bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolutionarily ancient BAH-PHD protein mediates Polycomb silencing
Authors: Wiles Elizabeth T. , McNaught Kevin J. , De Silva Saumya M. , Kaur Gurmeet , Selker Jeanne M. , Ormsby Tereza , Aravind L. , Musselman Catherine A. , Selker Eric U.
Published: December 2019

Methylation of histone H3 lysine 27 (H3K27) is widely recognized as a transcriptionally repressive chromatin modification but the mechanism of repression remains unclear. We devised and implemented a forward genetic scheme to identify factors required for H3K27 methylation-mediated silencing in the filamentous fungus Neurospora crassa and identified a bromo-adjacent homology (BAH)-plant homeodomain (PHD)-containing protein, EPR-1 (Effector of Polycomb Repression 1; NCU07505). EPR-1 associates with H3K27 methylation in vivo and in vitro, and loss of EPR-1 de-represses H3K27-methylated genes without loss of H3K27 methylation. EPR-1 is not fungal-specific; orthologs of EPR-1 are present in a diverse array of eukaryotic lineages, suggesting an ancestral EPR-1 was a component of a primitive Polycomb repression pathway.

Significance

Polycomb group (PcG) proteins are employed by a wide variety of eukaryotes for the maintenance of gene repression. Polycomb repressive complex 2 (PRC2), a multimeric complex of PcG proteins, catalyzes the methylation of histone H3 lysine 27 (H3K27). In the filamentous fungus, Neurospora crassa, H3K27 methylation represses scores of genes, despite the absence of canonical H3K27 methylation effectors that are present in plants and animals. We report the identification and characterization of an H3K27 methylation effector, EPR-1, in N. crassa and demonstrate its widespread presence and early eukaryotic origins with phylogenetic analyses. These findings indicate that an ancient EPR-1 may have been part of a nascent Polycomb repression system in eukaryotes.
Climate change and local host availability drive the northern range boundary in the rapid northward expansion of the eastern giant swallowtail butterfly
Authors: Wilson J. Keaton , Casajus Nicolas , Hutchinson Rebecca A. , McFarland Kent P. , Kerr Jeremy T. , Berteaux Dominique , Larrivée Maxim , Prudic Kathleen L.
Published: December 2019

Aims

Species distributions result from both biotic and abiotic interactions across large spatial scales. The interplay of these interactions as climate changes quickly has been understudied, particularly in herbivorous insects. Here, we investigate the relative impacts these influences on the putative northern range expansion of the giant swallowtail butterfly in North America.

Location

North America.

Time period

1959-2018.

Major taxa studied

Eastern Giant swallowtail,Papilio cresphontes(Lepidoptera: Papilionidae); common hop tree,Ptelea trifoliata; common prickly ash,Zanthoxylum americanum; southern prickly ash,Zanthoxylum clava-herculis(Saphidales: Rutaceae).

Methods

We used data from museum collections and citizen science repositories to generate species distribution models. Distribution models were built for each species over two time periods (T1 = 1959-1999; T2 = 2000-2018).

Results

Models forP. cresphontesand associated host plants had high predictive accuracy on spatially-explicit test data (AUC 0.810-0.996). Occurrence data align with model outputs, providing strong evidence for a northward range expansion in the last 19 years (T2) byP. cresphontes. Host plants have shifted in more complex ways, and result in a change in suitable habitat forP. cresphontesin its historic range.P. cresphonteshas a northern range which now closely aligns with its most northern host plant - continued expansion northward is unlikely, and historic northern range limits were likely determined by abiotic, not biotic, factors.

Main conclusions

Biotic and abiotic factors have driven the rapid northern range expansion in the giant swallowtail butterfly across North America in the last 20 years. A number of bioclimatic variables are correlated with this expansion, notably an increase in mean annual temperature and minimum winter temperature. We predict a slowing of northward range expansion in the next 20-50 years as butterflies are now limited by the range of host plants, rather than abiotic factors.
Deviant cortical sulcation related to schizophrenia, but not cognitive deficits, likely predate brain development in the second trimester
Authors: MacKinley ML. , Sabesan P. , Palaniyappan L.
Published: December 2019

Objectives

Aberrant cortical development, inferred from cortical folding measures, is linked to the risk of schizophrenia. Cortical folds develop in a time-locked fashion during fetal growth. We leveraged this temporal specificity of sulcation to investigate the approximate timing of the prenatal insult linked to schizophrenia as well as the cognitive impairment seen in this illness.

Methods

Anatomical T1 MRI scans from a publicly available dataset of 68 patients with schizophrenia and 72 controls were used to evaluate the sulcal depth. 5 major primary sulci that are invariable, representing lobar development (calcarine sulcus, superior temporal sulcus, superior frontal sulcus, intraparietal sulcus and inferior frontal sulcus) with formation representing distinct developmental periods were chosen. Sulcal depth was measured using BrainVISA software.

Results

A repeated measure Analysis of Variance with 5 sulci and 2 hemispheres as within-subject factors and gender, age and intracranial volume as covariates revealed a significant effect of diagnosis (F[1,134]=14.8, p=0.0002). Control subjects had had deeper superior temporal (left t=3.2, p=0.002; right t=2.8, p=0.006), right inferior frontal (t=2.7, p=0.007) and left calcarine (t=2.2, p=0.03) sulci. A deeper superior frontal sulcus predicted better overall cognitive scores (F[1,54]=8.7, p=0.005) among patients.

