bluuebunny/crossref_metadata_2025 huggingface dataset:
Exercise for Solid Organ Transplant Candidates and Recipients: A Joint Position Statement of the Canadian Society of Transplantation and CAN-RESTORE
Authors: Janaudis-Ferreira Tania , Mathur Sunita , Deliva Robin , Howes Nancy , Patterson Catherine , Räkel Agnès , So Stephanie , Wickerson Lisa , White Michel , Avitzur Yaron , Johnston Olwyn , Heywood Norine , Singh Sunita , Holdsworth Sandra
Published: June 2019

Background.

The objectives of this position statement were to provide evidence-based and expert-informed recommendations for exercise training in adult and children solid organ transplant (SOT) candidates and recipients and on the outcomes relevant to exercise training and physical function that should be evaluated in SOT.

Methods.

We identified randomized controlled trials (RCTs) and systematic reviews of exercise interventions in adult and pediatric SOT candidates and recipients. When RCTs were not available, studies of any design were reviewed. The key recommendations were based on scientific evidence and expert-informed opinion.

Results.

We recommended that exercise training should be offered in the pre- and posttransplant phase for both adults and children. In adults, exercise training pretransplant was safe, but there was insufficient evidence to provide specific guidelines on the training characteristics. RCTs in adult SOT recipients demonstrated that exercise training improved exercise capacity, lower extremity muscle strength, and health-related quality of life. To obtain benefits, exercise training should be of moderate to vigorous-intensity level, 3–5 times a week for a minimum of 8 weeks. In pediatrics, there is an urgent need for high-quality multicenter clinical trials in the pre- and posttransplant phases. Due to limited evidence, specific recommendations regarding training characteristics could not be provided for pediatrics.

Conclusions.

The clinical relevance of this position statement is that it provides a key step toward raising awareness of the importance of exercise training in SOT patients among transplant professionals. It also identifies key areas for further research.
Characterization of Clinical and Histological Rejection of Male Genital Tissues Using a Novel Microsurgical Rat Penile Transplantation Model
Authors: Fidder Samuel A.J. , Furtmüller Georg J. , Simons Brian , Oh Byoung Chol , Chicco Maria , Etra Joanna W. , Brayton Cory , Cooney Carisa M. , Vasilic Dalibor , Kern Barbara , Lough Denver , Lee WP Andrew , Redett Richard J. , Brandacher Gerald , Cooney Damon S.
Published: June 2019

Background.

Penis transplantation represents an exciting new avenue for restoration of male urogenitalia. However, little is known about the specific immunological features of penile transplants, limiting their application in complex urogenital reconstruction. To properly study this emerging form of transplantation, adequate preclinical models are a necessity. The purpose of this study is to establish a clinical and histological rejection classification of urogenital tissue transplants using a new rat heterotopic penile transplant model that includes preputial skin.

Methods.

Syngeneic and allogeneic heterotopic penile transplantations were performed on Lewis and Brown Norway rats using a new model designed by our group. Grafts were clinically and histologically monitored at postoperative days (POD) 3–30.

Results.

Six syngeneic and 25 allogeneic transplants were performed. All syngeneic and tacrolimus-treated grafts survived until endpoint. Allogeneic graft rejection is shown to follow a 4-stage clinical progression with all untreated allografts developing epidermal sloughing at POD7 and full rejecting between POD14 and POD16. Histological samples were used to develop a specific 4-grade rejection classification analogous to the 2007 Banff Criteria for skin-containing allografts.

Conclusions.

Graft skin and urethral lining tissue are first rejection targets followed by tunica albuginea and corpora cavernosa in a distal to proximal pattern. We established a robust and reproducible murine model to study the immunobiology of male genital tissue in the context of transplantation and developed a novel 4-grade clinical and histological rejection scale based on graft skin and urethral lining as the main targets of rejection.
BOS Is Associated With Decreased SIRT1 in Peripheral Blood Proinflammatory T, NK, and NKT-like Lymphocytes
Authors: Hodge Greg , Hodge Sandra , Liu Hong , Nguyen Phan , Holmes-Liew Chien-Li , Holmes Mark
Published: June 2019

Background.

Immunosuppression therapy is ineffective at preventing chronic rejection of lung allografts (bronchiolitis obliterans syndrome [BOS]) and proinflammatory cytokines by steroid-resistant lymphocytes. The class III NAD-sirtuin 1 (SIRT1) is an important negative regulator of inflammation; however, SIRT1 activity following lung transplant has not been studied. We hypothesized that SIRT1 expression is decreased in proinflammatory lymphocytes following lung transplant and that treatment with SIRT1 activators (resveratrol, curcumin) and agents that prevent NAD depletion (theophylline) upregulate SIRT1 and reduce proinflammatory cytokine expression in these cells.

Methods.

Intracellular proinflammatory cytokines and SIRT1 were measured in blood T, natural killer T-like cell (NKT-like), and natural killer (NK) cells from patients with BOS (n = 10), stable lung transplant patients (n = 11), and healthy aged-matched controls (n = 10). Blood was cultured in the presence of ±25 µM resveratrol, ±1 µM curcumin, ±5 mg/L theophylline, ±1µM prednisolone and cytokines, and SIRT1 assessed using flow cytometry.

