bluuebunny/crossref_metadata_2025 huggingface dataset:
Postoperative Complications of Panniculectomy and Abdominoplasty
Authors: Lesko Robert P. , Cheah Michael A. , Sarmiento Samuel , Cooney Carisa M. , Cooney Damon S.
Published: January 2020

Background

Recent studies of panniculectomy outcomes have reported variable complication rates ranging from 8.65% to 56%. Meanwhile, reported abdominoplasty complication rates are considerably lower (~4%). This discrepancy may be attributable to inaccurate inclusion of abdominoplasty patients in panniculectomy cohorts. We performed the current study to better characterize panniculectomy complication rates at a large tertiary care center.

Methods

We performed a retrospective review of patients who underwent abdominoplasty or panniculectomy at the Johns Hopkins Hospitals between 2010 and 2017. Patients were identified by Common Procedural Terminology codes (15847/17999, 15830) confirmed via the operative note. We examined postoperative complication rates including surgical site infection, seroma formation, wound dehiscence, readmission/reoperation, and postoperative length of stay (LOS). We used parametric and nonparametric methods to determine differences between abdominoplasty and panniculectomy outcomes, as well as logistic regression analysis to evaluate factors associated with patient outcomes following panniculectomy.

Results

Of the 306 patients included, 103 underwent abdominoplasty while 203 underwent panniculectomy. Initial complication rates following abdominoplasty and panniculectomy were 1.94% and 12.8%, respectively (P = 0.002). Thirty-day complication rates were 9.7% for abdominoplasty and 21.2% for panniculectomy (P = 0.012). The median LOS was 1 day (interquartile range, 0–1 day) for abdominoplasty and 2 days (interquartile range, 1–4 days) for panniculectomy (P = 0.002). No statistically significant differences in complication rates at 6 months and 1 year were observed.

Conclusions

Panniculectomy offers many functional benefits including improved hygiene and enhanced mobility. However, this study demonstrates that panniculectomy patients may have significantly higher complication rates initially and 30 days postoperatively and longer LOS than individuals undergoing abdominoplasty.
The impact of frailty on posttraumatic outcomes in older trauma patients: A systematic review and meta-analysis
Authors: Zhao Fangjie , Tang Bihan , Hu Chaoqun , Wang Bo , Wang Yincheng , Zhang Lulu
Published: January 2020

BACKGROUND

Frailty is a risk factor for mortality among the elderly. However, evidence from longitudinal studies linking trauma and frailty is fragmented, and a comprehensive analysis of the relationship between frailty and adverse outcomes is lacking. Therefore, we conducted a systematic review and meta-analysis to examine whether frailty is predictive of posttraumatic results including mortality, adverse discharge, complications, and readmission in trauma patients.

METHODS

This systematic review was registered with the PROSPERO international prospective register of systematic reviews. Articles in PubMed, Embase, and Web of Science databases from January 1, 1990, to October 31, 2019, were systematically searched. Articles in McDonald et al.'s study (J Trauma Acute Care Surg. 2016;80(5):824-834) and Cubitt et al.'s study (Injury 2019;50(11):1795-1808) were included for studies evaluating the association between frailty and outcomes in trauma patients. Cohort studies, both retrospective and prospective, were included. Study population was patients suffering trauma injuries with an average age of 50 years and older. Multivariate adjusted odds ratios (ORs) were calculated through a random-effects model, and the Newcastle-Ottawa Quality Assessment Scale was used to assess studies.

RESULTS

We retrieved 11,313 entries. Thirteen studies including seven prospective and six retrospective cohort studies involving 50,348 patients were included in the meta-analysis. Frailty was a significant predictor of greater than 30-day mortality (OR, 2.41; 95% confidence interval [CI], 1.17–4.95; I
2 = 88.1%), in-hospital and 30-day mortality (OR, 4.05; 95% CI, 2.02–8.11; I
2 = 0%), postoperative complications (OR, 2.23; 95% CI, 1.34–3.73; I
2 = 78.2%), Clavien-Dindo IV complications (OR, 4.16; 95% CI, 1.70–10.17; I
2 = 0%), adverse discharge (OR, 1.80; 95% CI, 1.15–2.84; I
2 = 78.6%), and readmission (OR, 2.16; 95% CI, 1.19–3.91; I
2 = 21.5%) in elderly trauma patients. Subgroup analysis showed that prospective studies (OR, 3.06; 95% CI, 1.43–6.56) demonstrated a greater correlation between frailty and postoperative complications.

CONCLUSION

Frailty has significant adverse impacts on the occurrence of posttraumatic outcomes. Further studies should focus on interventions for patients with frailty. Given the number of vulnerable elderly trauma patients grows, further studies are needed to determine the accuracy of these measures in terms of trauma outcomes.

LEVEL OF EVIDENCE

Systematic review and meta-analysis, level IV.
Does computed tomography scan add any diagnostic value to the evaluation of stab wounds of the anterior abdominal wall? A systematic review and meta-analysis
Authors: Gachabayov Mahir , Gogna Shekhar , Samson David , Latifi Rifat
Published: January 2020

BACKGROUND

The aim of this systematic review and meta-analysis was to evaluate whether computed tomography (CT) scan adds any diagnostic value in the evaluation of stab wounds of the anterior abdominal wall as compared with serial clinical examination (SCE).

