bluuebunny/crossref_metadata_2025 huggingface dataset:
Umbilical Ablation During Deep Inferior Epigastric Perforator Flap Harvest Decreases Donor Site Complications
Authors: Fisher Mark , Bank Jonathan , Alba Brandon , Light David , Korn Peter T. , Feingold Randall S. , Israeli Ron
Published: January 2020

Background

Donor site complications are a significant source of morbidity for patients undergoing abdominal-based free flap breast reconstruction, but there is a paucity of data regarding minimizing these postoperative complications. We hypothesize that selective ablation of the umbilicus at the time of deep inferior epigastric perforator (DIEP) harvest decreases the incidence of umbilical and abdominal wall complications in high-risk patients.

Methods

A retrospective review was performed of all patients (n = 117) who underwent DIEP harvest with concomitant umbilical ablation from 2010 to 2015. This cohort was paired with 117 patients who underwent DIEP harvest without umbilical ablation. Preoperative risk factors, intraoperative factors, and postoperative complications were compared.

Results

The umbilical ablation group had significantly higher body mass index (30.9 vs 27.4 kg/m2, P < 0.001), presence of umbilical scar (20.9% vs 5.3%, P < 0.001), umbilical hernia (82.9% vs 8.5% P < 0.001), ventral hernia (23.9% vs 1.7%, P < 0.001), and rectus diastasis (10.3% vs 2.6%, P = 0.016). There were no significant differences of smoking, diabetes mellitus, hypertension, prior abdominal surgery, or midline abdominal scar. The umbilical ablation group had a significantly lower rate of postoperative abdominal wound dehiscence and skin loss (11.1% vs 22.2%, P = 0.023) and overall donor site complications (24.8% vs 39.3%, P = 0.017). There was no significant difference in incidence of cellulitis, seroma, or abscess. Mean follow-up time was 1.8 years.

Conclusions

Selective umbilical ablation in high-risk patients at the time of abdominal flap harvest can result in significantly fewer donor site wound complications, even in the setting of increased risk factors for poor wound healing. This is likely due to avoidance of umbilical incisions and decreased upper abdominal skin undermining. We conclude that umbilical ablation is a viable option to minimize donor site complications, especially in high-risk patients.
The Biosynthetic Option as an Alternative in Complex Abdominal Wall Reconstruction
Authors: Anderson Bjorn , Hart Alexandra M. , Maxwell Daniel , Losken Albert
Published: January 2020

Synthetic mesh and acellular dermal matrix reinforcement during complex abdominal wall reconstruction (CAWR) have significantly improved outcomes. In an attempt to further improve outcomes, we combined both into a single biosynthetic by suturing a synthetic mesh on top of porcine acellular dermal matrix. Our aim was to review our experience with this new technique. Patients undergoing CAWR with the biosynthetic mesh were reviewed from a prospective database from 2015 to 2018. A total of 39 patients were 56.3 ± 10.9 years old, white (59.0%), and female (74.4%), with 31.9 ± 7.4 kg/m2 of body mass index. Eight repairs were performed on patients classified as greater than or equal to modified Ventral Hernia Working Group (mVHWG) class 3a, and 41.0% followed a concurrent resection of previously placed mesh. The biosynthetic mesh was placed as an underlay (51.3%) or inlay (46.2%) with primary closure in 51.3% and component separation in 12.8%. Recurrence at 3 years of follow-up occurred in 3 patients (7.7%). Complications within 60 days occurred in 6 patients (15.4%), including 4 soft tissue infections—one requiring explantation, with a total of 2 patients (5.1%) requiring explantation overall. Type 2 diabetes, previous mesh removal, component separation, and mVHWG class 3b independently predicted noninfectious complications. Male sex and mVHWG class 3b independently predicted surgical site infection. No predictors were found for recurrence. Biosynthetic mesh does not seem to increase the risk of early complications and may reduce recurrences and improve long-term outcomes after CAWR.
Retroperitoneal Approach for Ilioinguinal, Iliohypogastric, and Genitofemoral Neurectomies in the Treatment of Refractory Groin Pain After Inguinal Hernia Repair
Authors: Gangopadhyay Noopur , Pothula Aravind , Yao Amy , Geraghty Patrick J. , Mackinnon Susan E.
Published: January 2020

Inguinal hernia repair is one of the most commonly performed surgical procedures. Postoperative neuropathic groin pain is a potentially disabling complication and can be due to a neuroma of the ilioinguinal, iliohypogastric, and/or genitofemoral nerves. In this article, we present our operative technique—a retroperitoneal approach to the ipsilateral ilioinguinal, iliohypogastric, and genitofemoral nerves with neurectomy and proximal transposition of these nerves—for management of neuropathic pain. A retrospective review was performed of 12 of the patients who underwent this surgery at our institution. Three of 12 patients underwent a selective neurectomy, whereas 9 of 12 underwent a triple neurectomy; 3 of the 9 patients who underwent triple neurectomy also had a retroperitoneal peripheral nerve stimulator placed at the time of neurectomy. Pain visual analog scores (VASs) demonstrated significant improvement after neurectomy (preoperative pain VAS of 85 ± 11 vs postoperative pain VAS of 47 ± 32, P = 0.0027). Eight of 12 patients experienced partial or complete pain relief, whereas 4 of 12 patients had no pain relief. There were no major complications, and the minor complication rate was low for all patients and primarily related to peripheral nerve stimulator placement. This retroperitoneal approach to triple neurectomy for treatment of refractory groin pain in postoperative inguinal hernia repair patients is safe and effective for an otherwise devastating problem.
Evaluation of the (qSOFA) Tool in the Emergency Department Setting
Authors: Proffitt Robin D. , Hooper Gwendolyn
Published: January 2020