Results.

There was a loss of SIRT1 in T, NK-like, and NK cells in BOS patients compared with stable patients and controls (%CD8+ SIRT1+ T cells: 17 ± 10; 37 ± 10; 30 ± 10) (mean ± SEM BOS, stable, control, respectively) (P < 0.05 for all). Loss of SIRT1 was associated with increased T, NKT-like, and NK cells expressing interferon (IFN)γ and tumor necrosis factor (TNF)α. SIRT1 expression by T cells significantly associated with FEV1 (R = 0.655, P = 0.006) and with time posttransplant (R = −0.552, P = 0.041). All treatments upregulated SIRT1 and inhibited IFNγ and TNFα production by T, NK, and NKT-like cells additively.

Conclusions.

BOS is associated with decreased SIRT1 in peripheral blood proinflammatory T, NK, and NKT-like lymphocytes following lung transplant. Treatment options that increase SIRT1 may improve graft survival.
Utilization of Donor Kidneys With Acute Kidney Injury in Pediatric Kidney Transplant Recipients
Authors: Solomon Sonia , Hayde Nicole
Published: June 2019

Background.

An elevated terminal creatinine is frequently used as a reason for organ refusal in pediatric kidney transplantation. There is increasing evidence that adults who receive kidneys from donors with moderate to severe acute kidney injury (AKI) have similar outcomes to recipients who receive kidneys from donors with none to mild AKI.

Methods.

We used the Scientific Registry of Transplant Recipients to determine how many pediatric kidney transplant recipients developed delayed graft function (DGF) between 2000 and 2010.

Results.

When stratified by the donor terminal creatinine, there was no significant difference in the recipient discharge creatinine or the likelihood of developing DGF. In a logistic regression model, older donor age, male donors, and a longer cold ischemia time but not donor terminal creatinine were independent predictors of DGF. There were very few graft loss events documented in this study.

Conclusions.

Our results are in agreement with previously published data; a high donor terminal creatinine is not significantly associated with DGF in pediatric renal transplant recipients. Additional studies investigating the risk of rejection and long-term graft function are needed before adopting the practice of accepting kidneys with moderate to severe AKI in pediatric kidney transplant recipients.
Schizophrenia Phenotype Preceding Behavioral Variant Frontotemporal Dementia Related to C9orf72 Repeat Expansion
Authors: Sellami Leila , St-Onge Frédéric , Poulin Stéphane , Laforce Robert
Published: June 2019

Behavioral variant frontotemporal dementia (bvFTD) shares a constellation of clinical features with primary psychiatric disorders. The discovery of new FTD-related genetic mutations has brought attention to this overlap between bvFTD and psychotic disorders. The case reported here raises the question of whether C9orf72 repeat expansion may be involved in neuropsychiatric syndromes beyond the spectrum of neurodegenerative disease. A 61-year-old woman was referred to our memory clinic for behavioral changes and progressive cognitive decline over the last 3 years. Her medical history was significant for schizophrenia since age 36, with an exacerbation of psychotic symptoms at age 55, at which time she slowly worsened, became disorganized and apathetic, and presented new perseverative behaviors. Brain MRI showed mild bilateral frontal and temporal cortical atrophy, and 18F-fluorodeoxyglucose PET showed bilateral frontal and anterior temporal hypometabolism. Genetic analysis revealed C9orf72 hexanucleotide repeat expansion with more than 80 G4C2 repeats. Recently, FTD due to C9orf72 repeat expansion has been reported to show a high frequency of psychotic presentations. C9orf72 repeat expansion has previously been identified as a rare but possible cause of schizophrenia spectrum disorders. Our case report is characterized by a C9orf72-associated schizophrenia phenotype preceding bvFTD by 2 decades, which might reflect early prodromal neurodegeneration or neurodevelopmental and neurobiological effects of C9orf72 repeat expansion. Analysis of C9orf72 hexanucleotide repeat expansion may be appropriate in patients with schizophrenia spectrum disorders showing new behavioral and/or cognitive changes.
A Case of Capgras Syndrome With Frontotemporal Dementia
Authors: Metin Baris , Arikan Mehmet K. , Kalem Sukriye A. , Tarhan Nevzat
Published: June 2019

Capgras syndrome (CS), also called imposter syndrome, is a rare psychiatric condition that is characterized by the delusion that a family relative or close friend has been replaced by an identical imposter. Here, we describe a 69-year-old man with CS who presented to the Kemal Arikan Psychiatry Clinic with an ongoing belief that his wife had been replaced by an identical imposter. MRI showed selective anterior left temporal lobe atrophy. Quantitative EEG showed bilateral frontal and temporal slowing. Neuropsychological profiling identified a broad range of deficits in the areas of naming, executive function, and long-term memory. On the basis of these findings, we diagnosed frontotemporal dementia. This case demonstrates that CS can clinically accompany frontotemporal dementia.
“Need to Know” or the Strong Urge to Find Names of Unique Entities in Acquired Obsessive-Compulsive Disorder
Authors: Edelkraut Lisa , Berthier Marcelo L. , Green-Heredia Cristina , López-González Francisco J. , Roé-Vellvé Núria , Torres-Prioris María José , Tubío Javier , López-Barroso Diana
Published: June 2019

