bluuebunny/crossref_metadata_2025 huggingface dataset:
Replacement and Parallel Simplification of Nonhomologous Proteinases Maintain Venom Phenotypes in Rear-Fanged Snakes
Authors: Bayona-Serrano Juan David , Viala Vincent Louis , Rautsaw Rhett M , Schramer Tristan D , Barros-Carvalho Gesiele A , Nishiyama Milton Yutaka , Freitas-de-Sousa Luciana A , Moura-da-Silva Ana Maria , Parkinson Christopher L , Grazziotin Felipe Gobbi , Junqueira-de-Azevedo Inácio L M
Published: July 2020

Novel phenotypes are commonly associated with gene duplications and neofunctionalization, less documented are the cases of phenotypic maintenance through the recruitment of novel genes. Proteolysis is the primary toxic character of many snake venoms, and ADAM metalloproteinases, named snake venom metalloproteinases (SVMPs), are largely recognized as the major effectors of this phenotype. However, by investigating original transcriptomes from 58 species of advanced snakes (Caenophidia) across their phylogeny, we discovered that a different enzyme, matrix metalloproteinase (MMP), is actually the dominant venom component in three tribes (Tachymenini, Xenodontini, and Conophiini) of rear-fanged snakes (Dipsadidae). Proteomic and functional analyses of these venoms further indicate that MMPs are likely playing an “SVMP-like” function in the proteolytic phenotype. A detailed look into the venom-specific sequences revealed a new highly expressed MMP subtype, named snake venom MMP (svMMP), which originated independently on at least three occasions from an endogenous MMP-9. We further show that by losing ancillary noncatalytic domains present in its ancestors, svMMPs followed an evolutionary path toward a simplified structure during their expansion in the genomes, thus paralleling what has been proposed for the evolution of their Viperidae counterparts, the SVMPs. Moreover, we inferred an inverse relationship between the expression of svMMPs and SVMPs along the evolutionary history of Xenodontinae, pointing out that one type of enzyme may be substituting for the other, whereas the general (metallo)proteolytic phenotype is maintained. These results provide rare evidence on how relevant phenotypic traits can be optimized via natural selection on nonhomologous genes, yielding alternate biochemical components.
Microcephaly family protein MCPH1 stabilizes RAD51 filaments
Authors: Chang Hao-Yen , Lee Chia-Yi , Lu Chih-Hao , Lee Wei , Yang Han-Lin , Yeh Hsin-Yi , Li Hung-Wen , Chi Peter
Published: July 2020

Microcephalin 1 (MCPH1) was identified from genetic mutations in patients with primary autosomal recessive microcephaly. In response to DNA double-strand breaks (DSBs), MCPH1 forms damage-induced foci and recruits BRCA2–RAD51 complex, a key component of the DSB repair machinery for homologous recombination (HR), to damage sites. Accordingly, the efficiency of HR is significantly attenuated upon depletion of MCPH1. The biochemical characteristics of MCPH1 and its functional interaction with the HR machinery had remained unclear due to lack of highly purified MCPH1 recombinant protein for functional study. Here, we established a mammalian expression system to express and purify MCPH1 protein. We show that MCPH1 is a bona fide DNA-binding protein and provide direct biochemical analysis of this MCPH family protein. Furthermore, we reveal that MCPH1 directly interacts with RAD51 at multiple contact points, providing evidence for how MCPH1 physically engages with the HR machinery. Importantly, we demonstrate that MCPH1 enhances the stability of RAD51 on single-strand DNA, a prerequisite step for RAD51-mediated recombination. Single-molecule tethered particle motion analysis showed a ∼2-fold increase in the lifetime of RAD51–ssDNA filaments in the presence of MCPH1. Thus, our study demonstrates direct crosstalk between microcephaly protein MCPH1 and the recombination component RAD51 for DSB repair.
Canonical non-homologous end-joining promotes genome mutagenesis and translocations induced by transcription-associated DNA topoisomerase 2 activity
Authors: Olmedo-Pelayo Joaquín , Rubio-Contreras Diana , Gómez-Herreros Fernando
Published: July 2020

DNA topoisomerase II (TOP2) is a major DNA metabolic enzyme, with important roles in replication, transcription, chromosome segregation and spatial organisation of the genome. TOP2 is the target of a class of anticancer drugs that poison the DNA-TOP2 transient complex to generate TOP2-linked DNA double-strand breaks (DSBs). The accumulation of DSBs kills tumour cells but can also result in genome instability. The way in which topoisomerase activity contributes to transcription remains unclear. In this work we have investigated how transcription contributes to TOP2-dependent DSB formation, genome instability and cell death. Our results demonstrate that gene transcription is an important source of abortive TOP2 activity. However, transcription does not contribute significantly to apoptosis or cell death promoted by TOP2-induced DSBs. On the contrary: transcription-dependent breaks greatly contribute to deleterious mutations and translocations, and can promote oncogenic rearrangements. Importantly, we show that TOP2-induced genome instability is mediated by mutagenic canonical non-homologous end joining whereas homologous recombination protects cells against these insults. Collectively, these results uncover mechanisms behind deleterious effects of TOP2 abortive activity during transcription, with relevant implications for chemotherapy.
Developmental regulation of edited CYb and COIII mitochondrial mRNAs is achieved by distinct mechanisms in Trypanosoma brucei
Authors: Smith Jr. Joseph T , Doleželová Eva , Tylec Brianna , Bard Jonathan E , Chen Runpu , Sun Yijun , Zíková Alena , Read Laurie K
Published: July 2020

