bluuebunny/crossref_metadata_2025 huggingface dataset:
Using performance frontiers to differentiate elective and capacity-based surgical services
Authors: Ranney Stephen E. , Tsai Mitchell H. , Breidenstein Max W. , Sexton Kevin W. , Malhotra Ajai K.
Published: February 2021

BACKGROUND

Acute care surgery (ACS) model of care delivery has many benefits. However, since the ACS surgeon has limited control over the volume, timing, and complexity of cases, traditional metrics of operating room (OR) efficiency almost always measure ACS service as “inefficient.” The current study examines an alternative method—performance fronts—of evaluating changes in efficiency and tests the following hypotheses: (1) in an institution with a robust ACS service, performance front methodology is superior to traditional metrics in evaluating OR throughput/efficiency, and (2) introduction of an ACS service with block time allocation will improve OR throughput/efficiency.

METHODS

Operating room metrics 1-year pre–ACS implementation and post–ACS implementation were collected. Overall OR efficiency was calculated by mean case volumes for the entire OR and ACS and general surgery (GS) services individually. Detailed analysis of these two specific services was performed by gathering median monthly minutes—in block, out of block, after hours, and opportunity unused. The two services were examined using a traditional measure of efficiency and the “fronts” method. Services were compared with each other and also pre–ACS implementation and post–ACS implementation.

RESULTS

Overall OR case volumes increased by 5% (999 ± 50 to 1,043 ± 46: p < 0.05) with almost all of the increase coming through ACS (27 ± 4 to 68 ± 16: p < 0.05). By traditional metrics, ACS had significantly worse median efficiency versus GS in both periods: pre (0.67 [0.66–0.71] vs. 0.80 [0.78–0.81]) and post (0.75 [0.53–0.77] vs. 0.83 [0.84–0.85]) (p < 0.05). As compared with the pre, GS efficiency improved significantly in post (p < 0.05), but ACS efficiency remained unchanged (p > 0.05). The alternative fronts chart demonstrated the more accurate picture with improved efficiency observed for GS, ACS, and combined.

CONCLUSION

In an institution with a busy ACS service, the alternative fronts methodology offers a more accurate evaluation of OR efficiency. The provision of an OR for the ACS service improves overall throughput/efficiency.
Futile trauma transfers: An infrequent but costly component of regionalized trauma care
Authors: Follette Craig , Halimeh Bachar , Chaparro Annelise , Shi Alan , Winfield Robert
Published: February 2021

BACKGROUND

Appropriate interfacility transfers are a key component of highly functioning trauma systems but transfer of unsalvageable patients can overburden the resources of higher-level centers. We sought to identify the occurrence and associated reasons for futile transfers within our trauma system.

METHODS

Using prospectively collected data from our system database, a retrospective cohort study was conducted to identify patients who underwent interfacility transfer to our American College of Surgeons level I center. Adult patients from June 2017 to June 2019 who died, had comfort measures implemented, were discharged, or went to hospice care within 48 hours of admission without significant operation, procedure, or radiologic intervention were examined. Futility was defined as resulting in death or hospice discharge within 48 hours of transfer without major operative, endoscopic, or radiologic intervention.

RESULTS

A total of 1,241 patients transferred to our facility during the study period. Four hundred seven patients had a length of stay less than or equal to 48 hours. Eighteen (1.5%) met the criteria for futility. The most common reason for transfer in the futile population was traumatic brain injury (56%) and need for neurosurgical capabilities (62%). Futile patients had a median age and Injury Severity Score of 75 and 21. The main transportation method was ground 9 (50%) with 8 (44.4%) being transported by helicopter and 1 (5.6%) being transported by both. Combining transport costs with hospital charges, each futile transfer was estimated to cost US $56,396 (interquartile range, 41,889–106,393) with a total cost exceeding US $1.7 million. With an estimated 33,000 interfacility transfers annually for trauma in the United States, the cost of futile transfers to the American trauma system would exceed 27 million dollars each year.

CONCLUSION

Futile transfers represent a small but costly portion transfer volume. Identification of patients whose conditions preclude the benefit of transfer due to futility and development of appropriate support for referral will significantly improve appropriate allocation of health care resources.

LEVEL OF EVIDENCE

Economic; Care management, level IV.
Transplant Hepatectomy With Portacaval Shunt and MARS Therapy for Perioperative Catastrophe: A Series of Four Liver Transplant Cases
Authors: Cimeno Arielle , Sultan Samuel , Alvarez-Casas Josue , Hanish Steven I. , Bruno David A. , Hutson William R. , Stein Deborah M. , Scalea Thomas M. , Barth Rolf N. , LaMattina John C.
Published: February 2021

Background.

