bluuebunny/crossref_metadata_2025 huggingface dataset:
Complementary and integrative medicine in kidney transplantation
Authors: Tafaj-Reddy Olta , Brar Amarpali , Markell Mariana S.
Published: December 2018

Purpose of review

Complementary and integrative medicine (CIM) use is widely prevalent in kidney transplant recipients but studies of efficacy or potential harm are sparse. This review examines prevalence of use of CIM and discusses potential beneficial and harmful aspects of CIM in renal transplant recipients.

Recent findings

The prevalence of CIM use in kidney transplant patients varies from 12 to 45%. There is a knowledge gap regarding CIM modalities among healthcare professionals that may contribute to reluctance to discuss CIM use with patients. Patients often do not spontaneously disclose its use, and those that use it may be more likely to be nonadherent to allopathic therapies. Herbal supplements may be nephrotoxic or interact with pharmaceutical agents, including calcineurin inhibitors. More data are needed to assess the potential benefits of other modalities of CIM, including yoga, Tai Chi or meditation, as these modalities have been beneficial for people with diabetes or hypertension, both of which are common in the posttransplant period.

Despite a high prevalence of CIM use in kidney transplant recipients, data are limited regarding risks and benefits. Education of healthcare providers who care for kidney transplant recipients should be encouraged. Intervention studies should be designed to investigate the CIM modalities, including yoga, meditation and Tai Chi that have been shown to be beneficial in other chronic diseases.
Hypertriglyceridemia-Associated Drug-Induced Acute Pancreatitis
Authors: Elkhouly Mohamed A. , Salazar Miguel Jose , Simons-Linares Carlos Roberto
Published: December 2018

Objectives

The aim of our study was to investigate the cases of drug-induced acute pancreatitis (DIAP) with hypertriglyceridemia as the mechanism of injury.

Methods

A MEDLINE search (1963–2018) of the English language literature was performed looking for all human case reports of adults (>18 years old) with hypertriglyceridemia as the mechanism of DIAP. The latest search date was February 28, 2018. Drugs were classified into probability groups based on a classification used by Badalov et al (Clin Gastroenterol Hepatol. 2007;5:648–661).

Results

The search revealed a total of 76 cases in 59 published reports. A total of 25 medications were found to be implicated in DIAP secondary to hypertriglyceridemia mechanism. Most of acute pancreatitis cases were mild or moderately severe with favorable outcomes. In 3 cases involving tamoxifen, pagaspargase, and quetiapine, patient death was the outcome. Plasmapheresis was only used in 9 cases in an effort to decrease triglyceride levels.

Conclusions

Hypertriglyceridemia-associated DIAP is a rare phenomenon, and the current systematic review provides a summary of drugs that have been implicated in this phenomenon, which allow physicians to be oriented about this adverse effect when these drugs are used.
Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection and Other Conditions in Children
Authors: Davidovics Zev H. , Michail Sonia , Nicholson Maribeth R. , Kociolek Larry K. , Pai Nikhil , Hansen Richard , Schwerd Tobias , Maspons Aldo , Shamir Raanan , Szajewska Hania , Thapar Nikhil , de Meij Tim , Mosca Alexis , Vandenplas Yvan , Kahn Stacy A. , Kellermayer Richard ,   FMT Special Interest Group of the North American Society of Pediatric Gastroenterology Hepatology, Nutrition, the European Society for Pediatric Gastroenterology Hepatology, Nutrition
Published: December 2018

Fecal microbiota transplantation (FMT) is becoming part of the treatment algorithms against recurrent Clostridium difficile infection (rCDI) both in adult and pediatric gastroenterology practice. With our increasing recognition of the critical role the microbiome plays in human health and disease, FMT is also being considered as a potential therapy for other disorders, including inflammatory bowel disease (Crohn disease, ulcerative colitis), graft versus host disease, neuropsychiatric diseases, and metabolic syndrome. Controlled trials with FMT for rCDI have not been performed in children, and numerous clinical and regulatory considerations have to be considered when using this untraditional therapy. This report is intended to provide guidance for FMT in the treatment of rCDI in pediatric patients.
Association of Maternal Secretor Status and Human Milk Oligosaccharides With Milk Microbiota
Authors: Cabrera‐Rubio Raul , Kunz Clemens , Rudloff Silvia , García‐Mantrana Izaskun , Crehuá‐Gaudiza Elena , Martínez‐Costa Cecilia , Collado M. Carmen
Published: December 2018

Background and Objectives:

Breast milk contains several bioactive factors including human milk oligosaccharides (HMOs) and microbes that shape the infant gut microbiota. HMO profile is determined by secretor status; however, their influence on milk microbiota is still uncovered. This study is aimed to determine the impact of the FUT2 genotype on the milk microbiota during the first month of lactation and the association with HMO.

Methods:

Milk microbiota from 25 healthy lactating women was determined by quantitative polymerase chain reaction and 16S gene pyrosequencing. Secretor genotype was obtained by polymerase chain reaction‐random fragment length polymorphisms and by HMO identification and quantification.