METHODS

PubMed, EMBASE, Cochrane Library, and MEDLINE via Ovid were systematically searched for records published from 1980 to 2018 by two independent researchers (M.G., R.L.). Quality assessment, data extraction, and analysis were performed according to the Cochrane Handbook for Systematic Reviews of Interventions. Mantel-Haenszel method with odds ratio (OR) and 95% confidence interval (95% CI) as the measure of effect size was used for meta-analysis.

RESULTS

Three studies (1 randomized controlled trial and 2 observational studies) totaling 319 patients were included in the meta-analysis. Overall laparotomy rate was 12.8% (22 of 172 patients) in SCE versus 19% (28 of 147 patients) in CT. This difference was not significant (OR [95% CI], 0.63 [0.34–1.16]; p = 0.14). Negative laparotomy rate was 3.5% (6 of 172 patients) in SCE versus 5.4% (8 of 147 patients) in CT. The difference was not significant (OR [95% CI], 0.61 [0.20–1.83]; p = 0.37).

CONCLUSION

This meta-analysis compared SCE with CT scan in patients presenting with stab wounds of the anterior abdominal wall and provided level II evidence showing no additional benefit in CT scan. Further observational and experimental clinical studies are needed to confirm the findings of this meta-analysis.

LEVEL OF EVIDENCE

Systematic review and meta-analysis, level II.
Novel Organ Perfusion and Preservation Strategies in Transplantation – Where Are We Going in the United Kingdom?
Authors: O’Neill Stephen , Srinivasa Sanket , Callaghan Chris J. , Watson Christopher J.E. , Dark John H. , Fisher Andrew J. , Wilson Colin H. , Friend Peter J. , Johnson Rachel , Forsythe John L. , Ploeg Rutger J. , Mirza Darius F. , Wigmore Stephen J. , Oniscu Gabriel C.
Published: January 2020

This review article focuses on current clinical outcomes with novel perfusion strategies in organ transplantation. Broadly, these approaches can be divided into in situ regional perfusion in the donor and ex situ machine perfusion of individual organs. In both settings, hypothermic and normothermic techniques are in clinical use. Evidence from full text articles, abstracts, and data presented at scientific meetings has been considered. Animal studies have been excluded. The review focuses on kidney, liver, pancreas, heart, and lungs. The level of evidence ranges from quasi-experimental work in human pancreas to multiple meta-analyses of Randomized Controlled Trials for hypothermic machine perfusion of kidneys. The data in this review were presented to experts in organ perfusion and preservation at the National Health Service Blood and Transplant Preservation and Perfusion Future Strategy Summit in London in October 2018. The outcomes of the meeting are discussed in the review after due consideration of the available evidence base.
Applying the Alzheimer Disease ATN Diagnostic Framework in Atypical Dementia
Authors: Funnell Clark , Feldman Howard H. , Mackenzie Ian R.A. , DeMarco Mari L.
Published: January 2020

Cerebrospinal fluid (CSF) biomarkers amyloid-β and tau have been validated for the antemortem diagnosis of Alzheimer disease (AD) and are included in the AT(N) research framework for AD. Recently, an AT(N) CSF profile has been described for dementia with Lewy bodies (DLB), a disorder which is difficult to distinguish clinically from AD, particularly early in the disease course. Herein we describe a 71-year old male who presented with an atypical dementia syndrome including years of stability after an initial abrupt decline, marked visuospatial dysfunction, and relative sparing of memory. CSF biomarkers combined with the pattern of cognitive symptoms made AD unlikely and were consistent with DLB. This classification was confirmed clinically, with the emergence of classic DLB symptoms, and at postmortem pathologic examination. This case highlights the role for AD CSF biomarkers in facilitating earlier diagnosis of non-Alzheimer neurodegenerative dementias.
Crosslinking-guided geometry of a complete CXC receptor-chemokine complex and the basis of chemokine subfamily selectivity
Authors: Ngo Tony , Stephens Bryan S. , Gustavsson Martin , Holden Lauren G. , Abagyan Ruben , Handel Tracy M. , Kufareva Irina
Published: January 2020

Chemokines and their receptors are orchestrators of cell migration in humans. Because dysregulation of the receptor-chemokine system leads to inflammation and cancer, both chemokines and receptors are highly sought therapeutic targets. Yet one of the barriers for their therapeutic targeting is the limited understanding of the structural principles behind receptor-chemokine recognition and selectivity. The existing structures do not include CXC subfamily complexes and lack information about the receptor distal N-termini, despite the importance of the latter in signaling, regulation, and bias. Here we report the discovery of the geometry of the complex between full-length CXCR4, a prototypical CXC receptor and driver of cancer metastasis, and its endogenous ligand CXCL12. By comprehensive disulfide crosslinking, we establish the existence and the structure of a novel interface between the CXCR4 distal N-terminus and CXCL12 β1-strand, while also recapitulating earlier findings from NMR, modeling and crystallography of homologous receptors. A crosslinking-informed high-resolution model of the CXCR4-CXCL12 complex pinpoints the interaction determinants and reveals the occupancy of the receptor major subpocket by the CXCL12 proximal N-terminus. This newly found positioning of the chemokine proximal N-terminus provides a structural explanation of CXC receptor-chemokine selectivity against other subfamilies. Our findings challenge the traditional two-site understanding of receptor-chemokine recognition, suggest the possibility of new affinity and signaling determinants, and fill a critical void on the structural map of an important class of therapeutic targets. These results will aid the rational design of selective chemokine-receptor-targeting small molecules and biologics with novel pharmacology.
Maternally derived sex steroid hormones impact sex ratios of loggerhead sea turtles
Authors: Lockley Emma C. , Reischig Thomas , Eizaguirre Christophe
Published: January 2020