Increased worldwide focus on maximal donor utilization and transplantation of patients once considered too ill to survive liver transplantation may increase the otherwise rare frequency of catastrophic graft failure. Although the deleterious effects of an acutely failing allograft have been established for decades, the optimal strategy in this patient population in the perioperative period remains ill-defined.

Methods.

A retrospective review of all liver transplant recipients with perioperative failure leading to transplant hepatectomy between January 1, 2014 and June 30, 2017 was performed. All patients were supported with MARS therapy while awaiting retransplantation.

Results.

Four patients experienced catastrophic graft failure from massive exsanguination and liver fracture (1), portal vein and hepatic artery thrombosis (1), idiopathic necrosis (1), and necrosis from inadequate donor flushing/primary nonfunction (1). All patients improved following transplant hepatectomy with portacaval shunting. Patients were supported with intubation, vasopressors, renal replacement therapy, and Molecular Adsorbent Recirculating System therapy. All patients underwent retransplantation after a mean anhepatic phase of 48.8 (± 5.13) h. Survival to discharge was 75%.

Conclusions.

Although catastrophic liver failure is highly challenging, acceptable outcomes can be achieved with timely hepatectomy with portacaval shunt and retransplantation, particularly in patients supported with the Molecular Adsorbent Recirculating System device.
Peer Mentoring as an Avenue to Explore in Kidney Transplantation: Kidney Transplant Recipients’ Perspectives on Peer Mentoring
Authors: Pomey Marie-Pascale , Gallego Fabián Ballesteros , Affdal Alya , Fortin Marie-Chantal
Published: February 2021

Background.

Kidney transplant recipients (KTRs) face numerous challenges following transplantation. Given that healthcare professionals do not necessarily have first-hand experience living with or waiting for a transplant, it may be hard for them to communicate with and help patients when it comes to transplant-related issues. KTRs have experiential knowledge, which could enable them to help other patients going through similar situations. Peer mentoring involves pairing mentees with individuals who have had similar experiences, to provide training, information, and emotional support. The aim of this study was to gather KTRs’ perspectives on a potential peer mentoring program.

Methods.

A total of 13 KTRs took part in focus groups between June 2017 and March 2018. The focus group discussions were digitally recorded and transcribed. The content of the interviews was analyzed using the qualitative data analysis method, including deductive and inductive coding techniques.

Results.

All participants were supportive of a peer mentoring program as it is a convenient and user-friendly way to address posttransplant concerns. Peer mentoring was also viewed as a way to communicate with other patients who have gone through similar experiences and relieve the loneliness and isolation some participants experienced subsequent to their transplant. Young female participants expressed a need to connect with other young, female transplant recipients to be able to discuss issues such as pregnancy, sexuality, and body image.

Conclusions.

KTRs who participated in this study expressed a need for the development of a peer mentoring program to help other KTRs face the medical (including cardiovascular disease), social, and psychological challenges associated with kidney transplantation. The results of this study are the first step in the development of a structured peer mentoring program at the kidney transplantation clinic.
Imaging Errors in Distinguishing Pituitary Adenomas From Other Sellar Lesions
Authors: Altshuler David B. , Andrews Chris A. , Parmar Hemant A. , Sullivan Stephen E. , Trobe Jonathan D.
Published: February 2021

Background:

Pituitary adenomas and nonadenomatous lesions in the sellar region may be difficult to distinguish by imaging yet that distinction is critical in guiding management. The nature of the diagnostic errors in this setting has not been well documented.

Methods:

Two neurosurgeons and 2 neuroradiologists of differing experience levels viewed deidentified MRIs of 18 nonadenomatous sellar lesions and 21 adenomas. They recorded their diagnoses, the imaging features they used to make those diagnoses, and their confidence in making those diagnoses.

Results:

Among the 18 nonadenoma cases, 11 (61%) were incorrectly diagnosed as adenoma by at least 1 reader, including Rathke cleft cyst, plasmacytoma, aneurysm, craniopharyngioma, chordoma, Langerhans cell histiocytosis, metastasis, and undifferentiated sinonasal carcinoma. Among the 21 adenoma cases, 8 (38%) were incorrectly diagnosed by at least 1 reader as craniopharyngioma, Rathke cleft cyst, sinonasal carcinoma, hemangioblastoma, and pituitary hyperplasia. Incorrect imaging diagnoses were made with high confidence in 13% of readings. Avoidable errors among the nonadenomatous cases occurred when readers failed to appreciate that the lesion was separate from the pituitary gland. Unavoidable errors in those cases occurred when the lesions were so large that the pituitary gland had been obliterated or the imaging features of a nonadenomatous lesion resembled those of a cystic pituitary adenoma. Avoidable errors in misdiagnosis of adenomas as nonadenomas occurred when readers failed to appreciate features highly characteristic of adenomas. An unavoidable error occurred because a cystic adenoma had features correctly associated with craniopharyngioma.

