results from gene co-expression network analysis of Allen human brain transcriptome profiles in six donors, enrichment analysis of gene-sets and cellular structure from rodents and mediation analysis of BrainSpan proteome profile in six donors.

Results

We found convergent alterations of grey matter volume in MDD were associated with transcriptome profiles enriched for synaptic transmission, metabolism, immune processes and transmembrane transport. Genes with abnormal expression in post-mortem tissue in MDD were also associated with transcriptome signatures. Further gene co-expression network and enrichment analysis of MDD-related genes in these signatures revealed the modules with higher neuronal expression were enriched in the medial temporal cortex and temporo-parietal junction with genes differentially associated with neuronal development and metabolism. Also, the modules with higher non-neuronal (e.g. astrocyte and oligodendrocyte) expression were concentrated in the rostral and dorsal anterior cingulate cortex and were separately associated with immune response and transmembrane transport. Moreover, proteins as the gene expression products mediated the association between transcriptome signatures and brain volume changes in the visual and dorsolateral prefrontal cortex.

Conclusions

Our multidimensional analyses offer a novel approach to detect specific biological pathways that capture regional structural variations in MDD, which suggests structural endophenotypes associated with MDD.
Why do patients with psychosis listen to and believe derogatory and threatening voices? 21 reasons given by patients
Authors: Sheaves Bryony , Johns Louise , Griffith Laura , Isham Louise ,   The McPin Hearing Voices Lived Experience Advisory Panel, Kabir Thomas , Freeman Daniel
Published: July 2020

Background:

Around two-thirds of patients with auditory hallucinations experience derogatory and threatening voices (DTVs). Understandably, when these voices are believed then common consequences can be depression, anxiety and suicidal ideation. There is a need for treatment targeted at promoting distance from such voice content. The first step in this treatment development is to understand why patients listen to and believe voices that are appraised as malevolent.

Aims:

To learn from patients their reasons for listening to and believing DTVs.

Method:

Theoretical sampling was used to recruit 15 participants with non-affective psychosis from NHS services who heard daily DTVs. Data were obtained by semi-structured interviews and analysed using grounded theory.

Results:

Six higher-order categories for why patients listen and/or believe voices were theorised. These were: (i) to understand the voices (e.g. what is their motive?); (ii) to be alert to the threat (e.g. prepared for what might happen); (iii) a normal instinct to rely on sensory information; (iv) the voices can be of people they know; (v) the DTVs use strategies (e.g. repetition) to capture attention; and (vi) patients feel so worn down it is hard to resist the voice experience (e.g. too mentally defeated to dismiss comments). In total, 21 reasons were identified, with all participants endorsing multiple reasons.

Conclusions:

The study generated a wide range of reasons why patients listen to and believe DTVs. Awareness of these reasons can help clinicians understand the patient experience and also identify targets in psychological intervention.
Energy drink intake is associated with insomnia and decreased daytime functioning in young adult females
Authors: Trapp Georgina SA , Hurworth Miriam , Jacoby Peter , Maddison Kathleen , Allen Karina , Martin Karen , Christian Hayley , Ambrosini Gina L , Oddy Wendy , Eastwood Peter R
Published: July 2020

Objective:

To investigate the association between energy drink (ED) use and sleep-related disturbances in a population-based sample of young adults from the Raine Study.

Design:

Analysis of cross-sectional data obtained from self-administered questionnaires to assess ED use and sleep disturbance (Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire (FOSQ-10) and the Pittsburgh Sleep Symptoms Questionnaire–Insomnia (PSSQ-I)). Regression modelling was used to estimate the effect of ED use on sleep disturbances. All models adjusted for various potential confounders.

Setting:

Western Australia.

Participants:

Males and females, aged 22 years, from Raine Study Gen2–22 year follow-up.