The two forms of obsessive-compulsive disorder (OCD), idiopathic and acquired, have been linked to abnormalities in the fronto-striato-thalamo-cortical circuitry, involving the orbitofrontal cortex, anterior cingulate cortex, thalamus, and striatum. Accumulating evidence indicates that damage to other brain regions (ie, temporal lobes) is also implicated in the pathogenesis of both types of OCD. In addition, some discrete OCD symptoms have received less attention because of their presumed low occurrence and difficultly of categorization. Among these, one intriguing and potentially severe type of obsessive thinking is the so-called “need to know” (NtK), which is a strong urge to access certain information, particularly proper names. In some patients, this monosymptomatic presentation may constitute the major feature of OCD. Here we report the cases of two patients who developed NtK obsessions with tenacious time-consuming, answer-seeking compulsions as the only or more disabling symptomatology in association with malignant tumors involving the right temporal lobe and connected fronto-subcortical circuits.
Cognitive Profile, Emotional-Behavioral Features, and Parental Stress in Boys With 47,XYY Syndrome
Authors: Operto Francesca F. , Pastorino Grazia M.G. , Amadori Elisabetta , Mazza Roberta , Bernardo Pia , Campanozzi Stella , Margari Lucia , Coppola Giangennaro
Published: June 2019

Objective:

To describe (a) the observed cognitive, emotional, and behavioral phenotype in a cohort of male children with 47,XYY syndrome and (b) stress levels in their parents.

Methods:

We conducted a cross-sectional observational study of 11 boys diagnosed with 47,XYY syndrome and compared them with 11 age-matched boys with normal karyotype (46,XY). The participants performed standardized assessments of cognitive function, emotional state, and behavioral features; the parents completed a questionnaire evaluating parental stress. All data were analyzed using parametric and nonparametric statistical methods.

Results:

All of the boys exhibited a normal cognitive profile. However, emotional-behavioral profiling revealed that internalizing and externalizing problems were more prevalent in the 47,XYY group. In addition, the stress levels of the parents of the 47,XYY group were reportedly higher than those of the parents of the 46,XY group. We also found that the time of the diagnosis had an effect on the mothers’ stress levels; that is, postnatal fetal 47,XYY diagnosis was associated with higher maternal stress, whereas prenatal fetal 47,XYY diagnosis was not.

Conclusions:

Generally, 47,XYY syndrome is associated with certain cognitive, emotional, and behavioral features. High stress levels have been reported by the mothers of 47,XYY boys who had been diagnosed postnatally because of unexpected developmental delay and/or learning difficulties. The present study highlights the need to better define the neuropsychiatric phenotype of 47,XYY children; namely, the effect of the chromosomal abnormality on their cognitive function and emotional-behavioral (internalizing and externalizing) features. This study could improve prenatal counseling and pediatric surveillance.
Community Engagement during outbreak response: standards, approaches, and lessons from the 2014-2016 Ebola outbreak in Sierra Leone
Authors: Bedson Jamie , Jalloh Mohamed F. , Pedi Danielle , Bah Saiku M. , Owen Katharine , Oniba Allan , Sangarie Musa , Fofanah James , Jalloh Mohamed B. , Sengeh Paul , Skrip Laura A. , Althouse Benjamin M , Hébert-Dufresne Laurent
Published: June 2019

Summary points

The Social Mobilization Action Consortium (SMAC) was Sierra Leone’s largest coordinated community engagement initiative during the 2014 - 2016 Ebola outbreak. It worked in all 14 districts in Sierra Leone across >12,000 communities (approximately 70% of all communities), through 2,466 trained Community Mobilizers, a network of 2,000 mosques and churches, and 42 local radio stations.

We describe SMAC’s Theory of Change and utilization of the Community-Led Ebola Action (CLEA) approach. We present an extensive dataset of community engagement and monitoring with a focus on over 50,000 SMAC weekly reports collected by Community Mobilizers between December 2014 and September 2015.

Community engagement and real-time data collection at scale is achievable in the context of a health emergency if adequately structured, managed, coordinated and resourced.

We describe a correlation between systemic community engagement, community action planning and Ebola-safe behaviors at community-level.

The SMAC integrated approach demonstrates the scope of data – including surveillance data - that can be generated directly by communities through structured community engagement interventions implemented at scale during an Ebola outbreak.

We highlight important insights gleaned over time on how to informally integrate social mobilization into community-based surveillance of sick people and deaths.
Evaluating the ALERT algorithm for local outbreak onset detection in seasonal infectious disease surveillance data
Authors: Brown Alexandria C. , Lauer Stephen A. , Robinson Christine C. , Nyquist Ann-Christine , Rao Suchitra , Reich Nicholas G.
Published: June 2019