In the emergency department (ED) setting, nurses perform the initial evaluation of patients, thereby placing ED nurses in a prime position to recognize sepsis and greatly influence prompt implementation of treatment. The quick Sequential Organ Failure Assessment (qSOFA) tool was first introduced as part of the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) as a predictor of both increased mortality and longer intensive care unit (ICU) stays. Designed for use outside the ICU, the qSOFA tool functions as a simple bedside tool to quickly identify patients at risk for developing sepsis. As a method to improve detection of sepsis in the ED, an evidence-based screening tool based on the qSOFA criteria was developed. The project implemented over a 14-day period resulted in 106 surveys. Average time from patients entering the ED to actual triage evaluation was 13 min, and the median time from the completion of triage evaluation to the completion of the qSOFA screening tool was 4 min. To determine acceptance of the qSOFA tool for use in detecting sepsis in the ED, a second aim was to evaluate ED nurses' perceptions of the effectiveness, timeliness, and ease of use of the qSOFA evaluation tool. Anonymous postsurvey results revealed that participants were moderately familiar with the qSOFA tool and found it overall easy to complete. The majority of participants stated only a slight likelihood of using the qSOFA tool if it were implemented into clinical practice.
Noninvasive Wound Closure in the Emergency Department
Authors: Adams Bethany L. , Hadenfeldt Cynthia
Published: January 2020

Emergency department (ED) providers spend a significant amount of time treating low-acuity medical conditions, such as simple laceration repairs. Lacerations account for 5% of all ED visits in the United States (Centers for Disease Control and Prevention, 2016). An extended period of time by the provider is required for traditional wound repair, and there is perceived pain reported by patients (Song et al., 2017). The closure devices (Zip Closure device) are a latex-free, noninvasive alternative to staples, sutures, and glue and make wound closure an easy, fast process, allowing patients to remove the device after the wound has healed. The purpose/aim of this quality improvement project was to implement and evaluate the effectiveness of a noninvasive wound closure technique in the ED. The specific aims were to determine whether the Zip Closure device resulted in cost savings for the facility by decreasing the provider time that was needed for the laceration repair and determine whether there was an improved patient satisfaction compared with traditional wound closure methods. Following provider education regarding the use of the Zip Closure device, the device was available to providers over a 4-month period of time for use with patients in the ED. There were 63 lacerations seen in the ED during the 4 months of the quality improvement project, and an evaluation note was completed by a provider on all wounds. Six subjects were treated with the Zip Closure device, and 5 expressed satisfaction with the device. Providers stated that barriers to using the product on more wounds were that the lacerations were nonlinear, complex, high tension, and superficial or involved the finger, hand, scalp, face, or mouth; therefore, the device was inappropriate for treatment of the laceration. This was preliminary work of the noninvasive wound closure device. It is recommended that the study be repeated in a larger ED setting.
Atypical Variant of Cutaneous Tuberculosis Presentation in an Adult HIV-Infected Patient in an Emergency Department in Haiti
Authors: Fratianni Cara
Published: January 2020

The incidence of tuberculosis (TB) has increased in the 21st century due to a high prevalence of the human immunodeficiency virus (HIV) infection and multidrug-resistant (MDR) pulmonary TB. HIV infection, diabetes mellitus, and other immune deficiencies decrease cure rates, increase mortality, and increase the incidence of MDR pulmonary TB. Tuberculosis is the most virulent opportunistic pathogen worldwide for patients living with HIV. This case documents rare clinical manifestation of cutaneous tuberculosis (CTB) seen in an emergency department in Gonaives, Haiti. Cutaneous TB can occur either from the spread of TB from an endogenous origin or from the entry of mycobacteria into the skin. The host's immune response to mycobacteria is an important factor. There are several findings that support diagnosis of a tuberculid, including failure to detect mycobacterium TB in stains or cultures of affected tissue, frequent resolution of skin lesions with anti-TB therapy, a strongly positive tuberculin skin test, a positive interferon-γ release assay, presence of an endogenous TB infection, and granulomatous tissue present in histopathology. This case study illustrates the challenges providers face to diagnose a patient with CTB and the many differential diagnoses that must be considered. Once a definitive diagnosis has been made, this article highlights disease course, progression, and treatment plan.
Molecular mechanism of sulfur chemolithotrophy in the betaproteobacterium Pusillimonas ginsengisoli SBSA
Authors: Mandal Subhrangshu , Rameez Moidu Jameela , Chatterjee Sumit , Sarkar Jagannath , Pyne Prosenjit , Bhattacharya Sabyasachi , Shaw Rahul , Ghosh Wriddhiman
Published: January 2020

