bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct detection of circulating microRNA-122 using dynamic chemical labelling with single molecule detection overcomes stability and isomiR challenges for biomarker qualification
Authors: López-Longarela Barbara , Morrison Emma E. , Tranter John D. , Chahman-Vos Lianne , Léonard Jean-François , Gautier Jean-Charles , Laurent Sébastien , Lartigau Aude , Boitier Eric , Sautier Lucile , Carmona-Saez Pedro , Martorell-Marugan Jordi , Mellanby Richard J. , Pernagallo Salvatore , Ilyine Hugh , Rissin David M. , Duffy David C. , Dear James W. , Díaz-Mochón Juan J.
Published: September 2019

Circulating microRNAs are biomarkers reported to be stable and translational across species. miR-122 (miR-122-5p) is a hepatocyte-specific microRNA biomarker for drug-induced liver injury (DILI). Our objective was to develop an extraction-free and amplification-free detection method for measuring miR-122 that has translational utility in context of DILI. We developed a single molecule dynamic chemical labelling (DCL) assay based on miR-122 hybridization to an abasic peptide nucleic acid probe that contained a reactive amine instead of a nucleotide at a specific position in the sequence. The single molecule DCL assay specifically measured miR-122 directly from 10 µL of serum or plasma without any extraction steps, with a fit-for-purpose limit of detection of 1.32 pM. In 192 human serum samples, DCL accurately identified patients at risk of DILI (area under ROC curve 0.98 (95%CI 0.96-1), P<0.0001). The miR-122 assay also quantified liver injury in rats and dogs. When DCL beads were added to serum, the miR-122 signal was stabilised (no loss of signal after 14 days at room temperature). By contrast, there was substantial degradation of miR-122 in the absence of beads (≈60% lost in 1 day). RNA sequencing demonstrated the presence of multiple miR-122 isomiRs with DILI that were at low concentration or not present in healthy patient serum. Sample degradation over time produced more isomiRs, particularly rapidly with DILI. PCR was inaccurate when analysing miR-122 isomiRs, whereas the DCL assay demonstrated accurate quantification. In summary, the DCL assay can accurately measure miR-122 directly from serum and plasma to diagnose liver injury in humans and other species, and can overcome important microRNA biomarker analytical and biological challenges.
Lipid droplet biogenesis is driven by liquid-liquid phase separation
Authors: Zoni Valeria , Khaddaj Rasha , Campomanes Pablo , Thiam Abdou Rachid , Schneiter Roger , Vanni Stefano
Published: September 2019

Cells store energy in the form of neutral lipids packaged into micrometer-sized organelles named lipid droplets (LD). These structures emerge from the endoplasmic reticulum (ER), but their biogenesis remains poorly understood. Using molecular simulations, we found that fat accumulation and LD formation are described by a liquid-liquid phase separation (LLPS) process. Within this framework, we could identify how ER membrane properties modulate LD formation, and we could directly test our computational predictions by combining yeast genetics with fluorescence microscopy. Our data suggest that the specific lipid composition of the ER together with its peculiar physical properties, such as low membrane tension and membrane curvature, promote the packaging of neutral lipids into LD, preventing their accumulation in the ER membrane. Our results provide a new conceptual understanding of LD biogenesis in the context of ER homeostasis and function.
Coupling chromatin structure and dynamics by live super-resolution imaging
Authors: Barth R. , Bystricky K. , Shaban H. A.
Published: September 2019

Chromatin conformation regulates gene expression and thus constant remodeling of chromatin structure is essential to guarantee proper cell function. To gain insight into the spatio-temporal organization of the genome, we employ high-density photo-activated localization microscopy and deep learning to obtain temporally resolved super-resolution images of chromatin in living cells. In combination with high-resolution dense motion reconstruction, we confirm the existence of elongated ~ 45 to 90 nm wide chromatin ‘blobs’. A computational chromatin model suggests that these blobs are dynamically associating chromatin fragments in close physical and genomic proximity and adopt TAD-like interactions in the time-average limit. Experimentally, we found that chromatin exhibits a spatio-temporal correlation over ~ 4 μm in space and tens of seconds in time, while chromatin dynamics are correlated over ~ 6 μm and last 40 s. Notably, chromatin structure and dynamics are closely related, which may constitute a mechanism to grant access to regions with high local chromatin concentration.
Isolation housing exacerbates Alzheimer’s Disease phenotype in aged APP KI mice
Authors: Laroy M , Saito T , Saido TC , D’Hooge R , Van der Jeugd A
Published: September 2019

In January 2018, Britain was the first in the world to adopt a Minister of Loneliness. This illustrates the changing view on loneliness: being lonely is not just a feeling of a lack of companionship, but also a serious health problem. For example, we know that loneliness is as bad as smoking 15 cigarettes a day. Moreover, research has shown that lonely people express higher levels of cortical amyloid. Amyloid burden is an important marker of Alzheimer’s Disease (AD), a chronic neurodegenerative disease and the main cause of dementia worldwide. Together with other findings a link between loneliness, (perceived) social isolation and AD is now undeniable, but it is hard to tell from human studies whether it is the cause or the effect of AD. We need standardized animal studies to answer this question.