Global warming could drive species with temperature-dependent sex determination to extinction by persistently skewing offspring sex ratios. Evolved mechanisms that buffer these biases are therefore paramount for their persistence. Here, we tested whether maternally-derived sex steroid hormones affect the sex-determination cascade and provide a physiological mechanism to buffer sex ratio bias in the endangered loggerhead sea turtle (Caretta caretta). We quantified estradiol and testosterone in nesting females and their egg yolks at oviposition, before incubating nests in situ at standardised temperatures. Upon hatchling emergence, we developed a new, non-lethal method to establish the sex of individuals. Despite standardised incubation temperatures, sex ratios varied widely among nests, correlating non-linearly with the estradiol:testosterone ratio in egg yolks. Males were produced at an equal ratio, with females produced either side of this optimum. This result provides evidence that maternal hormone transfer forms a physiological mechanism that impacts sex determination in this endangered species.
One-to-one innervation of vocal muscles allows precise control of birdsong
Authors: Adam I. , Maxwell A. , Rössler H. , Hansen E.B. , Vellema M. , Elemans C.P.H.
Published: January 2020

The motor control resolution of any animal behavior is limited to the minimal force step available when activating muscles, which is set by the number and size distribution of motor units (MUs) and muscle specific force [1, 2]. Birdsong is an excellent model system for understanding sequence learning of complex fine motor skills [3], but we know surprisingly little how the motor pool controlling the syrinx is organized [4] and how MU recruitment drives changes in vocal output [5]. Here we combine measurements of syringeal muscle innervation ratios with muscle stress and anin vitrosyrinx preparation to estimate MU size distribution and the control resolution of fundamental frequency (fo), a key vocal parameter, in zebra finches. We show that syringeal muscles have extremely small MUs, with 50% innervating ≤ 3, and 13 – 17% innervating a single muscle fiber. Combined with the lowest specific stress (5 mN/mm2) known to skeletal vertebrate muscle, small force steps by the majorfocontrolling muscle provide control of 50 mHz to 4.2 Hz steps per MU. We show that the song system has the highest motor control resolution possible in the vertebrate nervous system and suggest this evolved due to strong selection on fine gradation of vocal output. Furthermore, we propose that high-resolution motor control was a key feature contributing to the radiation of songbirds that allowed diversification of song and speciation by vocal space expansion.
The assembly of Hfq into foci-like structures in response to long-term nitrogen starvation inEscherichia coli
Authors: McQuail Josh , Switzer Amy , Burchell Lynn , Wigneshweraraj Sivaramesh
Published: January 2020

The initial adaptive responses to nutrient depletion in bacteria often occur at the level of RNA metabolism. Hfq is an RNA-binding protein present in diverse bacterial lineages and contributes to many different aspects of RNA metabolism. We demonstrate that Hfq forms a distinct and reversible focus-like structure inE. colispecifically experiencing long-term nitrogen (N) starvation. Using the ability of T7 phage to replicate in N starved bacteria as a biological probe ofE. colicell function during N starvation, we demonstrate that Hfq foci have a role in the adaptive response to long-term N starvation. We further show that Hfq foci formation does not depend on gene expression during N starvation and occurs independently of the N regulatory protein C (NtrC) activated initial adaptive response to N starvation. The results serve as a paradigm to demonstrate that bacterial adaptation to long-term nutrient starvation can be spatiotemporally coordinated and can occur independently ofde novogene expression during starvation.

Significance Statement

Bacteria have evolved complex strategies to cope with conditions of nitrogen (N) adversity. We now reveal a role for a widely studied RNA binding protein, Hfq, in the processes involved in howEscherichia colicopes with N starvation. We demonstrate that Hfq forms a distinct and reversible focus-like structure in long-term N starvedE. coli. We provide evidence to suggest that the Hfq foci are important features required for adjustingE. colicell function during N starvation for optimal adaptation to long-term N starvation. The results have broad implications for our understanding of bacterial adaptive processes in response to stress.
Genome-wide transcriptomics identifies an early preclinical signature of prion infection
Authors: Sorce Silvia , Nuvolone Mario , Russo Giancarlo , Chincisan Andra , Heinzer Daniel , Avar Merve , Pfammatter Manuela , Schwarz Petra , Delic Mirzet , Hornemann Simone , Sanoudou Despina , Scheckel Claudia , Aguzzi Adriano
Published: January 2020