Estimation of epidemic onset timing is an important component of controlling the spread of seasonal infectious dis-eases within community healthcare sites. The Above Local Elevated Respiratory Illness Threshold (ALERT) algorithm uses a threshold-based approach to suggest incidence levels that historically have indicated the transition from endemic to epidemic activity. In this paper, we present the first detailed overview of the computational approach underlying the algorithm. In the motivating example section, we evaluate the performance of ALERT in determining the onset of increased respiratory virus incidence using laboratory testing data from the Children’s Hospital of Colorado. At a threshold of 10 cases per week, ALERT-selected intervention periods performed better than the observed hospital site periods (2004/2005-2012/2013) and a CUSUM method. Additional simulation studies show how data properties may effect ALERT performance on novel data. We found that the conditions under which ALERT showed ideal performance generally included high seasonality and low off-season incidence.
Ultraviolet radiation exposure and melanoma: evidence for gene-environment interaction in a large prospective cohort
Authors: Olsen Catherine M. , Pandeya Nirmala , Law Matthew H. , MacGregor Stuart , Iles Mark M. , Thompson Bridie S. , Green Adele C. , Neale Rachel E. , Whiteman David C. ,   for the QSkin Study
Published: June 2019

Melanoma develops as the result of complex interactions between sun exposure and genetic factors. Data on the relationship between sunlight and melanoma from prospective studies are scant, and the combination of ultraviolet exposure data collected before melanoma diagnosis and genetic information is rarer still. We aimed to quantify the association between ambient and personal UV exposure in relation to risk of incident melanoma (invasive; invasive+in situ) in a large population-based prospective study of men and women (n=38,833) residing in a high ambient UV setting, and to examine potential gene-environment interactions. During a median follow-up time of 4.4 years, 782 (1.5%) participants developed cutaneous melanoma (316 invasive, 466 in situ). Country of birth, age at migration and sunburns during all periods of life were significantly associated with melanoma risk. Histories of keratinocyte cancer and of other actinic lesions were both strongly associated with melanoma risk. An interaction with polygenic risk is possible; among people at low risk, markers of cumulative sun exposure were associated with melanoma. In contrast, among people at high polygenic risk, markers of high-level early life ambient exposure were associated with melanoma. Polygenic risk scores can assist in identifying individuals for whom sunlight exposure is most relevant.
The Non-random Location of Autosomal Genes that Participate in X Inactivation
Authors: Migeon Barbara R.
Published: June 2019

By transcribing XIST RNA, the human inactive X chromosome has a prime role in X-dosage compensation. Yet, the autosomes also play an important role in the process. In fact, multiple genes on human chromosome 1 interact with XIST RNA to silence the inactive Xs, no matter how many there are. And it is likely that multiple genes on human chromosome 19 prevent the silencing of thesingleactive X, which is a highly dosage sensitive process. Previous studies of the organization of chromosomes in the nucleus and their genomic interactions indicate that most contacts are intra-chromosomal. Coordinate transcription or dosage regulation could explain the clustered organization of these autosomal genes on these two chromosomes that are critical for X dosage compensation in human cells. Unlike those on chromosome 1, the genes within the critical eight MB region of chromosome 19, have remained together in all mammals assayed, except rodents, indicating that their proximity in non-rodent mammals is evolutionarily conserved.
Two distinct functional axes of positive feedback-enforced PRC2 recruitment in mouse embryonic stem cells
Authors: Perino Matteo , van Mierlo Guido , Wardle Sandra M.T. , Marks Hendrik , Veenstra Gert Jan C.
Published: June 2019

Polycomb Repressive Complex 2 (PRC2) plays an essential role in development by catalysing trimethylation of histone H3 lysine 27 (H3K27me3), resulting in gene repression. PRC2 consists of two sub-complexes, PRC2.1 and PRC2.2, in which the PRC2 core associates with distinct ancillary subunits such as MTF2 and JARID2, respectively. Both MTF2, present in PRC2.1, and JARID2, present in PRC2.2, play a role in core PRC2 recruitment to target genes in mouse embryonic stem cells (mESCs). However, it remains unclear how these distinct sub-complexes cooperate to establish Polycomb domains. Here, we combine a range of Polycomb mutant mESCs with chemical inhibition of PRC2 catalytic activity, to systematically dissect their relative contributions to PRC2 binding to target loci. We find that PRC2.1 and PRC2.2 mediate two distinct paths for recruitment, with mutually reinforced binding. Part of the cross-talk between PRC2.1 and PRC2.2 occurs via their catalytic product H3K27me3, which is bound by the PRC2 core-subunit EED, thereby mediating a positive feedback. Strikingly, removal of either JARID2 or H3K27me3 only has a minor effect on PRC2 recruitment, whereas their combined ablation largely attenuates PRC2 recruitment. This strongly suggests an unexpected redundancy between JARID2 and EED-H3K27me3-mediated recruitment of PRC2. Furthermore, we demonstrate that all core PRC2 recruitment occurs through the combined action of MTF2-mediated recruitment of PRC2.1 to DNA and PRC1-mediated recruitment of JARID2-containing PRC2.2. Both axes of binding are supported by EED-H3K27me3 positive feedback, but to a different degree. Finally, we provide evidence that PRC1 and PRC2 mutually reinforce reciprocal binding. Together, these data disentangle the interdependent and cooperative interactions between Polycomb complexes that are important to establish Polycomb repression at target sites.

Highlights

Systematic analysis of Polycomb complex binding to target loci in mESCs using null mutations and chemical inhibition.