In an effort to study how social isolation and AD interact, we used APP KI mice bearing human transgenes known to cause AD, and isolated part of the mice in order to mimic loneliness in late-life while part of them remained group-housed. We next looked at the effects of isolation on the behaviour and symptomatology typically present in AD patients to tap cognition.

Our study reveals mixed results. Results indicate that at before isolation, at the age of 16 and 24 months, APPNL/NLand APPNL-G-F/NL-G-Fmice do not differ to a significant extent on both the behavioural level. The APPNL-G-F/NL-G-Fdifferentiated slightly worse between the conditioned context and a new context compared to the APPNL/NLmice. However, the difference appeared to be more pronounced after a period of social isolation. Social isolation had distinct effects on the AD-related anxiogenic and dementia-like phenotype. Spatial learning in the MWM task revealed distinct differences between our two models. After isolation APPNL-G-F/NL-G-Fmice used less spatial search strategies, compared to control mice, thus reflecting perseveration and less behavioural flexibility due to the isolation period.
Massively parallel CRISPRi assays reveal concealed thermodynamic determinants of dCas12a binding
Authors: Specht David A. , Xu Yasu , Lambert Guillaume
Published: September 2019

The versatility of CRISPR-Cas endonucleases as a tool for biomedical research has lead to diverse applications in gene editing, programmable transcriptional control, and nucleic acid detection. Most CRISPR-Cas systems, however, suffer from off-target effects and unpredictable non-specific binding that negatively impact their reliability and broader applicability. To better evaluate the impact of mismatches on DNA target recognition and binding, we develop a massively parallel CRISPR interference (CRISPRi) assay to measure the binding energy between tens of thousands of CRISPR RNA (crRNA) and target DNA sequences. By developing a general thermodynamic model of CRISPR-Cas binding dynamics, our results unravel a comprehensive map of the energetic landscape of Francisella novicida Cas12a (FnCas12a) as it searches for its DNA target. Our results reveal concealed thermodynamic factors affecting FnCas12a DNA binding which should guide the design and optimization of crRNA that limit off-target effects, including the crucial role of an extended PAM sequence and the impact of the specific base composition of crRNA-DNA mismatches. Our generalizable approach should also provide a mechanistic understanding of target recognition and DNA binding when applied to other CRISPR-Cas systems.
Enhanced maturation of human stem cell derived interneurons by mTOR activation
Authors: Chu Jianhua , Fitzgerald Megan L. , Sehgal Neha , Manley William , Fitzgerald Shane , Naung Harrison , Goldberg Ethan M. , Anderson Stewart A.
Published: September 2019

The use of stem cell derived neurons for cell-based therapies is limited by a protracted maturation. We present a novel approach for accelerating the post-mitotic maturation of human stem cell derived interneurons via the activation of mTOR signaling. Lox sites were placed within PTEN, a key mTOR inhibitor, in a cortical interneuron (CIn) reporter line. Following directed differentiation and purification by FACS, the CIns were exposed to Cre-expressing lentivirus, then transplanted into mouse neocortex or plated onto cultured rat neocortex. Input synaptogenesis and dendritogenesis was greatly enhanced in the PTEN-deleted CIns. Whole-cell recording of the PTEN-deleted CIns in slices of transplanted neocortex revealed multiple indices of enhanced maturation. Finally, we observed similar effects using transient, doxycycline-inducible activation of AKT. We thus present an inducible, reversible approach for accelerating the maturation of human stem cell derived CIns, and to study the influences of this disease-related signaling system in human neurons.
Melanoma plasticity is controlled by a TRIM28-JUNB mediated switch
Authors: Nyberg William A , He Tianlin , Sjöstrand Maria , Velasquez-Pulgarin Diego A , Pellé Lucia , Covacu Ruxandra , Espinosa Alexander
Published: September 2019

The introduction of immune checkpoint blockade has revolutionized the treatment of metastatic melanoma1. However, 40-60% of patients with metastatic melanoma do not respond to immune checkpoint blockade, and a significant fraction of patients acquire resistance to treatment2,3. This resilience and aggressiveness of melanoma tumors is partly due to their ability to switch between invasive and proliferative states4,5. The transition between phenotypic states indicates that phenotype switching occurs through reversible epigenetic mechanisms rather than by acquisition of mutations6,7. Identifying the epigenetic mechanisms that underlie phenotype switching of melanoma cells could potentially lead to new therapeutic strategies. Here we report that the bromodomain protein TRIM28 (KAP1/TIF1β) regulates a JUNB dependent phenotypic switch in melanoma cells. Knockdown of TRIM28 in melanoma cells reduced the expression of pro-invasive YAP1 signature genes, and led to reduced invasiveness and lung colonization. In contrast, TRIM28 knockdown increased the expression of KRAS signature genes and promoted tumor growth. TRIM28 interacted with the transcriptional elongation factors CDK9 and HEXIM1, and negatively regulated the transcriptional elongation of JUNB by RNA polymerase II. Rescue experiments demonstrated that the effects of TRIM28 knockdown were directly mediated by JUNB. Mechanistically, JUNB played a pivotal role in phenotype switching by inhibiting the invasiveness of melanoma cells and increasing the growth of melanoma tumors. Our results contribute to the understanding of melanoma plasticity, and suggest that cancer drugs inhibiting the transcriptional elongation of RNA polymerase II should be carefully evaluated in melanoma to exclude the risk for increased metastasis.
Elevated levels of interleukin-27 in early life compromise protective immunity during neonatal sepsis
Authors: Seman Brittany G. , Vance Jordan K. , Rawson Travis W. , Witt Michelle R. , Huckaby Annalisa B. , Povroznik Jessica M. , Bradford Shelby D. , Barbier Mariette , Robinson Cory M.
Published: September 2019