Chemolithotrophic sulfur oxidation represents a significant part of the biogeochemical cycling of this element. Due to its long evolutionary history, this ancient metabolism is well known for its extensive mechanistic and phylogenetic diversification across a diverse taxonomic spectrum. Here we carried out whole-genome sequencing and analysis of a new betaproteobacterial isolate,

Pusillimonas ginsengisoli

SBSA, which is found to oxidize thiosulfate via the formation of tetrathionate as an intermediate. The 4.7 Mb SBSA genome was found to encompass a soxCDYZAXOB operon, plus single thiosulfate dehydrogenase (tsdA) and sulfite : acceptor oxidoreductase (sorAB) genes. Recombination-based knockout of tsdA revealed that the entire thiosulfate is first converted to tetrathionate by the activity of thiosulfate dehydrogenase (TsdA) and the Sox pathway is not functional in this bacterium despite the presence of all necessary sox genes. The ∆soxYZ and ∆soxXA knockout mutants exhibited a wild-type-like phenotype for thiosulfate/tetrathionate oxidation, whereas ∆soxB, ∆soxCD and soxO::KanR mutants only oxidized thiosulfate up to tetrathionate intermediate and had complete impairment in tetrathionate oxidation. The substrate-dependent O2 consumption rate of whole cells and the sulfur-oxidizing enzyme activities of cell-free extracts, measured in the presence/absence of thiol inhibitors/glutathione, indicated that glutathione plays a key role in SBSA tetrathionate oxidation. The present findings collectively indicate that the potential glutathione : tetrathionate coupling in

P. ginsengisoli

involves a novel enzymatic component, which is different from the dual-functional thiol dehydrotransferase (ThdT), while subsequent oxidation of the sulfur intermediates produced (e.g. glutathione : sulfodisulfane molecules) may proceed via the iterative action of soxBCD .
The logic of containing tumors
Authors: Viossat Yannick , Noble Robert
Published: January 2020

Challenging the paradigm of the maximum tolerated dose, recent studies have shown that a strategy aiming for containment, not elimination, can control tumor burden more effectivelyin vitro, in mouse models, and in the clinic. These outcomes are consistent with the hypothesis that emergence of resistance to cancer therapy may be prevented or delayed by exploiting competitive ecological interactions between drug-sensitive and resistant tumor cell subpopulations. However, although various mathematical and computational models have been proposed to explain the superiority of particular containment strategies, this evolutionary approach to cancer therapy lacks a rigorous theoretical foundation. Here we combine extensive mathematical analysis and numerical simulations to establish general conditions under which a containment strategy is expected to control tumor burden more effectively than applying the maximum tolerated dose. We show that when resistant cells are present, an idealized strategy of containing a tumor at a maximum tolerable size maximizes time to treatment failure (that is, the time at which tumor burden becomes intolerable). These results are very general and do not depend on any fitness cost of resistance. We further provide formulas for predicting the clinical benefits attributable to containment strategies in a wide range of scenarios, and we compare outcomes of theoretically optimal treatments with those of more practical protocols. Our results strengthen the rationale for clinical trials of evolutionarily-informed cancer therapy.
Evolution and maintenance of microbe-mediated protection under occasional pathogen infection
Authors: Kloock A. , Bonsall M.B. , King K.C.
Published: January 2020

Every host is colonized by a variety of microbes, some of which can protect their hosts from pathogen infection. However, pathogen presence naturally varies over time in nature, such as in the case of seasonal epidemics. We experimentally coevolved populations ofCaenorhabditis elegansworm hosts with bacteria possessing protective traits (Enterococcus faecalis), in treatments varying the infection frequency with pathogenicStaphylococcus aureusevery host generation, alternating host generations, every fifth host generation or never. We additionally investigated the effect of initial pathogen presence at the formation of the defensive symbiosis. Our results show that enhanced microbe-mediated protection evolved during host-protective microbe coevolution when faced with rare infections by a pathogen. Initial pathogen presence had no effect on the evolutionary outcome of microbe-mediated protection. We also found that protection was only effective at preventing mortality during the time of pathogen infection. Overall, our results suggest that resident microbes can be a form of transgenerational immunity against rare pathogen infection.
Estimated effectiveness of traveller screening to prevent international spread of 2019 novel coronavirus (2019-nCoV)
Authors: Gostic Katelyn M. , Gomez Ana C. R. , Mummah Riley O. , Kucharski Adam J. , Lloyd-Smith James O.
Published: January 2020

Traveller screening is being used to limit further global spread of 2019 novel coronavirus (nCoV) following its recent emergence. Here, we project the impact of different travel screening programs given remaining uncertainty around the values of key nCoV life history and epidemiological parameters. Even under best-case assumptions, we estimate that screening will miss more than half of infected travellers. Breaking down the factors leading to screening successes and failures, we find that most cases missed by screening are fundamentally undetectable, because they have not yet developed symptoms and are unaware they were exposed. These findings emphasize the need for measures to track travellers who become ill after being missed by a travel screening program. We make our model available for interactive use so stakeholders can explore scenarios of interest using the most up-to-date information. We hope these findings contribute to evidence-based policy to combat the spread of nCoV, and to prospective planning to mitigate future emerging pathogens.
Risk of 2019 novel coronavirus importations throughout China prior to the Wuhan quarantine
Authors: Du Zhanwei , Wang Lin , Cauchemez Simon , Xu Xiaoke , Wang Xianwen , Cowling Benjamin J. , Meyers Lauren Ancel
Published: January 2020