PRC1, PRC2.1 and PRC2.2 are all mutually dependent for binding to chromatin, mediated in part by H3K27me3.

PRC2.1 recruitment is dependent on MTF2

PRC2.2 recruitment by JARID2 is dependent on PRC1 and largely redundant with recruitment by H3K27me3
Targeting of the dosage-compensated male X-chromosome during earlyDrosophiladevelopment
Authors: Rieder LE , Jordan WT , Larschan EN
Published: June 2019

The essential process of dosage compensation, which corrects for the imbalance in X-linked gene expression between XX females and XY males, represents a key model for how genes are targeted for coordinated regulation. However, the mechanism by which dosage compensation complexes identify the X-chromosome during early development remained unknown because of the difficulty of sexing embryos prior to zygotic transcription. We used meiotic drive to sexDrosophilaembryos prior to zygotic transcription and ChIP-seq to measure dynamics of dosage compensation factor targeting. TheDrosophilaMale-Specific Lethal dosage compensation complex (MSLc) requires the ubiquitous zinc-finger protein Chromatin-Linked Adaptor for MSL Proteins (CLAMP) to identify the X-chromosome. We observe a multi-stage process in which MSLc first identifies CLAMP binding sites throughout the genome followed by concentration at the strongest X-linked MSLc sites. We provide insight into the dynamic mechanism by which a large transcription complex identifies its binding sites during early development.
Strategies for Integrating Single-Cell RNA Sequencing Results With Multiple Species
Authors: Hart Ronald P.
Published: June 2019

Single-cell RNA sequencing (scRNAseq) is a robust technology for parsing gene expression in individual cells from a tissue or other complex source. One application involves experiments where cells from multiple species are recovered from a single sample, such as when human cells are transplanted into an animal model. We transplanted microglial precursor cells into newborn mouse brain and then recovered unenriched cortical tissue six months later. Dissociated cells were assessed by scRNAseq. The default method for analyzing these results begins by aligning sequencing reads with a mixture of both mouse and human reference genomes. While this clearly identifies the human cells as a distinct cluster, the clustering is artificially driven by expression from non-comparable gene identifiers from different species. We devised a method for translating expression counts from human to mouse and evaluated four algorithms for parsing mixed-species scRNAseq data. Our optimal approach split raw sequencing reads according to the best alignment score in each genome, and then re-aligned reads only with the appropriate genome. After gene symbol translation, pooled results indicate that cell types are more appropriately clustered and that differential expression analysis identifies species-specific patterns. This method should be applicable to any mixed-species scRNAseq experiment.

Summary of optimal strategy

Mixed-species scRNAseq data are aligned with mixture of mouse and human reference genomes

The BAM file is scanned to find the best alignment score for each sequencing read identifier; these are used to split the paired FASTQ files into two sets of files

Each set of species-specific, paired FASTQ files is re-aligned with only the appropriate reference genome

Raw counts imported into Seurat

The human counts table is translated to mouse gene symbols using a custom HomoloGene translation table

Results are merged and analyzed
Central Nervous System Delivery and Biodistribution Analysis of an Antibody-Enzyme Fusion for the Treatment of Lafora Disease
Authors: Austin Grant L. , Simmons Zoe R. , Klier Jack E. , Hodges Brad L. , Shaffer Robert , McKnight Tracy R. , Pauly James R. , Armstrong Dustin , Kooi Craig W. Vander , Gentry Matthew S.
Published: June 2019

Lafora disease is a fatal juvenile epilepsy, characterized by the malignant accumulation of aberrant glucan inclusions called Lafora Bodies (LBs). Cerebral delivery of protein-based therapeutics for the clearance of Lafora Bodies remain a unique challenge in the field. Recently, a humanized antigen-binding fragment (hFab) derived from a murine systemic lupus erythematosus DNA autoantibody (3E10) has been shown to mediate cell penetration and been proposed as a broadly applicable carrier to mediate cellular targeting and uptake. We report studies on cerebral delivery of VAL-0417, an antibody-enzyme fusion composed of the 3E10 hFab and human pancreatic α-amylase for the clearance of LBs in a mouse model of lafora disease. Herein, we report development of an enzyme-linked immunosorbant-based bioassay to detect VAL-0417 post treatment as a measure of delivery efficacy. We demonstrate the robust and sensitive detection of the fusion protein in multiple tissue types. Using our method, we measured biodistribution in different methods of delivery. We found intracerebroventricular administration provided the most robust delivery, while intrathecal administration only showed modest biodistribution. These data define critical steps in the translational pipeline of VAL-0417for the treatment of Lafora disease.
Viral satellites exploit phage proteins to escape degradation of the bacterial host chromosome
Authors: McKitterick Amelia C. , Hays Stephanie G. , Alam Munirul , Seed Kimberley D.
Published: June 2019