Conclusions:

Errors in imaging differentiation of pituitary adenoma from nonadenomatous lesions occurred often and sometimes with high confidence among a small sample of neurosurgeons and neuroradiologists. In the misdiagnosis of nonadenomatous lesions as adenomas, errors occurred largely from failure to appreciate a separate pituitary gland, but unavoidable errors occurred when large lesions had obliterated this distinguishing feature. In the misdiagnosis of adenomas as nonadenomatous lesions, avoidable errors occurred because readers failed to recognize imaging features more characteristic of adenomas and because cystic adenomas share features with craniopharyngiomas and Rathke cleft cysts. Awareness of these errors should lead to improved management of sellar lesions.
Peripapillary Hyper-reflective Ovoid Mass-like Structure (PHOMS): An Optical Coherence Tomography Marker of Axoplasmic Stasis in the Optic Nerve Head
Authors: Fraser J. Alexander , Sibony Patrick A. , Petzold Axel , Thaung Caroline , Hamann Steffen ,   for the ODDS Consortium
Published: February 2021

Background:

With the development and widespread adoption of spectral-domain optical coherence tomography (OCT), peripapillary hyper-reflective ovoid mass-like structures (PHOMS) have become a frequent OCT finding in neuro-ophthalmic practice. Although originally assumed to represent a form of buried optic disc drusen (ODD), PHOMS differ from ODD in many important ways. The histopathological underpinnings of PHOMS are now becoming more clearly understood.

Evidence acquisition:

Review of literature.

Results:

PHOMS can be broadly classified as disk edema–associated PHOMS, ODD-associated PHOMS, or anomalous disk–associated PHOMS. PHOMS are seen in many conditions, including papilledema, nonarteritic anterior ischemic optic neuropathy, central retinal vein occlusion, acute demyelinating optic neuritis, ODD, and tilted disks (myopic obliquely inserted disks) and in many cases resolve along with the underlying condition. The histopathological study of these diverse entities reveals the common feature of a bulge of optic nerve fibers herniating centrifugally over Bruch membrane opening into the peripapillary space, correlating exactly with the location, shape, and space-occupying nature of PHOMS on OCT. Because of the radial symmetry of these herniating optic nerve fibers, PHOMS are best thought of as a complete or partial torus (i.e., donut) in 3 dimensions.

Conclusions:

PHOMS are a common but nonspecific OCT marker of axoplasmic stasis in the optic nerve head. They are not themselves ODD or ODD precursors, although they can be seen in association with ODD and a wide spectrum of other conditions. They do not exclude papilledema and often accompany it. The circumferential extent and characteristic 3D toroidal nature of a PHOMS are best appreciated by scrolling through consecutive OCT images.
Tongue as a Wire? Glossokinetic Artifact and Insights From Intracranial EEG
Authors: Bayram Ayşe Kaçar , Spencer Dennis D. , Alkawadri Rafeed
Published: February 2021

Background:

Glossokinetic artifact (GKA) is a well-known scalp EEG artifact characterized by deflections within the delta to low-theta frequency bands and dynamic polarity typically attributed to the direction of tongue movement. This study aims to investigate intracranial EEG correlations of scalp-GKA. If the tongue is a dipole, per the conventional view, then volume-conducted deflections are expected in the nearest frontal intracranial EEG contacts.

Materials and Methods:

Simultaneous scalp and intracranial EEG recordings were evaluated in five consecutive medically resistant epilepsy patients at Yale Epilepsy Center in 2017 and 2018, who had classic GKA deflections on scalp EEG. The EEG was sampled at 2,048 to 4,096 Hz and analyzed visually, using a reference placed in the diploic space or over the convexity, and confirmed quantitatively by a statistical framework. Ten GKA deflections were analyzed per case.

Results:

The medians of age at the time of recording, contacts per case, and amplitude of scalp GKA deflections were 35 years (range: 20–41 years), 171 contacts (range: 165–241 contacts), and 56 μV (range: 51–72 μV), respectively. There were no slow discharges in the frontal intracranial EEG contacts synchronized with the scalp GKA, either in the delta (1–3 Hz) or in the sub-delta (0.1–1 Hz) bands. However, the expected physiologic attenuation of alpha and beta rhythms and the emergence of high-gamma activity were observed over the peri-Rolandic regions in the invasive recordings.

Conclusions:

The traditional view of the tongue as a dipole generator of scalp GKA is simplistic and does not account for the findings reported herein. The tongue most probably shunts other scalp and soft-tissue currents. Knowledge of tongue potentials is of interest in the education and the design of tongue–computer interfaces.
Neurophysiological Findings in Critical COVID-19 Patients With Peripheral Nervous System Manifestations
Authors: Santiago-Pérez Susana , Espinosa-García Sandra , Martínez-Pérez Almudena , Herráez-Sánchez Erika , Rizea Cristian , Ruiz-Ávila Lilia Alejandrina
Published: February 2021

Introduction:

Coronavirus disease 2019 patients hospitalized in intensive care units develop neuromuscular manifestations. However, to our knowledge, a study describing the neurophysiological findings in these patients has not been reported. The objective of this study was to diagnose the cause of neuromuscular deficit in severe coronavirus disease 2019 patients, through neurophysiological examination.