Results:

Of the 1115 participants, 66 % were never/rare users (i.e. once/month to <once/week) and 17 % were frequent users (≥once/week). Compared with females, a greater proportion of males used ED occasionally (19 %v. 15 %) or frequently (24 %v. 11 %). Among females, frequent ED users experienced significantly higher symptoms of daytime sleepiness (FOSQ-10:β= 0·93, 95 % CI 0·32, 1·54,P= 0·003) and were five times more likely to experience insomnia (PSSQ-I: OR = 5·10, 95 % CI 1·81, 14·35,P= 0·002) compared with never/rare users. No significant associations were observed in males for any sleep outcomes.

Conclusions:

We found a positive association between ED use and sleep disturbances in young adult females. Given the importance of sleep for overall health, and ever-increasing ED use, intervention strategies are needed to curb ED use in young adults, particularly females. Further research is needed to determine causation and elucidate reasons for gender-specific findings.
Changes to dietary and health outcomes following implementation of the 2012 updated US Department of Agriculture school nutrition standards: analysis using National Health and Nutrition Examination Survey, 2005–2016
Authors: Jia Jenny , Moore Lynn L , Cabral Howard , Hanchate Amresh , LaRochelle Marc R
Published: July 2020

Objective:

In 2012, the US government overhauled school nutrition standards, but few studies have evaluated the effects of these standards at the national level. The current study examines the impact of the updated school nutrition standards on dietary and health outcomes of schoolchildren in a nationally representative data set.

Design:

Difference-in-differences. We compared weekday fruit and vegetable intake between students with daily school lunch participation and students without school lunch participation before and after implementation of updated school nutrition standards using a multivariable linear regression model. Secondary outcomes included weekday solid fat and added sugar (SoFAS) intake and overweight and obesity prevalence. We adjusted analyses for demographic and family socio-economic factors.

Setting:

USA.

Participants:

K-12 students, aged 6–20 years (n 9172), from the National Health and Nutrition Examination Survey, 2005–2016.

Results:

Implementation of updated school nutrition standards was not associated with a change in weekday fruit and vegetable intake (β = 0·02 cups, 95 % CI −0·23, 0·26) for students with daily school lunch participation. However, implementation of the policy was associated with a 1·5 percentage point (95 % CI −3·0, −0·1) decline in weekday SoFAS intake and a 6·1 percentage point (95 % CI −12·1, −0·1) decline in overweight and obesity prevalence.

Conclusions:

Changes to US school nutrition standards were associated with reductions in the consumption of SoFAS as well as a decrease in overweight and obesity in children who eat school lunch. However, we did not detect a change in weekday intake of fruits and vegetables associated with the policy change.
The Democracy of Dating: How Political Affiliations Shape Relationship Formation
Authors: Easton Matthew J. , Holbein John B.
Published: July 2020

How much does politics affect relationship building? Previous experimental studies have come to vastly different conclusions – ranging from null to truly transformative effects. To explore these differences, this study replicates and extends previous research by conducting five survey experiments meant to expand our understanding of how politics does/does not shape the formation of romantic relationships. We find that people, indeed, are influenced by the politics of prospective partners; respondents evaluate those in the political out-group as being less attractive, less dateable, and less worthy of matchmaking efforts. However, these effects are modest in size – falling almost exactly in between previous study estimates. Our results shine light on a literature that has, up until this point, produced a chasm in study results – a vital task given concerns over growing levels of partisan animus in the USA and the rapidly expanding body of research on affective polarization.
Suicide Deaths in University Students in a UK City Between 2010 and 2018 – Case Series
Authors: McLaughlin Joanna C. , Gunnell David
Published: July 2020

Abstract. Background: There are longstanding concerns over the mental health and suicide risk of university students in the UK and internationally. Aims: This study aimed to identify risk factors for suicide among students attending universities in a UK city. Method: Suicide deaths between January 2010 and July 2018 were identified from university records. An audit tool was used to collate data from university records and coroners' inquest files. Results: A total of 37 student deaths were identified. Only 10.8% of the students had disclosed a mental health issue at university entry. There was strong statistical evidence that students who died by suicide were more likely to have been male, experiencing academic difficulties (repeated years, changing course, and suspension of studies were all associated with a 5–30-fold increased risk), and in need of financial support compared with other students. Limitations: The coroners' records were only available for around half of the deaths. Healthcare records were not available. Conclusion: Markers of academic and financial difficulty should be considered as flags to identify students at heightened risk. Whilst the relative risk associated with academic difficulties is high, the absolute risk is low. Improved disclosure of mental health issues at university registration could facilitate targeted support for vulnerable students.
Process Accountability as a De-Escalation Technique
Authors: Moser Klaus , Wolff Hans-Georg , Soucek Roman
Published: July 2020