Results:

The most abundant bacteria were Staphylococcus and Streptococcus, followed by Enterobacteriaceae‐related bacteria. The predominant HMO in secretor milk samples were 2'FL and lacto‐N‐fucopentaose I, whereas non‐secretor milk was characterized by lacto‐N‐fucopentaose II and lacto‐N‐difucohexaose II. Differences in microbiota composition and quantity were found depending on secretor/non‐secretor status. Lactobacillus spp, Enterococcus spp, and Streptococcus spp were lower in non‐secretor than in secretor samples. Bifidobacterium genus and species were less prevalent in non‐secretor samples. Despite no differences on diversity and richness, non‐secretor samples had lower Actinobacteria and higher relative abundance of Enterobacteriaceae, Lactobacillaceae, and Staphylococcaceae.

Conclusions:

Maternal secretor status is associated with the human milk microbiota composition and is maintained during the first 4 weeks. Specific associations between milk microbiota, HMO, and secretor status were observed, although the potential biological impact on the neonate remains elusive. Future studies are needed to reveal the early nutrition influence on the reduction of risk of disease.
Validation of Lipase and Systemic Inflammatory Response Syndrome as Prognostic Indicators in Pediatric Acute Pancreatitis
Authors: Nauka Peter C. , Weinstein Toba A. , Dolinger Michael T. , Miller Jonathan M. , Kohn Nina , Bitton Samuel , Rilo Horacio L. Rodriguez
Published: December 2018

Introduction:

Acute pancreatitis (AP) is understudied in the pediatric population despite increasing incidence. Although many cases are mild and resolve with supportive care, severe acute pancreatitis (SAP) can be associated with significant morbidity and mortality. There is a lack of pediatric‐specific predictive tools to help stratify risk of SAP in children.

Methods:

A retrospective cohort study of patients with AP or recurrent AP at Cohen Children's Medical Center between 2011 and 2016 was performed. Lipase level and the presence of pediatric systemic inflammatory response syndrome (SIRS) on admission were examined as potential predictors of SAP and length of stay (LOS). A multivariate logistic regression or analysis of covariance was used to conduct the multivariate analysis.

Results:

Seventy‐nine pediatric patients met inclusion criteria. Approximately 37% (29/79) had SIRS on admission, 22% (17/79) developed SAP, and there were no mortalities. In both the univariate and multivariate models, SIRS was a predictor of SAP. Mean (SD) LOS for patients with SIRS compared with without SIRS was 9.6 ± 8.3 compared with 6.3 ± 6.9 days (P < 0.05). The mean LOS of patients with one or more comorbidity (48%, 38/79) was 10.0 ± 9.5 compared with 5.2 ± 4.0 days (P < 0.01) for those patients without any comorbidities. Only the presence of comorbidities predicted length of time spent nil per os (NPO; P = 0.0022). Patients with comorbidities stayed an average of 5.6 ± 7.6 days NPO, whereas those without comorbidities spent 2.8 ± 2.4 days NPO. Lipase was not predictive of SAP, LOS, or length of time spent NPO.

Conclusions:

These results support the use of SIRS as a simple screening tool on admission to identify children at risk for the development of SAP. The presence of any comorbidity was predictive of LOS and length of NPO in the multivariate model. This may reflect that comorbidities prolong pancreatitis or influence disposition planning.
Clinical Management of Pediatric Achalasia
Authors: van Lennep Marinde , van Wijk Michiel P. , Omari Taher I.M. , Salvatore Silvia , Benninga Marc A. , Singendonk Maartje M.J. ,   European Society for Paediatric Gastroenterology, Hepatology and Nutrition Motility Working Group
Published: December 2018

Objectives:

Pediatric achalasia is a rare neurodegenerative disorder of the esophagus that requires treatment. Different diagnostic and treatment modalities are available, but there are no data that show how children can best be diagnosed and treated. We aimed to identify current practices regarding the diagnostic and therapeutic approach toward children with achalasia.

Methods:

Information on the current practice regarding the management of pediatric achalasia was collected by an online‐based survey sent to members of the European and North American Societies for Pediatric Gastroenterology Hepatology and Nutrition involved in pediatric achalasia care.

Results:

The survey was completed by 38 centers from 24 countries. Within these centers, 108 children were diagnosed with achalasia in the last year (median 2, range 0–15). Achalasia was primarily managed by a pediatric gastroenterologist (76%) and involved a multidisciplinary team in 84% of centers, also including a surgeon (87%), radiologist (61%), dietician (37%), speech pathologist (8%), and psychologist (5%). Medical history taking and physical examination were considered most important to establish the diagnosis (50%), followed by (a combination of) manometry (45%) or contrast swallow (21%). Treatment of first choice was Heller myotomy (58%), followed by pneumatic dilation (46%) and peroral endoscopic myotomy (29%).

Conclusion:

This study shows a great heterogeneity in the management of pediatric achalasia amongst different centers worldwide. These findings stress the need for well‐designed intervention trials in children with achalasia. Given the rarity of this disease, we recommend that achalasia care should be managed in centers with access to appropriate diagnostic and treatment modalities.
Esophageal IgG4
Authors: Pope Amanda E. , Stanzione Nicholas , Naini Bita V. , Garcia‐Lloret Maria , Ghassemi Kevin A. , Marcus Elizabeth A. , Martin Martin G. , Wozniak Laura J.
Published: December 2018

Objective:

Recent studies show increased serum and esophageal IgG4 in patients with eosinophilic esophagitis (EoE), suggesting a possible IgG4‐involved process. The role of IgG4 in pediatric EoE has not been extensively investigated. Our aim was to analyze IgG4 in esophageal tissue in children in parallel to that in adults with EoE.