Trypanosoma brucei is a parasitic protozoan that undergoes a complex life cycle involving insect and mammalian hosts that present dramatically different nutritional environments. Mitochondrial metabolism and gene expression are highly regulated to accommodate these environmental changes, including regulation of mRNAs that require extensive uridine insertion/deletion (U-indel) editing for their maturation. Here, we use high throughput sequencing and a method for promoting life cycle changes in vitro to assess the mechanisms and timing of developmentally regulated edited mRNA expression. We show that edited CYb mRNA is downregulated in mammalian bloodstream forms (BSF) at the level of editing initiation and/or edited mRNA stability. In contrast, edited COIII mRNAs are depleted in BSF by inhibition of editing progression. We identify cell line-specific differences in the mechanisms abrogating COIII mRNA editing, including the possible utilization of terminator gRNAs that preclude the 3′ to 5′ progression of editing. By examining the developmental timing of altered mitochondrial mRNA levels, we also reveal transcript-specific developmental checkpoints in epimastigote (EMF), metacyclic (MCF), and BSF. These studies represent the first analysis of the mechanisms governing edited mRNA levels during T. brucei development and the first to interrogate U-indel editing in EMF and MCF life cycle stages.
Bone evaluation in paediatric chronic kidney disease: clinical practice points from the European Society for Paediatric Nephrology CKD-MBD and Dialysis working groups and CKD-MBD working group of the ERA-EDTA
Authors: Bakkaloglu Sevcan A , Bacchetta Justine , Lalayiannis Alexander D , Leifheit-Nestler Maren , Stabouli Stella , Haarhaus Mathias , Reusz George , Groothoff Jaap , Schmitt Claus Peter , Evenepoel Pieter , Shroff Rukshana , Haffner Dieter ,   the European Society for Paediatric Nephrology (ESPN) Chronic Kidney Disease Mineral and Bone Disorder (CKD-MBD) and Dialysis working groups and CKD-MBD working group of the European Renal Association–European Dialysis and Transplant Association (ERA-EDTA)
Published: July 2020

Mineral and bone disorder (MBD) is widely prevalent in children with chronic kidney disease (CKD) and is associated with significant morbidity. CKD may cause disturbances in bone remodelling/modelling, which are more pronounced in the growing skeleton, manifesting as short stature, bone pain and deformities, fractures, slipped epiphyses and ectopic calcifications. Although assessment of bone health is a key element in the clinical care of children with CKD, it remains a major challenge for physicians. On the one hand, bone biopsy with histomorphometry is the gold standard for assessing bone health, but it is expensive, invasive and requires expertise in the interpretation of bone histology. On the other hand, currently available non-invasive measures, including dual-energy X-ray absorptiometry and biomarkers of bone formation/resorption, are affected by growth and pubertal status and have limited sensitivity and specificity in predicting changes in bone turnover and mineralization. In the absence of high-quality evidence, there are wide variations in clinical practice in the diagnosis and management of CKD-MBD in childhood. We present clinical practice points (CPPs) on the assessment of bone disease in children with CKD Stages 2–5 and on dialysis based on the best available evidence and consensus of experts from the CKD-MBD and Dialysis working groups of the European Society for Paediatric Nephrology and the CKD-MBD working group of the European Renal Association–European Dialysis and Transplant Association. These CPPs should be carefully considered by treating physicians and adapted to individual patients’ needs as appropriate. Further areas for research are suggested.
Haematological disorders following kidney transplantation
Authors: Malyszko Jolanta , Basak Grzegorz , Batko Krzysztof , Capasso Giavambatista , Capasso Anna , Drozd-Sokolowska Joanna , Krzanowska Katarzyna , Kulicki Pawel , Matuszkiewicz-Rowinska Joanna , Soler Maria Jose , Sprangers Ben , Malyszko Jacek
Published: July 2020

Transplantation offers cure for some haematological cancers, end-stage organ failure, but at the cost of long-term complications. Renal transplantation is the best-known kidney replacement therapy and it can prolong end-stage renal disease patient lives for decades. However, patients after renal transplantation are at a higher risk of developing different complications connected not only with surgical procedure but also with immunosuppressive treatment, chronic kidney disease progression and rejection processes. Various blood disorders can develop in post-transplant patients ranging from relatively benign anaemia through cytopenias to therapy-related myelodysplasia and acute myeloid leukaemia (AML) and post-transplant lymphoproliferative disorders followed by a rare and fatal condition of thrombotic microangiopathy and haemophagocytic syndrome. So far literature mainly focused on the post-transplant lymphoproliferative disease. In this review, a variety of haematological problems after transplantation ranging from rare disorders such as myelodysplasia and AML to relatively common conditions such as anaemia and iron deficiency are presented with up-to-date diagnosis and management.
New Philosophy, Clinical Pearls, and Methods for Intraoperative Cognition Mapping and Monitoring “à la carte” in Brain Tumor Patients
Authors: Duffau Hugues
Published: July 2020

The purpose of surgery for brain tumors involving eloquent neural circuits is to maximize the extent of resection while preserving an optimal quality of life. To this end, especially in diffuse glioma, the goal is to remove the cerebral parenchyma invaded by the neoplasm up to the individual cortico-subcortical networks critical for brain functions. Intraoperative mapping combined with real-time cognitive monitoring throughout the resection in awake patient is thus highly recommended to resume a normal life. Indeed, beyond avoiding hemiplegia or aphasia, enjoying a familial, social, and professional life implies that motor and language mapping is not sufficient. Identifying and sparing neural networks that subserve cognition (movement control, visuospatial cognition, executive functions, multimodal semantics, metacognition) and mentalizing (theory of mind, which plays a key role for social cognition) is essential to preserve an adapted behavior.