The clinical course of prion diseases is accurately predictable despite long latency periods, suggesting that prion pathogenesis is driven by precisely timed molecular events. We constructed a searchable genome-wide atlas of mRNA abundance, splicing and editing alterations during the course of disease in prion-inoculated mice. Prion infection induced transient changes in mRNA abundance and processing already at eight weeks post inoculation, well ahead of any neuropathological and clinical signs. In contrast, microglia-enriched genes displayed an increase simultaneous with the appearance of clinical symptoms, whereas neuronal-enriched transcripts remained unchanged until the very terminal stage of disease. This suggests that glial pathophysiology, rather than neuronal demise, represents the final driver of disease. The administration of young plasma attenuated the occurrence of early mRNA abundance alterations and delayed symptoms in the terminal phase of the disease. The early onset of prion-induced molecular changes might thus point to novel biomarkers and potential interventional targets.
Stromal Amyloid β drives Neutrophil extracellular trap formation to augment tumour growth
Authors: Munir Hafsa , Jones James O. , Janowitz Tobias , Martins Carla P. , Welsh Sarah J. , Shields Jacqueline D.
Published: January 2020

Tumors are comprised of cancer cells and a network of non-cancerous stromal cells. Cancer-associated fibroblasts (CAFs) are well known to support tumorigenesis and are emerging as immune modulators. While many leukocyte populations are well studied in cancer, neutrophils have received less attention. Neutrophils can release histone-bound nuclear DNA and cytotoxic granules as extracellular traps (NETs) in a process termed NETosis. Here, we show that CAFs induce formation of NETs both within the tumor microenvironment and at systemic levels in the blood and bone marrow. These tumor-induced NETs (t-NETs) are driven by a ROS-mediated pathway dependent on PAD4 and CD11b. Remarkably, CAF-derived Amyloid β was identified as the key factor driving t-NETosis, a protein with significance in both neurodegenerative and inflammatory disorders. Therapeutic inhibition of NETs in established tumors prevented growth, skewing neutrophils to a pro-inflammatory phenotype. Reciprocally, t-NETs enhanced CAF activation phenotypes. Mirroring murine observations, NETs were detected juxtaposed to CAFs in human melanoma and pancreatic adenocarcinoma, and elevated expression of amyloid and β-Secretase correlated with poor prognosis. In summary, we report the existence of cross-talk between CAFs and neutrophils within the tumour microenvironment whereby CAF-induced t-NETosis supports cancer progression, identifying Amyloid β as the protagonist and potential therapeutic target.

Significance

This study defines the existence of a pro-tumor immunomodulatory function of the stroma showing the induction of Neutrophil Extracellular Traps through CAF-derived Amyloid β. We term this novel process “Tumor-induced NETosis” (t-NETosis) and propose that therapeutic inhibition of this mechanism, which we observe in human melanoma and pancreatic cancer, has the potential to improve patient outcome.
Generation of Monophasic Action Potentials and Intermediate Forms
Authors: Iravanian Shahriar , Uzelac Ilija , Herndon Conner , Langberg Jonathan J , Fenton Flavio H
Published: January 2020

The Monophasic Action Potential (MAP) is a near replica of the transmembrane potential recorded when an electrode is pushed firmly against cardiac tissue. Despite its many practical uses, the mechanism of MAP signal generation and the reason it is so different from unipolar recordings is not completely known and is a matter of controversy. It is hypothesized that partial depolarization of the cells directly underneath the electrode contributes to the generation of MAP signals. In this paper, we describe a parametric, semi-quantitative method to generate realistic MAP and intermediate forms – multiphasic electrograms different from an ideal MAP – that does not require the partial depolarization hypothesis. The key ideas of our method are the formation of junctional spaces, i.e., electrically isolated pockets between the surface of an electrode and tissue, and the presence of a complex network of passive components that acts as a high-pass filter to distort the signal that reaches the recording amplifier. The passive network is formed by the interaction between the passive tissue properties and the double-layer capacitance of electrodes. We show that it is possible to generate different electrograms by the change of the model parameters and that both the MAP and intermediate forms reside on a continuum of signals. Our model helps to decipher the mechanisms of signal generation and can lead to a better design for electrodes, recording amplifiers, and experimental setups.

SIGNIFICANCE

Recording the Monophasic Action Potential (MAP) is potentially very useful in both experimental and clinical cardiac electrophysiology and can provide valuable information about the repolarization phase of the action potential. However, despite its benefits, it currently has only a small and niche role. The main challenge is the technical difficulties of recording an ideal MAP. Our results provide a better understanding of the mechanisms of the generation of cardiac electrograms and may help to optimize experiments and improve tools to achieve the full potentials of recording the MAP signals.
An image-computable model of human visual shape similarity
Authors: Morgenstern Yaniv , Hartmann Frieder , Schmidt Filipp , Tiedemann Henning , Prokott Eugen , Maiello Guido , Fleming Roland W.
Published: January 2020

Shape is a defining feature of objects. Yet, no image-computable model accurately predicts how similar or different shapes appear to human observers. To address this, we developed a model (‘ShapeComp’), based on over 100 shape features (e.g., area, compactness, Fourier descriptors). When trained to capture the variance in a database of >25,000 animal silhouettes, ShapeComp predicts human shape similarity judgments almost perfectly (r2>0.99) without fitting any parameters to human data. To test the model, we created carefully selected arrays of complex novel shapes using a Generative Adversarial Network trained on the animal silhouettes, which we presented to observers in a wide range of tasks. Our findings show that human shape perception is inherently multidimensional and optimized for comparing natural shapes. ShapeComp outperforms conventional metrics, and can also be used to generate perceptually uniform stimulus sets, making it a powerful tool for investigating shape and object representations in the human brain.
Identification ofPhotorhabdussymbionts by MALDI-TOF mass spectrometry
Authors: Hill Virginia , Kuhnert Peter , Erb Matthias , Machado Ricardo A. R.
Published: January 2020