Neonates are at increased risk for bacterial sepsis as a result of immature immunity. We established that the immune suppressive cytokine interleukin (IL)-27 is elevated in early life. In the present work, we hypothesized that increased levels of IL-27 may predispose the neonatal population to more severe infection during sepsis. In a neonatal sepsis model, systemic IL-27 levels continued to rise during infection. Peripheral tissue analysis revealed systemic IL-27 expression, while myeloid cell profiling identified Gr-1 and F4/80-expressing cells as the most abundant producers of IL-27 during infection. Increased IL-27 levels were consistent with increased mortality that was improved in WSX-1-/-mice that lack a functional IL-27 receptor. Infected WSX-1-/-pups exhibited improved weight gain and reduced morbidity. IL-27 signaling in WT mice promoted increased bacterial burdens and systemic inflammation compared to WSX-1-/-neonates. This was consistent with more efficient bacterial killing by Ly6B.2+myeloid cells and macrophages from WSX-1-deficient compared to wild-type neonates. Live animal imaging further supported a more severe and disseminated infection in WT neonates. This is the first report to describe the impact of elevated early life IL-27 on the host response in neonates while also defining the cell and tissue sources of cytokine. IL-27 is frequently associated with suppressed inflammation. In contrast, our findings demonstrate that IL-27 promotes inflammation during neonatal sepsis by directly compromising control of bacteria that drive the inflammatory response. Collectively, our results suggest that IL-27 represents a therapeutic target to limit susceptibility and improve infectious outcomes in neonatal sepsis.

IMPORTANCE

A number of differences in the neonatal immune response compared with adults have been well described. However, a mechanistic understanding of what needs to be overcome in the neonate to generate a more protective immune response during acute bacterial infection has been limited. The work described here helps fill the gap of what is necessary to overcome in order to achieve improved host response to infection. To further the novelty, IL-27 has not previously been attributed to dysfunction or deficiency in neonatal immunity. Our results enhance the understanding of IL-27 biology in the neonatal population while providing evidence that elevated IL-27 levels limit a protective immune response and are detrimental during neonatal sepsis. Strategies aimed at targeting circulating IL-27 concentrations early in life have the potential to improve control of bacterial infection in neonates.
Interleukin-33 promotes type 1 cytokine expression via p38 MAPK in human natural killer cells
Authors: Ochayon David E. , Ali Ayad , Alarcon Pablo C. , Krishnamurthy Durga , Kottyan Leah C. , Borchers Michael , Waggoner Stephen N.
Published: September 2019

This study tests the hypothesis that activation of mitogen-activated protein kinase (MAPK) by physiologically-relevant concentrations of interleukin-33 (IL-33) contributes to enhanced cytokine expression by IL-12 stimulated human natural killer (NK) cells. While IL-33 canonically triggers type 2 cytokine responses, this cytokine can also synergize with type 1 cytokines like IL-12 to provoke interferon-gamma (IFN-γ). We show that picogram concentrations of IL-12 and IL-33 are sufficient to promote robust secretion of IFN-γ by human NK cells that greatly exceeds responses to either cytokine alone. Nanogram doses of IL-33, potentially consistent with levels in tissue microenvironments, synergize with IL-12 to induce secretion of additional cytokines, including tumor necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). IL-33-induced activation of the p38 MAPK pathway in human NK cells is crucial for enhanced release of IFN-γ and TNF in response to IL-12. Mechanistically, IL-33-induced p38 MAPK signaling enhances stability ofIFNGtranscripts and triggers ADAM17-mediated cleavage of TNF from the cell surface. These data support our hypothesis and suggest that altered sensitivity of NK cells to IL-12 in the presence of IL-33 may have important consequences in diseases associated with mixed cytokine milieus, like asthma and chronic obstructive pulmonary disease.

Graphical Abstract
Boiling Acid Mimics Intracellular Giant Virus Genome Release
Authors: Schrad Jason R. , Abrahão Jônatas S. , Cortines Juliana R. , Parent Kristin N.
Published: September 2019

Since their discovery, giant viruses have expanded our understanding of the principles of virology. Due to their gargantuan size and complexity, little is known about the life cycles of these viruses. To answer outstanding questions regarding giant virus infection mechanisms, we set out to determine biomolecular conditions that promote giant virus genome release. We generated four metastable infection intermediates in Samba virus (lineage AMimiviridae) as visualized by cryo-EM, cryo-ET, and SEM. Each of these four intermediates reflects a stage that occursin vivo. We show that these genome release stages are conserved in other, diverse giant viruses. Finally, we identified proteins that are released from Samba and newly discovered Tupanvirus through differential mass spectrometry. Our work revealed the molecular forces that trigger infection are conserved amongst disparate giant viruses. This study is also the first to identify specific proteins released during the initial stages of giant virus infection.
Specific detection of Trichophyton rubrum and Trichophyton interdigitale based on loop‐mediated isothermal amplification (LAMP) from onychomycosis specimens
Authors: Watanabe Shinichi , Okubo Akihiro , Miyajima Yoshiharu , Satoh Kazuo , Makimura Koichi
Published: September 2019