Here, the aim is to review when and how to map these critical functions, which have nonetheless been neglected for many decades by neurosurgeons. In fact, the disorders generated by surgical injuries of circuits underpinning nonmotor and nonspeech functions are usually not immediately visible on postoperative standard clinical examination, leading the physician to believe that the patient has no deficit. Yet, cognitive or emotional disturbances may subsequently prevent to resume an active life, as to work full time. Therefore, a systematic neuropsychological assessment should be performed before, during, and after mapping-guided surgery, regardless of the tumor location, to preserve the functional connectome intraoperatively and to plan a postoperative tailored cognitive rehabilitation according to the patient's needs.
Measles or Not Measles? That is the Question!
Authors: Ibraheim Marina Kristy , Awadh Hesham , Allana Ambreen , Ostrosky-Zeichner Luis , Arias Cesar A
Published: July 2020

We present a diagnostically challenging case of a patient who presented with fever and rash during a measles outbreak. The diagnosis was complicated by the interpretation of the results of serological tests, which resulted in implementation of major preventive measures in the hospital. The patient was later confirmed to have murine typhus.
Gray Matter Structural Alterations in Chronic and Episodic Migraine: A Morphometric Magnetic Resonance Imaging Study
Authors: Planchuelo-Gómez Álvaro , García-Azorín David , Guerrero Ángel L , Rodríguez Margarita , Aja-Fernández Santiago , de Luis-García Rodrigo
Published: July 2020

Objective

This study evaluates different parameters describing the gray matter structure to analyze differences between healthy controls, patients with episodic migraine, and patients with chronic migraine.

Design

Cohort study.

Setting

Spanish community.

Subjects

Fifty-two healthy controls, 57 episodic migraine patients, and 57 chronic migraine patients were included in the study and underwent T1-weighted magnetic resonance imaging acquisition.

Methods

Eighty-four cortical and subcortical gray matter regions were extracted, and gray matter volume, cortical curvature, thickness, and surface area values were computed (where applicable). Correlation analysis between clinical features and structural parameters was performed.

Results

Statistically significant differences were found between all three groups, generally consisting of increases in cortical curvature and decreases in gray matter volume, cortical thickness, and surface area in migraineurs with respect to healthy controls. Furthermore, differences were also found between chronic and episodic migraine. Significant correlations were found between duration of migraine history and several structural parameters.

Conclusions

Migraine is associated with structural alterations in widespread gray matter regions of the brain. Moreover, the results suggest that the pattern of differences between healthy controls and episodic migraine patients is qualitatively different from that occurring between episodic and chronic migraine patients.
Validation of the OWLS, a Screening Tool for Measuring Prescription Opioid Use Disorder in Primary Care
Authors: Picco Louisa , Middleton Melissa , Bruno Raimondo , Kowalski Michala , Nielsen Suzanne
Published: July 2020

Objective

The OWLS is a screening tool for prescription opioid use disorder designed for use in primary care. This study aimed to confirm the optimal wording, scoring methods, and cutoff for the OWLS.

Design and Setting

Cross-sectional analysis of an online sample.

Subjects

Participants comprised those with chronic noncancer pain who regularly used prescription opioids.

Methods

Eligible participants self-completed an online version of the OWLS prescription opioid use disorder screening tool and the Composite International Diagnostic Interview Substance Abuse module. Receiver operating characteristics were calculated for three scoring methods for the OWLS, and these were compared with DSM-5 classification of any use disorder and moderate to severe opioid use disorder.

Results

Among the sample (N = 324), utilizing scoring method (i) (i.e., positive endorsement ≥ response option “a little bit”) and a cutoff of 3 increased the percentage of correctly classified participants, with concurrent increases in specificity and decreases in false discovery rate, and false positive rate.

Conclusion

OWLS utilizing scoring method (i) with a cutoff of 3 was shown to be the optimal version and scoring method of this tool. This represents a time-efficient, simple scoring method, allowing for quick and accurate screening for opioid use disorder to occur.
The risk of infections in adult patients with systemic lupus erythematosus: systematic review and meta-analysis
Authors: Pego-Reigosa José María , Nicholson Lindsay , Pooley Nick , Langham Sue , Embleton Nina , Marjenberg Zoe , Barut Volkan , Desta Barnabas , Wang Xia , Langham Julia , Hammond Edward R
Published: July 2020

Objectives

We conducted a systematic review and meta-analysis to determine the magnitude of infection risk in patients with SLE and evaluate the effect of general and SLE-related factors on infection risk.

Methods

We searched MEDLINE and Embase from inception to July 2018, screening for observational studies that evaluated infection risk in patients with SLE compared with the general population/healthy controls. Outcomes of interest included overall severe infection, herpes zoster infection/reactivation, opportunistic infections, pneumonia and tuberculosis. Random-effects models were used to calculate pooled risk ratios (RRs) for each type of infection. Sensitivity analysis assessed the impact of removing studies with high risk of bias.

Results

Eleven retrospective or prospective cohort studies were included in the meta-analysis: overall severe infection (n = 4), pneumonia (n = 6), tuberculosis (n = 3) and herpes zoster (n = 2). Pooled RRs for overall severe infection significantly increased for patients with SLE compared with the general population/healthy controls [RR 2.96 (95% CI 1.28, 6.83)]. Pooled RRs for pneumonia, herpes zoster and tuberculosis showed significantly increased risk compared with the general population/healthy controls [RR 2.58 (1.80, 3.70), 2.50 (2.36, 2.65) and 6.11 (3.61, 10.33), respectively]. Heterogeneity and evidence of publication bias were present for all analyses, except herpes zoster. Sensitivity analyses confirmed robustness of the results.

