bluuebunny/crossref_metadata_2025 huggingface dataset:
Influenza Vaccine Effectiveness in the Inpatient Setting: Evaluation of Potential Bias in the Test-Negative Design by Use of Alternate Control Groups
Authors: Segaloff Hannah E , Cheng Bonnie , Miller Andrew V , Petrie Joshua G , Malosh Ryan E , Cheng Caroline , Lauring Adam S , Lamerato Lois E , Ferdinands Jill M , Monto Arnold S , Martin Emily T
Published: October 2019

The test-negative design is validated in outpatient, but not inpatient, studies of influenza vaccine effectiveness. The prevalence of chronic pulmonary disease among inpatients can lead to nonrepresentative controls. Test-negative design estimates are biased if vaccine administration is associated with incidence of noninfluenza viruses. We evaluated whether control group selection and effects of vaccination on noninfluenza viruses biased vaccine effectiveness in our study. Subjects were enrolled at the University of Michigan and Henry Ford hospitals during the 2014–2015 and 2015–2016 influenza seasons. Patients presenting with acute respiratory infection were enrolled and tested for respiratory viruses. Vaccine effectiveness was estimated using 3 control groups: negative for influenza, positive for other respiratory virus, and pan-negative individuals; it was also estimated for other common respiratory viruses. In 2014–2015, vaccine effectiveness was 41.1% (95% CI: 1.7, 64.7) using influenza-negative controls, 24.5% (95% CI: −42.6, 60.1) using controls positive for other virus, and 45.8% (95% CI: 5.7, 68.9) using pan-negative controls. In 2015–2016, vaccine effectiveness was 68.7% (95% CI: 44.6, 82.5) using influenza-negative controls, 63.1% (95% CI: 25.0, 82.2) using controls positive for other virus, and 71.1% (95% CI: 46.2, 84.8) using pan-negative controls. Vaccination did not alter odds of other respiratory viruses. Results support use of the test-negative design among inpatients.
Multiple founder events explain the genetic diversity and structure of the model allopolyploid grass Brachypodium hybridum in the Iberian Peninsula hotspot
Authors: Shiposha Valeriia , Marques Isabel , López-Alvarez Diana , Manzaneda Antonio J , Hernandez Pilar , Olonova Marina , Catalán Pilar
Published: October 2019

Background and Aims

It is accepted that contemporary allopolyploid species have originated recurrently, but very few cases have been documented using multiple natural formations of the same species. To extend our knowledge, we have investigated the multiple origins, genetic variation, and structure of the allotetraploid grass Brachypodium hybridum with respect to its progenitor diploid species B. distachyon (D genome) and B. stacei (S genome). For this, our primary focus is the Iberian Peninsula, an evolutionary hotspot for the genus Brachypodium.

Methods

We analysed 342 B. hybridum individuals from 36 populations using 10 nuclear SSR loci and two plastid loci. The B. hybridum genetic profiles were compared with those previously reported for B. stacei and B. distachyon. In addition, phylogenetic analysis of the plastid data was performed for a reduced subset of individuals.

Key Results

The nuclear SSR genetic analysis detected medium to high genetic diversity, with a strong south-to-north genetic structure cline, and a high selfing rate in B. hybridum. Comparative genetic analysis showed a close relatedness of current B. hybridum D allelic profiles with those of B. distachyon, but a lack of similarity with those of B. stacei, suggesting another B. stacei source for the B. hybridum S alleles. Plastid analysis detected three different bidirectional allopolyploidization events: two involved distinct B. distachyon-like ancestors and one involved a B. stacei-like ancestor. The Southeastern (SE) Iberian Peninsula B. hybridum populations were more genetically diverse and could have originated from at least two hybridization events whereas Northeaster-Northwestern (NE-NW) Iberian Peninsula B. hybridum populations were less diverse and may have derived from at least one hybridization event.

Conclusions

The genetic and evolutionary evidence support the plausible in situ origin of the SE and northern Iberian Peninsula B. hybridum allopolyploids from their respective local B. distachyon and unknown B. stacei ancestors. The untapped multiple origins and genetic variation detected in these B. hybridum populations opens the way to future evolutionary analysis of allopolyploid formation and genomic dominance and expression in the B. hybridum – B. distachyon – B. stacei grass model complex.
The Colorado Cognitive Assessment (CoCA): Development of an Advanced Neuropsychological Screening Tool
Authors: Gurnani Ashita S , Lin Shayne S-H , Gavett Brandon E
Published: October 2019

Objective

The Colorado Cognitive Assessment (CoCA) was designed to improve upon existing screening tests in a number of ways, including enhanced psychometric properties and minimization of bias across diverse groups. This paper describes the initial validation study of the CoCA, which seeks to describe the test; demonstrate its construct validity; measurement invariance to age, education, sex, and mood symptoms; and compare it to the Montreal Cognitive Assessment (MoCA).

Method

Participants included 151 older adults (MAge = 71.21, SD = 8.05) who were administered the CoCA, MoCA, Judgment test from the Neuropsychological Assessment Battery (NAB), 15-item version of the Geriatric Depression Scale (GDS-15), and 10-item version of the Geriatric Anxiety Scale (GAS-10).

Results

A single-factor confirmatory factor analysis model of the CoCA fit the data well, CFI = 0.955; RMSEA = 0.033. The CoCA factor score reliability was .84, compared to .74 for the MoCA. The CoCA had stronger disattenuated correlations with the MoCA (r = .79) and NAB Judgment (r = .47) and weaker correlations with the GDS-15 (r = −.36) and GAS-10 (r = −.15), supporting its construct validity. Finally, when analyzed using multiple-indicators, multiple-causes (MIMIC) modeling, the CoCA showed no evidence of measurement noninvariance, unlike the MoCA.