Methods:

In a retrospective institutional review board–approved study, we performed immunohistochemical staining of IgG4 in esophageal biopsy specimens from 39 subjects: children with EoE (n = 16), adults with EoE (n = 15), children with reflux esophagitis (n = 4), and pediatric controls (n = 4). We assessed the relationships between IgG4 staining and clinical, endoscopic, and histopathologic characteristics.

Results:

Patients with EoE were significantly more likely to stain positively for IgG4 than children with reflux esophagitis or controls (P = 0.015). Fifteen of 31 (48%) EoE cases stained positively for IgG4. None of the reflux esophagitis or control cases stained positively. IgG4 staining had 48% sensitivity and 100% specificity for EoE. There was a trend toward IgG4 staining being associated with foreign body/food impaction (P = 0.153). There was a strong association between distal IgG4 staining and basal zone hyperplasia (P = 0.003).

Conclusions:

Our study suggests IgG4 is not a consistent finding of EoE at disease diagnosis. Although IgG4 staining was specific for EoE, it had a poor sensitivity with positive staining in only 48% of EoE patients. Further studies are warranted to fully elucidate the role of IgG4 in EoE.
Miniplates Versus Reconstruction Plates in Vascularized Osteocutaneous Flap Reconstruction of the Mandible
Authors: Zhang Ze-Liang , Wang Shuai , Sun Chang-Fu , Xu Zhong-Fei
Published: December 2018

Purpose:

The main aim of this article is to compare the complication rate associated with the use of miniplates versus reconstruction plates in vascularized osteocutaneous flap reconstruction of the mandible.

Patients and Methods:

The authors searched PubMed, Web of Science, EMBASE, Chinese BioMedical Literature Database (CBM), Cochrane Library, and clinicaltrials.gov up to September 2017 to identify studies that compared the complication rate of miniplates versus reconstruction plates in patients undergoing mandibular reconstruction. Two reviewers individually extracted the data and performed a quality assessment. Plate exposure, plate fracture/removal, infection, and overall complications were evaluated.

Results:

Five studies with 511 cases were included in our analysis. No significant difference was found between the groups. However, the reconstruction plate led to fewer overall complications and plate exposure postoperatively than did the miniplate.

Conclusion:

Our meta-analysis suggests that miniplates and reconstruction plates are suitable for mandibular reconstruction with a vascularized osteocutaneous flap.
Bimaxillary Orthognathic Surgery Is Associated With an Increased Risk of Early Complications
Authors: Kantar Rami S. , Cammarata Michael J. , Rifkin William J. , Alfonso Allyson R. , DeMitchell-Rodriguez Evellyn M. , Noel Daphney Y. , Greenfield Jason A. , Levy-Lambert Dina , Rodriguez Eduardo D.
Published: December 2018

Introduction:

Orthognathic surgery plays an important role in restoring aesthetic facial contour, correcting dental malocclusion, and the surgical treatment of obstructive sleep apnea. However, the rate of complications following bimaxillary as compared with single-jaw orthognathic surgery remains unclear. The authors therefore sought to evaluate complication rates following bimaxillary as compared with single-jaw orthognathic surgery

Materials and Methods:

The American College of Surgeons National Surgical Quality Improvement Program database was used to identify comparison groups. Preoperative characteristics and postoperative outcomes were compared between groups. The listed procedures have different operating times and characteristics with longer time expected in the bimaxillary osteotomies group. Regression analyses were performed to control for potential confounders.

Results:

The 3 groups of interest included patients who underwent mandibular osteotomies (n = 126), LeFort I osteotomy (n = 194), and bimaxillary osteotomies (n = 190). These procedures have different operating times, with a longer time expected with bimaxillary osteotomies. Patients undergoing bimaxillary osteotomies had significantly higher rates of early wound complications, overall complications, longer mean operative time, and mean hospital length of stay. Performing bimaxillary osteotomies in the outpatient setting was an independent risk factor for wound complications (OR = 12.58; 95% CI: 1.66–95.20; P = 0.01), while an ASA class of 3 or more was an independent risk factor for overall complications (OR = 3.61; 95% CI: 1.02–12.75; P = 0.04) and longer hospital length of stay (β = 4.96; 95% CI: 2.64 – 7.29; P < 0.001).

Conclusions:

Surgery in the outpatient setting as well as patient American Society of Anesthesiology physical status class 3 or higher were independent factors for postoperative adverse events in patients undergoing bimaxillary surgery. Our findings highlight the importance of addressing modifiable risk factors preoperatively and the need for closer postoperative monitoring in this patient population for optimal outcomes.
Application of Three-Dimensional Printing Technology for Improved Orbital-Maxillary-Zygomatic Reconstruction
Authors: Xue Runqi , Lai Qingguo , Sun Shaolong , Lai Lei , Tang Xiaopeng , Ci Jiangbo , Zhang Zhichao , Wang Yang
Published: December 2018