Phage defense systems are often found on mobile genetic elements (MGEs), where they constitutively defend against invaders or are induced to respond to new assaults. Some MGEs, the phage satellites, exploit phages for their own transmission after induction, reducing phage production and protecting their hosts in the process. One such satellite inVibrio cholerae, PLE, is triggered by the lytic phage ICP1 to excise from the chromosome, replicate, and transduce to neighboring cells, completely sabotaging phage production. Here, we found that ICP1 has evolved to possess one of two syntenic loci encoding an SF1B-type helicase, either of which PLE can exploit to directly drive PLE replication. Further, loss of PLE mobilization limits anti-phage activity due to phage-mediated degradation of the bacterial genome. Our work provides insight into the unique challenges imposed on the parasites of lytic phages and underscores the adaptions of these satellites to their ever-evolving target phage.
The turning and barrier course reveals gait parameters for detecting freezing of gait and measuring the efficacy of deep brain stimulation
Authors: O’Day Johanna , Syrkin-Nikolau Judy , Anidi Chioma , Kidzinski Lukasz , Delp Scott , Bronte-Stewart Helen
Published: June 2019

Freezing of gait (FOG) is a devastating motor symptom of Parkinson’s disease that leads to falls, reduced mobility, and decreased quality of life. Reliably eliciting FOG has been difficult in the clinical setting, which has limited discovery of pathophysiology and/or documentation of the efficacy of treatments, such as different frequencies of subthalamic deep brain stimulation (STN DBS). In this study we validated an instrumented gait task, the turning and barrier course (TBC), with the international standard FOG questionnaire question 3 (FOG-Q3, r = 0.74,p< 0.001). The TBC is easily assembled and mimics real-life environments that elicit FOG. People with Parkinson’s disease who experience FOG (freezers) spent more time freezing during the TBC compared to during forward walking (p= 0.007). Freezers also exhibited greater arrhythmicity during non-freezing gait when performing the TBC compared to forward walking (p= 0.006); this difference in gait arrhythmicity between tasks was not detected in non-freezers or controls. Freezers’ non-freezing gait was more arrhythmic than that of non-freezers or controls during all walking tasks (p< 0.05). A logistic regression model determined that a combination of gait arrhythmicity, stride time, shank angular range, and asymmetry had the greatest probability of classifying a step as FOG (area under receiver operating characteristic curve = 0.754). Freezers’ percent time freezing and non-freezing gait arrhythmicity decreased, and their shank angular velocity increased in the TBC during both 60 Hz and 140 Hz STN DBS (p< 0.05) to non-freezer values. The TBC is a standardized tool for eliciting FOG and demonstrating the efficacy of 60 Hz and 140 Hz STN DBS for gait impairment and FOG. The TBC revealed gait parameters that differentiated freezers from non-freezers and best predicted FOG; these may serve as relevant control variables for closed loop neurostimulation for FOG in Parkinson’s disease.
Histopathological Study Of Different Organs Of Charles Foster Rats Under The Exposure Of Pueraria tuberosa
Authors: Pandey Harsh , Srivastava Shivani , Kumar Mohan , Tripathi Yamini Bhusan
Published: June 2019

The present study was undertaken to investigate the safe doses of Pueraria tuberosa water extract (PTWE) on different organs. The OECD guidelines 407 of repeated toxicity was followed with respect to the selection of dose and days for different organs. The selected doses of PTWE were 250, 500, 1000 and 2000 mg/kg b wt for 7, 14, 21 and 28 days. Haematoxylin and eosin staining was used to study the morphological alterations in heart, intestine, testis, adrenal gland and spleen. In the present study, no adverse alterations in cardiac fibers of the heart, size and shapes in crypts and villi of intestine, seminiferous tubules and spermatozoa count in testis, three zones of adrenal gland, and spleen were seen in all treated groups of PTWE. There were no adverse morphological alterations found in described organs. The PTWE are safe at 1000 mg/kg b wt. up to 28 days and 2000 mg/ kg b. wt up to 21 days, respectively.
RamaNet: Computational de novo helical protein backbone design using a long short-term memory generative neural network
Authors: Sabban Sari , Markovsky Mikhail
Published: June 2019

The ability to perform de novo protein design will allow researchers to expand the variety of available proteins. By designing synthetic structures computationally, they can utilise more structures than those available in the Protein Data Bank, design structures that are not found in nature, or direct the design of proteins to acquire a specific desired structure. While some researchers attempt to design proteins from first physical and thermodynamic principals, we decided to attempt to test whether it is possible to perform de novo helical protein design of just the backbone statistically using machine learning by building a model that uses a long short-term memory (LSTM) architecture. The LSTM model used only the ϕ and ψ angles of each residue from an augmented dataset of only helical protein structures. Though the network’s generated backbone structures were not perfect, they were idealised and evaluated post generation where the non-ideal structures were filtered out and the adequate structures kept. The results were successful in developing a logical, rigid, compact, helical protein backbone topology. This paper is a proof of concept that shows it is possible to generate a novel helical backbone topology using an LSTM neural network architecture using only the ϕ and ψ angles as features. The next step is to attempt to use these backbone topologies and sequence design them to form complete protein structures.