Conclusions

These results provide initial evidence to suggest that the CoCA is a valid cognitive screening tool that offers numerous advantages over the MoCA, including superior psychometric properties and measurement noninvariance. Additional validation and normative studies are warranted.
Serotonin differentially affects morph-specific behavior in divergent populations of a horned beetle
Authors: Newsom Keeley D , Moczek Armin P , Schwab Daniel B
Published: October 2019

Associations between animal weapons and corresponding aggressive behaviors are among the most characteristic features of species, yet at the same time their co-expression is itself often strongly dependent on context, such as male condition or population ecology. Yet the mechanisms that modulate associations between aggression, morphology, and biological context remain poorly understood. The biogenic amine serotonin has been shown to regulate a wide range of aggressive and morph-specific behaviors in diverse insect species. However, the extent to which serotonin may coordinate the expression of behavior with morphology across biological contexts remains unclear. In this study, we pharmacologically increased serotonin biosynthesis in males of the polyphenic beetle, Onthophagus taurus, and assessed how this manipulation affects both aggressive and non-aggressive behaviors in alternative fighter and sneaker morphs, as well as in males derived from two rapidly diverging populations characterized by disparate levels of competition for mates. We find (i) that enhancing serotonin biosynthesis increases most measures of aggressive behaviors, but influences only a subset of nonaggressive behaviors, (ii) that similar serotonin-mediated behavioral changes manifest in both morphs within populations more often than just a single morph, and (iii) that males derived from the two focal populations have diverged in their behavioral responsiveness to serotonin up-regulation. Collectively, our study suggests that serotonin signaling plays a critical role in the regulation of male behavior and its evolution, including in the context of rapid, short-term population divergence.
Inferring subgroup-specific driver genes from heterogeneous cancer samples via subspace learning with subgroup indication
Authors: Xi Jianing , Yuan Xiguo , Wang Minghui , Li Ao , Li Xuelong , Huang Qinghua
Published: October 2019

Motivation

Detecting driver genes from gene mutation data is a fundamental task for tumorigenesis research. Due to the fact that cancer is a heterogeneous disease with various subgroups, subgroup-specific driver genes are the key factors in the development of precision medicine for heterogeneous cancer. However, the existing driver gene detection methods are not designed to identify subgroup specificities of their detected driver genes, and therefore cannot indicate which group of patients is associated with the detected driver genes, which is difficult to provide specifically clinical guidance for individual patients.

Results

By incorporating the subspace learning framework, we propose a novel bioinformatics method called DriverSub, which can efficiently predict subgroup-specific driver genes in the situation where the subgroup annotations are not available. When evaluated by simulation datasets with known ground truth and compared with existing methods, DriverSub yields the best prediction of driver genes and the inference of their related subgroups. When we apply DriverSub on the mutation data of real heterogeneous cancers, we can observe that the predicted results of DriverSub are highly enriched for experimentally validated known driver genes. Moreover, the subgroups inferred by DriverSub are significantly associated with the annotated molecular subgroups, indicating its capability of predicting subgroup-specific driver genes.

Availability and implementation

The source code is publicly available at https://github.com/JianingXi/DriverSub.

Supplementary information

Supplementary data are available at Bioinformatics online.
Pentachloronitrobenzene alters progesterone production and primordial follicle recruitment in cultured granulosa cells and rat ovary†
Authors: Kuai Yanrong , Gao Xiaobo , Yang Huixia , Luo Haiyan , Xu Yang , Liu Chenchen , Yu Haiying , Wang Yihan , Zhang Chen , Ma Xu , Lu Cailing
Published: October 2019

Pentachloronitrobenzene (PCNB) is an organochlorine fungicide widely used for crop production and has become an environmental concern. Little is known about the effect of PCNB on ovarian steroidogenesis and follicular development. We found that PCNB stimulated Star expression and progesterone production in cultured rat granulosa cells in a dose-dependent manner. PCNB activated mitogen-activated protein kinase (MAPK3/1) extracellulat regulated kinase (ERK1/2), thus inhibition of either protein kinase A (PKA) or MAPK3/1 signaling pathway significantly attenuated progesterone biosynthesis caused by PCNB, suggesting that PCNB induced progesterone production by activating the cyclic adenosine monophosphate (cAMP/PKA) and MAPK3/1 signaling pathways. Further investigation demonstrated that PCNB induced Star expression and altered MAPK3/1 signaling in ovary tissues of immature SD rats treated with PCNB at the dose of 100, 200, or 300 mg/kg by daily gavage for 7 days, while serum progesterone level was dose-dependently decreased. We demonstrated that PCNB exposure accelerated the recruitment of primordial follicles into the growing follicle pool in ovary tissues, accompanied by increased levels of anti-Mullerian hormone (AMH) in both ovary tissues and serum. Taken together, our data demonstrate for the first time that PCNB stimulated Star expression, altered MAPK3/1 signaling and progesterone production in vivo and in vitro, and accelerated follicular development with a concomitant increase in AMH in ovary tissues and serum. Our findings provide novel insight into the toxicity of PCNB to animal ovary function.
Intersectional coproduction and infrastructural violence: experiences from Pakistan
Authors: Sawas Amiera , Castán Broto Vanesa , Anwar Nausheen H , Rehman Abdul
Published: October 2019