The reconstruction of orbital-maxillary-zygomatic complex (OMZC) on patients suffering from trauma and space-occupying lesions is challenging due to the irregularity of craniomaxillofacial bones. To overcome the challenge in precise OMZC reconstruction, individual three-dimensional (3D) disease models and mirror-imaged 3D reconstruction models were printed on the basis of the computer tomography. Preoperative planning by rehearsing surgical procedures was made on the 3D disease models and the scaffolds including titanium and absorbable meshes or plates were anatomically premolded using the mirror-imaged 3D models as guide. Many benefits were achieved including more precise OMZC reconstruction, fluent and smooth procedures of surgeries, shorter operation time, less blood loss, and improved cosmetic outcomes of craniomaxillofacial shapes. There were no complications such as diplopia, infection, foreign body reaction, exophthalmos, enophthalmos, disordered occlusal relationship, and hematoma. And patients were satisfied with the functional and esthetic outcome during the following-up time. Therefore, OMZC reconstruction can be optimized and successful through preoperative planning and premolded scaffolds with 3D printing bone model by computer-aid design and manufacturing.
Standardization of Cranial Index Measurement in Sagittal Craniosynostosis
Authors: Al-Shaqsi Sultan Z. , Rai Ahsan , Forrest Christopher , Phillips John
Published: December 2018

Cranial index is a widely used 2-dimensional measure of skull form. It has traditionally been calculated as a ratio of the maximal cranial width divided by the maximal skull length. Nevertheless, the points of maximal skull length change dramatically in sagittal craniosynostosis due to variable degrees of frontal and occipital bossing. Therefore, such anatomical changes influence the calculated cranial index.

Method:

This is a retrospective comparative study of 2 methods of measuring cranial index; the traditional method that measures the skull length from glabella to opithcranion versus a modified method that measures the maximal skull length from the most anterior point of the frontal bossing to opithcranion. Cranial indices for 115 patients of radiologically and clinically diagnosed nonsyndromic sagittal craniosynostosis were calculated using both methods. Correlation and Agreements Limits were calculated for comparison between the 2 methods.

Results:

Males constituted 74.8% (n = 86) of the total sample size with the remaining 29 participants identified as female. The mean age of the study participants was 4.8 months (range 8 days–12 months). The 2 methods were strongly correlated (r = 0.94). The Agreement Limits were calculated to be between 4.02% and 0.18%.

Conclusion:

Typical anatomical changes such as variable degrees of frontal and occipital bossing influence the accuracy of cranial index measurement in sagittal craniosynostosis. Traditional method of cephalic index measurement could underestimate the severity of scaphocephaly.
The importance of neutral over niche processes in structuring Ediacaran early animal communities
Authors: Mitchell Emily G. , Harris Simon , Kenchington Charlotte G. , Vixseboxse Philip , Roberts Lucy , Clark Catherine , Dennis Alexandra , Liu Alexander G. , Wilby Philip R.
Published: December 2018

The relative influence of niche versus neutral processes in ecosystem dynamics is a fundamental question in community ecology, but the extent to which they structured early animal communities is unknown. The oldest known metazoan-dominated paleocommunities occur in Ediacaran age (~565 million years old) strata in Newfoundland, Canada and Charnwood Forest, UK. These comprise large and diverse in-situ populations of sessile organisms that are amenable to spatial point process analyses, enabling inference of the most likely underlying niche or neutral processes governing their community structure. We conducted comprehensive spatial mapping of seven of the largest Ediacaran paleocommunities using LiDAR, photogrammetry and a laser-line probe. We find neutral processes to dominate these paleocommunities with limited influence of niche processes. Our results differ from the niche-dominated dynamics of modern marine ecosystems, revealing that the dynamics of environmental interactions prompted very different ecosystem structuring for these early animal communities.
Cell-to-cell variation in defective virus expression and effects on host responses during influenza virus infection
Authors: Wang Chang , Forst Christian V. , Chou Tsui-wen , Geber Adam , Wang Minghui , Hamou Wissam , Smith Melissa , Sebra Robert , Zhang Bin , Zhou Bin , Ghedin Elodie
Published: December 2018

Virus and host factors contribute to cell-to-cell variation in viral infections and determine the outcome of the overall infection. However, the extent of the variability at the single cell level and how it impacts virus-host interactions at a systems level are not well understood. To characterize the dynamics of viral transcription and host responses, we used single-cell RNA sequencing to quantify at multiple time points the host and viral transcriptomes of human A549 cells and primary bronchial epithelial cells infected with influenza A virus. We observed substantial variability of viral transcription between cells, including the accumulation of defective viral genomes (DVGs) that impact viral replication. We show a correlation between DVGs and viral-induced variation of the host transcriptional program and an association between differential induction of innate immune response genes and attenuated viral transcription in subpopulations of cells. These observations at the single cell level improve our understanding of the complex virus-host interplay during influenza infection.

IMPORTANCE

Defective influenza virus particles generated during viral replication carry incomplete viral genomes and can interfere with the replication of competent viruses. These defective genomes are thought to modulate disease severity and pathogenicity of the influenza infection. Different defective viral genomes also introduce another source of variation across a heterogeneous cell population. Evaluating the impact of defective virus genomes on host cell responses cannot be fully resolved at the population level, requiring single cell transcriptional profiling. Here we characterized virus and host transcriptomes in individual influenza-infected cells, including that of defective viruses that arise during influenza A virus infection. We established an association between defective virus transcription and host responses and validated interfering and immunostimulatory functions of identified dominant defective virus genome speciesin vitro. This study demonstrates the intricate effects of defective viral genomes on host transcriptional responses and highlights the importance of capturing host-virus interactions at the single-cell level.
Improved yield of AAV2 and rAAV2-retro serotypes following sugar supplementation during the viral production phase
Authors: Rego Meghan , Hanley Luke Makana , Ersing Ina , Guerin Karen , Tasissa Meron , Haery Leila , Mueller Isabelle , Sanders Erin , Fan Melina
Published: December 2018