In diagnosing onychomycosis, diseases with similar features must be excluded by demonstrating the presence of fungal infection and identifying the fungal species. However, fungal culture of onychomycosis‐derived samples usually takes many weeks to yield species identification results, and is associated with a low successful culture rate. Loop‐mediated isothermal amplification (LAMP) is a highly sensitive and specific molecular biological method that can amplify DNA at a constant temperature, allowing for a simpler testing procedure, shorter detection time and less cost than conventional techniques including quantitative polymerase chain reaction. We have developed a new LAMP method specifically to detect Trichophyton rubrum (T. rubrum) and Trichophyton interdigitale (T. interdigitale), major causative dermatophytes for onychomycosis, and analyzed the correlation between LAMP results and those of the existing fungal culture method for the detection and identification of Trichophyton species from onychomycosis‐derived samples. The results showed that all 59 specimens in which T. rubrum or T. interdigitale was identified by fungal culture also tested positive by LAMP, giving a 100% positivity concordance rate between the two methods. Moreover, all 55 and four specimens in which T. rubrum and T. interdigitale were identified by fungal culture, respectively, also tested positive for each species by LAMP, again giving a 100% species‐identification concordance rate. The high correlation demonstrated between LAMP and fungal culture results in detection and identification of Trichophyton species from onychomycosis‐derived samples suggests high reliability of LAMP as a promising, alternative mycological detection and identification technique which can serve as an alternative to the fungal culture method.
Enacting alcohol realities: gendering practices in Australian studies on ‘alcohol‐related presentations’ to emergency departments
Authors: Moore David , Keane Helen , Duncan Duane
Published: September 2019

‘Alcohol‐fuelled violence’ and its prevention has been the subject of recent intense policy debate in Australia, with the content of this debate informed by a surprisingly narrow range of research resources. In particular, given the well‐established relationship between masculinities and violence, the meagre attention paid to the role of gender in alcohol research and policy recommendations stands out as a critical issue. In this article, which draws on recent work in feminist science studies and science and technology studies, we focus on the treatment of gender, alcohol and violence in Australian research on ‘alcohol‐related presentations’ to emergency departments (EDs), analysing this type of research because of its prominence in policy debates. We focus on four types of ‘gendering practice’ through which research genders ‘alcohol‐related presentations’ to EDs: omitting gender from consideration, overlooking clearly gendered data when making gender‐neutral policy recommendations, rendering gender invisible via methodological considerations, and addressing gender in terms of risk and vulnerability. We argue that ED research practices and their policy recommendations reproduce normative understandings of alcohol's effects and of the operations of gender in social arrangements, thereby contributing to the ‘evidence base’ supporting unfair policy responses.
Triaging women with human papillomavirus infection and normal cytology or low‐grade dyskaryosis: evidence from 10‐year follow up of the ARTISTIC trial cohort
Authors: Gilham C , Sargent A , Peto J
Published: September 2019

Objectives

To estimate long‐term cervical intraepithelial neoplasia grade 3 (CIN3) risks associated with different triage strategies for human papillomavirus positive (HPV+) women with a view to reducing unnecessary referrals.

Design

The ARTISTIC trial cohort was recruited in Manchester in 2001–03 and was followed up for CIN3 and cancer notification through national registration until December 2015.

Results

The 10‐year cumulative risk of CIN3+ was much higher for women with HPV16/18 infection (19.4%, 95% CI 15.8–23.8% with borderline/low‐grade cytology and 10.7%, 95% CI 8.3–13.9% with normal cytology) than for those with other HPV types (7.3%, 95% CI 5.4–9.7% with borderline/low‐grade cytology and 3.2%, 95% CI 2.2–4.5% with normal cytology). Among the 379 women with normal to low‐grade cytology and new HPV infection, the 10‐year cumulative CIN3+ risk was 2.9% (95% CI 1.6–5.2%).

Conclusions

The CIN3 risk is confined to women with persistent type‐specific HPV so partial genotyping test assays identifying HPV16/18 as a minimum are essential for efficient risk stratification. Immediate referral to colposcopy for HPV+ women with borderline or low‐grade cytology and referral after a year if still HPV+ with normal cytology may be unnecessary. Low‐grade lesions can safely be retested to identify those with persistent HPV. Recall intervals of 1 year for HPV16/18 and 2 years for other high‐risk HPVs are justified for women with normal cytology and might also be considered for women with borderline/low‐grade cytology. The minimal risk of invasive cancer that has progressed beyond stage 1A must be weighed against the advantages for patients and the NHS of reducing the number of referrals to colposcopy.