The delivery of projects for the coproduction of services raises multiple questions about how different structural barriers prevent and hinder the participation of various sectors of the population. Intersectionality theory provides a critical lens to examine the delivery of such coproduction projects to refine any strategies to include vulnerable perspectives or perspectives that get silenced by existing hierarchies. This paper presents an intersectionality-led analysis of the delivery of a project to improve public safety in Pakistan. The project mapped existing concerns about urban violence of different groups of the population. The project used a multilayered approach to facilitate the engagement of excluded views, both in the constitution of the research team and in the involvement of communities. An intersectionality framework is applied to analyse the deployment of the project in terms of design, innovation, planning, and signification. The analysis shows that there are limitations to how far coproduction exercises can challenge existing social structural barriers.
Sex-specific Difference of Hippocampal Synaptic Plasticity in Response to Sex Neurosteroids
Authors: Brandt Nicola , Vierk Ricardo , Fester Lars , Anstötz Max , Zhou Lepu , Heilmann Lukas F , Kind Simon , Steffen Paul , Rune Gabriele M
Published: October 2019

Numerous studies provide increasing evidence, which supports the ideas that every cell in the brain of males may differ from those in females due to differences in sex chromosome complement as well as in response to hormonal effects. In this study, we address the question as to whether actions of neurosteroids, thus steroids, which are synthesized and function within the brain, contribute to sex-specific hippocampal synaptic plasticity. We have previously shown that predominantly in the female hippocampus, does inhibition of the conversion of testosterone to estradiol affect synaptic transmission. In this study, we show that testosterone and its metabolite dihydrotestosterone are essential for hippocampal synaptic transmission specifically in males. This also holds true for the density of mushroom spines and of spine synapses. We obtained similar sex-dependent results using primary hippocampal cultures of male and female animals. Since these cultures originated from perinatal animals, our findings argue for sex-dependent differentiation of hippocampal neurons regarding their responsiveness to sex neurosteroids up to birth, which persist during adulthood. Hence, our in vitro findings may point to a developmental effect either directly induced by sex chromosomes or indirectly by fetal testosterone secretion during the perinatal critical period, when developmental sexual priming takes place.
Predictive Pattern Classification Can Distinguish Gender Identity Subtypes from Behavior and Brain Imaging
Authors: Clemens Benjamin , Derntl Birgit , Smith Elke , Junger Jessica , Neulen Josef , Mingoia Gianluca , Schneider Frank , Abel Ted , Bzdok Danilo , Habel Ute
Published: October 2019

The exact neurobiological underpinnings of gender identity (i.e., the subjective perception of oneself belonging to a certain gender) still remain unknown. Combining both resting-state functional connectivity and behavioral data, we examined gender identity in cisgender and transgender persons using a data-driven machine learning strategy. Intrinsic functional connectivity and questionnaire data were obtained from cisgender (men/women) and transgender (trans men/trans women) individuals. Machine learning algorithms reliably detected gender identity with high prediction accuracy in each of the four groups based on connectivity signatures alone. The four normative gender groups were classified with accuracies ranging from 48% to 62% (exceeding chance level at 25%). These connectivity-based classification accuracies exceeded those obtained from a widely established behavioral instrument for gender identity. Using canonical correlation analyses, functional brain measurements and questionnaire data were then integrated to delineate nine canonical vectors (i.e., brain-gender axes), providing a multilevel window into the conventional sex dichotomy. Our dimensional gender perspective captures four distinguishable brain phenotypes for gender identity, advocating a biologically grounded reconceptualization of gender dimorphism. We hope to pave the way towards objective, data-driven diagnostic markers for gender identity and transgender, taking into account neurobiological and behavioral differences in an integrative modeling approach.
Resistance-Guided Antimicrobial Therapy Using Doxycycline–Moxifloxacin and Doxycycline–2.5 g Azithromycin for the Treatment of Mycoplasma genitalium Infection: Efficacy and Tolerability
Authors: Durukan Duygu , Read Tim R H , Murray Gerald , Doyle Michelle , Chow Eric P F , Vodstrcil Lenka A , Fairley Christopher K , Aguirre Ivette , Mokany Elisa , Tan Lit Y , Chen Marcus Y , Bradshaw Catriona S
Published: October 2019

Background

Macrolide resistance in Mycoplasma genitalium (MG) exceeds 50% in many regions, and quinolone resistance is increasing. We recently reported that resistance-guided therapy (RGT) using doxycycline followed by sitafloxacin or 2.5 g azithromycin cured 92% and 95% of macrolide-resistant and macrolide-susceptible infections, respectively. We present data on RGT using doxycycline–moxifloxacin, the regimen recommended in international guidelines, and extend data on the efficacy of doxycycline–2.5 g azithromycin and de novo macrolide resistance.

Methods

Patients attending Melbourne Sexual Health Centre between 2017 and 2018 with sexually transmitted infection syndromes were treated with doxycycline for 7 days and recalled if MG-positive. Macrolide-susceptible cases received 2.5 g azithromycin (1 g, then 500 mg daily for 3 days), and resistant cases moxifloxacin (400 mg daily, 7 days). Test of cure was recommended 14–28 days post-antimicrobials.

Results

There were 383 patients (81 females/106 heterosexual males/196 men who have sex with men) included. Microbial cure following doxycycline–azithromycin was 95.4% (95% confidence interval [CI], 89.7–98.0) and doxycycline–moxifloxacin was 92.0% (95% CI, 88.1–94.6). De novo macrolide resistance was detected in 4.6% of cases. Combining doxycycline–azithromycin data with our prior RGT study (n = 186) yielded a pooled cure of 95.7% (95% CI, 91.6–97.8). ParC mutations were present in 22% of macrolide-resistant cases.