Conclusion

Patients with SLE have significantly higher risk of infection compared with the general population/healthy controls. Efforts to strengthen strategies aimed at preventing infections in SLE are needed.

Protocol registration

PROSPERO number: CRD42018109425.
Assessing outcomes in a lupus nephritis cohort over a 40-year period
Authors: Gisca Eugeniu , Duarte Leila , Farinha Filipa , Isenberg David A
Published: July 2020

Objectives

To characterize a LN cohort over 40 years, assessing its evolution, analysing two major outcomes: the development of end-stage renal disease and mortality rates in the first 5 years after LN diagnosis.

Methods

An observational retrospective study of patients with LN, followed up from 1975 at University College Hospital. Patients were divided into four groups, depending on the decade of LN diagnosis: 1975–1985 (D1), 1986–1995 (D2), 1996–2005 (D3) and 2006–2015 (D4). Comparison between groups was performed with respect to demographic, clinical, serological and histological characteristics and outcome.

Results

Two hundred and nineteen patients with LN were studied. There was a change in ethnic distribution, with a decreasing proportion of Caucasians (58.6% in D1 to 31.3% in D4, P = 0.018) and increase in African-ancestry (17.2% in D1 to 39.6% in D4, P = 0.040). Serological and histological patterns changed throughout time, with a reduction in class IV nephritis (51.7% in D1 to 27.1% in D4, P = 0.035), and increase in class II nephritis (10% in D2 to 18.8% in D4, P = 0.01) and anti-extractable nuclear antigen antibody positivity (17.2% in D1 to 83.3% in D4, P = 0.0001). The 5-year mortality rates decreased from D1 (24.1%) to D2 (4%), stabilizing for the next 30 years. The 5-year progression to end-stage renal disease remained stable over the decades.

Conclusion

Despite the changes in treatment of LN in the past 20 years, we have reached a plateau in 5-year mortality and progression to end-stage renal disease rates, suggesting that new therapeutic and management approaches, and strategies to enhance adherence, are needed to improve outcomes further in LN patients.
Temporal artery compression sonography for the diagnosis of giant cell arteritis in elderly patients with acute ocular arterial occlusions
Authors: Czihal Michael , Köhler Anton , Lottspeich Christian , Prearo Ilaria , Hoffmann Ulrich , Schulze-Koops Hendrik , Priglinger Siegfried G , Mackert Marc J , Dechant Claudia
Published: July 2020

Objectives

To validate cut-off values of quantitative high-resolution temporal artery compression sonography (TCS) for the diagnosis of cranial GCA (cGCA) in patients with acute arterial ocular occlusions and in an independent control group.

Methods

Consecutive patients who underwent TCS as part of the diagnostic workup of acute arterial ocular occlusions and controls not suffering from ocular ischaemia/systemic vasculitis were included. The diagnostic accuracy of the established TCS cut-off value of maximum temporal artery wall thickness (≥0.7 mm) and a novel numeric TCS score incorporating the degree of wall thickening in the four temporal artery segments assessed (0–3 points per segment) was tested by receiver operating characteristics analysis. Subgroup analyses were performed for female and male patients and patients older and younger than age of 70 years.

Results

Of 114 patients with acute ocular arterial occlusions, 30 patients received a final clinical diagnosis of cGCA. The sensitivity and specificity of the ≥0.7 mm TCS cut-off for the diagnosis of cGCA were 100 and 84.5% in the overall cohort. The TCS score did not improve the diagnostic yield (cut-off ≥5; sensitivity 100%, specificity 85.7%). In male patients >70 years of age, the specificity of TCS was limited, secondary to age- and sex-related differences in temporal artery wall thickness, which we confirmed in the independent control group.

Conclusion

TCS yields high diagnostic accuracy in the diagnosis of cGCA in patients with acute ocular arterial occlusions. Age- and sex-related differences in temporal artery wall thickness influence the diagnostic accuracy of TCS.
Genetic diversity of Staphylococcus aureus influences disease phenotype of systemic lupus erythematosus
Authors: Ceccarelli Fulvia , Lo Presti Alessandra , Olivieri Giulio , Angeletti Silvia , Perricone Carlo , Garufi Cristina , Iaiani Giancarlo , De Florio Lucia , Antonelli Francesca , De Cesaris Marina , Giordano Alessandra , Amori Luigino , Spinelli Francesca Romana , Alessandri Cristiano , Valesini Guido , Ciccozzi Massimo , Conti Fabrizio
Published: July 2020

Objective

We investigated the genetic diversity, molecular epidemiology and evolutionary dynamics of Staphylococcus aureus (SA) isolated from SLE patients by means of phylogenetic analysis.

Methods

Consecutive SLE patients (ACR 1997 criteria) were enrolled: clinical/laboratory data were collected and nasal swab for SA identification was performed. On the basis of the translation elongation factor (tuf) gene, a phylogenetic analysis was performed to investigate relationships and to assess significant clades. Selective pressure analysis was used to investigate the evolution of the SA tuf gene. The gene sequences from non-SLE individuals, downloaded from the GenBank database, were compared through phylogenetic analysis with the tuf gene from SLE patients.