Conclusion

Our results suggest that the gestational cortical disruption underlying schizophrenia is likely to predate, if not, coincide with the appearance of calcarine sulcus (early 2nd trimester) and affects frontal, temporal and occipital lobes. Nevertheless, the burden of cognitive deficits may relate specifically to aberrant superior frontal development occurring in late 2nd trimester.
Perinatal selective serotonin reuptake inhibitor exposure and behavioral outcomes: a systematic review and meta-analyses of animal studies
Authors: Ramsteijn A.S. , Van de Wijer L. , Rando J. , van Luijk J. , Homberg J.R. , Olivier J.D.A.
Published: December 2019

In the Western world, 2-5% of pregnant women use selective serotonin reuptake inhibitor (SSRI) antidepressants. There is no consensus on the potential long-term neurodevelopmental outcomes of early SSRI exposure. Our aim was to determine whether there is an overall effect of perinatal SSRI exposure in animals on a spectrum of behavioral domains. After a comprehensive database search in PubMed, PsycINFO, and Web of Science, we included 99 publications. We performed nine meta-analyses and two qualitative syntheses corresponding to different behavioral categories, aggregating data from thousands of animals. We found evidence for reduced activity and exploration behavior (standardized mean difference (SMD) −0.28 [-0.38, −0.18]), more passive stress coping (SMD −0.37 [-0.52, −0.23]), and less efficient sensory processing (SMD −0.37 [-0.69, −0.06]) in SSRI-versus vehicle-exposed animals. No differences were found for anxiety (p=0.06), social behavior, learning and memory, ingestive- and reward behavior, motoric behavior, or reflex and pain sensitivity. Exposure in the period equivalent to the human third trimester was associated with the strongest effects.

Highlights

Perinatal SSRI exposure in rodents alters outcomes in three behavioral domains.

It leads to reduced activity, passive stress coping, and weaker sensory processing.

Females are understudied but seem to be less vulnerable than males.

Early postnatal exposure in rodents leads to the largest effects on behavior.

This is equivalent to the third trimester of pregnancy in humans.
Efficient Manipulation and Generation of Kirchhoff Polynomials for the Analysis of Non-equilibrium Biochemical Reaction Networks
Authors: Yordanov Pencho , Stelling Jörg
Published: December 2019

Kirchhoff polynomials are central for deriving symbolic steady-state expressions of models whose dynamics are governed by linear diffusion on graphs. In biology, such models have been unified under a common linear framework subsuming studies across areas such as enzyme kinetics, G-protein coupled receptors, ion channels, and gene regulation. Due to “history dependence” away from thermodynamic equilibrium these models suffer from a (super) exponential growth in the size of their symbolic steady-state expressions and respectively Kirchhoff polynomials. This algebraic explosion has limited applications of the linear framework. However, recent results on the graph-based prime factorisation of Kirchhoff polynomials may help subdue the combinatorial complexity. By prime decomposing the graphs contained in an expression of Kirchhoff polynomials and identifying the graphs giving rise to equal polynomials, we formulate a coarse-grained variant of the expression suitable for symbolic simplification. We devise criteria to efficiently test the equality of Kirchhoff polynomials and propose two heuristic algorithms to explicitly generate individual Kirchhoff polynomials in a compressed form; they are inspired by algebraic simplifications but operate on the corresponding graphs. We illustrate the practicality of the developed theory and algorithms for a diverse set of graphs of different sizes and for non-equilibrium gene regulation analyses.
Metrics for conservation success: using the ‘Bird-Friendliness Index’ to evaluate grassland and aridland bird community resilience across the Northern Great Plains ecosystem
Authors: Michel Nicole L. , Burkhalter Curtis , Wilsey Chad B. , Holloran Matt , Holloran Alison , Langham Gary M.
Published: December 2019

Aim

Evaluating conservation effectiveness is essential to protect at-risk species and to maximize the limited resources available to land managers. Over 60% of North American grassland and aridlands have been lost since the 1800s. Birds in these habitats are among the most imperiled in North America, yet most remaining habitats are unprotected. Despite the need to measure impact, conservation efforts on private and working lands are rarely evaluated, due in part to limited availability of suitable methods.

Location

Northern Great Plains

Methods

We developed a novel metric to evaluate grassland and aridland bird community response to habitat management practices, the Bird-Friendliness Index (BFI), consisting of density estimates of grassland and aridland birds weighted by conservation need and a functional diversity metric to incorporate resiliency. We used the BFI to inform three assessments: 1) a spatial prioritization to identify ecologically significant areas for grassland and aridland birds, 2) estimation of temporal trends in grassland and aridland bird community resilience, and 3) evaluation of the effects of land management practices on grassland and aridland bird communities.

Results

The most resilient bird communities were found in the Prairie Potholes region of Alberta, Saskatchewan, northern Montana, and North Dakota, and the lowest BFI values in the southern and western regions of the Northern Great Plains. BFI values varied little over time on average, but trends varied regionally, largely in response to interannual relative variability in grassland and aridland bird densities.