Conclusions

These findings support the inclusion of moxifloxacin in resistance-guided strategies and extend the evidence for 2.5 g azithromycin and presumptive use of doxycycline. These data provide an evidence base for current UK, Australian, and European guidelines for the treatment of MG.
A simple modification of dialysate potassium: its impact on plasma potassium concentrations and the electrocardiogram
Authors: Delanaye Pierre , Krzesinski François , Dubois Bernard E , Delcour Alexandre , Robinet Sébastien , Piette Caroline , Krzesinski Jean-Marie , Lancellotti Patrizio
Published: October 2019

Background

Sudden death is frequent in haemodialysis (HD) patients. Both hyperkalaemia and change of plasma potassium (K) concentrations induced by HD could explain this. The impact of increasing dialysate K by 1 mEq/L on plasma K concentrations and electrocardiogram (ECG) results before and after HD sessions was studied.

Methods

Patients with pre-dialysis K >5.5 mEq/L were excluded. ECG and K measurements were obtained before and after the first session of the week for 2 weeks. Then, K in the dialysate was increased (from 1 or 3 to 2 or 4 mEq/L, respectively). Blood and ECG measurements were repeated after 2 weeks of this change.

Results

Twenty-seven prevalent HD patients were included. As expected, a significant decrease in K concentrations was observed after the dialysis session, but this decrease was significantly lower after the switch to an increased dialysate K. The pre-dialysis K concentrations were not different after changing, but post-dialysis K concentrations were higher after switching (P < 0.0001), with a lower incidence of post-dialysis hypokalaemia. Regarding ECG, before switching, the QT interval (QT) dispersion increased during the session, whereas no difference was observed after switching. One week after switching, post-dialysis QT dispersion [38 (34–42) ms] was lower than post-dialysis QT dispersion 2 weeks and 1 week before switching [42 (38–57) ms, P = 0.0004; and 40 (35–50) ms, P = 0.0002].

Conclusions

A simple increase of 1 mEq/L of K in the dialysate is associated with a lower risk of hypokalaemia and a lower QT dispersion after the dialysis session. Further study is needed to determine if such a strategy is associated with a lower risk of sudden death.
Physicians as Advisors Not Leaders of Multidisciplinary Teams: A Qualitative Study of an Innovative Practice
Authors: Mendelev Eliezer , Mazumdar Madhu , Keefer Laurie , Gorbenko Ksenia
Published: October 2019

Background and Aims

As various models of team-based chronic disease management have proliferated, physicians have assumed the leadership role in most of them. However, physician time is costly, and regular attendance of team meetings adds another task to a long list of responsibilities. This is the first study to explore the role of physicians as advisors rather than leaders of a multidisciplinary team.

Methods

We conducted an exploratory qualitative research study of a subspecialty medical home located within a tertiary academic medical center that cares for highly complex pediatric and adult patients with inflammatory bowel diseases. The medical home team consists of a psychologist, dieticians, social workers, a clinical pharmacist, and nurses. No physicians regularly attend team meetings. We conducted semi-structured interviews with nonphysician team members (N = 11) and gastroenterologists (N = 6). Two authors coded interview transcripts in NVivo 11 for themes related to “physician role” using an inductive qualitative analysis approach.

Results

Nonphysician participant believed gastroenterologists did not need to attend weekly meetings. Having only nonphysician personnel in the room made them feel more empowered to openly express their views. Gastroenterologists expressed interest in attending one or more, but not all meetings, in order to better understand the process of the team and desired a more formal feedback loop for staying informed about their patients’ progress.

Conclusions

Our findings suggest that gastroenterologist participation may not require regular attendance of team meetings. Team meeting consisting of nonphysician providers would result in cost savings and may empower nonphysician providers.
The effect of scissor-type versus non-scissor-type knives on the technical outcomes in endoscopic submucosal dissection for superficial esophageal cancer: a multi-center retrospective study
Authors: Esaki Mitsuru , Hayashi Yasuyo , Ikehara Hisatomo , Ihara Eikichi , Horii Toshiki , Tamura Yu , Ichijima Ryoji , Yamakawa Shun , Irie Akira , Shibuya Hitoshi , Suzuki Sho , Kusano Chika , Minoda Yosuke , Akiho Hirotada , Ogawa Yoshihiro , Gotoda Takuji
Published: October 2019