Methods:

This is a retrospective, observational case series. Data were collected from April 13, 2020, to May 31, 2020. Twenty-two coronavirus disease 2019 patients with generalized neuromuscular deficit during intensive care unit hospitalization were studied. Neurophysiological examinations included motor and sensory peripheral nerve conductions, needle electromyography, F waves, and repetitive nerve stimulation.

Results:

The subjects were 14 men (63.6%) and eight women, ranged from 35 to 74 years old (58.0, interquartile ranges 50.7–66.2). Intensive care unit hospitalization time ranged from 14 to 82 days (median 37.5, interquartile ranges 22.7–55.0). Through neurophysiological examination, myopathy was diagnosed in 17 patients (77.3%) and polyneuropathy in four (18.2%). Focal neuropathies were diagnosed in 12 patients (54.6%), with a total of 19 affected nerves. Common peroneal nerve lesions at the fibular head (68.4%) and ulnar nerve lesions at the elbow level (21.1%) were the most frequent locations. No significant differences were established between neurophysiological findings and clinical or analytical data.

Conclusions:

In critical coronavirus disease 2019 patients with neuromuscular complaints, neurophysiological examination provides an accurate diagnosis—useful to select treatment measures and establish the prognosis of recovery. Neurophysiological findings are similar to those described for critical illness neuromuscular disease, with myopathy being the most frequent diagnosis.
The relationship between rheumatoid arthritis and diabetes mellitus: a systematic review and meta-analysis
Authors: Tian Zixing , Mclaughlin John , Verma Arpana , Chinoy Hector , Heald Adrian H.
Published: February 2021

Objective

This systematic review/meta-analysis was conducted to investigate the relationship between rheumatoid arthritis and the incidence of diabetes mellitus.

Methods

A comprehensive search was conducted up to 10 March 2020 in Medline (via Ovid), Embase (via Ovid) and Web of Science core collection to identify cohort studies comparing the risk of diabetes mellitus incidence in people with rheumatoid arthritis with the general population. The I2 statistic was used to test heterogeneity. Pooled relative risks were calculated using random-effects models. Publication bias was assessed using Egger’s test and Begg’s test.

Results

The initial search provided 3669 articles. Of those, five journal articles/two conference abstracts comprising 1 629 854 participants were included in this study. The funnel plot showed potential publication bias, proven by Egger’s test (−3.15, P < 0.01), but not Begg’s test (−0.05, P = 1.00). Heterogeneity was observed in I2 test (I2 = 96%, P < 0.01). We found that rheumatoid arthritis was associated with a higher risk of diabetes mellitus incidence (pooled relative risk, 1.23; 95% confidence interval, 1.07–1.40). Exploration of potential sources of heterogeneity found significant heterogeneity in different countries/regions (P = 0.002), but heterogeneity was NS in different study designs (P = 0.30). Sensitivity analyses confirmed that the association between rheumatoid arthritis and diabetes mellitus incidence was robust.

Conclusion

Rheumatoid arthritis is associated with an increased risk of diabetes mellitus incidence. This finding supports the notion that inflammatory pathways are involved in the pathogenesis of diabetes. More intensive interventions targeting diabetes risk factors should be considered in people with rheumatoid arthritis.
Trends for Electroconvulsive Therapy Utilization in Children and Adolescents in the United States From 2002 to 2017
Authors: Trivedi Chintan , Motiwala Fatima , Mainali Pranita , Mansuri Zeeshan , Jain Shailesh
Published: February 2021

Objectives

Electroconvulsive therapy (ECT) is controversial in children and adolescents (C/A). The primary objective of this study was to evaluate baseline characteristics of C/A in the utilization of ECT compared with the non-ECT group with the same primary indication. The secondary objective was to assess the trends in ECT utilization over 16 years and explore the predictors of length of stay.

Methods

Using the Nationwide Inpatient Sample database from the years 2002 to 2017, we identified patients (age ≤18 years) undergoing ECT in the United States using International Classification of Diseases, Ninth Revision and Tenth Revision, Clinical Modification/Procedure Coding System codes and compared with non-ECT C/A patients with the same primary diagnosis. Baseline clinical characteristics were assessed using descriptive analysis methods. Multilevel regression analysis and trend analysis were performed.