Hyperosmolarity has been used as a means to improve yields in various processes such as antibody production in hybridoma cells and retroviral and adenoviral production systems. In this study we demonstrate that treatment of AAVpro 293T packaging cells with the sugars sucrose or sorbitol during adeno-associated virus (AAV) production improves the yields of AAV2 and rAAV2-retro serotypes 1.8-fold and 1.5-fold, respectively. Using an iodixanol gradient centrifugation strategy followed by a column-based buffer exchange, we show that the sugar supplements are not carried over to the final viral preparation and have no effect on the purity or infectivity of the virus. Given the wide availability, low cost, and ease of use of these sugars, we believe that this strategy can be easily adopted by vector cores and laboratories to improve yields of their AAV preparations.
Rapid screening of engineered microbial therapies in a 3-D multicellular model
Authors: Harimoto Tetsuhiro , Singer Zakary S. , Velazquez Oscar S. , Zhang Joanna , Castro Samuel , Hinchliffe Taylor E. , Mather William , Danino Tal
Published: December 2018

Synthetic biology is transforming therapeutic paradigms by engineering living cells and microbes to intelligently sense and respond to diseases including inflammation1,2, infections3-5, metabolic disorders6,7, and cancer8,9. However, the ability to rapidly engineer new therapies far outpaces the throughput of animal-based testing regimes, creating a major bottleneck for clinical translation10,11. In vitro approaches to address this challenge have been limited in scalability and broad-applicability. Here, we present a bacteria-in-spheroid co-culture (BSCC) platform that simultaneously tests host species, therapeutic payloads and synthetic gene circuits of engineered bacteria within multicellular spheroids over a timescale of weeks. Long-term monitoring of bacterial dynamics and disease progression enables quantitative comparison of critical therapeutic parameters such as efficacy and biocontainment. Specifically, we screen S. typhimurium strains expressing and delivering a library of antitumor therapeutic molecules via several synthetic gene circuits. We identify novel candidates exhibiting significant tumor reduction and demonstrate high similarity in their efficacies using a syngeneic mouse model. Lastly, we show that our platform can be expanded to dynamically profile diverse microbial species including L. monocytogenes, P. mirabilis, and E. coli in various host cell types. This high-throughput framework may serve to accelerate synthetic biology for clinical applications and understanding the host-microbe interactions in disease sites.
A generic multi-level stochastic modelling framework in computational epidemiology
Authors: Picault Sébastien , Huang Yu-Lin , Sicard Vianney , Hoch Thierry , Vergu Elisabeta , Beaudeau François , Ezanno Pauline
Published: December 2018

There is currently an overwhelming increased interest in predictive biology and computational modelling. The development of reliable, reproducible and revisable simulation models in computational life sciences is often pointed out as a challenging issue. Population dynamics, including epidemiology, has not yet developed a language to formalize complex models in a univocal and automatable way, hence hindering the capability to implement in short time reliable, revisable and expert-friendly models intended for realistic mechanistic simulations. In epidemiology specifically, models aim not only at understanding pathogen spread but also at assessing control measures at several scales. To achieve this goal efficiently, best software practices should be supported by Artificial Intelligence methods to handle experts’ knowledge. The framework EMULSION presented here intends to both tackle multiple modelling paradigms in epidemiology and facilitate the automation of model design. We therefore built both a domain-specific language (DSL) for the modular description of complex epidemiological models, and a generic simulation engine designed to embed existing modelling paradigms within a homogeneous architecture based on adaptive software agents. The diversity of concerns (biology, economics, human activities) involved in real pathosystems requires an explicit, comprehensive and intelligible way to describe epidemiological models, to involve experts without computer science skills throughout the modelling, simulation and output analysis steps. This approach was applied to compare hypotheses in modelling a zoonosis (Q fever), to study its transmission dynamics within and between cattle herds at a regional scale, and to assess the contribution of transmission pathways. Separating model description from the simulation engine allowed epidemiologists to be involved in assumption revision, while guaranteeing very few code modifications. We assessed the added value of EMULSION by applying the DSL and the simulation engine to a concrete disease. Future extensions of EMULSION towards a broader range of epidemiological concerns will reduce significantly the time required to design and assess models and control measures against endemic and epidemic diseases. Ultimately, we believe this effort is a major lever to increase scientists’ preparedness to face emerging threats for public health and provide rapid, reliable, and reasoned assessments of control measures.
In vivo epigenetic editing of sema6a promoter reverses impaired transcallosal connectivity caused by C11orf46/ARL14EP neurodevelopmental risk gene
Authors: Peter Cyril J. , Saito Atsushi , Hasegawa Yuto , Tanaka Yuya , Perez Gabriel , Alway Emily , Espeso-gil Sergio , Fayyad Tariq , Ratner Chana , Dincer Aslihan , Gupta Achla , Devi Lakshmi , Pappas John G. , Lalonde François M. , Butman John A. , Han Joan C. , Akbarian Schahram , Kamiya Atsushi
Published: December 2018