Main conclusions

BFI values increased in response to simulated habitat management, suggesting that practices recommended for use in bird-friendly grassland habitat management plans will increase the abundance and resilience of the grassland and aridland bird community, and will be detected using the BFI. The BFI is a tool by which conservationists and managers can carry out accountable conservation now and into the future.
Phagocytic glia are obligatory intermediates in transmission of mutant huntingtin aggregates across neuronal synapses
Authors: Donnelly Kirby M. , DeLorenzo Olivia R. , Zaya Aprem D.A. , Pisano Gabrielle E. , Thu Wint M. , Luo Liqun , Kopito Ron R. , Panning Pearce Margaret M.
Published: December 2019

Emerging evidence supports the hypothesis that pathogenic protein aggregates associated with neurodegenerative diseases spread from cell to cell through the brain in a manner akin to infectious prions. Here, we show that mutant huntingtin (mHtt) aggregates associated with Huntington disease transfer anterogradely from presynaptic to postsynaptic neurons in the adult Drosophila olfactory system. Trans-synaptic transmission of mHtt aggregates is inversely correlated with neuronal activity and blocked by inhibiting caspases in presynaptic neurons, implicating synaptic dysfunction and cell death in aggregate spreading. Remarkably, mHtt aggregate transmission across synapses requires the glial scavenger receptor Draper and involves a transient visit to the glial cytoplasm, indicating that phagocytic glia act as obligatory intermediates in aggregate spreading between synaptically-connected neurons. These findings expand our understanding of phagocytic glia as double-edged players in neurodegeneration—by clearing neurotoxic protein aggregates, but also providing an opportunity for prion-like seeds to evade phagolysosomal degradation and propagate further in the brain.
Baseline characteristics and long‐term outcomes of eosinophilic fasciitis in 89 patients seen at a single center over 20 years
Authors: Mango Robert L. , Bugdayli Kubra , Crowson Cynthia S. , Drage Lisa A. , Wetter David A. , Lehman Julia S. , Peters Margot S. , Davis Mark D. , Chowdhary Vaidehi R.
Published: December 2019

Aim

Eosinophilic fasciitis (EF) is a rare, fibrosing disorder of skin and subcutaneous tissue. This study was undertaken to describe its clinical and laboratory features and identify prognostic factors associated with outcome.

Methods

We conducted a retrospective review of all EF patients evaluated at our institution from 1 January1997 to 30 December 2016. Kaplan‐Meier methods were used to determine treatment response rates over time. Potential associations between baseline characteristics and complete response were examined using Cox models adjusted for age and sex. Time‐dependent covariates were used to examine treatment effects.

Results

We identified 89 EF patients, with a female‐to‐male ratio of 1:1. Clinical features included groove sign in 26 (29%), peau d'orange/dimpling in 22 (25%), inflammatory arthritis in 9 (10%) and muscle weakness in 9 (10%). Aldolase was elevated in 11/36 (31%). Complete response rate was 60% (95% confidence interval [CI]: 35‐75) at 3 years. Diagnostic delay was inversely associated with treatment response (hazards ratio: 0.84 per 1 month increase; 95% CI: 0.73‐0.98). No baseline characteristics correlated with treatment response, but a trend toward positive association of elevated aldolase, hypergammaglobulinemia and presence of hematologic disorders was noted. Methotrexate was the most commonly used immunosuppressant in 79%, hydroxychloroquine in 45%, mycophenolate mofetil in 18% and azathioprine in 8%. No single immunosuppressant agent was associated with a superior response during treatment.

Conclusions

EF is characterized by relatively high response rates. Consensus diagnostic criteria, standardized management algorithms, and large prospective multi‐center cohorts are needed to develop an evidence‐directed approach to this challenging condition.
Blunt Traumatic Aortic Injury in the Pan‐scan Era
Authors: Yu Louis , Baumann Brigitte M. , Raja Ali S. , Mower William R. , Langdorf Mark I. , Medak Anthony J. , Anglin Deirdre R. , Hendey Gregory W. , Nishijima Daniel , Rodriguez Robert M.
Published: December 2019

Background

In the era of frequent head‐to‐pelvis computed tomography (CT) for adult blunt trauma evaluation, we sought to update teachings regarding aortic injury by determining 1) the incidence of aortic injury; 2) the proportion of patients with isolated aortic injury (without other concomitant thoracic injury); 3) the clinical implications of aortic injury (hospital mortality, length of stay [LOS], and rate of surgical interventions); and 4) the screening value of traditional risk factors/markers (such as high‐energy mechanism and widened mediastinum on chest x‐ray [CXR]) for aortic injury, compared to newer criteria from the recently developed NEXUS Chest CT decision instrument (DI).

Methods

We conducted a preplanned analysis of patients prospectively enrolled in the NEXUS Chest studies at 10 Level I trauma centers with the following inclusion criteria: age > 14 years, blunt trauma within 6 hours of ED presentation, and receiving chest imaging during ED trauma evaluation.

Results

Of 24,010 enrolled subjects, 42 (0.17%, 95% confidence interval [CI] = 0.13% to 0.24%) had aortic injury. Most patients (79%, 95% CI = 64% to 88%) had an associated thoracic injury, with rib fractures, pneumothorax/hemothorax, and pulmonary contusion occurring most frequently. Compared to patients without aortic injury this cohort had similar mortality (9.5%, 95% CI = 3.8% to 22.1% vs. 5.8%, 95% CI = 5.4% to 6.3%), longer median hospital LOS (11 days vs. 3 days, p < 0.01), and higher median Injury Severity Score (29 vs. 5, p < 0.001). High‐energy mechanism and widened mediastinum on CXR had low sensitivity for aortic injury (76% [95% CI = 62% to 87%] and 33% [95% CI = 21% to 49%], respectively), compared to the NEXUS Chest CT DI (sensitivity 100% [95% CI = 92% to 100%]).