Results

Children and adolescent patients (n = 159,158) receiving (ECT: n = 1870) were more likely to be men (43.3% vs 36.7%) and of White race (58% vs 49%) (P < 0.001). The hospital stay was longer (19 days vs 6 days, P < 0.001) for the ECT group than controls. ECT receiving C/A patients were more likely to have private insurance (72% vs 42%, P < 0.001). African American patients undergoing ECT treatment increased in number over the course of years (2002 to 2017), whereas the privately insured C/A patients receiving ECT decreased over the same period (P < 0.001). There was an upward trend in ECT utilization for small bed size hospitals (P < 0.001). Length of stay for C/A receiving ECT was longer for males (P < 0.001) and patients with nonprivate insurance (p: 0.003).

Conclusions

Electroconvulsive therapy is not optimally used in C/A; therefore, formulated treatment guidelines are required.
A Tad-like apparatus is required for contact-dependent prey killing in predatory social bacteria
Authors: Seef Sofiene , Herrou Julien , de Boissier Paul , My Laetitia , Brasseur Gael , Robert Donovan , Jain Rikesh , Mercier Romain , Cascales Eric , Habermann Bianca , Mignot Tâm
Published: February 2021

Myxococcus xanthus, a soil bacterium, predates collectively using motility to invade prey colonies. Prey lysis is mostly thought to rely on secreted factors, cocktails of antibiotics and enzymes, and direct contac withMyxococcuscells. In this study, we show that on surfaces the coupling of A-motility and contact-dependent killing is the central predatory mechanism driving effective prey colony invasion and consumption. At the molecular level, contact-dependent killing involves a newly discovered type IV filament-like machinery (Kil) that both promotes motility arrest and prey cell plasmolysis. In this process, Kil proteins assemble at the predator-prey contact site, suggesting that they allow tight contact with prey cells for their intoxication. Kil-like systems form a new class of Tad-like machineries in predatory bacteria, suggesting a conserved function in predator-prey interactions. This study further reveals a novel cell-cell interaction function for bacterial pili-like assemblages.
Chronic wireless neural population recordings with common marmosets
Authors: Walker Jeffrey D. , Pirschel Friederice , Sundiang Marina , Niekrasz Marek , MacLean Jason N. , Hatsopoulos Nicholas G.
Published: February 2021

Marmosets are an increasingly important model system for neuroscience in part due to genetic tractability and enhanced cortical accessibility, due to a lissencephalic neocortex. However, many of the techniques generally employed to record neural activity in primates inhibit the expression of natural behaviors in marmosets precluding neurophysiological insights. To address this challenge, we developed methods for recording neural population activity in unrestrained marmosets across multiple ethological behaviors, multiple brain states, and over multiple years. Notably, our flexible methodological design allows for replacing electrode arrays and removal of implants providing alternative experimental endpoints. We validate the method by recording sensorimotor cortical population activity in freely moving marmosets across their natural behavioral repertoire and during sleep.

HIGHLIGHTS

– Simultaneous and chronic wireless neural population recordings in multiple freely moving marmosets

– Neural recording approach enables studies of natural repertoire of behaviors and sleep

– Methyl-methacrylate free surgical approach designed to promote biocompatibility and longitudinal success of the implant

– Modular headstage configuration requires minimal daily animal handling for daily neural recordings

– Alternative experimental endpoints: implant removal, healing, and electrode array replacement
A public broadly neutralizing antibody class targets a membrane-proximal anchor epitope of influenza virus hemagglutinin
Authors: Guthmiller Jenna J. , Han Julianna , Utset Henry A. , Li Lei , Lan Linda Yu-Ling , Henry Carole , Stamper Christopher T. , Stovicek Olivia , Gentles Lauren , Dugan Haley L. , Zheng Nai-Ying , Richey Sara T. , Tepora Micah E. , Bitar Dalia J. , Changrob Siriruk , Strohmeier Shirin , Huang Min , García-Sastre Adolfo , Nachbagauer Raffael , Palese Peter , Bloom Jesse D. , Krammer Florian , Coughlan Lynda , Ward Andrew B. , Wilson Patrick C.
Published: February 2021

Broadly neutralizing antibodies against influenza virus hemagglutinin (HA) have the potential to provide universal protection against influenza virus infections. Here, we report a distinct class of broadly neutralizing antibodies targeting an epitope toward the bottom of the HA stalk domain where HA is “anchored” to the viral membrane. Antibodies targeting this membrane-proximal anchor epitope utilized a highly restricted repertoire, which encode for two conserved motifs responsible for HA binding. Anchor targeting B cells were common in the human memory B cell repertoire across subjects, indicating pre-existing immunity against this epitope. Antibodies against the anchor epitope at both the serological and monoclonal antibody levels were potently induced in humans by a chimeric HA vaccine, a potential universal influenza virus vaccine. Altogether, this study reveals an underappreciated class of broadly neutralizing antibodies against H1-expressing viruses that can be robustly recalled by a candidate universal influenza virus vaccine.
GUIdEStaR (G-quadruplex, uORF, IRES, Epigenetics, Small RNA, Repeats), the integrated metadatabase in conjunction with neural network methods
Authors: Kang Jee Eun
Published: February 2021