The Clutch Cutter was invented as a scissor-type knife for endoscopic submucosal dissection (ESD) of gastrointestinal neoplasms. ESD with the scissor-type knife (ESD-S) may be considered a technically easier procedure than ESD with non-scissor-type knives (ESD-NS). Therefore, this study aimed to compare the technical outcomes of ESD-S with those of ESD-NS for superficial esophageal cancer. This was a multicenter retrospective study. Patients with superficial esophageal cancer treated with ESD between October 2015 and March 2018 at three hospitals were retrospectively reviewed. The ESD-S group had 48 patients and the ESD-NS group had 114 patients. A propensity score matching analysis was performed to compensate for the confounding bias between both groups. Multivariate analyses and propensity score matching were used to adjust for age, sex, the tumor size, tumor location, tumor depth, degree of tumor circumference, operator level, usage of the traction method, and the sedation method. The primary outcome was the procedure time of the ESD. Secondary outcomes were the rate of en-bloc/complete resection and the rate of complications including perforation, delayed bleeding, and stricture. Propensity score matching analysis provided 36 matched pairs. Median procedure time in the ESD-S group was significantly shorter than that in the ESD-NS group (44.0 min vs. 66.5 min, P = 0.020). In addition, the treatment outcomes were similar in both groups (en-bloc resection: 100% vs. 97.2%, P = 1; complete resection: 88.9% vs. 86.1%, P = 1; curative resection: 80.6% vs. 77.8%, P = 1; perforation: 0% vs. 5.6%, P = 0.49; delayed bleeding: 0% in both groups; stricture: 2.8% vs. 8.3%, P = 0.61). ESD-S was associated with a shorter procedure time than ESD-NS, without an increase in the incidence of complications. Therefore, the scissor-type knife should be considered as an endo-knife for ESD of superficial esophageal cancers.
Utility of stent double palliation for esophageal cancer with airway involvement: the extremis of care
Authors: Roseira J , Mão de Ferro S , Moleiro J , Currais P , Lemos J , Dionísio J , Ferreira S , Rosa I , Lage P , Szantho A , Duro da Costa J , Dias Pereira A
Published: October 2019

Primary esophageal cancer (EC) frequently presents as a locally advanced disease with airway involvement. Placement of combined esophageal and airway stents has been reported in small series to be an effective palliation strategy. Our aims are to present the largest cohort of EC patients who underwent double stent palliation and to evaluate the safety and efficacy of this approach. Longitudinal cohort study of patients with primary EC undergoing two-stage esophageal and airway stent placement at an oncology referral institute (January 2000–January 2019). Assessments: baseline demographics and clinical variables; baseline and week 2 dysphagia, dyspnea and performance status (PS) scores; baseline and week 8 body mass index (BMI); overall survival. Statistics: paired t-test; Kaplan–Meier method. Seventy patients (89% men, mean age 60.20 ± 8.41) underwent double stenting. Esophageal stent was placed for esophageal stenosis and dysphagia (n = 41; placement of a second stent due to recurrence in nine cases) or esophagorespiratory fistulas (ERFs) (n = 29); airway stent was required for ERF sealing (n = 29 + 7 new ERFs after esophageal stent) and to ensure airway patency due to malignant stenosis (n = 29; placement of a second stent due to recurrence in 13 cases) or compression (n = 5). There were 13, endoscopically managed, major complications after esophageal stent [hemorrage (n = 1), migration (n = 5) and new fistulas (n = 7)]. As for airway stents, four major complications were recorded [hemorrage (n = 1) and three deaths due to respiratory infection and ultimately respiratory failure 3–7 days after the procedure]. Overall, patients showed significant improvement in dysphagia and dyspnea symptoms (3.21 vs. 1.31 e 15.56 vs. 10.87; P < 0.001). There was a PS improvement for 89.2% (n = 58) of the patients. BMI at week 8 was comparable to baseline records. Mean survival was 137.83 ± 24.14 days (95% CI: 90.51–185.15). Survival was longer for better PS (PS1, 249.95 days; PS2, 83.74 days; PS3, 22.43 days; PS4, 30.00 days). This is the largest comprehensive assessment of double stent palliation in advanced incurable EC. For both esophageal or airway stenosis and fistula, placement of combined esophageal and airway stents was a feasible, effective, fast-acting and safe modality for symptom palliation and body mass maintenance. Patient autonomy followed symptom improvement. Since it is impossible to provide treatment for cure in most of these cases, this endoscopic strategy, performed in differentiated units with the required technical capacity, may guarantee treatment for the relief of palliative EC.
Myocardial fibrosis in arrhythmogenic cardiomyopathy: a genotype–phenotype correlation study
Authors: Segura-Rodríguez Diego , Bermúdez-Jiménez Francisco José , Carriel Víctor , López-Fernández Silvia , González-Molina Mercedes , Oyonarte Ramírez José Manuel , Fernández-Navarro Laura , García-Roa María Dolores , Cabrerizo Elisa M , Durand-Herrera Daniel , Alaminos Miguel , Campos Antonio , Macías Rosa , Álvarez Miguel , Tercedor Luis , Jiménez-Jáimez Juan
Published: October 2019

Aims

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a life-threatening entity with a highly heterogeneous genetic background. Cardiac magnetic resonance (CMR) imaging can identify fibrofatty scar by late gadolinium enhancement (LGE). Our aim is to investigate genotype–phenotype correlation in ARVC/D mutation carriers, focusing on CMR-LGE and myocardial fibrosis patterns.

Methods and results

A cohort of 44 genotyped patients, 33 with definite and 11 with borderline ARVC/D diagnosis, was characterized using CMR and divided into groups according to their genetic condition (desmosomal, non-desmosomal mutation, or negative). We collected information on cardiac volumes and function, as well as LGE pattern and extension. In addition, available ventricular myocardium samples from patients with pathogenic gene mutations were histopathologically analysed. Half of the patients were women, with a mean age of 41.6 ± 17.5 years. Next-generation sequencing identified a potential pathogenic mutation in 71.4% of the probands. The phenotype varied according to genetic status, with non-desmosomal male patients showing lower left ventricular (LV) systolic function. LV fibrosis was similar between groups, but distribution in non-desmosomal patients was frequently located at the posterolateral LV wall; a characteristic LV subepicardial circumferential LGE pattern was significantly associated with ARVC/D caused by desmin mutation. Histological analysis showed increased fibrillar connective tissue and intercellular space in all the samples.