Conclusions

Aortic injury is rare in adult ED blunt trauma patients who survive to receive imaging. Most ED aortic injury patients have associated thoracic injuries and survive to hospital discharge. Widened mediastinum on CXR and high‐energy mechanism have relatively low screening sensitivity for aortic injury, but the NEXUS Chest DI detected all cases.
Prophylactic phenylephrine and fluid co‐administration to reduce spinal hypotension during elective caesarean section in a resource‐limited setting: a prospective alternating intervention study
Authors: Buthelezi A. S. , Bishop D. G. , Rodseth R. N. , Dyer R. A.
Published: December 2019

Spinal hypotension is a common and clinically important problem during caesarean section. Current consensus recommendations for resource‐rich settings suggest the use of a titrated phenylephrine infusion, in combination with fluid coloading, for prevention of maternal hypotension. In resource‐limited settings, where syringe drivers are unavailable, these recommendations advise the addition of 500 μg phenylephrine to the first 1 l of intravenous fluid given after initiation of spinal anaesthesia, with additional vasopressor boluses as required. This prospective, alternating intervention study compared the use of a conventional phenylephrine rescue bolus strategy for prevention of hypotension, defined as systolic arterial pressure < 90 mmHg, with a phenylephrine infusion given according to the consensus recommendation. We studied 300 women having elective caesarean section. There were 77 (51%) women who developed hypotension in the bolus group vs. 55 (37%) in the phenylephrine infusion group (p = 0.011). This represented a 29% reduction in hypotension, with a number needed to treat of 6.8. The six highest systolic arterial pressure readings occurred in the phenylephrine infusion group (range 166–188 mmHg), and there were four instances of bradycardia (heart rate < 50 beats.min−1) with preserved systolic arterial pressure in each group. There were no adverse clinical sequelae, and no differences in neonatal Apgar scores in either group. The consensus recommendation for phenylephrine and fluid co‐administration in resource‐limited settings appears effective in preventing maternal hypotension, but at the cost of sporadic systolic hypertension.
Predictive role of ventricular repolarization parameters for the occurrence of complete heart block in patients undergoing transcatheter aortic valve implantation
Authors: Karacop Erdem , Enhos Asim
Published: December 2019

Background

We investigated the role of ventricular repolarization parameters to predict complete atrioventricular block in patients undergoing transcatheter aortic valve implantation (TAVI).

Methods

A total of 150 patients undergoing TAVI due to severe aortic stenosis were included in this retrospective cohort study. Patients were assigned in two groups based on the presence (n: 49) or absence (n: 101) of complete atrioventricular block after TAVI. Ventricular repolarization intervals (QT, QTc, JT, JTc, TP‐E), indices (QT dispersion), and ratios (TP‐E/QT, TP‐E/QTc, TP‐E/JTc) were measured.

Results

Electrocardiographic repolarization parameters such as Tp‐e interval: 74.2 ± 5.1 versus 59.2 ± 6.1 ms, p < .001; QTc interval: 397.6 ± 3.4 versus 368.1 ± 7.8 ms, p < .001; JTc interval: 317.4 ± 11.3 versus 291.1 ± 6.7 ms, p < .001; Tp‐e/QT ratio: 0.28 ± 0.04 versus 0.20 ± 0.04, p < .001; Tp‐e/QTc ratio: 0.29 ± 0.04 versus 0.19 ± 0.03, p < .001; Tp‐e/JT ratio: 0.32 ± 0.03 versus 0.23 ± 0.03, p < .001; Tp‐e/JTc ratio: 0.30 ± 0.02 versus 0.2 ± 0.03, p < .001; and QT dispersion: 34.4 ± 3.0 versus 17.8 ± 3.6 ms, p < .01 were significantly higher in post‐TAVI permanent pacemaker group. In a univariate regression analysis, pulmonary artery pressure, heart rate, coronary artery disease, Tp‐e/QTc, Tp‐e/JTc, and PR interval were significantly associated with complete heart block. Tp‐e/JTc (OR 0.373, p = .067) and PR interval (OR 0.898, p = .079) were found to be independent predictors of these type of arrhythmias in a multivariate analysis. But it is not statistically significant.

Conclusion

Our results suggest that repolarization parameters may play a role in predicting complete atrioventricular block. Tp‐e/JTc was found to be potential independent risk marker for this setting.
Utility of digitally supported surgical competency assessments in a work‐based setting: a systematic review of the literature
Authors: Oh Daniel D. , Bains Harinder , Agostinho Nelson , Young Christopher J. , Storey David , Hong Jonathan S.
Published: December 2019

Background

Adequate training and assessment of competency in surgical trainees are important in minimizing adverse events and achieving good patient outcomes. The purpose was to investigate the current literature on digitally supported methods of facilitating work‐based competency assessment of surgical trainees.

Methods

Two concurrent literature searches were performed by two independent researchers using three databases: MEDLINE, Embase and Education Resources Information Center. Eligible studies reported on digitally supported tools for assessing surgical competency in a work‐based setting for interns, residents or trainees of a post‐graduate surgical programme. Studies focusing primarily on training courses, simulations or other tools for assessing surgical skills in a setting outside of work were excluded. Articles published as abstracts only, articles not published in English and review articles that did not contain original data were excluded.

Results

A total of 11 eligible studies were included, with six of these implementing smartphone application‐based programmes, and five utilizing web‐based programmes. Five studies implemented the ‘System for Improving and Measuring Procedural Learning’ smartphone application. Studies were based predominantly on general surgery residents, and were limited to the North American context. There was significant variability between studies regarding methodology, including the scoring system used to assess competency.

Conclusion

This review confirms that digitally supported competency assessment of surgical trainees in a work‐based setting is both feasible and effective. Digital platforms allow evaluations to be performed in a timely fashion without significant disturbance to workflow.
Prevalence, risk factors and management strategies for otological problems in girls with Turner syndrome
Authors: Lim David , Hassani Sarah , Lupton Kenneth , Gault Emma Jane , Wynne David , Clement William , Kubba Haytham , Mason Avril , Donaldson Malcolm
Published: December 2019

Aim

To determine the prevalence and risk factors of ear disease in Turner syndrome (TS), propose an algorithm for future surveillance and recommend preventative strategies.