On January 23, 2020, China quarantined Wuhan to contain an emerging coronavirus (2019-nCoV). Here, we estimate the probability of 2019-nCoV importations from Wuhan to 369 cities throughout China before the quarantine. The expected risk exceeds 50% in 128 [95% CI 75 186] cities, including five large cities with no reported cases by January 26th.
Only ten percent of the global terrestrial protected area network is connected via intact land
Authors: Ward Michelle , Saura Santiago , Williams Brooke , Ramírez-Delgado Juan Pablo , Arafeh-Dalmau Nur , Allan James R. , Venter Oscar , Dubois Grégoire , Watson James E.M.
Published: January 2020

Land free of direct anthropogenic disturbance is considered essential for achieving biodiversity conservation outcomes but is rapidly eroding. In response, many nations are increasing their protected area estates but little consideration is given to the context of the surrounding landscape. This is despite the fact that connectivity between protected areas is critical in a changing climate and mandated in international protected area targets. By utilizing the latest human pressure assessment, which shows that ∼40% of the terrestrial planet is still intact, and a connectivity method, we found just 9.7% of Earth’s terrestrial protected network can be considered ‘connected’. On average, 11% of each nation’s protected area estate is connected via intact land. As the global community commits to bolder action on abating biodiversity loss, only an increased focus on landscape-scale habitat retention and restoration efforts will ensure those critical areas safeguarded for conservation outcomes will remain (or become) connected.

One Sentence Summary

Only 9.7% of the global protected area network can be considered ‘connected’ by intact land.
Pan-cancer analysis demonstrates that integrating polygenic risk scores with modifiable risk factors improves risk prediction
Authors: Kachuri Linda , Graff Rebecca E. , Smith-Byrne Karl , Meyers Travis J. , Rashkin Sara R. , Ziv Elad , Witte John S. , Johansson Mattias
Published: January 2020

Cancer risk is determined by a complex interplay of environmental and heritable factors. Polygenic risk scores (PRS) provide a personalized genetic susceptibility profile that may be leveraged for disease prediction. Using data from the UK Biobank (413,753 individuals; 22,755 incident cancer cases), we quantify the added predictive value of integrating cancer-specific PRS with family history and modifiable risk factors for 16 cancers. We show that incorporating PRS measurably improves prediction accuracy for most cancers, but the magnitude of this improvement varies substantially. We also demonstrate that stratifying on levels of PRS identifies significantly divergent 5-year risk trajectories after accounting for family history and modifiable risk factors. At the population level, the top 20% of the PRS distribution accounts for 4.0% to 30.3% of incident cancer cases, exceeding the impact of many lifestyle-related factors. In summary, this study illustrates the potential for improving cancer risk assessment by integrating genetic risk scores.
Industrialization is associated with elevated rates of horizontal gene transfer in the human microbiome
Authors: Groussin Mathieu , Poyet Mathilde , Sistiaga Ainara , Kearney Sean M. , Moniz Katya , Noel Mary , Hooker Jeff , Gibbons Sean M. , Segurel Laure , Froment Alain , Said Mohamed Rihlat , Fezeu Alain , Juimo Vanessa A. , Girard Catherine , Nguyen Le Thanh Tu , Shapiro B. Jesse , Lehtimäki Jenni M. S. , Ruokolainen Lasse , Kettunen Pinja P. , Vatanen Tommi , Sigwazi Shani , Mabulla Audax , Domínguez-Rodrigo Manuel , Summons Roger E. , Xavier Ramnik J. , Alm Eric J.
Published: January 2020

Horizontal Gene Transfer, the process by which bacteria acquire new genes and functions from non-parental sources, is common in the human microbiome1,2. If the timescale of HGT is rapid compared to the timescale of human colonization, then it could have the effect of ‘personalizing’ bacterial genomes by providing incoming strains with the genes necessary to adapt to the diet or lifestyle of a new host. The extent to which HGT occurs on the timescale of human colonization, however, remains unclear. Here, we analyzed 6,188 newly isolated and sequenced gut bacteria from 34 individuals in 9 human populations, and show that HGT is more common among bacteria isolated from the same human host, indicating that the timescale of transfer is short compared to the timescale of human colonization. Comparing across 9 human populations reveals that high rates of transfer may be a recent development in human history linked to industrialization and urbanization. In addition, we find that the genes involved in transfer reflect the lifestyle of the human hosts, with elevated transfer of carbohydrate metabolism genes in hunter gatherer populations, and transfer of antibiotic resistance genes among pastoralists who live in close contact with livestock. These results suggest that host-associated bacterial genomes are not static within individuals, but continuously acquire new functionality based on host diet and lifestyle.
Polarization of microbial communities between competitive and cooperative metabolism
Authors: Machado Daniel , Maistrenko Oleksandr M. , Andrejev Sergej , Kim Yongkyu , Bork Peer , Patil Kaustubh R. , Patil Kiran R.
Published: January 2020