Tweetable abstract

Cervical screening would be better for women and cheaper for the NHS if women with HPV and normal to low‐grade cytology were retested after a year or two when many infections will have cleared.
Management of mesh complications following surgery for stress urinary incontinence or pelvic organ prolapse: a systematic review
Authors: Carter P , Fou L , Whiter F , Delgado Nunes V , Hasler E , Austin C , Macbeth F , Ward K , Kearney R
Published: September 2019

Background

Mesh surgery for stress urinary incontinence or pelvic organ prolapse can result in complications such as mesh exposure, mesh extrusion, voiding dysfunction, dyspareunia, and pain. There is limited knowledge or guidance on the effective management for mesh‐related complications.

Objective

To determine the best management of mesh complications; a systematic review was conducted as part of the national clinical guideline ‘Urinary incontinence (update) and pelvic organ prolapse in women: management’.

Search strategy

Search strategies were developed for each indication for referral.

Selection criteria

Relevant interventions included complete or partial mesh removal, mesh division, and non‐surgical treatments such as vaginal estrogen.

Data collection and analysis

Characteristics and outcome data were extracted, and as a result of the heterogeneous nature of the data a narrative synthesis was conducted.

Main results

Twenty‐four studies were included; five provided comparative data and four studies stated the indication for referral. Reported outcomes (including pain, dyspareunia, satisfaction, quality of life, incontinence, mesh exposure, and recurrence) and the reported incidences of these varied widely.

Conclusions

The current evidence base is limited in quantity and quality and does not permit firm recommendations to be made on the most effective management for mesh‐related complications. Robust data are needed so that mesh complications can be managed effectively in the future.

Tweetable abstract

Systematic review demonstrates that the outcomes following mesh revision surgery are highly variable.
Prevalence of risk—drinking in critically ill patients, screened with carbohydrate‐deficient transferrin and AUDIT‐C score: A retrospective study
Authors: Uljas Eliisa , Jalkanen Ville , Kuitunen Anne , Hynninen Marja , Hästbacka Johanna
Published: September 2019

Background

Studies demonstrate that up to one‐third of intensive care unit (ICU) admissions are directly or indirectly related to alcohol. Screening for alcohol use is not routine. This study examined the prevalence of elevated %CDT (carbohydrate‐deficient transferrin) and above risk‐level AUDIT‐C (Alcohol Use Disorders Identification Test, Consumption) in patients admitted to ICU.

Methods

We conducted a retrospective analysis of clinical and laboratory data from a single ICU where %CDT and AUDIT‐C were included in routine assessment. After excluding readmissions, 2532 adult patients from a 21‐month period were included. Admission values of %CDT were available for 2049 patients, and AUDIT‐C was available for 1617 patients. The association of %CDT and AUDIT‐C with short‐ and long‐term outcome was studied by using univariate and multivariate logistic regression analysis.

Results

%CDT was above the reference value in 23.7% (486/2048) of patients with available %CDT. Of patients with available AUDIT‐C, 33% (544/1617) had a risk‐level AUDIT‐C score. Patients with a risk‐level AUDIT‐C score were significantly younger than those with a lower score (51 vs 64 years, P < .0001). Increased %CDT was associated with higher severity of illness. AUDIT‐C was associated independently with increased risk of long‐term mortality in multivariate analysis (P = .007).

Conclusion

One in three of ICU patients are risk‐level alcohol users as measured with AUDIT‐C score, and one in four are analysed with %CDT. The prevalence varies according to the method used and any method alone may be insufficient to detect risk‐level consumption reliably.

Editorial Comment

Alcohol overconsumption is associated with need for ICU admission and with less favorable outcomes. Diagnosis of alcohol overconsumption though is problematic due to low sensitivity in screening. In a pilot study, a biomarker and a screening tool are compared. The finding is that multiple tools are needed to achieve an adequate sensitivity for detection.
Abnormal returns and asymmetric information surrounding strategic and financial acquisitions
Authors: Osborne Sarah
Published: September 2019

Using takeover bids from the United States, we investigate the importance of information asymmetry in self‐selection when evaluating the abnormal returns of financial versus strategic takeover targets during a period of possible informed trade. Sample selection bias due to differences in financial versus strategic takeover bid information environments is controlled for using Heckman's model. Results show that takeover announcements are not randomised, indicative of timed announcements, and further that private equity firms exhibit lower price impact post‐announcement. We conclude that the long‐term financial motive of private equity takeovers, coupled with higher private information pre‐announcement, leads to lower abnormal returns post‐announcement.
Exploring the nexus between place of residence, daily activity patterns, and the socio‐spatial isolation of mothers on parental leave
Authors: Frantál Bohumil , Klapka Pavel
Published: September 2019