Many neuropsychiatric risk genes contribute to epigenetic regulation of gene expression but very little is known about specific chromatin-associated mechanisms governing the formation and maintenance of neuronal connectivity. Here we show that transcallosal connectivity is critically dependent on C11orf46 (also known as ARL14EP), a small nuclear protein encoded in the chromosome 11p13 Wilms Tumor, Aniridia, Genitourinary Abnormalities, intellectual disability (formerly referred to as Mental Retardation) (WAGR) risk locus. C11orf46 haploinsufficiency in WAGR microdeletion cases was associated with severe hypoplasia of the corpus callosum. In utero short hairpin RNA-mediated C11orf46 knockdown disrupted transcallosal projections of cortical pyramidal neurons, a phenotype that was rescued by wild type C11orf46 but not the C11orf46R236H mutant associated with autosomal recessive intellectual disability. Multiple genes encoding key regulators of axonal growth and differentiation, including Sema6A, were hyperexpressed in C11orf46-knockdown neurons. Importantly, RNA-guided epigenetic editing of neuronal Sema6a gene promoters via a dCas9 protein-conjugated SunTag scaffold with multimeric (10x) C11orf46 binding during early developmental periods, resulted in normalization of expression and rescue of transcallosal dysconnectivity via repressive chromatin remodeling, including up-regulated histone H3K9 methylation by the KAP1-SETDB1 repressor complex. Our study demonstrates that interhemispheric communication is highly sensitive to locus-specific remodeling of neuronal chromatin, revealing the therapeutic potential for shaping the brain’s connectome via gene-targeted designer activators and repressor proteins.
Stability of spontaneous, correlated activity in mouse auditory cortex
Authors: Betzel Richard , Wood Katherine C , Angeloni Christopher , Neimark Geffen Maria , Bassett Danielle S
Published: December 2018

Neural systems can be modeled as complex networks in which neural elements are represented as nodes linked to one another through structural or functional connections. The resulting network can be analyzed using mathematical tools from network science and graph theory to quantify the system's topological organization and to better understand its function. While the network-based approach has become common in the analysis of large-scale neural systems probed by non-invasive neuroimaging, few studies have used network science to study the organization of biological neuronal networks reconstructed at the cellular level, and thus many very basic and fundamental questions remain unanswered. Here, we used two-photon calcium imaging to record spontaneous activity from the same set of cells in mouse auditory cortex over the course of several weeks. We reconstruct functional networks in which cells are linked to one another by edges weighted according to the maximum lagged correlation of their fluorescence traces. We show that the networks exhibit modular structure across multiple topological scales and that these multi-scale modules unfold as part of a hierarchy. We also show that, on average, network architecture becomes increasingly dissimilar over time, with similarity decaying monotonically with the distance (in time) between sessions. Finally, we show that a small fraction of cells maintain strongly-correlated activity over multiple days, forming a stable temporal core surrounded by a fluctuating and variable periphery. Our work provides a careful methodological blueprint for future studies of spontaneous activity measured by two-photon calcium imaging using cutting-edge computational methods and machine learning algorithms informed by explicit graphical models from network science. The methods are flexible and easily extended to additional datasets, opening the possibility of studying cellular level network organization of neural systems and how that organization is modulated by stimuli or altered in models of disease.
Long-range sensitization in the vertebrate retina and human perception
Authors: Naecker Benjamin , Baccus Stephen A
Published: December 2018

Sensory stimuli have extensive correlations, which should be exploited by an efficient detector of specific sensory features according to theoretical principles. Here we show that visual stimulation far outside the classical receptive field center causes ganglion cells to subsequently increase their sensitivity to local stimuli in a process we term long-range sensitization. This increased sensitivity improves detection and discrimination of weak stimuli and exhibits pattern specificity, increasing sensitivity more when peripheral and central stimuli share spatial frequency statistics. This process requires input from wide-field, nonlinear inhibitory amacrine cells, supporting a simple circuit model that reproduces sensitization. We further show that long-range sensitization parallels a novel perceptual effect in humans, in which surround stimulation subsequently improves discrimination of a small central stimulus. We conclude that the retina uses long-range statistics of the visual world to better encode local visual features, and that such improved encoding may play a role in perception.
Regulation of Exocytosis and Mitochondrial Relocalization by Alpha-Synuclein in a Mammalian Cell Model
Authors: Ramezani Meraj , Wilkes Marcus M. , Das Tapojyoti , Holowka David , Eliezer David , Baird Barbara
Published: December 2018

We characterized phenotypes in RBL-2H3 mast cells transfected with human alpha synuclein (a-syn) using stimulated exocytosis of recycling endosomes as a proxy for similar activities of synaptic vesicles in neurons. We found that low expression of a-syn inhibits stimulated exocytosis and that higher expression causes slight enhancement. NMR measurements of membrane interactions correlate with these functional effects: they are eliminated differentially by mutants that perturb helical structure in the helix 1 (A30P) or NAC/helix-2 (V70P) regions of membrane-bound a-syn, but not by other PD-associated mutants or C-terminal truncation. We further found that a-syn (but not A30P or V70P mutants) associates weakly with mitochondria, but this association increases markedly under conditions of cellular stress. These results highlight the importance of specific structural features of a-syn in regulating vesicle release, and point to a potential role for a-syn in perturbing mitochondrial function under pathological conditions.
A connectional hub in the rostral anterior cingulate cortex links areas of emotion and cognitive control
Authors: Tang Wei , Jbabdi Saad , Cottaar Michiel , Zhu Ziyi , Grisot Giorgia , Yendiki Anastasia , Haber Suzanne N
Published: December 2018