Resource competition and metabolic cross-feeding are among the main drivers of microbial community assembly. Yet, the degree to which these two conflicting forces are reflected in the composition of natural communities has not been systematically investigated. Here, we use genome-scale metabolic modeling to assess resource competition and metabolic cooperation potential in large co-occurring groups, with up to 40 member species, across thousands of habitats. Our analysis revealed two distinct community types, clustering at opposite ends in a trade-off landscape between competition and cooperation. On one end lie highly cooperative communities, characterized by smaller genomes and multiple auxotrophies, reminiscent of the black queen hypothesis. At the other end lie highly competitive communities, conforming to the red queen hypothesis, featuring larger genomes and overlapping nutritional requirements. While the latter are mainly present in soils, the former are found both in free-living and host-associated habitats. Community-scale flux simulations showed that, while the competitive communities can better resist species invasion but not nutrient shift, the cooperative communities are susceptible to species invasion but resilient to nutrient change. In accord, we show, through analyzing an additional independent dataset, the colonization of the human gut by probiotic species is positively associated with the presence of cooperative species in the recipient microbiome. Together, our analysis highlights the bifurcation between competition and cooperation in the assembly of natural communities and its implications for community modulation.
Parametrising diffusion-taxis equations from animal movement trajectories using step selection analysis
Authors: Potts Jonathan R. , Schlägel Ulrike E.
Published: January 2020

Mathematical analysis of partial differential equations (PDEs) has led to many insights regarding the effect of organism movements on spatial population dynamics. However, their use has mainly been confined to the community of mathematical biologists, with less attention from statistical and empirical ecologists. We conjecture that this is principally due to the inherent difficulties in fitting PDEs to data.

To help remedy this situation, in the context of movement ecology, we show how the popular technique of step selection analysis (SSA) can be used to parametrise a class of PDEs, calleddiffusion-taxismodels, from an animal’s trajectory. We examine the accuracy of our technique on simulated data, then demonstrate the utility of diffusion-taxis models in two ways. First, we derive the steady-state utilisation distribution in a closed analytic form. Second, we give a simple recipe for deriving spatial pattern formation properties that emerge from inferred movement-and-interaction processes: specifically, do those processes lead to heterogeneous spatial distributions and if so, do these distributions oscillate in perpetuity or eventually stabilise? The second question is demonstrated by application to data on concurrently-tracked bank voles (Myodes glareolus).

Our results show that SSA can accurately parametrise diffusion-taxis equations from location data, providing the frequency of the data is not too low. We show that the steady-state distribution of our diffusion-taxis model, where it exists, has an identical functional form to the utilisation distribution given by resource selection analysis (RSA), thus formally linking (fine scale) SSA with (broad scale) RSA. For the bank vole data, we show how our SSA-PDE approach can give predictions regarding the spatial aggregation and segregation of different individuals, which are difficult to predict purely by examining results of SSA.

Our methods give a user-friendly way in to the world of PDEs, via a well-used statistical technique, which should lead to tighter links between the findings of mathematical ecology and observations from empirical ecology. By providing a non-speculative link between observed movement behaviours and space use patterns on larger spatio-temporal scales, our findings will also aid integration of movement ecology into understanding spatial species distributions.
Microbiome structure of ecologically important bioeroding sponges (family Clionaidae): The role of host phylogeny and environmental plasticity
Authors: Sacristán-Soriano Oriol , Turon Xavier , Hill Malcolm
Published: January 2020

The potential of increased bioerosion by excavating sponges in future environmental scenarios represents a potential threat to coral reef structure and function. If we are to predict changes to coral reef habitats, it is important to understand the biology of these sponges. Little is known about prokaryotic associations in excavating sponges despite the fact that evidence indicates they contribute to the sponge growth through their heterotrophic metabolism and may even act as microborers. Here, we provide the first detailed description of the microbial community of multiple bioeroding sponges from the Clionaidae family (Cliona varians,C. tumula,C. delitrix,Spheciospongia vesparium,Cervicornia cuspidifera) collected in inshore and offshore coral reefs in the Florida Keys. A total of 6,811 prokaryote OTUs identified using 16S rRNA gene sequencing was detected in the samples studied, including ambient water, belonging to 39 bacterial phyla and 3 archaeal phyla. The microbiomes of species harboringSymbiodinium(Cliona varians,C. tumula,Cervicornia cuspidifera) and the azooxanthellateS. vespariumwere dominated by Alphaproteobacteria that represented from 83 to 96% of total sequences. These clionaid sponges presented species-specific core microbiomes, with 4 OTUs being shared by all sponge samples, albeit with species-specific enrichments. The microbiomes ofC. variansandS. vespariumwere stable but showed certain plasticity between offshore and inshore reefs. The distantly relatedCliona delitrixdoes not harborSymbiodinium,and had a microbiome dominated by Gammaproteobacteria, which represented 82% of all sequences. Most of the sponge-exclusive OTUs are found in low abundance and belong to the “rare biosphere” category, highlighting the potential importance of these microbes in the ecology of the holobiont. Sponge microbiomes may enhance functional redundancy for the sponge holobiont and allow it to respond to shifting environments over much short time scales than evolutionary change would permit. This work establishes the basis for future research to explore how microbial shifts in bioeroding sponges contribute to bioerosion in the face of a changing environment.
A single-cell transcriptomic and anatomic atlas of mouse dorsal raphePet1neurons
Authors: Okaty Benjamin W. , Sturrock Nikita , Lozoya Yasmin Escobedo , Chang YoonJeung , Senft Rebecca A. , Lyon Krissy A. , Alekseyenko Olga V. , Dymecki Susan M.
Published: January 2020