Species of the bacterial genusPhotorhabuslive in a symbiotic relationship withHeterorhabditisentomopathogenic nematodes. Besides their use as biological control agents against agricultural pests, somePhotorhabdusspecies are also a source of natural products and are of medical interest due to their ability to cause tissue infections and subcutaneous lesions in humans. Given the diversity ofPhotorhabdusspecies, rapid and reliable methods to resolve this genus to the species level are needed. In this study, we evaluated the potential of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for the identification ofPhotorhabdusspecies. To this end, we established a collection of 54 isolates consisting of type strains and multiple field strains that belong to each of the validly described species and subspecies of this genus. Reference spectra for the strains were generated and used to complement a currently available database. The extended reference database was then used for identification based on the direct transfer sample preparation method and protein fingerprint of single colonies. High discrimination of distantly related species was observed. However, lower discrimination was observed with some of the most closely related species and subspecies. Our results, therefore, suggest that MALDI-TOF MS can be used to correctly identifyPhotorhabdusstrains at the genus and species level, but has limited resolution power for closely related species and subspecies. Our study demonstrates the suitability and limitations of MALDI-TOF-based identification methods for the assessment of the taxonomical position and identification ofPhotorhabdusisolates.

Impact Statement

Species of the bacterial genusPhotorhabuslive in close association with soil-born entomopathogenic nematodes. Under natural conditions, these bacteria are often observed infecting soil-associated arthropods, but under certain circumstances, can also infect humans. They produce a large variety of natural products including antibiotics, insecticides, and polyketide pigments that have substantial agricultural, biotechnological and medical potential. In this study, we implement MALDI-TOF MS-based identification method to resolve the taxonomic identity of this bacterial genus, providing thereby a rapid identification tool to understanding its taxonomic diversity to boost scientific progress in medical, agricultural, and biotechnological settings.
Genomic rearrangements generate hypervariable mini-chromosomes in host-specific lineages of the blast fungus
Authors: Langner Thorsten , Harant Adeline , Gomez-Luciano Luis B. , Shrestha Ram K. , Win Joe , Kamoun Sophien
Published: January 2020

Supernumerary mini-chromosomes–a unique type of genomic structural variation–have been implicated in the emergence of virulence traits in plant pathogenic fungi. However, the mechanisms that facilitate the emergence and maintenance of mini-chromosomes across fungi remain poorly understood. In the blast fungusMagnaporthe oryzae, mini-chromosomes have been first described in the early 1990s but, until very recently, have been overlooked in genomic studies. Here we investigated structural variation in four isolates of the blast fungusM. oryzaefrom different grass hosts and analyzed the sequences of mini-chromosomes in the rice, foxtail millet and goosegrass isolates. The mini-chromosomes of these isolates turned out to be highly diverse with distinct sequence composition. They are enriched in repetitive elements and have lower gene density than core-chromosomes. We identified several virulence-related genes in the mini-chromosome of the rice isolate, including the polyketide synthaseAce1and the effector geneAVR-Pik. Macrosynteny analyses around these loci revealed structural rearrangements, including inter-chromosomal translocations between core- and mini-chromosomes. Our findings provide evidence that mini-chromosomes independently emerge from structural rearrangements of core-chromosomes and might contribute to adaptive evolution of the blast fungus.

Author summary

The genomes of plant pathogens often exhibit an architecture that facilitates high rates of dynamic rearrangements and genetic diversification in virulence associated regions. These regions, which tend to be gene sparse and repeat rich, are thought to serve as a cradle for adaptive evolution. Supernumerary chromosomes, i.e. chromosomes that are only present in some but not all individuals of a species, are a special type of structural variation that have been observed in plants, animals, and fungi. Here we identified and studied supernumerary mini-chromosomes in the blast fungusMagnaporthe oryzae, a pathogen that causes some of the most destructive plant diseases. We found that rice, foxtail millet and goosegrass isolates of this pathogen contain mini-chromosomes with distinct sequence composition. All mini-chromosomes are rich in repetitive genetic elements and have lower gene densities than core-chromosomes. Further, we identified virulence-related genes on the mini-chromosome of the rice isolate. We observed large-scale genomic rearrangements around these loci, indicative of a role of mini-chromosomes in facilitating genome dynamics. Taken together, our results indicate that mini-chromosomes facilitate genome rearrangements and possibly adaptive evolution of the blast fungus.
Talin Folding as the Tuning Fork of Cellular Mechanotransduction
Authors: Tapia-Rojo Rafael , Alonso-Caballero Alvaro , Fernandez Julio M.
Published: January 2020