This paper examines issues concerning mothering and childcare, with an emphasis on two crucial aspects which are based on the fact that mothers’ individual behaviours are undoubtedly time‐space dependent. First, unlike the majority of studies which have investigated mothers’ isolation by applying qualitative methods, this exploratory study using data from the Czech Republic is based on a time‐geographical approach using time‐space diaries, a questionnaire survey, and statistical analyses of quantitative data. Second, the paper examines the interrelationship between real time‐space activity patterns and perceived senses of loneliness and isolation. The model of socio‐spatial isolation developed here suggests that such isolation is significantly affected by the place of residence, work activity, household income, and frequency of performing leisure activities, particularly making trips into the countryside, attending cultural events, meeting friends, and taking time for self‐care. Mothers’ clubs, which are significantly more often visited by urban mothers, serve as places for sharing common problems, but they do not reduce perceptions of isolation. Isolation is more likely to be perceived by rural mothers, and mothers from lower income households who do not have any part‐time work during parental leave. One‐third of Czech mothers, however, still hold the traditional view that responsible mothers primarily care for children and do not work during parental leave. The absence of any part‐time work negatively affects not only women's professional and personal lives but also their economic status, which further limits their possibilities for leisure‐time activities and increases their socio‐spatial isolation. In this respect, policy interventions should seek to improve the possibilities of flexible working for mothers as well as to develop programmes and options for leisure‐time activities, particularly for mothers from low‐income families living in rural areas.
When fieldwork falls apart: Navigating disruption from political turmoil in research
Authors: Chambers Joseph
Published: September 2019

For many researchers, conducting fieldwork can often form a significant component of data collection. With a rich history across many disciplines, fieldwork has received significant reflexive examination, notably around when it is conducted in dangerous areas or used for researching high‐risk situations. Less attended to, however, are the equally disruptive but less dangerous situations that researchers can face, such as conducting fieldwork during political turmoil. The aim of this paper is to explore the impact of political turmoil on fieldwork, and reflectively examine both the consequences of this and possible ways of mitigation. Through examining fieldwork notes and journals, the findings identified that despite political turmoil's significant disruption on processes of data collection, the researcher utilised notions of flexible positionalities and developed adaptive methodologies to circumvent these challenges. The paper provides new insights for managing the impact of disruption on fieldwork from political turmoil and encourages the continuation of publications focusing on reflective fieldwork accounts.
Depletion of DNA damage binding protein 2 sensitizes triple‐negative breast cancer cells to poly ADP‐ribose polymerase inhibition by destabilizing Rad51
Authors: Zhao Lin , Si Cheng‐Shuai , Yu Yue , Lu Jian‐Wei , Zhuang Yan
Published: September 2019

Poly ADP‐ribose polymerase inhibitors (PARPi) have shown promising therapeutic efficacy in triple‐negative breast cancer (TNBC) patients. However, resistance ultimately develops, preventing a curative effect from being attained. Extensive investigations have indicated the diversity in the mechanisms underlying the PARPi sensitivity of breast cancer. In this study, we found that DNA damage binding protein 2 (DDB2), a DNA damage‐recognition factor, could protect TNBC cells from PARPi by regulating DNA double‐strand break repair through the homologous recombination pathway, whereas the depletion of DDB2 sensitizes TNBC cells to PARPi. Furthermore, we found that DDB2 was able to stabilize Rad51 by physical association and disrupting its ubiquitination pathway‐induced proteasomal degradation. These findings highlight an essential role of DDB2 in modulating homologous recombination pathway activity and suggest a promising therapeutic target for TNBC.
Children Learn From Both Embodied and Passive Pretense: A Replication and Extension
Authors: Thompson Brittany N. , Goldstein Thalia R.
Published: September 2019

Research suggests that children can learn new information via pretense. However, a fundamental problem with existing studies is that children are passive receivers of the pretense rather than active, engaged participants. This preregistered study replicates previous learning from pretense findings (Sutherland & Friedman, 2012, Child Development), in which children are passive observers of pretense, and extends to two additional conditions that require children to partially (with puppets) or fully (with costumes) embody a character. Children (N = 144, 24–79 months) learned equally well, and better than those in the control condition, from all three play scenarios. At a 2‐week follow‐up, learning was equally retained across embodiment conditions for older, but not younger, preschoolers. Future research should consider embodiment’s role for more complex material.
Homologous tropomyosins from vertebrate and invertebrate: Recombinant calibrator proteins in functional biological assays for tropomyosin allergenicity assessment of novel animal foods
Authors: Klueber Julia , Costa Joana , Randow Stefanie , Codreanu‐Morel Françoise , Verhoeckx Kitty , Bindslev‐Jensen Carsten , Ollert Markus , Hoffmann‐Sommergruber Karin , Morisset Martine , Holzhauser Thomas , Kuehn Annette
Published: September 2019

Background

Novel foods may provide new protein sources for a growing world population but entail risks of unexpected food‐allergic reactions. No guidance on allergenicity assessment of novel foods exists, while for genetically modified (GM) crops it includes comparison of sequence identity with known allergens, digestibility tests and IgE serum screening.

Objective

As a proof of concept, to evaluate non‐/allergenic tropomyosins (TMs) regarding their potential as new calibrator proteins in functional biological in vitro assays for the semi‐quantitative allergy risk assessment of novel TM‐containing animal foods with mealworm TM as an example.

Methods

Purified TMs (shrimp, Penaeus monodon; chicken Gallus gallus; E coli overexpression) were compared by protein sequencing, circular dichroism analysis and in vitro digestion. IgE binding was quantified using shrimp‐allergic patients' sera (ELISA). Biological activities were investigated (skin testing; titrated basophil activation tests, BAT), compared to titrated biological mediator release using humanized rat basophil leukaemia (RBL) cells.