Results

We enrolled 118 patients [M/F 10/108; median (interquartile range (IQR)) age 45.5 (13.2) years; median (IQR) disease duration 120 (144) months]. Twenty-four patients (20.3%) were SA carriers (SA+), three of them MRSA. SA+ SLE showed significantly higher SLEDAI-2k values [SA+: median (IQR) 2 (3.75); SA−: 0 (2); P = 0.04]. The phylogenetic analysis, restricted to 21 non-MRSA SA+, revealed a statistically supported larger clade (A, n = 17) and a smaller one (B, n = 4). Patients located in clade A showed a significantly higher prevalence of joint involvement (88.2%) in comparison with clade B (50.0%, P < 0.0001) and SA− (62.7%, P < 0.0001). Haematological manifestations were significantly more frequent in clade A (64.7%) compared with B (50.0%, P = 0.004).

Conclusion

We suggest a possible role of SA nasal carriage status in SLE disease activity. Moreover, our findings support the hypothesis that bacterial genetic variants may be associated with specific disease features.
Resting-state functional connectivity of neural circuits associated with primary and secondary rewards in patients with bipolar disorder
Authors: Shi Jing , Guo Hua , Liu Sijia , Xue Wei , Fan Fengmei , Fan Hongzhen , An Huimei , Wang Zhiren , Tan Shuping , Yang Fude , Tan Yunlong
Published: July 2020

Objective

We used resting-state functional connectivity (rsFC) to evaluate the integrity of the neural circuits associated with primary and secondary rewards in bipolar disorder (BD) with different mood phases.

Methods

Sixty patients with BD [21 patients with depressive episode of BD (BDD) and 41 patients with maniac episode of BD (BDM)] and 42 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging. rsFC was assessed using region of interest-wise analyses.

Results

Attenuation of rsFC at the orbitofrontal cortex (OFC) and the left ventral striatum (LVS) was observed in the secondary reward circuit of patients with BD compared to that of HCs. Among BDD, BDM and HCs, the rsFC between OFC and LVS in BDM was intermediate, while the rsFC between OFC and right ventral striatum/right amygdala in BDM was the highest; the corresponding rsFC values in BDD were the lowest. Furthermore, a positive correlation was found between rsFC and Young Mania Rating Scale scores in BDM.

Conclusions

This study suggests that there may be an abnormal rsFC between OFC and LVS in the second reward of patients with BD and the discrepant patterns of rsFC may exist between different mood states in patients with BD.
Comparative Effectiveness of Antipsychotics for Risk of Attempted or Completed Suicide Among Persons With Schizophrenia
Authors: Taipale Heidi , Lähteenvuo Markku , Tanskanen Antti , Mittendorfer-Rutz Ellenor , Tiihonen Jari
Published: July 2020

Objective

The objective of our study was to investigate the comparative effectiveness of antipsychotics for the risk of attempted or completed suicide among all patients with schizophrenia in Finland and Sweden.

Methods

Two nationwide register-based cohort studies were conducted, including all individuals with schizophrenia in Finland (n = 61 889) and Sweden (n=29 823). The main exposure was 10 most commonly used antipsychotic monotherapies; also, adjunctive pharmacotherapies were investigated. The main outcome measure was attempted or completed suicide, which was analyzed with within-individual models by comparing use and nonuse periods in the same individual to minimize selection bias. Sensitivity analyses included attempted suicide (hospitalization only) as an outcome.

Results

Compared with no use of antipsychotics, clozapine use was the only antipsychotic consistently associated with a decreased risk of suicidal outcomes. Hazard ratios (HRs) and 95% CIs for attempted or completed suicide were 0.64 (0.49–0.84) in the Finnish cohort and 0.66 (0.43–0.99) in the Swedish cohort. No other antipsychotic was associated with a reduced risk of attempted and/or completed suicide. Benzodiazepines and Z-drugs were associated with an increased risk of attempted or completed suicide (HRs: 1.29–1.30 for benzodiazepines and 1.33–1.62 for Z-drugs).

Conclusion

Clozapine was the only antipsychotic associated with decreased risk of attempted or completed suicide among patients with schizophrenia, and it should be considered as first-line treatment for high-risk patients.
Changes in Posttraumatic Cognitions Mediate the Effects of Trauma-Focused Therapy on Paranoia
Authors: van der Vleugel Berber M , Libedinsky Ilan , de Bont Paul A J M , de Roos Carlijn , van Minnen Agnes , de Jongh Ad , van der Gaag Mark , van den Berg David
Published: July 2020

Background

Evidence suggests that in individuals with psychosis, paranoia is reduced after trauma-focused therapy (TFT) aimed at comorbid posttraumatic stress disorder (PTSD).

Objective

To identify mediators of the effect of TFT on paranoia.

Method

In a multicenter single-blind randomized controlled trial 155 outpatients in treatment for psychosis were allocated to 8 sessions Prolonged Exposure (PE; n = 53), 8 sessions Eye Movement Desensitization and Reprocessing (EMDR) therapy (n = 55), or a waiting-list condition (WL; n = 47) for treatment of comorbid PTSD. Measures were performed on (1) paranoia (GPTS); (2) DSM-IV-TR PTSD symptom clusters (CAPS-IV; ie, intrusions, avoidance, and hyperarousal); (3) negative posttraumatic cognitions (PTCI; ie, negative self posttraumatic cognitions, negative world posttraumatic cognitions and self-blame); (4) depression (BDI-II); and (5) cognitive biases (ie, jumping to conclusion, attention to threat, belief inflexibility, and external attribution), cognitive limitations (ie, social cognition problems and subjective cognitive problems), and safety behaviors (DACOBS). Outcome in terms of symptoms of paranoia (1) and potential mediators (2–5) were evaluated at posttreatment, controlling for baseline scores.