Cells continually sample their mechanical environment using exquisite force sensors such as talin, whose folding status triggers mechanotransduction pathways by recruiting binding partners. Mechanical signals in biology change quickly over time and are often embedded in noise; however, the mechanics of force-sensing proteins have only been tested using simple force protocols, such as constant or ramped forces. Here, using our magnetic tape head tweezers design, we measure the folding dynamics of single talin proteins in response to external mechanical noise and cyclic force perturbations. Our experiments demonstrate that talin filters out external mechanical noise but detects periodic force signals over a finely-tuned frequency range. Hence, talin operates as a mechanical bandpass filter, able to read and interpret frequency-dependent mechanical information through its folding dynamics. We describe our observations in the context of stochastic resonance, which we propose as a mechanism by which mechanosensing proteins could respond accurately to force signals in the naturally noisy biological environment.
The Architecture of GluD2 Ionotropic Delta Glutamate Receptor Elucidated by cryo-EM
Authors: Burada Ananth Prasad , Kumar Janesh
Published: January 2020

GluD2 receptors belong to the orphan delta receptor family of glutamate receptor ion channels. These receptors play key roles in synaptogenesis and synaptic plasticity and are associated with multiple neuronal disorders like schizophrenia, autism spectrum disorder, cerebellar ataxia, intellectual disability, paraplegia, retinal dystrophy, etc. Despite the importance of these receptors in CNS, insights into full-length GluD2 receptor structure is missing till-date. Here we report cryo-electron microscopy structure of the rat GluD2 receptor in the presence of calcium ions and the ligand 7-chlorokynurenic acid, elucidating its 3D architecture. The structure reveals a non-swapped architecture at the extracellular aminoterminal (ATD), and ligand-binding domain (LBD) interface similar to that observed in GluD1; however, the organization and arrangement of the ATD and LBD domains are unique. While our results demonstrate that non-swapped architecture is conserved in the delta receptor family, they also highlight the differences that exist between the two member receptors; GluD1 and GluD2.
PhyteByte: Identification of foods containing compounds with specific pharmacological properties
Authors: Westerman Kenneth , Harrington Sean , Ordovas Jose M , Parnell Laurence D
Published: January 2020

Background

Phytochemicals and other molecules in foods elicit positive health benefits, often by poorly established or unknown mechanisms. While there is a wealth of data on the biological and biophysical properties of drugs and therapeutic compounds, there is a notable lack of similar data for compounds commonly present in food. Computational methods for high-throughput identification of food compounds with specific biological effects, especially when accompanied by relevant food composition data, could enable more effective and more personalized dietary planning. We have created a machine learning-based tool (PhyteByte) to leverage existing pharmacological data to predict bioactivity across a comprehensive molecular database of foods and food compounds.

Results

PhyteByte uses a cheminformatic approach to structure-based activity prediction and applies it to uncover the putative bioactivity of food compounds. The tool takes an input protein target and develops a random forest classifier to predict the effect of an input molecule based on its molecular fingerprint, using structure and activity data available from the ChEMBL database. It then predicts the relevant bioactivity of a library of food compounds with known molecular structures from the FooDB database. The output is a list of food compounds with high confidence of eliciting relevant biological effects, along with their source foods and associated quantities in those foods, where available. Applying PhyteByte to thePPARGgene, we identified irigenin, sesamin, fargesin, and delta-sanshool as putative agonists of PPARG, along with previously identified agonists of this important metabolic regulator.

Conclusions

PhyteByte identifies food-based compounds that are predicted to interact with specific protein targets. The identified relationships can be used to prioritize food compounds for experimental or epidemiological follow-up and can contribute to the rapid development of precision approaches to new nutraceuticals as well as personalized dietary planning.
A novel phylogenetic analysis and machine learning predict pathogenicity of human mtDNA variants
Authors: Akpınar Bala Anı , Carlson Paul O. , Paavilainen Ville O. , Dunn Cory D.
Published: January 2020

Linking mitochondrial DNA (mtDNA) variation to clinical outcomes remains a formidable challenge. Diagnosis of mitochondrial disease is hampered by the multicopy nature and potential heteroplasmy of the mitochondrial genome, differential distribution of mutant mtDNAs among various tissues, genetic interactions among alleles, and environmental effects. Here, we describe a new approach to the assessment of which mtDNA variants may be pathogenic. Our method takes advantage of site-specific conservation and variant acceptability metrics that minimize previous classification limitations. Using our novel features, we deploy machine learning to predict the pathogenicity of thousands of human mtDNA variants. Our work demonstrates that a substantial fraction of mtDNA changes not yet characterized as harmful are, in fact, likely to be deleterious. Our findings will be of direct relevance to those at risk of mitochondria-associated metabolic disease.
Fully Automated Peptide Mapping Protocol for Multi-Attribute Method by Liquid Chromatography–Tandem Mass Spectroscopy with a High-Throughput Robotic Liquid Handling System
Authors: Qian Chen , Niu Ben , Jimenez Rod Brian , Wang Jihong , Albarghouthi Methal , Chen Xiaoyu
Published: January 2020