Author summary

This research project stemmed from the desire to expand the pool of protein structures that can be used as scaffolds in computational vaccine development, since the number of structures available from the Protein Data Bank was not sufficient to allow for great diversity and increase the probability of grafting a target motif onto a protein scaffold. Since a protein structure’s backbone can be defined by the ϕ and ψ angles of each amino acid in the polypeptide and can effectively translate a protein’s 3D structure into a table of numbers, and since protein structures are not random, this numerical representation of protein structures can be used to train a neural network to mathematically generalise what a protein structure is, and therefore generate new a protein backbone. Instead of using all proteins in the Protein Data Bank a curated dataset was used encompassing protein structures with specific characteristics that will, theoretically, allow them to be evaluated computationally. This paper details how a trained neural network was able to successfully generate helical protein backbones.
Real-time detection of neural oscillation bursts allows behaviourally relevant neurofeedback
Authors: Karvat Golan , Schneider Artur , Alyahyaey Mansour , Steenbergen Florian , Diester Ilka
Published: June 2019

Neural oscillations are increasingly interpreted as transient bursts, yet a method to measure these short-lived events in real-time is missing. Here we present a real-time data analysis system, capable to detect short and narrowband bursts, and demonstrate its usefulness for volitional increase of beta-band burst-rate in rats. This neurofeedback-training induced changes in overall oscillatory power, and bursts could be decoded from the movement of the rats, thus enabling future investigation of the role of oscillatory bursts.
Long-term impact of fecal transplantation in healthy volunteers
Authors: Goloshchapov Oleg V , Olekhnovich Evgenii I , Sidorenko Sergey V , Moiseev Ivan S , Kucher Maxim A , Fedorov Dmitry E. , Pavlenko Alexander V , Manolov Alexander I , Gostev Vladimir V , Veselovsky Vladimir A , Klimina Ksenia M , Kostryukova Elena S , Bakin Evgeny A , Shvetcov Alexander N , Gumbatova Elvira D , Klementeva Ruslana V , Shcherbakov Alexander A , Gorchakova Margarita V , Egozcue Juan José , Pawlowsky-Glahn Vera , Suvorova Maria A , Chukhlovin Alexey B , Govorun Vadim M , Ilina Elena N , Afanasyev Boris V
Published: June 2019

Background

Fecal microbiota transplantation (FMT) is now approved for the treatment of refractory recurrent clostridial colitis, but a number of studies are ongoing in inflammatory bowel diseases, i.e., Crohn’s disease, nonspecific ulcerative colitis, and in other autoimmune conditions. In most cases, the effects of FMT are evaluated on patients with initially altered microbiota. The aim of the present study was to evaluate effects of FMT on the gut microbiota composition in healthy volunteers and to track long-term changes.

Results

We have performed a combined analysis of three healthy volunteers before and after FMT with frozen capsules, followed by evaluation of their general condition, adverse clinical effects, changes of basic laboratory parameters, and several immune markers. Intestinal microbiota samples were evaluated by 16S rRNA gene sequencing (16S seq) and shotgun sequencing (or whole-genome sequencing – WGS). The data analysis demonstrated the profound shift towards the donor microbiota taxonomic composition in all volunteers. Following FMT, all the volunteers exhibited gut colonization with donor gut bacteria, and persistence of this effect for almost ~1 year of observation. Transient changes of immune parameters were consistent with suppression of T-cell cytotoxicity. FMT was well tolerated with mild gastrointestinal adverse events and systemic inflammatory response in one volunteer.

Conclusions

The FMT procedure leads to significant long-term changes of the gut microbiota in healthy volunteers with the shift towards donor microbiota composition, being relatively safe to the recipients without long-term adverse events.
Disrupted information flow in resting-state in adolescents with sports related concussion
Authors: Hristopulos Dionissios T. , Babul Arif , Babul Shazia’Ayn , Brucar Leyla R. , Virji-Babul Naznin
Published: June 2019

Children and youth are at a greater risk of concussions than adults, and once injured, take longer to recover. A key feature of concussion is a diffuse increase in functional connectivity; yet it remains unclear how changes in functional connectivity relate to the patterns of information flow within resting state networks following concussion and how these relate to brain function. We applied a data-driven measure of directed effective brain connectivity to compare the patterns of information flow in healthy adolescents and adolescents with subacute concussion during the resting state condition. Data from 32 healthy adolescents (mean age =16 years) and 24 concussed adolescents (mean age = 13.8 years) with subacute concussion (< 3 months post injury) took part in the study. Five minutes of resting state data EEG were collected while participants sat quietly with their eyes closed. We applied the Kleeman-Liang information flow rate to measure the transfer of information between the EEG time series of each individual at different source locations, and therefore between different brain regions. Based on the ensemble means of the magnitude of normalized information flow rate, our analysis shows that information flow in the healthy adolescents is characterized by a predominantly (L) lateralized pattern with bidirectional information flow between frontal regions, between frontal and central/temporal regions and between parietal and occipital regions. In contrast, adolescents with concussion show distinct differences in information flow marked by a more symmetrical pattern with connections evenly distributed across the entire brain, increased information flow in the posterior regions of the brain and the emergence of bidirectional, inter-hemispheric connections between the left and right temporal regions of the brain. We also find that the statistical distribution of the normalized information flow rates in each group (control and concussed) is significantly different. Our results are the first to describe altered patterns of information flow in adolescents with concussion as well as differences in the statistical distribution of information flow rate. We hypothesize that the observed changes in information flow in the concussed group are a consequence of the brain injury and indicate functional reorganization of resting state networks.
Corruption of the Pearson correlation coefficient by measurement error: estimation, bias, and correction under different error models
Authors: Saccenti Edoardo , Hendriks Margriet H. W. B. , Smilde Age K.
Published: June 2019