Abstract. Escalation of commitment occurs when a course of action is continued despite repeated drawbacks (e.g., maintaining an employment relationship despite severe performance problems). We analyze process accountability (PA) as a de-escalation technique that helps to discontinue a failing course of action and show how time moderates both the behavioral and cognitive processes involved: (1) Because sound decisions should be based on (hopefully unbiased) information search, which requires time to gather, the effect of PA on de-escalation increases over time. (2) Because continuing information search creates behavioral commitment, the debiasing effect of PA on information search diminishes over time. (3) Consistent with the tunnel vision notion, the effects of less biased information search on de-escalation decrease over time.
COVID-19 Lockdown Reduces Forest Fires in the Western Himalayas
Authors: Supriya Lakshmi
Published: July 2020

The overlap between peak fire season and pandemic response has made for a serendipitous experiment in forest fires in two Indian states. Humans, not lightning, seem to be the likeliest culprit.
Dominant Roles of High Harmonics on Interactions Between AKR and Radiation Belt Relativistic Electrons
Authors: Zhang Sai , Shang Xiongjun , He Yihua , Liu Si , Xiao Fuliang
Published: July 2020

Auroral kilometric radiations (AKR) are widely existing superluminous waves in the magnetosphere. Due to rarely available measurements of AKR magnetic field components, we derive the explicit expression of diffusion coefficients in terms of electric field components, which can be applied to various space plasma waves. Using Van Allen Probes data, we calculate diffusion coefficients with different harmonic orders for two AKR events. It is found that the first (higher) harmonic order contributes to diffusion coefficients at small (larger) pitch angles. The effect of higher harmonic orders becomes more significant as the electron energy increases. These results are contrary to the case of chorus wave, in which the first order usually contributes much to wave‐particle interactions. Estimations show that the phase space density of 0.5 MeV electrons can increase ∼10 times within 6 hr by AKR. This study is important for better modeling of AKR‐induced radiation belt electron dynamics.
Revisit the Analytical Approximation of Transit‐Time Scattering for Fast Magnetosonic Waves
Authors: Yu Xiongdong , Yuan Zhigang , Yu Jiang
Published: July 2020

Nonresonant interactions between fast magnetosonic waves and magnetospheric particles have obtained more and more attention. Through such nonresonant interactions, magnetosonic waves can lead to the so‐called transit‐time scattering on particles. The previous analytical approximation has been demonstrated capable of capturing the main results of test particle simulations but takes a computation time about 4 order of magnitude faster than the latter. However, the typical ripples in the diffusion coefficient maps are usually left out. In this paper, we have first discussed the reason for the lack of these typical ripples produced by previous analytical approximation. Then the previous algorithm has been modified to be capable of producing typical ripples in the electron diffusion coefficient maps. Our new analytical expression can be applied to wave models with a Gaussian distribution or a rectangular distribution in wave amplitude. Finally, it is shown that the modified algorithm can be also applied to ring current protons.
Constraints on Thermal History of Mars From Depth of Pore Closure Below InSight
Authors: Gyalay Szilárd , Nimmo Francis , Plesa Ana‐Catalina , Wieczorek Mark
Published: July 2020