The multi-attribute method (MAM) based on liquid chromatography–tandem mass spectroscopy is emerging as a powerful tool to directly monitor multiple product quality attributes simultaneously. Preparation of samples for MAM, however, is labor intensive, involving protein denaturation, disulfide bond reduction, free cysteine alkylation, and enzymatic digestion steps, which require significant analyst hands-on time while limiting result turnaround. Such complexity can also render nontrivial variations across analysts and laboratories. We describe the development of a fully automated peptide mapping procedure with a high-throughput robotic liquid handling system to improve sample handling capability and outcome reproducibility while saving analyst hands-on time. The automated procedure is completely hands-free, and setup requires the analyst only to prenormalize the sample concentrations and load buffers and reagents at their designated positions on the robotic deck. The robotic liquid handler performs all the subsequent preparation steps and stores the digested samples on a chiller unit to await retrieval. The convenience and flexibility provided by this automated peptide mapping method provides substantial benefits over manual sample preparation protocols. The optimized, automated procedure showed good reproducibility and results that were comparable to those of the manual procedure with respect to sequence coverage, digestion completeness, and quantification of posttranslational modifications. With this increased throughput, coupled with fast MAM analysis, more comprehensive characterization can be achieved.
Comparing Phylogeographies: Incompatible Geographical Histories in Pathogens’ Genomes
Authors: Singer Benjamin , Di Nardo Antonello , Hein Jotun , Ferretti Luca
Published: January 2020

Modern phylogeography aims at reconstructing the geographic diffusion of organisms based on their genomic sequences and spatial information. Phylogeographic approaches usually ignore the possibility of recombination, which decouples the evolutionary and geographic histories of different parts of the genome. Genomic regions of recombining or reassorting pathogens often originate and evolve at different times and locations, which characterised their unique spatial histories. Measuring the extent of these differences requires new methods to compare geographic information on phylogenetic trees reconstructed from different parts of the genome. Here we develop for the first time a set of measures ofphylogeographic incompatibilityaimed at detecting differences between geographical histories in terms of distances between phylogeographies. We study the effect of varying demography and recombination on phylogeographic incompatibilities using coalescent simulations. We further apply these measures to the evolutionary history of human and livestock pathogens, either reassorting or recombining, such as the Victoria and Yamagata lineages of influenza B and the O/Ind-2001 foot-and-mouth disease virus strain. Our results reveal diverse geographical paths of diffusion that characterise the origins and evolutionary histories of different viral genes and genomic segments. phylogeography, recombination, viral evolution
Imidacloprid Movement into Fungal Conidia is Lethal to Mycophagous Beetles
Authors: Choudhury Robin A. , Sutherland Andrew M. , Hengel Mathew J. , Parrella Michael P. , Gubler W. Douglas
Published: January 2020

Applications of systemic pesticides can have unexpected direct and indirect effects on nontarget organisms, producing ecosystem-level impacts.

We investigated whether a systemic insecticide (imidacloprid) could be absorbed by a plant pathogenic fungus infecting treated plants and whether the absorbed levels were high enough to have detrimental effects on the survival of a mycophagous beetle. Beetle larvae fed on these fungi were used to assess the survival effects of powdery mildew and imidacloprid in a factorial design. Fungal conidia were collected from treated and untreated plants and were tested for the presence and concentration of imidacloprid.

Survival of beetles fed powdery mildew from imidacloprid-treated leaves was significantly lower than that of beetles from all other treatments.

Imidacloprid accumulated in fungal conidia and hyphae was detected at levels considered lethal to other insects, including coccinellid beetles.

Water-soluble systemic insecticides may disrupt mycophagous insects as well as other nontarget organisms, with significant implications for biodiversity and ecosystem function.
Tyrosine-Derived Polycarbonate Nerve Guidance Tubes Elicit Pro-Regenerative Extracellular Matrix Deposition When Used to Bridge Segmental Nerve Defects in Swine
Authors: Burrell JC , Bhatnagar D , Brown DP , Murthy NS , Dutton J , Browne KD , Laimo FA , Ali Z , Rosen JM , Kaplan HM , Kohn J , Cullen DK
Published: January 2020

Promising biomaterials should be tested in appropriate large animal models that recapitulate human inflammatory and regenerative responses. Previous studies have shown tyrosine-derived polycarbonates (TyrPC) are versatile biomaterials with a wide range of applications across multiple disciplines. The library of TyrPC has been well studied and consists of thousands of polymer compositions with tunable mechanical characteristics and degradation and resorption rates that are useful for nerve guidance tubes (NGTs). NGTs made of different TyrPCs have been used in segmental nerve defect models in small animals. The current study is an extension of this work and evaluates NGTs made using two different TyrPC compositions in a 1 cm porcine peripheral nerve repair model. We first evaluated a nondegradable TyrPC formulation, demonstrating proof-of-concept chronic regenerative efficacy up to 6 months with similar nerve/muscle electrophysiology and morphometry to the autograft repair control. Next, we characterized the acute regenerative response using a degradable TyrPC formulation. After 2 weeksin vivo, TyrPC NGT promoted greater deposition of pro-regenerative extracellular matrix (ECM) constituents (in particular collagen I, collagen III, collagen IV, laminin and fibronectin) compared to commercially available collagen-based NGTs. This corresponded with dense Schwann cell infiltration and axon extension across the lumen. These findings confirmed results reported previously in a mouse model and reveal that TyrPC NGTs were well tolerated in swine and facilitated host axon regeneration and Schwann cell infiltration in the acute phase across segmental defects - likely by eliciting a favorable neurotrophic ECM milieu. This regenerative response ultimately can contribute to functional recovery.
Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development
Authors: Lima Ana , Lubatti Gabriele , Burgstaller Jörg , Hu Di , Green Alistair , Gregorio Aida Di , Zawadzki Tamzin , Pernaute Barbara , Mahammadov Elmir , Montero Salvador Perez , Dore Marian , Sanchez Juan Miguel , Bowling Sarah , Sancho Margarida , Karimi Mohammad , Carling David , Jones Nick , Srinivas Shankar , Scialdone Antonio , Rodriguez Tristan A.
Published: January 2020