We investigated afferent inputs from all areas in the frontal cortex (FC) to different subregions in the rostral anterior cingulate cortex (rACC). Using retrograde tracing in macaque monkeys, we quantified projection strength by counting retrogradely labeled cells in each FC area. The projection from different FC regions varied across injection sites in strength, following different spatial patterns. Importantly, a site at the rostral end of the cingulate sulcus stood out as having strong inputs from many areas in diverse FC regions. Moreover, it was at the integrative conjunction of three projection trends across sites. This site marks a connectional hub inside the rACC that integrates FC inputs across functional modalities. Tractography with monkey diffusion magnetic resonance imaging (dMRI) located a similar hub region comparable to the tracing result. Applying the same tractography method to human dMRI data, we demonstrated that a similar hub can be located in the human rACC.
Wd*-test: Robust Distance-Based Multivariate Analysis of Variance
Authors: Hamidi Bashir , Wallace Kristin , Vasu Chenthamarakshan , Alekseyenko Alexander V.
Published: December 2018

Background

Community-wide analyses provide an essential means for evaluation of the effect of interventions or design variables on the composition of the microbiome. Applications of these analyses are omnipresent in microbiome literature, yet some of their statistical properties have not been tested for robustness towards common features of microbiome data. Recently, it has been reported that PERMANOVA can yield wrong results in the presence of heteroscedasticity and unbalanced sample sizes.

Findings

We develop a method for multivariate analysis of variance, , based on Welch MANOVA that is robust to heteroscedasticity in the data. We do so by extending a previously reported method that does the same for two-level independent factor variables. Our approach can accommodate multi-level factors, stratification, and multiple post hoc testing scenarios. An R language implementation of the method is available at https://github.com/alekseyenko/WdStar.

Conclusion

Our method resolves potential for confounding of location and dispersion effects in multivariate analyses by explicitly accounting for the differences in multivariate dispersion in the data tested. The methods based on have general applicability in microbiome and other ‘omics data analyses.
Niche adaptation limits bacteriophage predation of Vibrio cholerae in a nutrient-poor aquatic environment
Authors: Silva-Valenzuela Cecilia A. , Camilli Andrew
Published: December 2018

Vibrio cholerae, the causative agent of cholera, has reservoirs in fresh and brackish water where it interacts with virulent bacteriophages. Phages are the most abundant biological entity on earth and co-evolve with bacteria. It was reported that concentrations of phage and V. cholerae inversely correlate in aquatic reservoirs and in the human small intestine, and therefore that phages may quench cholera outbreaks. Although there is strong evidence for phage predation in cholera patients, evidence is lacking for phage predation of V. cholerae in aquatic environments. Here, we used three virulent phages, ICP1, ICP2, and ICP3, commonly shed by cholera patients in Bangladesh, as models to understand the predation dynamics in microcosms simulating aquatic environments. None of the phages were capable of predation in fresh water, and only ICP1 was able to prey on V. cholerae in estuarine water due to a requirement for salt. We conclude that ICP2 and ICP3 are better adapted for predation in a nutrient rich environment. Our results point to the evolution of niche-specific predation by V. cholerae-specific virulent phages, which complicates their use in predicting or monitoring cholera outbreaks as well as their potential use in reducing aquatic reservoirs of V. cholerae in endemic areas.

Significance statement

Virulent phages can reduce populations of bacteria and help shape bacterial evolution. Here, we used three virulent phages to understand their equilibrium with V. cholerae in nutrient-limiting aquatic microcosms. It has been proposed that phages quench cholera outbreaks, but no direct evidence of phage predation in aquatic environments had been established. Here we show that different phages possess varied abilities to infect in certain niches or stages of the host bacterial life cycle. Unveiling the phage/bacterial interactions in their natural setting is important to the understanding of cholera outbreaks and could be ultimately used to help develop a method for outbreak prediction and/or control.
Agonist binding affinity determines palmitoylation of the glucagon-like peptide-1 receptor and its functional interaction with plasma membrane nanodomains in pancreatic beta cells
Authors: Buenaventura Teresa , Laughlin William E , Bitsi Stavroula , Burgoyne Thomas , Lyu Zekun , Oqua Affiong I , Norman Hannah , McGlone Emma R , Klymchenko Andrey S , Corrêa Ivan R , Walker Abigail , Inoue Asuka , Hanyaloglou Aylin , Rutter Guy A , Bloom Stephen R , Jones Ben , Tomas Alejandra
Published: December 2018