Results

The effects of TFT on paranoia were primarily mediated by negative self and negative world posttraumatic cognitions, representing almost 70% of the total indirect effect. Safety behaviors and social cognition problems were involved in the second step mediational pathway models.

Conclusions

Targeting the cognitive dimension of PTSD in TFT in psychosis could be an effective way to influence paranoia, whereas addressing safety behaviors and social cognition problems might enhance the impact of TFT on paranoia.
Tepary bean (Phaseolus acutifolius) lectin fraction provokes reversible adverse effects on rats’ digestive tract
Authors: Pita-López Wendoline , Gomez-Garay Mery , Blanco-Labra Alejandro , Aguilera-Barreyro Araceli , Reis-de Souza Tércia C , Olvera-Ramírez Andrea , Ferriz-Martinez Roberto , García-Gasca Teresa
Published: July 2020

The Tepary bean (Phaseolus acutifolius) lectin fraction (TBLF) exhibits differential cytotoxicity on colon cancer cells and inhibition of early tumorigenesis in the colon (50 mg/kg, three times per week, for 6 weeks). TBLF showed low toxicity with the ability to activate the immune system; however, some adverse effects are the loss in body weight gain, intestinal atrophy, and pancreatic hyperplasia. After a recovery period of 2 weeks after treatment, reversion of pancreatic hyperplasia but no recovery of intestinal atrophy was observed. As TBLF has shown anticancer effects on the colon, it is important to characterize the adverse effects and how they can be reversed. Sprague Dawley rats were administered with TBLF (50 mg/kg) for 6 weeks, three times per week, and then allowed to recover for 6 weeks post-treatment. After TBLF administration, small intestine atrophy, villus atrophy, and cryptic hyperplasia were confirmed, as well as increased intestinal mucus production, increased permeability and a decrease in the apparent ileal digestibility of crude proteins. The colon showed damage in the simple prismatic tissue and decreased crypt depth, and changes in microbiota and a decrease in the apparent fecal digestibility of crude protein were determined. Our results show that the adverse effects provoked by TBLF were partially reversed after 6 weeks of recovery post-treatment, suggesting that increasing the recovery period it could be possible to reverse all adverse effects observed.
Polycyclic Aromatic Hydrocarbon-induced Pulmonary Carcinogenesis in Cytochrome P450 (CYP)1A1- and 1A2-Null Mice: Roles of CYP1A1 and CYP1A2
Authors: Gastelum Grady , Jiang Weiwu , Wang Lihua , Zhou Guodong , Borkar Roshan , Putluri Nagireddy , Moorthy Bhagavatula
Published: July 2020

In 2019, lung cancer was estimated to be the leading cause of cancer deaths in humans. Polycyclic aromatic hydrocarbons (PAHs) are known to increase the risk of lung cancer. PAHs are metabolized by the cytochrome P450 (CYP)1A subfamily, comprised of the CYP1A1 and 1A2 monooxygenases. These enzymes bioactivate PAHs into reactive metabolites that induce mutagenic DNA adducts, which can lead to cancer. Past studies have investigated the role of CYP1A1 in PAH bioactivation; however, the individual roles of each CYP1A enzyme are still unknown. In this investigation, we tested the hypothesis that mice lacking the genes for Cyp1a1 or Cyp1a2 will display altered susceptibilities to PAH-induced pulmonary carcinogenesis. Wild-type, Cyp1a1-null (Cyp1a1−/−), and Cyp1a2-null (Cyp1a2−/−) male and female mice were treated with 3-methylcholanthrene for cancer initiation and tumor formation studies. In wild-type mice, CYP1A1 and 1A2 expression was induced by 3-methylcholanthrene. Cyp1a1−/− and Cyp1a2−/− mice treated with PAHs displayed a compensatory pattern, where knocking out 1 Cyp1a gene led to increased expression of the other. Cyp1a1−/− mice were resistant to DNA adduct and tumor formation, whereas Cyp1a2−/− mice displayed increased levels of both. UALCAN analysis revealed that lung adenocarcinoma patients with high levels of CYP1A2 expression survive significantly better than patients with low/medium expression. In conclusion, Cyp1a1−/− mice were less susceptible to PAH-induced pulmonary carcinogenesis, whereas Cyp1a2−/− mice were more susceptible. In addition, high CYP1A2 expression was found to be protective for lung adenocarcinoma patients. These results support the need to develop novel CYP1A1 inhibitors to mitigate human lung cancer.
Predicting the Activation of the Androgen Receptor by Mixtures of Ligands Using Generalized Concentration Addition
Authors: Schlezinger Jennifer J , Heiger-Bernays Wendy , Webster Thomas F
Published: July 2020

Concentration/dose addition is widely used for compounds that act by similar mechanisms. But it cannot make predictions for mixtures of full and partial agonists for effect levels above that of the least efficacious component. As partial agonists are common, we developed generalized concentration addition, which has been successfully applied to systems in which ligands compete for a single binding site. Here, we applied a pharmacodynamic model for a homodimer receptor system with 2 binding sites, the androgen receptor, that acts according to the classic homodimer activation model: Each cytoplasmic monomer protein binds ligand, undergoes a conformational change that relieves inhibition of dimerization, and binds to DNA response elements as a dimer. We generated individual dose-response data for full (dihydroxytestosterone, BMS564929) and partial (TFM-4AS-1) agonists and a competitive antagonist (MDV3100) using reporter data generated in the MDA-kb2 cell line. We used the Schild method to estimate the binding affinity of MDV3100. Data for individual compounds fit the homodimer pharmacodynamic model well. In the presence of a full agonist, the partial agonist had agonistic effects at low effect levels and antagonistic effects at high levels, as predicted by pharmacological theory. The generalized concentration addition model fits the empirical mixtures data—full/full agonist, full/partial agonist, and full agonist/antagonist—as well or better than relative potency factors or effect summation. The ability of generalized concentration addition to predict the activity of mixtures of different types of androgen receptor ligands is important as a number of environmental compounds act as partial androgen receptor agonists or antagonists.
Towards a unified classification for human respiratory syncytial virus genotypes
Authors: Ramaekers Kaat , Rector Annabel , Cuypers Lize , Lemey Philippe , Keyaerts Els , Van Ranst Marc
Published: July 2020