Correlation coefficients are abundantly used in the life sciences. Their use can be limited to simple exploratory analysis or to construct association networks for visualization but they are also basic ingredients for sophisticated multivariate data analysis methods. It is therefore important to have reliable estimates for correlation coefficients. In modern life sciences, comprehensive measurement techniques are used to measure metabolites, proteins, gene-expressions and other types of data. All these measurement techniques have errors. Whereas in the old days, with simple measurements, the errors were also simple, that is not the case anymore. Errors are heterogeneous, non-constant and not independent. This hampers the quality of the estimated correlation coefficients seriously. We will discuss the different types of errors as present in modern comprehensive life science data and show with theory, simulations and real-life data how these affect the correlation coefficients. We will briefly discuss ways to improve the estimation of such coefficients.
Structural basis of p62/SQSTM1 helical filaments, their presence in p62 bodies and role in cargo recognition in the cell
Authors: Jakobi Arjen J. , Huber Stefan T. , Mortensen Simon A. , Schultz Sebastian W. , Palara Anthimi , Kuhm Tanja , Shrestha Birendra Kumar , Lamark Trond , Hagen Wim J.H. , Wilmanns Matthias , Johansen Terje , Brech Andreas , Sachse Carsten
Published: June 2019

p62/SQSTM1 is an autophagy receptor and signaling adaptor with an N-terminal PB1 domain that forms the scaffold of phase-separated p62 bodies in the cell. The molecular determinants that govern PB1 domain filament formation in vitro remain to be determined and the role of p62 filaments inside the cell is currently unclear. We determined four high-resolution cryo-EM structures of different human and Arabidopsis PB1 domain assemblies and observed a filamentous ultrastructure of phase-separated p62/SQSTM1 bodies using correlative cellular EM. We show that oligomerization or polymerization, driven by a double arginine finger in the PB1 domain, is a general requirement for lysosomal targeting of p62. Furthermore, the filamentous assembly state of p62 is required for autophagosomal processing of the p62-specific cargo KEAP1. Our results show that using such mechanisms, p62 filaments can be critical for cargo recognition and are an integral part of phase separated p62 bodies.
Salience-weighted agreement feature hierarchy modulates language comprehension
Authors: Muralikrishnan R. , Idrissi Ali
Published: June 2019

The brain establishes relations between elements of an unfolding sentence in order to incrementally build a representation of who is doing what based on various linguistic cues. Many languages systematically mark the verb and/or its arguments to imply the manner in which they are related. A common mechanism to this end is subject-verb agreement, whereby the marking on the verb covaries with one or more of the features such as person, number and gender of the subject argument in a sentence. The cross-linguistic variability of these features would suggest that they may modulate language comprehension differentially based on their relative weightings in a given language. To test this, we investigated the processing of subject-verb agreement in simple intransitive Arabic sentences in a visual event-related brain potential (ERP) study. Specifically, we examined the differences, if any, that ensue in the processing of person, number and gender features during online comprehension, employing sentences in which the verb either showed full agreement with the subject noun (singular or plural) or did not agree in one of the features. ERP responses were measured at the post-nominal verb. Results showed a biphasic negativity−late-positivity effect when the verb did not agree with its subject noun in one of the features, in line with similar findings from other languages. Crucially however, the biphasic effect for agreement violations was systematically graded based on the feature that was violated, which is a novel finding in view of results from other languages. Furthermore, this graded effect was qualitatively different for singular and plural subjects based on the differing salience of the features for each subject-type. These results suggest that agreement features, varying in their salience due to their language-specific weightings, differentially modulate language comprehension. We postulate a Salience-weighted Feature Hierarchy based on our findings and argue that this parsimoniously accounts for the diversity of existing cross-linguistic neurophysiological results on verb agreement processing.
Geometrical constraints greatly hinder formin mDia1 activity
Authors: Suzuki Emiko L. , Guichard Bérengère , Romet-Lemonne Guillaume , Jégou Antoine
Published: June 2019

Formins are one of the central players in the assembly of most actin networks in cells. The sensitivity of these processive molecular machines to mechanical tension is now well established. However, how the activity of formins is affected by geometrical constraints related to network architecture, such as filament crosslinking and formin spatial confinement, remains largely unknown. Combining microfluidics and micropatterning, we reconstituted in vitro mDia1 formin-elongated filament bundles induced by fascin, with different geometrical constraints on the formins, and measured the impact of these constraints on formin elongation rates and processivity. When filaments are not bundled, formins can be anchored to static or fluid surfaces, by either end of the proteins, without affecting their activity. We show that filament bundling by fascin reduces both unanchored formin elongation rate and processivity. Strikingly, when filaments elongated by surface-anchored formins are cross-linked together, formin elongation rate immediately decreases and processivity is reduced, up to 24-fold, depending on the cumulative impact of formin rotational and translational freedoms. Our results reveal an unexpected crosstalk between the constraints at the filament and the formin levels. We anticipate that in cells, the molecular details of formin anchoring to the plasma membrane, strongly modulate formin activity at actin filament barbed ends.