GUIdEStaR integrates existing databases of various types of G-quadruplex, upstream Open Reading Frame (uORF), Internal Ribosome Entry Site (IRES), methylation to RNA and histone protein, small RNA, and repeats. GUIdEStaR consists of approx. 40,000 genes and 320,000 transcripts. An mRNA transcript is divided into 5 regions (5’UTR, 3’UTR, exon, intron, and biological region) where each region contains presence-absence data of 169 different types of elements. Recently, artificial intelligence (AI) based analysis of sequencing data has been gaining popularity in the area of bioinformatics. GUIdEStaR generates datasets that can be used as inputs to AI methods. At the GUIdEStaR homepage, users submit gene symbols by clicking a “Send” button, and shortly result files in CSV format are available for download at the result website. Users have an option to send the result files to their email addresses. Additionally, the entire database and the example Java codes are also freely available for download. Here, we demonstrate the database usage with three neural network classification studies-1) small RNA study for classifying transcription factor (TF) genes into either one of TF mediated by small RNA originated from SARS-CoV-2 or by human microRNA (miRNA), 2) cell membrane receptor study for classifying receptor genes as either with virus interaction or without one, and 3) nonsense mediated mRNA decay (NMD) study for classifying cell membrane and nuclear receptors as either NMD target or non-target. GUIdEStaR is available for access to the easy-to-use web-based database atwww.guidestar.krand for download athttps://sourceforge.net/projects/guidestar.
AMBIENT: Accelerated Convolutional Neural Network Architecture Search for Regulatory Genomics
Authors: Zhang Zijun , Cofer Evan M. , Troyanskaya Olga G.
Published: February 2021

Convolutional neural networks (CNN) have become a standard approach for modeling genomic sequences. CNNs can be effectively built by Neural Architecture Search (NAS) by trading computing power for accurate neural architectures. Yet, the consumption of immense computing power is a major practical, financial, and environmental issue for deep learning. Here, we present a novel NAS framework, AMBIENT, that generates highly accurate CNN architectures for biological sequences of diverse functions, while substantially reducing the computing cost of conventional NAS.
Calprotectin-mediated zinc chelation inhibitsPseudomonas aeruginosaprotease activity in cystic fibrosis sputum
Authors: Vermilyea Danielle M. , Crocker Alex W. , Gifford Alex H. , Hogan Deborah A.
Published: February 2021

Pseudomonas aeruginosainduces pathways indicative of low zinc availability in the cystic fibrosis (CF) lung environment. To learn more aboutP. aeruginosazinc access in CF, we grewP. aeruginosastrain PAO1 directly in expectorated CF sputum. TheP. aeruginosaZur transcriptional repressor controls the response to low intracellular zinc, and we used the NanoString methodology to monitor levels of Zur-regulated transcripts including those encoding a zincophore system, a zinc importer, and paralogs of zinc containing proteins that do not require zinc for activity. Zur-controlled transcripts were induced in sputum-grownP. aeruginosacompared to control cultures, but not if the sputum was amended with zinc. Amendment of sputum with ferrous iron did not reduce expression of Zur-regulated genes. A reporter fusion to a Zur-regulated promoter had variable activity inP. aeruginosagrown in sputum from different donors, and this variation inversely correlated with sputum zinc concentrations. Recombinant human calprotectin (CP), a divalent-metal binding protein released by neutrophils, was sufficient to induce a zinc-starvation response inP. aeruginosagrown in laboratory medium or zinc-amended CF sputum indicating that CP is functional in the sputum environment. Zinc metalloproteases comprise a large fraction of secreted zinc-bindingP. aeruginosaproteins. Here we show that recombinant CP inhibited both LasB-mediated casein degradation and LasA-mediated lysis ofStaphylococcus aureus, which was reversible with added zinc. These studies reveal the potential for CP-mediated zinc chelation to post-translationally inhibit zinc metalloprotease activity and thereby impact the protease-dependent physiology and/or virulence ofP. aeruginosain the CF lung environment.

Importance

The factors that contribute to worse outcomes in individuals with cystic fibrosis (CF) with chronicPseudomonas aeruginosainfections are not well understood. Therefore, there is a need to understand environmental factors within the CF airway that contribute toP. aeruginosacolonization and infection. We demonstrate that growing bacteria in CF sputum induces a zinc-starvation response that inversely correlates with sputum zinc levels. Additionally, both calprotectin and a chemical zinc chelator inhibit the proteolytic activities of LasA and LasB proteases suggesting that extracellular zinc chelators can influence proteolytic activity and thusP. aeruginosavirulence and nutrient acquisitionin vivo.
Functional characterization of ovine dorsal root ganglion neurons reveals peripheral sensitization after osteochondral defect
Authors: Chakrabarti Sampurna , Ai Minji , Katherine Wong Wai Ying , Newell Karin , Henson Frances M.D. , John Smith Ewan St.
Published: February 2021

Objective

Knee joint trauma can cause an osteochondral defect (OD), a risk factor for osteoarthritis and cause of debilitating pain in patients. Modelling OD in rodents is difficult due to their smaller joint size. This study proposes sheep as a translationally relevant model to understand the neuronal basis of OD pain.