Methods

Review of TS patients seen in the West of Scotland between 1989 and 2015, with questionnaire follow‐up in 2015.

Results

Of 168 girls, median age 27.3 (3.8‐47.2) years, ear problems occurred more frequently with 45,X and 45,X/46,XiXq than other karyotypes: 71/103 (69%) versus 23/65 (35%). Recurrent acute otitis media (AOM) first developed at 0‐5 years in 23 (40%) girls, persisting in 16 (10%) at 5‐10 years; and first developing at 5‐10 years in 11 (7%). Persistent otitis media with effusion (OME) first developed at 0‐5 and 5‐10 years in 23 (40%) and 14 (8%) girls. Recurrent AOM was significantly linked with cholesteatoma in 8 (4.9%) girls (7 aged >10 years). Permanent hearing loss was documented in 28 girls (16.7%), with 16 (9.5%) receiving hearing aids (bone‐anchored in 3).

Conclusion

Acute otitis media and OME occur commonly in preschool TS girls and may persist or newly develop in later childhood. Recurrent AOM predisposes to cholesteatoma. Strategies to reduce otological morbidity include: intensive patient education, annual audiology, vaccinations and a randomised trial of antibiotic prophylaxis in high‐risk groups.
A new Swedish reference for total and prepubertal height
Authors: Albertsson‐Wikland Kerstin , Niklasson Aimon , Holmgren Anton , Gelander Lars , Nierop Andreas F. M.
Published: December 2019

Aim

We aimed to develop up‐to‐date references with standard deviation scores (SDS) for prepubertal and total height.

Methods

Longitudinal length/height measures from 1572 healthy children (51.5% boys) born at term in 1989‐1991 to non‐smoking mothers and Nordic parents were obtained from the GrowUp 1990 Gothenburg cohort. A total height SDS reference from birth to adult height was constructed from Quadratic‐Exponential‐Pubertal‐Stop (QEPS) function estimated heights based on individual growth curves. A prepubertal height SDS reference, showing growth trajectory in the absence of puberty, was constructed using the QE functions.

Results

The total height reference showed taller prepubertal mean heights (for boys 1‐2 cm; for girls 0.5‐1.0 cm) with a narrower normal within ± 2SDS range vs the GrowUp 1974 Gothenburg reference. Adult height was increased by + 0.9 cm for women (168.6 cm) and by + 1.6 cm for men (182.0 cm). Height in children growing at −2SDS (the cut‐off used for referrals) differed up to 2 cm vs the GrowUp 1974 Gothenburg reference, 3 cm vs Swedish 1981 references and World Health Organisation (WHO) 0‐5 years standard, and 6‐8 cm vs the WHO 5‐19 years reference.

Conclusion

Up‐to‐date total and prepubertal height references offer promise of improved growth monitoring compared with the references used in Sweden today.
The first wide‐scale drug repurposing screen using the Prestwick Chemical Library (1200 bioactive molecules) against Neisseria gonorrhoeae identifies high in vitro activity of auranofin and many additional drugs
Authors: Foerster Sunniva , Gustafsson Tomas N. , Brochado Anna Rita , Desilvestro Valentino , Typas Athanasios , Unemo Magnus
Published: December 2019

Treatment options for gonorrhoea are scarce. Drug repurposing of bioactive molecules approved for other conditions might therefore be of value. We developed a method for wide‐scale, systematic drug repurposing screen to identify molecules with activity against Neisseria gonorrhoeae and screened the Prestwick Chemical Library (1200 FDA‐approved drugs). As a proof‐of‐concept, we further examined one promising and interesting screening hit (auranofin; antirheumatic agent). Three WHO gonococcal reference strains (WHO F, O, P) were used for the Library screening. The strains were grown in presence of a fixed concentration of the library drugs in 384‐well plates for 12 h, and the remaining bacterial respiration, to reflect growth, was then quantitatively measured using optical density (OD) 450 nm and a resazurin assay. The activity of auranofin was further examined using in vitro susceptibility testing (minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC)) against genetically diverse antimicrobial‐resistant N. gonorrhoeae strains and time‐kill assays. Sixty‐eight molecules significantly inhibited bacterial growth of WHO F, O and P. Auranofin showed potent in vitro bactericidal activity (in MIC‐, MBC‐ and time‐kill assays) against four WHO reference strains. No cross‐resistance between auranofin and any antimicrobial currently or previously used for gonorrhoea treatment was found when examining 51 selected antimicrobial‐resistant gonococcal strains. In conclusion, this is the first wide‐scale systematic screening effort for repurposing drugs for future treatment of gonorrhoea. Additional studies examining mechanism(s) of action, resistance development, in vivo anti‐gonococcal activity and pharmacokinetics/pharmacodynamics for gonococcal infections of auranofin and several other significant screening hits would be valuable.
Impact of imaging modality on clinical outcome in Hodgkin lymphoma in a resource constraint setting
Authors: Korula Anu , Devasia Anup Joseph , Kulkarni Uday , Abubacker Fouzia N. , Lakshmi Kavitha M. , Abraham Aby , Srivastava Alok , George Biju , Mathews Vikram
Published: December 2019