Results

Shrimp and chicken TMs showed high sequence homology, both alpha‐helical structures and thermal stability. Shrimp TM was stable during in vitro gastric digestion, chicken TM degraded quickly. Both TMs bound specific IgE from shrimp‐allergic patients (significantly higher for shrimp TM), whereas skin reactivity was mostly positive with only shrimp TM. BAT and RBL cell assays were positive with shrimp and chicken TM, although at up to 100‐ to 1000‐times lower allergen concentrations for shrimp than chicken TM. In RBL cell assays using both TM as calibrators, an activation of effector cells by mealworm TM similar to that by shrimp TM confirmed the already reported high allergenic potency of mealworm TM as a novel protein source.

Conclusions & clinical relevance

According to current GM crops' allergenicity assessment, non‐allergenic chicken TM could falsely be considered an allergen on a weight‐of‐evidence approach. However, calibrating allergenic potency in functional BAT and RBL cell assays with clinically validated TMs allowed for semi‐quantitative discrimination of novel food protein's allergenicity. With TM calibration as a proof of concept, similar systems of homologous protein might be developed to scale on an axis of allergenicity.
A cohort study on short mini‐implants for mandibular overdentures compared to those of standard length
Authors: Kovačić Ines , Peršić Sanja , Kranjčić Josip , Čelebić Asja
Published: September 2019

Objectives

To assess peri‐implant bone level, survival and success rates of short (6 or 8 mm long) one‐piece mini‐implants (MDIs) in edentulous patients with extremely resorbed alveolar ridge (interforaminal height <10 mm) rehabilitated with mandibular implant overdentures and to compare them with patients having standard length MDIs in 1‐year prospective clinical study.

Material and methods

The Short MDI group consisted of 28 participants with interforaminal height ≤10 mm. Implants being, both, short and slim (short MDIs: 6 or 8 mm long, 2 or 2.5 mm wide) were inserted. The Standard‐MDI group included 35 participants (interforaminal height >13 mm) who received standard length MDIs (10–14 mm long, 2 or 2.5 mm wide). Primary outcomes were assessments of MDI peri‐implant bone level, survival and success rates; secondary outcomes were assessments of peri‐implant tissue, oral hygiene, and prosthodontic maintenance.

Results

The Short MDI group had mean marginal bone loss (MBL) of 0.26 ± 0.35 mm, 6.4% of failure, and 92.6% of, both, success and survival rates. The Standard‐MDI group had mean MBL of 0.34 ± 0.40 mm, 5% of failure, 95% of survival, and 94.3% success. There were no significant differences in MBL (p = .420), survival (p = .414), and success (p = .571) between the groups. The Short MDI group had significantly less plaque (p = .001) and bleeding on probing (p < .001).

Conclusion

Within the limitations of this study, short MDIs (6 or 8 mm long) in extremely atrophied mandibles (interforaminal height <10 mm) showed good clinical results in the first year of function.
Single‐staged implant placement using the bone ring technique with and without membrane placement: Micro‐CT analysis in a preclinical in vivo study
Authors: Nakahara Ken , Haga‐Tsujimura Maiko , Igarashi Kensuke , Kobayashi Eizaburo , Schaller Benoit , Lang Niklaus P. , Saulacic Nikola
Published: September 2019

Objectives

To assess the impact of collagen membrane application on bone formation surrounding implants placed simultaneously with the bone ring technique.

Material and methods

Dental implants were inserted simultaneously with the bone ring technique in standardized, vertical alveolar bony defects in the mandible of dogs. On one side of the mandible, the augmented sites were covered with a collagen membrane (M‐Group). On the contralateral side, no membranes were used (NM‐Group). Implants were left to heal with osseointegration for three and six months. The harvested samples were analyzed by means of micro‐CT.

Results

A nonparametric analysis of data revealed that the membranes were not a significant negative factor for bone volume (BV), but for bone‐to‐implant contact (BIC, p = .04). Absence of healing caps impaired BV (p = .04) and BIC (p = .02) as well. Furthermore, loss of healing caps and exposure to the oral environment significantly and negatively affected BV (p < .001) and bone mineral density (p < .05) within 2 mm below the implant shoulder. Implant exposure and healing time had a negative interaction effect on both BV (p = .01) and BIC (p = .01).

Conclusions

Within its limitations, the present study revealed no benefit of membrane application to implant placement simultaneous with the bone ring technique. Disruption of soft tissue healing was identified as a risk factor for decrease in BV and BIC.
Rate of colorectal neoplasia in patients with Hodgkin lymphoma
Authors: Abu‐Sbeih H. , Ali F. S. , Tang T. , Coronel E. , Lee H. J. , Pande M. , Bresalier R. S. , Raju G. S. , Wang Y.
Published: September 2019

Aim

Survivors of Hodgkin lymphoma (HL) are at increased risk of breast, lung, thyroid, stomach, pancreatic and colon cancer. There is limited information on the utility of endoscopic screening for colon cancer. We aimed to describe the adenoma detection rate (ADR) in patients with HL to determine the appropriate timing of colonoscopy screening.

Method

We retrospectively studied patients with HL who underwent colonoscopy between 2000 and 2017.