Methods

Unilateral 6 mm deep OD was induced in adult sheep, 2-6 weeks after which dorsal root ganglion neurons (DRG neurons) were cultured from the control and OD side. Functional assessment of neuronal excitability and activity of the pain-related ion channels, TRPV1 and P2X3, was carried out using electrophysiology and Ca2+-imaging. Immunohistochemistry was utilized to verify expression of pain-related proteins.

Results

An increased proportion of OD DRG neurons (sheep, n = 3, Ctrl neurons, n =15, OD neurons, n = 16) showed spontaneous electrical excitability (p = 0.009, unpaired t-test) and hyperexcitability upon TRPV1 agonist (capsaicin) application (p = 0.04, chi-sq test). Capsaicin also produced Ca2+influx in an increased proportion of OD DRG neurons isolated (p = 0.001, chi-sq test). By contrast, neither protein expression, nor functionality of the P2X3 ion channel were altered in OD neurons.

Conclusions

We provide evidence of increased excitability of DRG neurons (which is an important neural correlate of pain) and TRPV1 function in an OD sheep model. Our data show that functional assessment of sheep DRG neurons can provide important insights into the neural basis of OD pain and thus potentially prevent its progression into arthritic pain.
Genomic analyses of the extinct Sardinian dhole (Cynotherium sardous) reveal its evolutionary history
Authors: Ciucani Marta Maria , Jensen Julie Kragmose , Sinding Mikkel-Holger S. , Smith Oliver , Lucenti Saverio Bartolini , Rosengren Erika , Rook Lorenzo , Tuveri Caterinella , Area Marisa , Cappellini Enrico , Galaverni Marco , Randi Ettore , Guojie Chunxue , Zhang Guojie , Sicheritz-Pontén Thomas , Dalén Love , Gilbert M. Thomas P. , Gopalakrishnan Shyam
Published: February 2021

The Sardinian dhole (Cynotherium sardous)1 was an iconic and unique canid species of canid that was endemic of Sardinia and Corsica until it became extinct at the end of the Late Pleistocene2–5. Given its peculiar dental morphology, small body size and high level of endemism, several canids have been proposed as possible ancestors of the Sardinian dhole, including the Asian dhole and African hunting dog ancestor 3,6–9. Morphometric analyses3,6,8–12 have failed to clarify the evolutionary relationship with other canids.

We sequenced the genome of a ca 21,100 year old Sardinian dhole in order to understand its genomic history and clarify its phylogenetic position. We found it represents a separate taxon from all other living canids from Eurasia, Africa and North America, and that the Sardinian and Asian dhole lineages diverged ca 885 ka. We additionally detected historical gene flow between the Sardinian and Asian dhole lineages, that ended approximately 500-300 ka, when the landbridge between Sardinia and mainland Italy was broken, severing their population connectivity. Our sample showed low genome-wide diversity compared to other extant canids - probably a result of the long-term isolation - that could have contributed to the subsequent extinction of the Sardinian dhole.
A Regression Framework for Brain Network Distance Metrics
Authors: Tomlinson Chal E. , Laurienti Paul J. , Lyday Robert G. , Simpson Sean L.
Published: February 2021

Analyzing brain networks has long been a prominent research topic in neuroimaging. However, statistical methods to detect differences between these networks and relate them to phenotypic traits are still sorely needed. Our previous work developed a novel permutation testing framework to detect differences between two groups. Here we advance that work to allow both assessing differences by continuous phenotypes and controlling for confounding variables. To achieve this, we propose an innovative regression framework to relate distances between brain network features to functions of absolute differences in continuous covariates and indicators of difference for categorical variables. We explore several similarity metrics for comparing distances between connection matrices, and adapt several standard methods for estimation and inference within our framework: Standard F-test, F-test with individual level effects (ILE), Feasible Generalized Least Squares (FGLS), and Permutation. Via simulation studies, we assess all approaches for estimation and inference while comparing them with existing Multivariate Distance Matrix Regression (MDMR) methods. We then illustrate the utility of our framework by analyzing the relationship between fluid intelligence and brain network distances in Human Connectome Project (HCP) data.

Highlights

Related distances between connection matrices to differences in covariates.

Adapted methods for estimation and inference in this framework.

Assessment of methods and distance metrics via simulation.

Compared our methods to existing MDMR methods via simulation.