Among the brainstem raphe nuclei, the dorsal raphe nucleus (DR) contains the greatest number ofPet1-lineage neurons, a predominantly serotonergic group distributed throughout DR subdomains. These neurons collectively regulate diverse physiology and behavior and are often therapeutically targeted to treat affective disorders. CharacterizingPet1neuron molecular heterogeneity and relating it to anatomy is vital for understanding DR functional organization, with potential to inform therapeutic separability. Here we use high-throughput and DR subdomain-targeted single-cell transcriptomics and intersectional genetic tools to map molecular and anatomical diversity of DR-Pet1neurons. We describe up to fourteen neuron subtypes, many showing biased cell body distributions across the DR. We further show thatP2ry1-Pet1DR neurons – the most molecularly distinct subtype – possess unique efferent projections and electrophysiological properties. These data complement and extend previous DR characterizations, combining intersectional genetics with multiple transcriptomic modalities to achieve fine-scale molecular and anatomic identification ofPet1neuron subtypes.
FMR1loss results in early changes to intrinsic membrane excitability in human cellular models
Authors: Susco Sara G. , Arias-Garcia Mario A. , Lopez-Huerta Violeta G. , Beccard Amanda , Bara Anne M. , Moffitt Jessica , Korn Justin , Fu Zhanyan , Barrett Lindy E.
Published: January 2020

Fragile X mental retardation 1 (FMR1)encodes the RNA binding protein FMRP. Loss of FMRP drives Fragile X syndrome (FXS), the leading inherited cause of intellectual disability and a leading monogenic cause of autism. Cortical hyperexcitability is a hallmark of FXS, however, the underlying mechanisms reported, including alterations in synaptic transmission and ion channel expression and properties, are heterogeneous and at times contradictory. Here, we generated isogenicFMR1y/+andFMR1y/-human pluripotent stem cell (hPSC) lines using CRISPR-Cas9, differentiated these stem cell tools into excitatory cortical neurons and systematically assessed the impact of FMRP loss on intrinsic membrane and synaptic properties over the course ofin vitrodifferentiation. Using whole-cell patch clamp analyses at five separate time-points, we observed significant changes in multiple metrics following FMRP loss, including decreased membrane resistance, increased capacitance, decreased action potential half-width and higher maximum frequency, consistent withFMR1y/-neurons overall showing an increased intrinsic membrane excitability compared with age-matchedFMR1y/+controls. Surprisingly, a majority of these changes emerged early duringin vitrodifferentiation and some were not stable over time. Although we detected significant differences in intrinsic properties, no discernable alterations were observed in synaptic transmission. Collectively, this study provides a new isogenic hPSC model to study the mechanisms ofFMR1gene function, identifies electrophysiological impacts of FMRP loss on human excitatory cortical neurons over timein vitro, and underscores that early developmental changes to intrinsic membrane properties may be a critical cellular pathology contributing to cortical hyperexcitability in FXS.
Protein evolution is structure dependent and non-homogeneous across the tree of life
Authors: Pandey Akanksha , Braun Edward L.
Published: January 2020

Motivation

Protein sequence evolution is a complex process that varies among-sites within proteins and across the tree of life. Comparisons of evolutionary rate matrices for specific taxa (‘clade-specific models’) have the potential to reveal this variation and provide information about the underlying reasons for those changes. To study changes in patterns of protein sequence evolution we estimated and compared clade-specific models in a way that acknowledged variation within proteins due to structure.

Results

Clade-specific model fit was able to correctly classify proteins from four specific groups (vertebrates, plants, oomycetes, and yeasts) more than 70% of the time. This was true whether we used mixture models that incorporate relative solvent accessibility or simple models that treat sites as homogeneous. Thus, protein evolution is non-homogeneous over the tree of life. However, a small number of dimensions could explain the differences among models (for mixture models ~50% of the variance reflected relative solvent accessibility and ~25% reflected clade). Relaxed purifying selection in taxa with lower long-term effective population sizes appears to explain much of the among clade variance. Relaxed selection on solvent-exposed sites was correlated with changes in amino acid side-chain volume; other differences among models were more complex. Beyond the information they reveal about protein evolution, our clade-specific models also represent tools for phylogenomic inference.

Availability

Model files are available fromhttps://github.com/ebraun68/clade_specific_prot_models.