Conclusion

Desmosomal and non-desmosomal mutation carriers showed different morphofunctional features but similar LV LGE presence. DES mutation carriers can be identified by a specific and extensive LV subepicardial circumferential LGE pattern. Further studies should investigate the specificity of LGE in ARVC/D.
Reducing distance through online international collaboration
Authors: Schreiber Brooke R , Jansz Mihiri
Published: October 2019

Online and hybrid courses offer many benefits for ESL teacher education, but can be hampered by ‘transactional distance’, a lack of interpersonal closeness which can cause misunderstanding and disengagement. This article describes a pedagogical project in which in-service teachers studying in a distance-learning MA TESL programme in Sri Lanka participated in an asynchronous discussion forum with peers from a university in New York City to discuss varieties of World Englishes. The project increased dialogue between learners, and between learners and the instructor, providing space for informal interactions through text, images, and video, as well as multiple methods for responding to feedback, ultimately reducing transactional distance. This article discusses the benefits of the project as well as the pedagogical and technological challenges, offering suggestions for other MA TESL educators about implementing such collaborations.
Cloning and characterization of a thermostable glutathione reductase from a psychrophilic Arctic bacterium Sphingomonas sp
Authors: VuThi Hai , Jang Sei-Heon , Lee ChangWoo
Published: October 2019

Glutathione reductase is an important oxidoreductase that helps maintain redox homeostasis by catalyzing the conversion of glutathione disulfide to glutathione using NADPH as a cofactor. In this study, we cloned and characterized a glutathione reductase (hereafter referred to as SpGR) from Sphingomonas sp. PAMC 26621, an Arctic bacterium. SpGR comprises 449 amino acids, and functions as a dimer. Surprisingly, SpGR exhibits characteristics of thermophilic enzymes, showing optimum activity at 60°C and thermal stability up to 70°C with ∼50% residual activity at 70°C for 2 h. The amino acid composition analysis of SpGR showed a 1.9-fold higher Arg content (6%) and a 2.7-fold lower Lys/Arg ratio (0.75) compared to the Arg content (3.15%) and the Lys/Arg ratio (2.01) of known psychrophilic glutathione reductases. SpGR also exhibits its activity at 4°C, and circular dichroism and fluorescence spectroscopy results indicate that SpGR maintains its secondary and tertiary structures within the temperature range of 4–70°C. Taken together, the results of this study indicate that despite its origin from a psychrophilic bacterium, SpGR has high thermal stability. Our study provides an insight into the role of glutathione reductase in maintaining the reducing power of an Arctic bacterium in a broad range of temperatures.
Prolyl Hydroxylase Inhibition Mitigates Pouchitis
Authors: Harnoss Jonathan M , Gebhardt Jasper M , Radhakrishnan Praveen , Leowardi Christine , Burmeister Julius , Halligan Doug N , Yuan Shuai , Kennel Kilian B , Strowitzki Moritz J , Schaible Anja , Lasitschka Felix , Taylor Cormac T , Schneider Martin
Published: October 2019

Background

Pouchitis is the most common long-term complication after restorative proctocolectomy with ileal pouch–anal anastomosis (IPAA) for ulcerative colitis (UC) or familial adenomatous polyposis (FAP), which can eventually progress to pouch failure, necessitating permanent stoma construction. Hypoxia-inducible transcription factor prolyl hydroxylase–containing enzymes (PHD1, PHD2, and PHD3) are molecular oxygen sensors that control adaptive gene expression through hypoxia-inducible factor (HIF). Emerging evidence supports PHDs as being therapeutic targets in intestinal inflammation. However, pharmacological inhibition of PHDs has not been validated as a treatment strategy in pouchitis.

Methods

PHD1-3 mRNA and protein expression were analyzed in mucosal pouch and prepouch ileal patient biopsies. After establishment of a preclinical IPAA model in rats, the impact of the pan-PHD small-molecule inhibitor dimethyloxalylglycine (DMOG) on dextran sulfate sodium (DSS)–induced pouchitis was studied. Clinical and molecular parameters were investigated.

Results

PHD1, but not PHD2 or PHD3, was overexpressed in pouchitis in biopsies of patients with IPAA for UC but not FAP. In addition, PHD1 expression correlated with disease activity. DMOG treatment profoundly mitigated DSS-induced pouchitis in a rodent IPAA model. Mechanistically, DMOG restored intestinal epithelial barrier function by induction of tight junction proteins zona occludens-1 and claudin-1 and alleviation of intestinal epithelial cell apoptosis, thus attenuating pouch inflammation.

Conclusions

Together, these results establish a strong therapeutic rationale for targeting PHD1 with small-molecule inhibitors in pouchitis after IPAA for UC.
One-bit compressed sensing with partial Gaussian circulant matrices
Authors: Dirksen Sjoerd , Jung Hans Christian , Rauhut Holger
Published: October 2019

In this paper we consider memoryless one-bit compressed sensing with randomly subsampled Gaussian circulant matrices. We show that in a small sparsity regime and for small enough accuracy $\delta$, $m\simeq \delta ^{-4} s\log (N/s\delta )$ measurements suffice to reconstruct the direction of any $s$-sparse vector up to accuracy $\delta$ via an efficient program. We derive this result by proving that partial Gaussian circulant matrices satisfy an $\ell _1/\ell _2$ restricted isometry property property. Under a slightly worse dependence on $\delta$, we establish stability with respect to approximate sparsity, as well as full vector recovery results, i.e., estimation of both vector norm and direction.
Criteria for Embedded Eigenvalues for Discrete Schrödinger Operators
Authors: Liu Wencai
Published: October 2019