Since the first human respiratory syncytial virus (HRSV) genotype classification in 1998, inconsistent conclusions have been drawn regarding the criteria that define HRSV genotypes and their nomenclature, challenging data comparisons between research groups. In this study, we aim to unify the field of HRSV genotype classification by reviewing the different methods that have been used in the past to define HRSV genotypes and by proposing a new classification procedure, based on well-established phylogenetic methods. All available complete HRSV genomes (>12,000 bp) were downloaded from GenBank and divided into the two subgroups: HRSV-A and HRSV-B. From whole-genome alignments, the regions that correspond to the open reading frame of the glycoprotein G and the second hypervariable region (HVR2) of the ectodomain were extracted. In the resulting partial alignments, the phylogenetic signal within each fragment was assessed. Maximum likelihood phylogenetic trees were reconstructed using the complete genome alignments. Patristic distances were calculated between all pairs of tips in the phylogenetic tree and summarized as a density plot in order to determine a cutoff value at the lowest point following the major distance peak. Our data show that neither the HVR2 fragment nor the G gene contains sufficient phylogenetic signal to perform reliable phylogenetic reconstruction. Therefore, whole-genome alignments were used to determine HRSV genotypes. We define a genotype using the following criteria: a bootstrap support of ≥70 per cent for the respective clade and a maximum patristic distance between all members of the clade of ≤0.018 substitutions per site for HRSV-A or ≤0.026 substitutions per site for HRSV-B. By applying this definition, we distinguish twenty-three genotypes within subtype HRSV-A and six genotypes within subtype HRSV-B. Applying the genotype criteria on subsampled data sets confirmed the robustness of the method.
Origin, extinction and ancient DNA of a new fossil insular viper: molecular clues of overseas immigration
Authors: Torres-Roig Enric , Mitchell Kieren J , Alcover Josep Antoni , Martínez-Freiría Fernando , Bailón Salvador , Heiniger Holly , Williams Matthew , Cooper Alan , Pons Joan , Bover Pere
Published: July 2020

Viperinae is a subfamily of viperid snakes whose fossil record in the Mediterranean islands is, until now, restricted to 12 palaeontological deposits on seven islands. Revision of the material excavated 30 years ago from the Middle/Late Pleistocene–Holocene deposit of Es Pouàs [Eivissa (= Ibiza), Balearic Islands, western Mediterranean] revealed about 6000 bones of a small-sized viper across different stratigraphic levels. Its morphological characteristics are different enough to known species of Vipera to warrant the description of a new species, but the nearly complete mitochondrial genome obtained from this snake based on a sample dated to 16 130 ± 45 bp, suggested it belonged to a new insular population of Lataste’s viper (Vipera latastei), Vipera latastei ebusitana subsp. nov. Phylogenetic analysis indicates that the dispersal of the ancestors of V. l. ebusitana to Eivissa, most probably from a north-east Iberian population, occurred via overwater colonization < 1.5 Mya, well after the Messinian Salinity Crisis (5.97–5.32 Mya) when land bridges allowed terrestrial colonization of the Balearic Islands by mainland faunas. The morphological differences between V. l. ebusitana and the Iberian populations suggest that it is a new dwarf taxon resulting from insular evolutionary processes, becoming extinct shortly after the first human arrival to this island about 4000 years ago.
Complete Genome Resource of Serratia plymuthica C-1 that Causes Root Rot Disease in Korean Ginseng
Authors: Kim Hyo Jeong , Kim Young Cheol
Published: July 2020

Serratia plymuthica C-1, a biocontrol agent, was isolated from soil collected from a mountain forest in Korea. Previous studies have shown that certain strains of S. plymuthica cause root rot disease in ginseng. To the best of our knowledge, this is the first report of the sequence of the circular chromosome of S. plymuthica C-1, which plays a dual role by causing root rot in ginseng and exhibiting biocontrol activity. The findings of this study will assist in analyzing the genes associated with the pathogenicity and biocontrol properties of S. plymuthica.
Differential Response ofMeloidogyne,Pratylenchus,Globodera, andXiphinemaSpecies to the Nematicide Fluazaindolizine
Authors: Wram Catherine L. , Zasada Inga
Published: July 2020