Contact

ebraun68@ufl.edu

Supplementary information

Supplementary data are appended to this preprint.
Modifiers and Mediators of Craniosynostosis Severity Revealed by Differential Gene Expression
Authors: Dudakovic Amel , Nam Hwa Kyung , vanWijnen Andre , Hatch Nan E.
Published: January 2020

Severity of craniosynostosis in humans varies widely even in patients with identical genetic mutations. In this study we compared RNA sequencing data from cranial tissues of a severe form of Crouzon craniosynostosis syndrome (C57BL/6 FGFR2C342Y/+mice) with those of a less severe form of Crouzon craniosynostosis (BALB/c FGFR2C342Y/+mice) to identify genetic modifiers that influence craniosynostosis phenotype severity. Comparison of the mice revealed neonatal onset of coronal suture fusion in the form of suture obliteration in C57BL/6 mice (88% incidence, p<.001 between genotypes). Coronal suture fusion in the form of point fusions across the suture occurred at approximately 4 weeks after birth, with less severe skull shape abnormalities, in BALB/c mice. Substantially fewer genes were differentially expressed in BALB/c FGFR2+/+vs. FGFR2C342Y/+mice (87 out of 15,893 expressed genes) than C57BL/6 FGFR2C+/+vs. FGFR2C342Y/+mice (2,043 out of 19,097 expressed genes). Further investigation revealed differential expression of coronal suture fusion associated genes, eph/ephrin boundary genes, cell proliferation genes, osteoblast differentiation genes and epigenetic regulators, among others. The most striking pattern in the data was the minimal change in gene expression seen for most genes in BALB/c FGFR2+/+vs. FGFR2C342Y/+mice. Analysis of protein processing and lysosomal components support the hypothesis that the craniosynostosis phenotype is less severe in BALB/c mice because the mutant FGFR2C342Yprotein is not expressed to the same extent as that seen in C57BL/6 mice. Together, these results suggest that a strategy aimed at increasing degradation of the mutant receptor or downstream signaling inhibition could lead to diminished phenotype severity.
The Landscape of Receptor-Mediated Precision Cancer Combination Therapy: A Single-Cell Perspective
Authors: Ahmadi Saba , Sukprasert Pattara , Vegesna Rahulsimham , Sinha Sanju , Schischlik Fiorella , Artzi Natalie , Khuller Samir , Schäffer Alejandro A. , Ruppin Eytan
Published: January 2020

The availability of single-cell transcriptomics data opens new opportunities for rational design of combination cancer treatments. Mining such data, we employed combinatorial optimization techniques to explore the landscape of optimal combination therapies in solid tumors including brain, head and neck, melanoma, lung, breast and colon cancers. We assume that each individual therapy can target any one of 1269 genes encoding cell surface receptors, which may be targets of CAR-T, conjugated antibodies or coated nanoparticle therapies. As a baseline case, we studied the killing of at least 80% of the tumor cells while sparing more than 90% of the non-tumor cells in each patient, as a putative regimen. We find that in most cancer types, personalized combinations composed of at most four targets are then sufficient. However, the number of distinct targets that one would need to assemble to treat all patients in a cohort accordingly would be around 10 in most cases. Further requiring that the target genes be also lowly expressed in healthy tissues uncovers qualitatively similar trends. However, as one asks for more stringent and selective killing beyond the baseline regimen we focused on, we find that the number of targets needed rises rapidly. Emerging individual promising receptor targets includePTPRZ1, which is frequently found in the optimal combinations for brain and head and neck cancers, andEGFR, a recurring target in multiple tumor types. In sum, this systematic single-cell based characterization of the landscape of combinatorial receptor-mediated cancer treatments establishes first of their kind estimates on the number of targets needed, identifying promising ones for future development.
Pharmacodynamic Markers of LRRK2 Inhibition in Biofluids
Authors: Wang Shijie , Kelly Kaela , Schussler Nathalie , Boularand Sylviane , Dubois Laurent , Hsieh Frank , Tengstrand Elizabeth , Brotchie Jonathan M. , Koprich James B. , West Andrew B.
Published: January 2020

Hyper-activated LRRK2 is linked to Parkinson’s disease susceptibility and progression. Quantitative measures of LRRK2 inhibition, especially in the brain, may be critical in the clinical development of successful LRRK2-targeting therapeutics. In this study, three different brain-penetrant and selective LRRK2 small-molecule kinase inhibitors (PFE-360, MLi2, and RA283) were orally administered to groups of cynomolgus macaques at different doses. Biofluid markers with proposed pharmacodynamic properties for assessing LRRK2 inhibition were measured from samples of blood, urine, and cerebral-spinal fluid (CSF). LRRK2 kinase inhibition led to consistent reduced pS935-LRRK2 and pRab10 proteins in blood mononuclear cells, reduced exosome LRRK2 protein and di-docosahexaenoyl (22:6) bis (monoacylglycerol) phosphate in urine, and reduced exosome LRRK2 and autophosphorylated pS1292-LRRK2 protein in CSF. Incomplete LRRK2 kinase inhibition reduced LRRK2 protein secretion in exosomes whereas high drug exposures may reduce both exosome and tissue levels of LRRK2 protein. These orthogonal markers for LRRK2 inhibition in urine and CSF can be used in combination with blood markers to non-invasively monitor the potency of LRRK2-targeting therapeutics in the brain and periphery.
Trimmed Constrained Mixed Effects Models: Formulations and Algorithms
Authors: Zheng Peng , Barber Ryan , Sorensen Reed , Murray Christopher , Aravkin Aleksandr
Published: January 2020

Mixed effects (ME) models inform a vast array of problems in the physical and social sciences, and are pervasive in meta-analysis. We consider ME models where the random effects component is linear. We then develop an efficient approach for a broad problem class that allows nonlinear measurements, priors, and constraints, and finds robust estimates in all of these cases using trimming in the associated marginal likelihood.