In this paper, we consider discrete Schrödinger operators of the form, $$\begin{equation*} (Hu)(n) = u({n+1})+u({n-1})+V(n)u(n). \end{equation*}$$We view $H$ as a perturbation of the free operator $H_0$, where $(H_0u)(n)= u({n+1})+u({n-1})$. For $H_0$ (no perturbation), $\sigma _{\textrm{ess}}(H_0)=\sigma _{\textrm{ac}}(H)=[-2,2]$ and $H_0$ does not have eigenvalues embedded into $(-2,2)$. It is an interesting and important problem to identify the perturbation such that the operator $H_0+V$ has one eigenvalue (finitely many eigenvalues or countable eigenvalues) embedded into $(-2,2)$. We introduce the almost sign type potentials and develop the Prüfer transformation to address this problem, which leads to the following five results.

1: We obtain the sharp spectral transition for the existence of irrational type eigenvalues or rational type eigenvalues with even denominators.

2: Suppose $\limsup _{n\to \infty } n|V(n)|=a<\infty .$ We obtain a lower/upper bound of $a$ such that $H_0+V$ has one rational type eigenvalue with odd denominator.

3: We obtain the asymptotical behavior of embedded eigenvalues around the boundaries of $(-2,2)$.

4: Given any finite set of points $\{ E_j\}_{j=1}^N$ in $(-2,2)$ with $0\notin \{ E_j\}_{j=1}^N+\{ E_j\}_{j=1}^N$, we construct the explicit potential $V(n)=\frac{O(1)}{1+|n|}$ such that $H=H_0+V$ has eigenvalues $\{ E_j\}_{j=1}^N$.

5: Given any countable set of points $\{ E_j\}$ in $(-2,2)$ with $0\notin \{ E_j\}+\{ E_j\}$, and any function $h(n)>0$ going to infinity arbitrarily slowly, we construct the explicit potential $|V(n)|\leq \frac{h(n)}{1+|n|}$ such that $H=H_0+V$ has eigenvalues $\{ E_j\}$.
Quantum Variance for Eisenstein Series
Authors: Huang Bingrong
Published: October 2019

In this paper, we prove an asymptotic formula for the quantum variance for Eisenstein series on $\operatorname{PSL}_2(\mathbb{Z})\backslash \mathbb{H}$. The resulting quadratic form is compared with the classical variance and the quantum variance for cusp forms. They coincide after inserting certain subtle arithmetic factors, including the central values of certain L-functions.
Volume Growth, Curvature, and Buser-Type Inequalities in Graphs
Authors: Benson Brian , Ralli Peter , Tetali Prasad
Published: October 2019

We study the volume growth of metric balls as a function of the radius in discrete spaces and focus on the relationship between volume growth and discrete curvature. We improve volume growth bounds under a lower bound on the so-called Ollivier curvature and discuss similar results under other types of discrete Ricci curvature.

Following recent work in the continuous setting of Riemannian manifolds (by the 1st author), we then bound the eigenvalues of the Laplacian of a graph under bounds on the volume growth. In particular, $\lambda _2$ of the graph can be bounded using a weighted discrete Hardy inequality and the higher eigenvalues of the graph can be bounded by the eigenvalues of a tridiagonal matrix times a multiplicative factor, both of which only depend on the volume growth of the graph. As a direct application, we relate the eigenvalues to the Cheeger isoperimetric constant. Using these methods, we describe classes of graphs for which the Cheeger inequality is tight on the 2nd eigenvalue (i.e. the 1st nonzero eigenvalue). We also describe a method for proving Buser’s Inequality in graphs, particularly under a lower bound assumption on curvature.
Substrate-based kinase activity inference identifies MK2 as driver of colitis
Authors: Strasser Samantha Dale , Ghazi Phaedra C , Starchenko Alina , Boukhali Myriam , Edwards Amanda , Suarez-Lopez Lucia , Lyons Jesse , Changelian Paul S , Monahan Joseph B , Jacobsen Jon , Brubaker Douglas K , Joughin Brian A , Yaffe Michael B , Haas Wilhelm , Lauffenburger Douglas A , Haigis Kevin M
Published: October 2019

Inflammatory bowel disease (IBD) is a chronic and debilitating disorder that has few treatment options due to a lack of comprehensive understanding of its molecular pathogenesis. We used multiplexed mass spectrometry to collect high-content information on protein phosphorylation in two different mouse models of IBD. Because the biological function of the vast majority of phosphorylation sites remains unknown, we developed Substrate-based Kinase Activity Inference (SKAI), a methodology to infer kinase activity from phosphoproteomic data. This approach draws upon prior knowledge of kinase-substrate interactions to construct custom lists of kinases and their respective substrate sites, termed kinase-substrate sets that employ prior knowledge across organisms. This expansion as much as triples the amount of prior knowledge available. We then used these sets within the Gene Set Enrichment Analysis framework to infer kinase activity based on increased or decreased phosphorylation of its substrates in a dataset. When applied to the phosphoproteomic datasets from the two mouse models, SKAI predicted largely non-overlapping kinase activation profiles. These results suggest that chronic inflammation may arise through activation of largely divergent signaling networks. However, the one kinase inferred to be activated in both mouse models was mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2 or MK2), a serine/threonine kinase that functions downstream of p38 stress-activated mitogen-activated protein kinase. Treatment of mice with active colitis with ATI450, an orally bioavailable small molecule inhibitor of the MK2 pathway, reduced inflammatory signaling in the colon and alleviated the clinical and histological features of inflammation. These studies establish MK2 as a therapeutic target in IBD and identify ATI450 as a potential therapy for the disease.
DOCK family proteins: key players in immune surveillance mechanisms
Authors: Kunimura Kazufumi , Uruno Takehito , Fukui Yoshinori
Published: October 2019