This research focused on the effects of fluazaindolizine on a diversity of plant-parasitic nematodes. In microwell assays, 24-h dose-response curves were generated for several species and populations of Meloidogyne, Pratylenchus neglectus, P. penetrans, Globodera ellingtonae, and Xiphinema americanum. In a greenhouse study, the impact of fluazaindolizine on fecundity of M. incognita, M. hapla, and M. chitwoodi was tested by exposing nematodes for 24 h in solution and inoculating on tomato. The average 24-h ED50s (dose that resulted in the immobility of 50% of exposed nematodes) for M. hapla, M. chitwoodi, and M. incognita were 325.7, 223.4, and 100.7 ppm, respectively. M. hapla had the most variation among populations, with 24-h ED50s ranging from 72 to 788 ppm. G. ellingtonae had the lowest 24-h ED50at 30 ppm. Pratylenchus spp. were unaffected by fluazaindolizine. X. americanum was the only species where effects of fluazaindolizine were reversible, but had a 24-h ED50that fell in the range of the Meloidogyne spp. In the greenhouse study, M. chitwoodi was the least sensitive with reproduction reaching 62% of the untreated control after a pre-exposure to 47 ppm, whereas M. incognita and M. hapla at the same exposure dose had reproduction rates of 27 and 36% of the untreated control, respectively. Despite varying in in vitro responses to fluazaindolizine, reproduction of all Meloidogyne spp. was suppressed after only 24 h of exposure. This study expanded our understanding of how G. ellingtonae, P. thornei, P. penetrans, and X. americanum respond to fluazaindolizine.
A Novel Tool for Teaching Cardiac Point-of-Care Ultrasound: An Exploratory Application of the Design-Based Research Approach*
Authors: Brown Kyle A. , Riley Alan F. , Alade Kiyetta H. , Kyle William Buck , Castro Danny , Tcharmtchi Mohammad Hossein , Thammasitboon Satid
Published: July 2020

Objectives:

To develop a competency-based educational tool for cardiac point-of-care ultrasound image interpretation using the design-based research approach.

Design:

In accordance with design-based research, multiple methods were used to determine that learners would benefit from achieving competency in cardiac point-of-care ultrasound image interpretation before they attempted it at the bedside. A competency-based educational tool was designed and underwent a rapid prototyping process with experts. Evaluative data was used to redesign and reevaluate the educational tool with a new group of learners to improve its effectiveness.

Setting:

Large, university-based children’s hospital.

Subjects:

Pediatric critical care attending physicians, fellow physicians and advanced practice providers, and pediatric resident physicians.

Interventions:

Integrating mastery learning and deliberate practice as theoretical frameworks, the authors designed an online “Image Library” composed of 90 questions of cardiac point-of-care ultrasound image clips with varying degrees of pathology that were organized into three levels of difficulty. Learners answered a set of 10 questions, learned from feedback, and repeated an additional set in the same difficulty until achieving a predefined level of mastery.

Measurements and Main Results:

Two learning cycles were implemented with a total of 41 learners. Forty learners (98%) were able to demonstrate mastery on the Image Library and required a range of 30 to 210 questions to do so. On a 10-question final assessment, learners scored an average of 72%, while experts and novices scored 83% and 17%, respectively. On a 5-point scale, learners rated the quality of the Image Library for facilitation of learning (median 5), enjoyment of learning (5), and useful knowledge and skills to improve clinical practice (5).

Conclusions:

An effective and innovative tool for teaching cardiac point-of-care ultrasound image interpretation was developed using the design-based research approach. Our results demonstrate the importance of individualized learning timelines for ultrasound image interpretation.
Communication speeds up but impairs the consensus decision in a dyadic colour estimation task
Authors: Yu Liutao , Wang Chundi , Wu Si , Wang Da-Hui
Published: July 2020

Communication plays an important role in consensus decision-making which pervades our daily life. However, the exact role of communication in consensus formation is not clear. Here, to study the effects of communication on consensus formation, we designed a dyadic colour estimation task, where a pair of isolated participants repeatedly estimated the colours of discs until they reached a consensus or completed eight estimations, either with or without communication. We show that participants’ estimates gradually approach each other, reaching towards a consensus, and these are enhanced with communication. We also show that dyadic consensus estimation is on average better than individual estimation. Surprisingly, consensus estimation without communication generally outperforms that with communication, indicating that communication impairs the improvement of consensus estimation. However, without communication, it takes longer to reach a consensus. Moreover, participants who partially cooperate with each other tend to result in better overall consensus. Taken together, we have identified the effect of communication on the dynamics of consensus formation, and the results may have implications on group decision-making in general.
Synthesis and assessment of schwertmannite/few-layer graphene composite for the degradation of sulfamethazine in heterogeneous Fenton-like reaction
Authors: Wang Dianzhan , Gu Ye , Yang Zhaoshun , Zhou Lixiang
Published: July 2020

Schwertmannite (sch), an iron oxyhydrosulfate mineral, can catalyse a Fenton-like reaction to degrade organic contaminants, but the reduction of Fe(III) to Fe(II) on the surface of schwertmannite is a limiting step for the Fenton-like process. In the present study, the sch/few-layer graphene (sch–FLG) composite was synthesized to promote the catalytic activity of sch in a Fenton-like reaction. It was found that sch can be successfully carried by FLG in sch–FLG composite, mainly via the chemical bond of Fe–O–C on the surface of sch–FLG. The sch–FLG exhibited a much higher catalytic activity than sch or FLG for the degradation of sulfamethazine (SMT) in the heterogeneous Fenton-like reaction, which resulted from the fact that the FLG can pass electrons efficiently. The degradation efficiency of SMT was around 100% under the reaction conditions of H
2
O
2
200–500 mg l
−1
, sch–FLG dosage 1–2 g l
−1
, temperature 28–38°C, and initial solution pH 1–9. During the repeated uses of sch–FLG in the Fenton-like reaction, it maintained a certain catalytic activity for the degradation of SMT and the mineral structure was not changed. In addition, SMT may be finally mineralized in the Fenton-like reaction catalysed by sch–FLG, and the possible degradation pathways were proposed. Therefore, the sch–FLG is an excellent catalyst for SMT degradation in a heterogeneous Fenton-like reaction.