The software accompanying this paper is disseminated as an open-source Python package calledLimeTr.LimeTris able to recover results more accurately in the presence of outliers compared to available packages for both standard longitudinal analysis and meta-analysis, and is also more computationally efficient than competing robust alternatives. Supplementary materials that reproduce the simulations, as well as runLimeTrand third party code are available online. We also present analyses of global health data, where we use advanced functionality ofLimeTr, including constraints to impose monotonicity and concavity for dose-response relationships. Nonlinear observation models allow new analyses in place of classic approximations, such as log-linear models. Robust extensions in all analyses ensure that spurious data points do not drive our understanding of either mean relationships or between-study heterogeneity.
Hierarchical Network Model Excitatory-Inhibitory Tone Shapes Alternative Strategies for Different Degrees of Uncertainty in Multi-Attribute Decisions
Authors: Pettine Warren Woodrich , Louie Kenway , Murray John D , Wang Xiao Jing
Published: January 2020

We investigated two-attribute, two-alternative decision-making in a hierarchical neural network with three layers: an input layer encoding choice alternative attribute values; an intermediate layer of modules processing separate attributes; and a choice layer producing the decision. Depending on intermediate layer excitatory-inhibitory (E/I) tone, the network displays three distinct regimes characterized by linear (I), convex (II) or concave (III) choice indifference curves. In regimes I and II, each option’s attribute information is additively integrated. To maximize reward at low environmental uncertainty, the system should operate in regime I. At high environmental uncertainty, reward maximization is achieved in regime III, with each attribute module selecting a favored alternative, and the ultimate decision based upon comparison between outputs of attribute processing modules. We then use these principles to examine multi-attribute decisions with autism-related deficits in E/I balance, leading to predictions of different choice patterns and overall performance between autism and neurotypicals.
Comparative genomics reveals different population structures associated with host and geographic origin in antimicrobial-resistantSalmonella enterica
Authors: Liao Jingqiu , Orsi Renato Hohl , Carroll Laura , Wiedmann Martin
Published: January 2020

Genetic variation in a pathogen, including the causative agent of salmonellosis,Salmonella enterica, can occur as a result of eco-evolutionary forces triggered by dissimilarities of ecological niches. Here, we applied comparative genomics to study 90 antimicrobial resistant (AMR)S. entericaisolates from bovine and human hosts in New York state and Washington state to understand host- and geographic-associated population structure. Results revealed distinct presence/absence profiles of functional genes and pseudogenes (e.g., virulence genes) associated with bovine and human isolates. Notably, bovine isolates contained significantly more transposase genes but fewer transposase pseudogenes than human isolates, suggesting the occurrence of large-scale transposition in genomes of bovine and human isolates at different times. The high correlation between transposase genes and AMR genes, as well as plasmid replicons, highlights the potential role of horizontally transferred transposons in promoting adaptation to antibiotics. By contrast, a number of potentially geographic-associated single-nucleotide polymorphisms (SNPs), rather than geographic-associated genes, were identified. Interestingly, 38% of these SNPs were in genes annotated as cell surface protein-encoding genes, including some essential for antibiotic resistance and host colonization. Overall, different evolutionary forces and limited recent inter-population transmission appear to shape AMRS. entericapopulation structure in different hosts and geographic origins.

Originality/Significance Statement

Salmonella enterica, which is the causative agent of salmonellosis, poses a growing public health concern due to the emergence and spread of antimicrobial resistant (AMR) strains. The mechanisms underlying the population structure associated with different hosts and geographic origins of AMRS. entericaare underexplored due to limited genome-wide studies assessing the impact of ecological niches on genetic variations. By employing comparative genomics, our study provided insights into the genomic profiles of AMRS. entericaassociated with two distinct hosts and two distant geographic locations, improving the mechanistic understanding of how bacterial population structure is shaped by different ecological niches. Our findings have broad implications for elucidating the impact of ecological and evolutionary forces on the adaptation, antimicrobial resistance, and pathogenicity of bacteria. Also, specific genetic markers we identified may help predict host or geographic origin of AMRSalmonellaisolates, which could benefit the source tracking (e.g., host and geographic origins) of human disease cases and contamination events caused by AMRS. enterica.
Responsive fluorophore aggregation provides spectral contrast for fluorescence lifetime imaging
Authors: Schleyer Kelton A. , Datko Benjamin D. , Burnside Brandon , Cui Chao , Ma Xiaowei , Grey John K. , Cui Lina
Published: January 2020

Fluorophores experience altered emission lifetimes when incorporated into and liberated from macromolecules or molecular aggregates; this trend suggests the potential for a fluorescent, responsive probe capable of undergoing self-assembly and aggregation and consequently altering the lifetime of its fluorescent moiety to provide contrast between the active and inactive probes. We developed a cyanobenzothioazole-fluorescein conjugate (1), and spectroscopically examined the lifetime changes caused by its reduction-induced aggregationin vitro. A decrease in lifetime was observed for compound1in a buffered system activated using the biological reducing agent glutathione, suggesting a possible approach for designing responsive self-aggregating lifetime imaging probes.