Treatment of Hodgkin lymphoma (HL) has evolved with risk‐stratified therapy based on PET‐CT scan at multiple timepoints. In a resource constraint setting even a single PET‐CT scan ($400) is inaccessible to many patients, who are re‐assessed with only clinical examination, abdominal ultrasonogram and/or x‐ray (C/U/X) ($10). To compare clinical outcomes in patients with HL who have had suboptimal imaging after completion of chemotherapy for HL, with those who had a CT or PET‐CT, 283 patients were treated for HL from 2011 to 2015, and 268 patients completed six cycles of ABVD therapy with response assessment modality by CT/PET in 185 patients and by C/U/X in 83. There was no difference in the number of patients with advanced (64·1% vs. 61·1%; P = 0·650) or bulk disease (8·1% vs. 7·2%). A significantly higher number of patients in the CT/PET group received IFRT (25·4% vs. 7·7%; P = 0·0005). The three‐year overall survival and progression‐free survival of all treated patients (n = 283) was 83·5 ± 2·3% and 76·7 ± 2·6% respectively [median follow‐up 36 months (range 2–93)]. At three years, the overall relapse‐free survival (RFS) was 80·1 ± 2·5%, with RFS of 77 ± 3·2% vs. 85 ± 4·0% in the CT/PET group and C/U/X groups respectively (P = 0·349). There was no difference in RFS between the two groups either in early‐stage disease (88·1 ± 4·6% vs. 91·8 ± 5·6%; P = 0·671) or late‐stage disease (73·9 ± 4·8% vs. 81·3 ± 6·0%; P = 0·747). The only significant factor adversely affecting RFS was advanced disease (P = 0·004). Factors not affecting RFS were age (P = 0·763), sex (P = 0·925), bulk disease (P = 0·889) and imaging modality (P = 0·352). There was no difference in relapse rates between patients who had suboptimal imaging compared to those who had a PET/CT. It is possible to use these basic imaging modalities when resources are a constraint, with acceptable outcomes.
Poor outcomes for double‐hit lymphoma patients treated with curative‐intent second‐line immunochemotherapy following failure of intensive front‐line immunochemotherapy
Authors: Landsburg Daniel J. , Ayers Emily C. , Bond David A. , Maddocks Kami J. , Karmali Reem , Behdad Amir , Curry Madeira , Wagner‐Johnston Nina D. , Modi Dipenkumar , Ramchandren Radhakrishnan , Assouline Sarit E. , Faramand Rawan , Chavez Julio C. , Torka Pallawi , Mier Hicks Angel , Medeiros L. Jeffrey , Li Shaoying
Published: December 2019

While patients with double‐hit lymphoma (DHL) are now frequently treated with intensive front‐line immunochemotherapy, outcomes for those who fail these regimens and subsequently receive curative‐intent second‐line immunochemotherapy are unknown. We identified 55 such patients who achieved an overall/complete response rate of 29%/11%, median progression‐free/overall survival (PFS/OS) of 2/5·1 months and one‐year PFS/OS of 10/19% following the start of second‐line therapy. These outcomes may serve as a standard against which future second‐line treatment strategies for relapsed/refractory DHL can be measured and justify investigation of non‐cytotoxic therapies in the second‐line setting for these patients.
Longitudinal associations between parental incarceration and children's emotional and behavioural development: Results from a population cohort study
Authors: Bradshaw Daragh , Hannigan Ailish , Creaven Ann‐Marie , Muldoon Orla T.
Published: December 2019

Background

Parental incarceration (PI) is associated with adverse developmental outcomes for children affected. However, research in this area often reports conflicting results with few studies following children across time in non‐U.S. populations. Additionally, more research is called for using multi‐informant perspectives rather than relying on adult reports of child outcomes alone.

Methods

This study used data from the first two waves of a nationally representative cohort study of 8,568 children aged 9 years and followed up at age 13 living in the Republic of Ireland (2007–2012). Propensity score matching was used to match children who had experienced PI by the age of nine to children who had not experienced PI by sociodemographics and experience of other stressful events. Mental health, as measured by self‐concept (Piers‐Harris II) and externalizing and internalizing difficulties (strength and difficulties questionnaire), was compared across both groups.

Results

Fifty of the 8,568 children (weighted percentage 0.9%) reported experiencing PI by the age of nine. These children came from more socially disadvantaged homes and were more likely to have experienced other potentially stressful life events. In comparison to a matched sample of children not affected by PI, children affected by PI reported higher levels of anxiety at age nine. Longitudinal analysis indicated these children affected by PI also reported lower levels of happiness at age 13 with higher levels of emotional difficulties reported by their primary caregiver.

Conclusions

Children of incarcerated parents face a greater array of life challenges. PI had an association with child‐reported levels of anxiety at age nine. PI also had a medium‐term association on caregiver assessments of emotional difficulties of children affected as well child‐reported levels of happiness over time.
Validity and reliability of three‐dimensional costal cartilage imaging for donor‐site assessment and clinical application in microtia reconstruction patients: A prospective study of 22 cases
Authors: Mao Xiaoyan , Li Xiaojian , Jia James , Kang Deni , Miao Yong , Lu Zijing , Hu Zhiqi
Published: December 2019

Objectives

This study assesses the ability to reconstruct costal cartilage images by using three‐dimensional visualisation software (Mimics) based on semi‐automated segmentation algorithm and to investigate its reliability and validity with an anthropometric analysis.

Design

Observational prospective study.

Setting

Plastic surgery department of a tertiary hospital.

Participants

Twenty‐two microtia patients who underwent autologous ear reconstruction.

Main outcome measures

Preoperative thoracic computed tomography data were processed to Mimics software for three‐dimensional costal cartilage imaging. The length, width, thickness and volume of the 9th costal cartilages were calculated from these images and compared with the direct measurements (DM) obtained intraoperatively.