Cell competition is emerging as a quality control mechanism that eliminates unfit cells in a wide range of settings from development to the adult. However, the nature of the cells normally eliminated by cell competition and what triggers their elimination remains poorly understood. In mouse, prior to gastrulation 35% of epiblast cells are eliminated. Here we have performed single cell transcriptional profiling of these cells and find that they show the hallmarks of cell competition and have mitochondrial defects. We demonstrate that mitochondrial defects are common to a range of different loser cell types and that manipulating mitochondrial function is sufficient to trigger competition. Importantly, we show that in the embryo cell competition eliminates cells with mitochondrial DNA mutations and that even non-pathological changes in mitochondrial DNA sequence can induce cell competition. Our results therefore suggest that cell competition is a purifying selection that optimises mitochondrial performance prior to gastrulation.
More filtering on SNP calling does not remove evidence of inter-nucleus recombination in dikaryotic arbuscular mycorrhizal fungi
Authors: Chen Eric C.H. , Mathieu Stephanie , Hoffrichter Anne , Ropars Jeanne , Dreissig Steven , Fuchs Jörg , Brachmann Andreas , Corradi Nicolas
Published: January 2020

We respond to a recent reanalysis of single nucleus sequence data from Chen et al. 2018eLife, which indicated that evidence of inter-nuclear recombination in dikaryotic arbuscular mycorrhizal fungi decreases when heterozygous, duplicated sites being supported by less than 5 reads, are removed from the dataset. Here, we show that applying a more stringent methodology for filtering SNP calls that focuses exclusively on single copy and homozygous regions with at least 5 reads supporting a given SNP, still recovers several hundreds putative inter-nucleus recombination events within the same dataset. We also provide evidence for retaining SNPs supported by less than 5 reads for genotyping individual nuclei using the same dataset.
Color Data v2: a user-friendly, open-access database with hereditary cancer and hereditary cardiovascular conditions datasets
Authors: Berger Mark J. , Williams Hannah E. , Barrett Ryan , Zimmer Anjali D. , McKennon Wendy , Hong Huy , Ginsberg Jeremy , Zhou Alicia Y. , Neben Cynthia L.
Published: January 2020

Publicly-available genetic databases promote data sharing and fuel scientific discoveries for the prevention, treatment, and management of disease. In 2018, we built Color Data, a user-friendly, open access database containing genotypic and self-reported phenotypic information from 50,000 individuals who were sequenced for 30 genes associated with hereditary cancer. In a continued effort to promote access to these types of data, we launched Color Data v2, an updated version of the Color Data database. This new release includes additional clinical genetic testing results from more than 18,000 individuals who were sequenced for 30 genes associated with hereditary cardiovascular conditions, as well as polygenic risk scores for breast cancer, coronary artery disease, and atrial fibrillation. In addition, we used self-reported phenotypic information to implement the following four clinical risk models: Gail Model for five-year risk of breast cancer, Claus Model for lifetime risk of breast cancer, simple office-based Framingham Coronary Heart Disease Risk Score for ten-year risk of coronary heart disease, and CHARGE-AF simple score for five-year risk of atrial fibrillation. These new features and capabilities are highlighted through two sample queries in the database. We hope that the broad dissemination of this data will help researchers continue to explore genotype-phenotype correlations and identify novel variants for functional analysis, enabling scientific discoveries in the field of population genomics.

Database URL:https://data.color.com/
Evidence for binary Smc complexes lacking kite subunits in archaea
Authors: Jeon Jae-Hyun , Lee Han-Sol , Shin Ho-Chul , Kwak Mi-Jeong , Kim Yeon-Gil , Gruber Stephan , Oh Byung-Ha
Published: January 2020

SMC complexes play a central role in chromosome organization in all domains of life. The bacterial Smc–ScpAB complex is a three-subunit complex composed of Smc, ScpA and ScpB. ScpA bridges the two ATPase domains of the Smc homodimer, while ScpB, which belongs to the kite family of proteins, interacts with ScpA. The three subunits are known to be equally important for the function of Smc–ScpAB in bacteria. From crystallographic and biochemical studies, evidence is provided that six archaeal ScpA proteins are unable to interact with the only putative ScpB found in these species. Structure-based sequence alignment reveals that these archaeal ScpAs lack the ScpB-binding segment that is commonly present in the middle of bacterial ScpA sequences, which is thus responsible for their inability to interact with ScpB. ScpA proteins lacking the ScpB-binding segment are found to prevail in archaea. Moreover, two archaeal ScpA proteins with a longer middle region also failed to bind their putative ScpB partner. Furthermore, all or most species belonging to five out of 14 euryarchaeotal orders contain Smc and ScpA but not a detectable ScpB homologue. These data support the notion that archaeal Smc-based complexes generally function as a two-subunit complex composed of only Smc and ScpA.