The glucagon-like peptide-1 receptor (GLP-1R), a key pharmacological target in type 2 diabetes and obesity, is known to undergo palmitoylation by covalent ligation of an acyl chain to cysteine 438 in its carboxyl-terminal tail. Work with other GPCRs indicates that palmitoylation can be dynamically regulated to allow receptors to partition into plasma membrane nanodomains that act as signaling hotspots. Here, we demonstrate that the palmitoylated state of the GLP-1R is increased by agonist binding, leading to its segregation and clustering into plasma membrane signaling nanodomains before undergoing internalization in a clathrin-dependent manner. Both GLP-1R signaling and trafficking are modulated by strategies targeting nanodomain segregation and cluster formation, including depletion of cholesterol or expression of a palmitoylation-defective GLP-1R mutant. Differences in receptor binding affinity exhibited by biased GLP-1R agonists, and modulation of binding kinetics with the positive allosteric modulator BETP, influence GLP-1R palmitoylation, clustering, nanodomain signaling, and internalization. Downstream effects on insulin secretion from pancreatic beta cells indicate that these processes are relevant to GLP-1R physiological actions and might be therapeutically targetable.
Polysaccharide A-dependent opposing effects of mucosal and systemic exposures to human gut commensalBacteroides fragilisin type 1 diabetes
Authors: Sofi M. Hanief. , Johnson Benjamin M. , Gudi Radhika R. , Jolly Amy , Gaudreau Marie-Claude , Vasu Chenthamarakshan
Published: December 2018

Bacteroides fragilis(BF) is an integral component of the human colonic commensal microbiota. BF is also the most commonly isolated organism from clinical cases of intra-abdominal abscesses suggesting its potential to induce pro-inflammatory responses, upon accessing the systemic compartment. Hence, we examined the impact of mucosal and systemic exposures to BF on type 1 diabetes (T1D) incidence in non-obese diabetic (NOD) mice. The impact of intestinal exposure to BF under chemically-induced enhanced gut permeability condition, which permits microbial translocation, in T1D was also examined. While oral administration of pre-diabetic mice with heat-killed (HK) BF caused enhanced immune regulation and suppression of autoimmunity resulting in delayed hyperglycemia, mice that received HK BF by i.v. injection showed rapid disease progression. Importantly, polysaccharide-A deficient (ΔPSA) BF failed to produce these opposing effects upon oral and systemic deliveries. Further, BF induced modulation of disease progression was observed in WT, but not TLR2-deficient, NOD mice. Interestingly, oral administration of BF under enhanced gut permeability condition resulted in accelerated disease progression and rapid onset of hyperglycemia in NOD mice. Overall, these observations suggest that BF-like gut commensals can cause pro-inflammatory responses upon gaining access to systemic compartment and contribute to T1D in at-risk subjects.
Structure of a cytochrome-based bacterial nanowire
Authors: Filman David J. , Marino Stephen F. , Ward Joy E. , Yang Lu , Mester Zoltán , Bullitt Esther , Lovley Derek R. , Strauss Mike
Published: December 2018

Electrically conductive pili from Geobacter species, termed bacterial “nanowires”, are intensely studied for their biological significance and potential in the development of new materials. We have characterized a unique nanowire from conductive G. sulfurreducens pili preparations by cryo-electron microscopy composed solely of the c-type cytochrome OmcS. We present here, at 3.4 Å resolution, a novel structure of a cytochrome-based filament and discuss its possible role in long-range biological electron transport.

Summary sentence

Cryo-electron microscopy reveals the remarkable assembly of a c-type cytochrome into filaments comprising a heme-based bacterial nanowire.
Quantification of microenvironmental metabolites in murine cancer models reveals determinants of tumor nutrient availability
Authors: Sullivan Mark R. , Danai Laura V. , Lewis Caroline A. , Chan Sze Ham , Gui Dan Y. , Kunchok Tenzin , Dennstedt Emily A. , Vander Heiden Matthew G. , Muir Alexander
Published: December 2018

Cancer cell metabolism is heavily influenced by microenvironmental factors, including nutrient availability. Therefore, knowledge of microenvironmental nutrient levels is essential to understand tumor metabolism. To measure the extracellular nutrient levels available to tumors, we developed a quantitative metabolomics method to measure the absolute concentrations of >118 metabolites in plasma and tumor interstitial fluid, the extracellular fluid that perfuses tumors. Comparison of nutrient levels in tumor interstitial fluid and plasma revealed that the nutrients available to tumors differ from those present in circulation. Further, by comparing interstitial fluid nutrient levels between autochthonous and transplant models of murine pancreatic and lung adenocarcinoma, we found that tumor type, anatomical location and animal diet affect local nutrient availability. These data provide a comprehensive characterization of the nutrients present in the tumor microenvironment of widely used models of lung and pancreatic cancer and identify factors that influence metabolite levels in tumors.

Impact Statement

Nutrient availability is an important tumor microenvironmental factor that impacts cancer cell biology; we developed methods to measure nutrients available to tumor cells and characterized factors that influence tumor nutrient availability.
Joint Estimation of Pedigrees and Effective Population Size Using Markov Chain Monte Carlo
Authors: Ko Amy , Nielsen Rasmus
Published: December 2018

Pedigrees provide a fine resolution of the genealogical relationships among individuals and serve an important function in many areas of genetic studies. One such use of pedigree information is in the estimation of short-term effective population size (Ne), which is of great relevance in fields such as conservation genetics. Despite the usefulness of pedigrees, however, they are often an unknown parameter and must be inferred from genetic data. In this study, we present a Bayesian method to jointly estimate pedigrees and Ne from genetic markers using Markov Chain Monte Carlo. Our method supports analysis of a large number of markers and individuals with the use of composite likelihood, which significantly increases computational efficiency. We show on simulated data that our method is able to jointly estimate relationships up to first cousins and Ne with high accuracy. We also apply the method on a real dataset of house sparrows to reconstruct their previously unreported pedigree.