Results

The intra‐examiner reliability and inter‐examiner reliability were high in terms of all four measurements (intraclass correlation coefficients, ICC: 0.876‐0.984). There were no significant differences between image‐based anthropometry and DM in the linear measurements except for the volume (P < .05). The mean volume calculation error of Mimics was −0.08 ± 0.13 mL. No correlation was found between the anthropometric variables and the absolute errors (P > .05). Furthermore, Bland‐Altman plots were used to evaluate the agreement between the two methods.

Conclusions

Despite a very small error was found in volume calculation, Mimics software was accurate and reliable in linear calculation. Three‐dimensional costal cartilage imaging was found to be an efficient tool for morphological evaluation of costal cartilages. We believe that with the application of individualised cartilage models based on three‐dimensional printing, the use of customised ear framework carving will be practicable in surgical training.
Shared and unique individual risk factors and clinical biomarkers in children with allergic rhinitis and obstructive sleep apnea syndrome
Authors: Ha Eun Kyo , Park Jun Hyeong , Lee Seung Jin , Yon Dong Keon , Kim Ju Hee , Jee Hye Mi , Lee Kyung Suk , Sung Myongsoon , Kim Mi Ae , Shin Youn Ho , Han Man Yong
Published: December 2019

Introduction

Rhinitis and obstructive sleep apnea syndrome (OSAS) are different diseases, but have some similar risk factors.

Objective

The aims of this study were to compare the risk factors and clinical biomarkers for rhinitis and OSAS in children.

Methods

We examined 3917 children (age 4‐13 years) who were enrolled in a cross‐sectional study conducted in Seongnam, Korea. Their parents completed the Pediatric Sleep Questionnaire (PSQ) for evaluation of OSAS and the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire for evaluation of rhinitis. Clinical biomarkers, including total eosinophil count and neutrophil‐lymphocyte ratio (NLR), were measured in a subset of these children.

Results

OSAS and rhinitis had prevalences of 4.0% and 43.5%, respectively. Body mass index (P < 0.001) and prematurity (P = 0.016) were significantly associated with OSAS, but not with rhinitis. Higher parental education and income increased the risk for rhinitis, but decreased the risk for OSAS. Having more siblings and birth by Cesarean delivery decreased the risk for rhinitis, but living in a new household increased the risk for rhinitis. A short distance of the residence to a main road during pregnancy significantly increased the risk of OSAS. Males, increased exposure to mould, and firstborns had increased risk of OSAS and rhinitis. The NLR was higher in OSAS patients than in those with allergic rhinitis (P = 0.001).

Conclusion

OSAS and rhinitis shared some risk factors, whereas other factors had inverse association with the two disorders. These results imply that different strategies might be used for prevention of rhinitis and OSAS.
Disentangling the far transfer of language comprehension gains using latent mediation models
Authors: Melby‐Lervåg Monica , Hagen Åste Mjelve , Lervåg Arne
Published: December 2019

While we know that interventions targeting oral language can be effective, little is known about what drives these effects. In this study, we examine whether gains in transfer measures are mediated through the specific words that are trained in a language intervention. Based on a large‐scale randomized controlled trial of language intervention in 4‐ to 5‐year‐old children, latent mediation models were used to disentangle oral language gains in transfer measures. The results first showed that the effects of the language intervention and the transfer effects are generated through expressive rather than receptive measures of language. Second, we found that the effects of the intervention on intermediate transfer measures of language were mediated through the ability to define the trained words. Third, and critically, for far transfer measures that did not contain any of the trained words, the effects were mediated through the trained words. The findings relate to theories of transfer and support the idea that far transfer is possible, at least within the same domain. In addition, it seems that effects on receptive language skills are difficult to obtain and that what is improved is instead the children's ability to express themselves and use procedures to explain words. Thus, to optimize intervention effects, future studies should focus on expressive language.
Mitochondrial DNA diversity and geographical distribution of sexual and asexual strains of the braconid parasitoid Meteorus pulchricornis
Authors: Fujie Shunpei , Wachi Nakatada , Umemoto Hironobu , Maeto Kaoru
Published: December 2019

Asexuality is an important tool with regard to the use of parasitoid wasps as biocontrol agents. Asexual (apomictic thelytokous) strains of Meteorus pulchricornis (Wesmael) (Hymenoptera: Braconidae), a polyphagous endoparasitoid of lepidopteran larvae, are sympatric with sexual (arrhenotokous) strains in Japan. The results of phylogenetic analyses of mitochondrial cytochrome c oxidase subunit I (COI) sequences indicated two major haplotype groups on the Japanese islands. The northern group I predominantly contained sexual strains, whereas the southern group II contained both sexual and asexual strains. Most asexual strains were likely derived within group II. An asexual strain recently established in New Zealand has the identical haplotype to a strain in Japan and was proven to have originated from East Asia. Three hypotheses on the evolution of asexuality are discussed for this parasitoid wasp: recessive gene, hybridization, and cytoplasmic element.
A single lycaenid caterpillar gets an ant‐constructed shelter and uninterrupted ant attendance
Authors: Ekka Priya Aradhya , Rastogi Neelkamal
Published: December 2019