Planetary crusts undergo viscous closure of pores at depth; if the thickness of this porous layer can be measured, constraints on crustal thermal evolution can be derived. We apply a pore closure model developed for the Moon to Mars and take into account the geological processes that may alter the depth of this transition region. If the 8–11 km deep discontinuity in seismic wave speed detected by the InSight lander marks the base of the porous layer, the heat flux at the time the porosity was created must have exceed 60 mW m−2, probably indicating a time prior to 4 Ga.
New Insights Into the Vertical Structure of Clouds in Polar Lows, Using Radar‐Lidar Satellite Observations
Authors: Listowski C. , Rojo M. , Claud C. , Delanoë J. , Rysman J.‐F. , Cazenave Q. , Noer G.
Published: July 2020

For the first time, we characterize the vertical distribution of cloud microphysical properties in polar lows (PLs). We base our investigation on colocations found between A‐Train satellites overpasses and 82 PL occurrences evidenced from AVHRR observations in the Nordic Seas. We use the raDAR/liDAR DARDAR satellite cloud products to retrieve the thermodynamic phase and ice microphysical properties of clouds (ice water content [IWC] and ice crystal effective radius [reff]). Two thirds of the investigated PLs show cloud tops higher than commonly documented (5 km), and up to 9 km. PLs are largely dominated by the ice phase, with more supercooled liquid occurrences in the eye. We also show that spiraliform clouds have larger average IWC in the few kilometers below cloud top, by up to a factor of 2, compared to comma‐shaped PLs.
Modulation by ENSO of the Relationship Between Stratospheric Sudden Warming and the Madden‐Julian Oscillation
Authors: Ma Ji , Chen Wen , Nath Debashis , Lan Xiaoqing
Published: July 2020

The ENSO modulation on the relationship between the Madden‐Julian Oscillation (MJO) and major stratospheric sudden warming (SSW) in the Northern Hemisphere winter is analyzed. The results indicate that the statistical relationship between the MJO and SSWs is robust during La Niña years but almost nonexistent during El Niño years. During La Niña years, a significant response of stratospheric temperature appears after certain MJO phases with a distribution consistent with MJO periodicity, whereas the response becomes nonsignificant during El Niño years. Further analysis indicates that ENSO influences the MJO‐related geopotential height anomalies in middle to high latitudes of the upper troposphere, which leads to an increase in wavenumber 2 in La Niña winters. And wavenumber 2 plays a key role in generating the strong heat flux anomalies in the stratosphere. The results may help to explain the more frequent occurrence of extreme events in the stratosphere, such as SSW during La Niña winters.
The Boundary of Alkali Surface Boundary Exospheres of Mercury and the Moon
Authors: Sarantos M. , Tsavachidis S.
Published: July 2020

Global exosphere models of alkali gases surrounding Mercury and the Moon assume that the primary effect of the porous soil is to reduce the effective desorption rates. We demonstrate with a kinetic simulation that, following adsorption, the complicated structure of soils has two additional effects on the fate of previously released alkali atoms: (1) trapping of free atoms at lunar temperatures by microscopic shadows and inward diffusion, which becomes the primary sink mechanism, and (2) high‐energy barriers for thermal desorption compared to what would be retrieved from experiments on thin films or compacted pellets, especially when surface diffusion of adsorbates is considered. Lunar soils retain one fifth to two thirds of recycled adsorbates, depending on the assumed adsorbate mobility, photodesorption cross section, and soil thermal gradient. A transition from a retentive surface to full outgassing at T > 500 K will produce complex feedback mechanisms of alkali circulation at Mercury.
A Satellite‐Detected Terrestrial Gamma Ray Flash Produced by a Cloud‐to‐Ground Lightning Leader
Authors: Pu Yunjiao , Cummer Steven A. , Huang Anjing , Briggs Michael , Mailyan Bagrat , Lesage Stephen
Published: July 2020