Results

A total of 251 patients underwent colonoscopy. Eighty (32%) patients had 151 colonic polyps. Thirty per cent of the polyps exhibited high‐grade dysplasia, and invasive colon adenocarcinoma was found in 10 patients. Patients with the nodular sclerosing subtype of HL had a significantly lower ADR than others (P = 0.002). The ADR was 5% in patients younger than 35 years (n = 64), 23% in patients between 35 and 40 years of age (n = 22), 39% in patients between 40 and 50 years of age (n = 51) and 46% in patients older than 50 years (n = 114).
Therapeutic living donor nephrectomy
Authors: Dale Leigh‐Anne , Silva Mark V. , Sandoval Pedro Rodrigo , Decastro Joel , Campenot Eric S. , Ratner Lloyd E.
Published: September 2019

Therapeutic living donor nephrectomy is defined as a nephrectomy that is performed as therapy for an underlying medical condition. The patient directly benefits from having their kidney removed, but the kidney is deemed transplantable. The kidney is subsequently used as an allograft for an individual with advanced renal disease. Therapeutic donor nephrectomy can be successfully utilized for a heterogenous cohort of disease processes as both treatment for the donor and to increase the number of suitable organs available for transplantation. We describe four cases of therapeutic donor nephrectomy that were performed at our institution. Of the four cases, two patients elected to undergo therapeutic donor nephrectomy as treatment for loin pain hematuria syndrome; one after blunt abdominal trauma that resulted in complete proximal ureteral avulsion; and the fourth after being diagnosed with a small renal mass. Based on our data presented to the United Network for Organ Sharing Board of Directors (UNOS) in December 2015, living donor evaluation has been made simpler for patients electing to undergo therapeutic donor nephrectomy. UNOS eliminated the requirement for a psychosocial evaluation for these patients. As the organ shortage continues to limit transplantation, therapeutic donor nephrectomy should be considered when appropriate.
Development curves of communication and social interaction in individuals with cerebral palsy
Authors: Tan Siok Swan , van Gorp Marloes , Voorman Jeanine M , Geytenbeek Joke JM , Reinders‐Messelink Heleen A , Ketelaar Marjolijn , Dallmeijer Annet J , Roebroeck Marij E ,   Perrin‐Decade study group
Published: September 2019

Aim

To determine development curves of communication and social interaction from childhood into adulthood for individuals with cerebral palsy (CP).

Method

This Pediatric Rehabilitation Research in the Netherlands (PERRIN)‐DECADE study longitudinally assessed 421 individuals with CP, aged from 1 to 20 years at baseline, after 13 years (n=121 at follow‐up). Communication and social interactions were assessed using the Vineland Adaptive Behavior Scales. We estimated the average maximum performance limit (level) and age at which 90% of the limit was reached (age90) using nonlinear mixed‐effects modeling.

Results

One‐hundred individuals without intellectual disability were aged 21 to 34 years at follow‐up (39 females, 61 males) (mean age [SD] 28y 5mo [3y 11mo]). Limits of individuals without intellectual disability, regardless of Gross Motor Function Classification System (GMFCS) level, approached the maximum score and were significantly higher than those of individuals with intellectual disability. Ages90 ranged between 3 and 4 years for receptive communication, 6 and 7 years for expressive communication and interrelationships, 12 and 16 years for written communication, 13 and 16 years for play and leisure, and 14 and 16 years for coping. Twenty‐one individuals with intellectual disability were between 21 and 27 years at follow‐up (8 females, 13 males) (mean age [SD] 24y 7mo [1y 8mo]). Individuals with intellectual disability in GMFCS level V showed the least favourable development, but variation between individuals with intellectual disability was large.

Interpretation

Individuals with CP and without intellectual disability show developmental curves of communication and social interactions similar to typically developing individuals, regardless of their level of motor function. Those with intellectual disability reach lower performance levels and vary largely in individual development.

What this paper adds

Communication and social interactions in individuals with cerebral palsy without intellectual disability develop similarly to typically developing individuals.

Communication and social interactions of individuals with intellectual disability develop less favourably and show large variation.
Recognizing and documenting undernutrition in hospitalized children with cerebral palsy
Authors: Aumar Madeleine , Gottrand Frederic
Published: September 2019

This paper is on the original article by Reyes et al. on pages 1432–1438 of this issue.
A practical guide to graphic communication for quality assurance, education, and patient care in echocardiography
Authors: Cohen Gerald I.
Published: September 2019

Graphic communication (GC) is useful for continuous quality improvement (CQI), education, and patient care when in‐person discussion is not possible because of geographic and schedule constraints. In echocardiography, these constraints can be mitigated by (a) capturing screenshots and device photos or videos and sharing them by email or text message, (b) simultaneous viewing of images on digital displays, and (c) broadcasting the study real time during acquisition to other mobile or stationary devices. Screenshots are useful for CQI and education and can be acquired, annotated, and shared with minimal impact on the flow of clinical echo interpretation. Providers at different locations can employ GC for shared clinical decision making by viewing echo studies from the same server, video conferencing or accessing real‐time broadcast from a device. Which GC tool is selected is determined by its ease of use, the provider's goals and whether immediate image review is needed.