Ant‐lycaenid associations range from mutualism to parasitism and the caterpillars of some species of lycaenids are reported to enter ant nests for shelter, diapause, or pupation. The present study aimed to examine the nature of the association between Euchrysops cnejus (Fabricius) (Lepidoptera: Lycaenidae) and Camponotus compressus (Fabricius) (Hymenoptera: Formicidae) worker ants on the extrafloral nectary‐bearing cowpea plant, Vigna unguiculata (L.) Walp. (Fabaceae). The abundance patterns of the ants and the lycaenid caterpillars together with the spatial patrolling patterns of the ants on the plants revealed that ant abundance increased with the occurrence of the lycaenid caterpillars and the ants preferred the lycaenids over the extrafloral nectar. Camponotus compressus worker ants constructed a shelter at the cowpea plant base after interaction with one or more lycaenid caterpillar(s) and tended the caterpillars and pupae till the emergence of the butterfly. The ant‐constructed shelters (ACSs) inhabited by the minor caste workers (13 ± 1.3 ants per ACS), were utilized by the caterpillars to undergo pupation. The ants confined their activities predominantly to tending the pod‐feeding caterpillars and the solitary pupa within each ACS. It appears that the behavior of the tending worker ants is modulated by the lycaenid vulnerable stages.
Influence of harmonic radar tag attachment on nymphal Halyomorpha halys mobility, survivorship, and detectability
Authors: Kirkpatrick Danielle M. , Rice Kevin B. , Ibrahim Aya , Morrison William R. , Leskey Tracy C.
Published: December 2019

The brown marmorated stink bug, Halyomorpha halys (Stål) (Hemiptera: Pentatomidae), is a polyphagous invasive insect and currently one of the most threatening agricultural pests in the USA and globally. Nymphs are highly mobile, moving among host plants, and causing significant damage. Thus, understanding dispersal biology for all life stages is critical for the development of reliable monitoring and management programs. Here, we evaluated the influence of harmonic radar as a tool to study dispersal ecology of nymphal H. halys; we measured the impact of glues and tag attachment on survivorship and mobility in the laboratory and validated in the field that tagged and released nymphs could be tracked on baited and unbaited host and non‐host plants using harmonic radar. In the laboratory, four glues were evaluated for attaching harmonic radar tags securely to nymphs, and survivorship with attached tags was measured. There were no significant differences in survivorship or vertical and horizontal movement among nymphs with tags affixed with the glue treatments compared with the untagged control. Based on numerically greater survivorship of nymphs with tags affixed with Loctite glass glue, a field validation study of tagged nymphs released in host (apple tree) and non‐host (mowed grass) with or without H. halys pheromonal stimuli present revealed that nymphs could be successfully relocated using harmonic radar after 48 h. Among treatments, 83% of nymphs remained in baited and unbaited apple trees, 50% of nymphs remained in baited mowed grass plots, and in unbaited mowed grass plots, 17% of fifth instars, and 0% of fourth instars were retained. The absence of negative effects on mobility, survivorship, and field tracking validates that harmonic radar can be used to study dispersal ecology of nymphal H. halys.
Soil conservation practices for insect pest management in highly disturbed agroecosystems – a review
Authors: Alyokhin Andrei , Nault Brian , Brown Bryan
Published: December 2019

Decline in soil health is a serious worldwide problem that decreases complexity and stability of agricultural ecosystems, commonly making them more prone to outbreaks of herbivorous insect pests. Potato (Solanum tuberosumL., Solanaceae) and onion (Allium cepaL., Amaryllidaceae) production is currently characterized by high soil disturbance and heavy reliance on synthetic inputs, including insecticides. Evidence suggests that adopting soil conservation techniques often (but not always) increases mortality and decreases reproductive output for the major insect pests of these important vegetable crops. Known mechanisms responsible for such an effect include increases in density and activity of natural enemy populations, enhanced plant defenses, and modified physical characteristics of respective agricultural habitats. However, most research efforts focused on mulches and organic soil amendments, with additional research needed on elucidating effects and their mechanisms for conservation tillage, cover crops, and arbuscular mycorrhizae.
All‐trans retinoic acid (ATRA)‐induced TFEB expression is required for myeloid differentiation in acute promyelocytic leukemia (APL)
Authors: Orfali Nina , O'Donovan Tracey R. , Cahill Mary R. , Benjamin Dalyia , Nanus David M. , McKenna Sharon L. , Gudas Lorraine J. , Mongan Nigel P.
Published: December 2019

Objective

In acute promyelocytic leukemia (APL), normal retinoid signaling is disrupted by an abnormal PML‐RARα fusion oncoprotein, leading to a block in cell differentiation. Therapeutic concentrations of all‐trans‐retinoic acid (ATRA) can restore retinoid‐induced transcription and promote degradation of the PML‐RARα protein. Autophagy is a catabolic pathway that utilizes lysosomal machinery to degrade intracellular material and facilitate cellular re‐modeling. Recent studies have identified autophagy as an integral component of ATRA‐induced myeloid differentiation.

Methods

As the molecular communication between retinoid signaling and the autophagy pathway is not defined, we performed RNA sequencing of NB4 APL cells treated with ATRA and examined autophagy‐related transcripts.

Results

ATRA altered the expression of >80 known autophagy‐related transcripts, including the key transcriptional regulator of autophagy and lysosomal biogenesis, TFEB (11.5‐fold increase). Induction of TFEB and its transcriptional target, sequestosome 1 (SQSTM1, p62), is reduced in ATRA‐resistant NB4R cells compared to NB4 cells. TFEB knockdown in NB4 cells alters the expression of transcriptional targets of TFEB and reduces CD11b transcript levels in response to ATRA.

Conclusions

We show for the first time that TFEB plays an important role in ATRA‐induced autophagy during myeloid differentiation and that autophagy induction potentiates leukemic cell differentiation (Note: this study includes data obtained from NCT00195156, https://clinicaltrials.gov/show/NCT00195156).