We report measurements of a terrestrial gamma ray flash (TGF) detected by the Fermi Gamma‐ray Burst Monitor that was produced during a negative cloud‐to‐ground (CG) lightning leader. This is the first report of a downward directed TGF occurring during a CG flash but detected by a space‐based instrument. The gamma ray photons are produced 3 ms preceding a return stroke (−146 kA) and are essentially simultaneous with an isolated low frequency radio pulse. Based on timing, the pulse is estimated to initiate at approximately 6 km altitude, and its polarity indicates downward moving negative charge, the opposite of regular satellite‐detected upward TGFs. A likely scenario is that the runaway electrons accelerate into the upper, positively charged end of the leader in a high field region, with the reverse positron beam generating upward gamma rays detectable from space. A search for similar waveform features indicates that this type of downward CG‐TGF may occur prior to 1% of high peak current CG strokes. Extrapolating gives a global rate of 5–10% of previously known TGFs and potentially a significant fraction of global TGFs.
Synaptic control of DNA methylation involves activity-dependent degradation of DNMT3A1 in the nucleus
Authors: Bayraktar Gonca , Yuanxiang PingAn , Confettura Alessandro D. , Gomes Guilherme M. , Raza Syed A. , Stork Oliver , Tajima Shoji , Suetake Isao , Karpova Anna , Yildirim Ferah , Kreutz Michael R.
Published: July 2020

DNA methylation is a crucial epigenetic mark for activity-dependent gene expression in neurons. Very little is known about how synaptic signals impact promoter methylation in neuronal nuclei. In this study we show that protein levels of the principal de novo DNA-methyltransferase in neurons, DNMT3A1, are tightly controlled by activation of N-methyl-D-aspartate receptors (NMDAR) containing the GluN2A subunit. Interestingly, synaptic NMDARs drive degradation of the methyltransferase in a neddylation-dependent manner. Inhibition of neddylation, the conjugation of the small ubiquitin-like protein NEDD8 to lysine residues, interrupts degradation of DNMT3A1. This results in deficits in promoter methylation of activity-dependent genes, as well as synaptic plasticity and memory formation. In turn, the underlying molecular pathway is triggered by the induction of synaptic plasticity and in response to object location learning. Collectively, the data show that plasticity-relevant signals from GluN2A-containing NMDARs control activity-dependent DNA-methylation involved in memory formation.
Molecular mechanisms and clinical management of cancer bone metastasis
Authors: Wang Manni , Xia Fan , Wei Yuquan , Wei Xiawei
Published: July 2020

As one of the most common metastatic sites of malignancies, bone has a unique microenvironment that allows metastatic tumor cells to grow and flourish. The fenestrated capillaries in the bone, bone matrix, and bone cells, including osteoblasts and osteoclasts, together maintain the homeostasis of the bone microenvironment. In contrast, tumor-derived factors act on bone components, leading to subsequent bone resorption or excessive bone formation. The various pathways involved also provide multiple targets for therapeutic strategies against bone metastases. In this review, we summarize the current understanding of the mechanism of bone metastases. Based on the general process of bone metastases, we specifically highlight the complex crosstalk between tumor cells and the bone microenvironment and the current management of cancer bone metastases.
Ex vivo editing of human hematopoietic stem cells for erythroid expression of therapeutic proteins
Authors: Pavani Giulia , Laurent Marine , Fabiano Anna , Cantelli Erika , Sakkal Aboud , Corre Guillaume , Lenting Peter J. , Concordet Jean-Paul , Toueille Magali , Miccio Annarita , Amendola Mario
Published: July 2020

Targeted genome editing has a great therapeutic potential to treat disorders that require protein replacement therapy. To develop a platform independent of specific patient mutations, therapeutic transgenes can be inserted in a safe and highly transcribed locus to maximize protein expression. Here, we describe an ex vivo editing approach to achieve efficient gene targeting in human hematopoietic stem/progenitor cells (HSPCs) and robust expression of clinically relevant proteins by the erythroid lineage. Using CRISPR-Cas9, we integrate different transgenes under the transcriptional control of the endogenous α-globin promoter, recapitulating its high and erythroid-specific expression. Erythroblasts derived from targeted HSPCs secrete different therapeutic proteins, which retain enzymatic activity and cross-correct patients’ cells. Moreover, modified HSPCs maintain long-term repopulation and multilineage differentiation potential in transplanted mice. Overall, we establish a safe and versatile CRISPR-Cas9-based HSPC platform for different therapeutic applications, including hemophilia and inherited metabolic disorders.