Dedicator of cytokinesis (DOCK) proteins constitute a family of evolutionarily conserved guanine nucleotide exchange factors (GEFs) for the Rho family of GTPases. Although DOCK family proteins do not contain the Dbl homology domain typically found in other GEFs, they mediate the GTP–GDP exchange reaction through the DOCK homology region-2 (DHR-2) domain. In mammals, this family consists of 11 members, each of which has unique functions depending on the expression pattern and the substrate specificity. For example, DOCK2 is a Rac activator critical for migration and activation of leukocytes, whereas DOCK8 is a Cdc42-specific GEF that regulates interstitial migration of dendritic cells. Identification of DOCK2 and DOCK8 as causative genes for severe combined immunodeficiency syndromes in humans has highlighted their roles in immune surveillance. In addition, the recent discovery of a naturally occurring DOCK2-inhibitory metabolite has uncovered an unexpected mechanism of tissue-specific immune evasion. On the other hand, GEF-independent functions have been shown for DOCK8 in antigen-induced IL-31 production in helper T cells. This review summarizes multifaced functions of DOCK family proteins in the immune system.
Heterogeneity of penicillin-non-susceptible group B streptococci isolated from a single patient in Germany
Authors: van der Linden Mark , Mamede Rafael , Levina Natascha , Helwig Peter , Vila-Cerqueira Pedro , Carriço João André , Melo-Cristino José , Ramirez Mário , Martins Elisabete R
Published: October 2019

Objectives

Streptococcus agalactiae [group B streptococci (GBS)] have been considered uniformly susceptible to penicillin. However, increasing reports from Asia and North America are documenting penicillin-non-susceptible GBS (PRGBS) with mutations in pbp genes. Here we report, to the best of our knowledge, the first two PRGBS isolates recovered in Europe (AC-13238-1 and AC-13238-2), isolated from the same patient.

Methods

Two different colony morphologies of GBS were noted from a surgical abscess drainage sample. Both were serotyped and antimicrobial susceptibility testing was performed by different methodologies. High-throughput sequencing was done to compare the isolates at the genomic level, to identify their capsular type and ST, to evaluate mutations in the pbp genes and to compare the isolates with the genomes of other PRGBS isolates sharing the same serotype and ST.

Results

Isolates AC-13238-1 and AC-13238-2 presented MICs above the EUCAST and CLSI breakpoints for penicillin susceptibility. Both shared the capsular type Ia operon and ST23. Genomic analysis uncovered differences between the two isolates in seven genes, including altered pbp genes. Deduced amino acid sequences revealed critical substitutions in PBP2X in both isolates. Comparison with serotype Ia clonal complex 23 PRGBS from the USA reinforced the similarity between AC-13238-1 and AC-13238-2, and their divergence from the US strains.

Conclusions

Our results support the in-host evolution of β-lactam-resistant GBS, with two PRGBS variants being isolated from one patient.
In vitro selection of aztreonam/avibactam resistance in dual-carbapenemase-producing Klebsiella pneumoniae
Authors: Niu Siqiang , Wei Jie , Zou Chunhong , Chavda Kalyan D , Lv Jingnan , Zhang Haifang , Du Hong , Tang Yi-Wei , Pitout Johann D D , Bonomo Robert A , Kreiswirth Barry N , Chen Liang
Published: October 2019

Objectives

To examine the in vitro selection of aztreonam/avibactam resistance among MBL-producing Klebsiella pneumoniae and to understand the mechanism of increased resistance.

Methods

The MICs of aztreonam were determined with and without avibactam (4 mg/L) using a broth microdilution method. Single-step and multi-step mutant selection was conducted on five MBL-producing K. pneumoniae strains, including two dual carbapenemase producers. Genomic sequencing and gene cloning were performed to investigate the mechanism of increased resistance.

Results

We examined the MICs for 68 MBL-producing K. pneumoniae isolates, including 13 dual carbapenemase producers. Compared with aztreonam alone, the addition of avibactam (4 mg/L) reduced the MICs for all isolates by >128-fold, with MIC50 and MIC90 values of 0.25 and 1 mg/L, respectively. One NDM-1-, OXA-48-, CTX-M-15- and CMY-16-positive ST101 K. pneumoniae strain was selected to be resistant to aztreonam/avibactam, with a >16-fold increase in MIC (>128 mg/L). WGS revealed that the resistant mutants lost the blaNDM-1 gene, but acquired amino acid substitutions in CMY-16 (Tyr150Ser and Asn346His). Construction of blaCMY-16 mutants confirmed that the substitutions (Tyr150Ser and Asn346His) were primarily responsible for the decreased susceptibility to aztreonam/avibactam. In addition, transfer of blaCMY-16 mutant (Tyr150Ser and Asn346His) plasmid constructs into certain clinical carbapenemase-producing isolates demonstrated >64-fold increased MICs of aztreonam/avibactam and aztreonam/avibactam/ceftazidime.

Conclusions

Aztreonam in combination with avibactam showed potent in vitro activity against MBL-producing K. pneumoniae. However, our study suggested the likelihood of aztreonam/avibactam resistance among MBL- and AmpC-co-producing strains and clinical practice should beware of the possibility of the emerging resistance.