Analysis of the HCP data with the best approach for each distance metric.
UV-B exposure and exogenous hydrogen peroxide application leads to cross-tolerance toward drought in Nicotiana tabacum L
Authors: Diana Sáenz-de la O , Morales Luis O. , Strid Åke , Torres-Pacheco Irineo , Guevara-González Ramón G.
Published: February 2021

Acclimation of plants to water deficit involves biochemical and physiological adjustments. Here, we studied how UV-B exposure and exogenously applied hydrogen peroxide (H2O2) potentiates drought tolerance in tobacco (Nicotiana tabacum L.). Separate and combined applications for 14 days of 1.75 kJ m−2 day−1 UV-B radiation and 0.2 mM H2O2 were assessed. Both factors, individually and combined, resulted in inhibition of growth. Furthermore, the combined treatment led to the most compacted plants. UV-B- and UV-B+H2O2-treated plants increased total antioxidant capacity and foliar epidermal flavonol content. H2O2- and UV-B+H2O2-pre-treated plants showed cross-tolerance to a subsequent 7-day drought treatment. Plant responses to the pre-treatment were notably different: i) H2O2 increased the activity of catalase, phenylalanine ammonia lyase and peroxidase activities, and ii) the combined treatment induced epidermal flavonols which were key to drought tolerance. We report synergistic effects of UV-B and H2O2 on transcription accumulation of UV RESISTANCE LOCUS 8, NAC DOMAIN PROTEIN 13 (NAC13), and BRI1-EMS-SUPPRESSOR 1 (BES1). Our data demonstrate a pre-treatment-dependent response to drought for NAC13, BES1 and CHALCONE SYNTHASE transcript accumulation. This study highlights the potential of combining UV-B and H2O2 to improve drought tolerance which could become a useful tool to reduce water use.
DENTIST – using long reads for closing assembly gaps at high accuracy
Authors: Ludwig Arne , Pippel Martin , Myers Gene , Hiller Michael
Published: February 2021

Background

Long sequencing reads allow increasing contiguity and completeness of fragmented, short-read based genome assemblies by closing assembly gaps, ideally at high accuracy. While several gap closing methods have been developed, these methods often close an assembly gap with sequence that does not accurately represent the true sequence.

Findings

Here, we present DENTIST, a sensitive, highly accurate and automated pipeline method to close gaps in short-read assemblies with long error-prone reads. DENTIST comprehensively determines repetitive assembly regions to identify reliable and unambiguous alignments of long reads to the correct loci, integrates a consensus sequence computation step to obtain a high base accuracy for the inserted sequence, and validates the accuracy of closed gaps. Unlike previous benchmarks, we generated test assemblies that have gaps at the exact positions where real short-read assemblies have gaps. Generating such realistic benchmarks forDrosophila(134 Mb genome),Arabidopsis(119 Mb), hummingbird (1 Gb) and human (3 Gb) and using simulated or real PacBio continuous long reads, we show that DENTIST consistently achieves a substantially higher accuracy compared to previous methods, while having a similar sensitivity.

Conclusion

DENTIST provides an accurate approach to improve the contiguity and completeness of fragmented assemblies with long reads. DENTIST’s source code including a Snakemake workflow, conda package and Docker container is available athttps://github.com/a-ludi/dentist. All test assemblies as a resource for future benchmarking are athttps://bds.mpi-cbg.de/hillerlab/DENTIST/.
Phylogenomic Analyses Of 2,786 Genes In 158 Lineages Support a Root of The Eukaryotic Tree of Life Between Opisthokonts (Animals, Fungi and Their Microbial Relatives) and All Other Lineages
Authors: Cerón-Romero Mario A. , Fonseca Miguel M. , de Oliveira Martins Leonardo , Posada David , Katz Laura A.
Published: February 2021

Advances in phylogenetics and high-throughput sequencing have allowed the reconstruction of deep phylogenetic relationships in the evolution of eukaryotes. Yet, the root of the eukaryotic tree of life remains elusive. The most popular hypothesis in textbooks and reviews is a root between Unikonta (Opisthokonta + Amoebozoa) and Bikonta (all other eukaryotes), which emerged from analyses of a single gene fusion. Subsequent highly-cited studies based on concatenation of genes supported this hypothesis with some variations or proposed a root within Excavata. However, concatenation of genes neither considers phylogenetically-informative events (i.e. gene duplications and losses), nor provides an estimate of the root. A more recent study using gene tree-species tree reconciliation methods suggested the root lies between Opisthokonta and all other eukaryotes, but only including 59 taxa and 20 genes. Here we apply a gene tree – species tree reconciliation approach to a gene-rich and taxon-rich dataset (i.e. 2,786 gene families from two sets of ~158 diverse eukaryotic lineages) to assess the root, and we iterate each analysis 100 times to quantify tree space uncertainty. We estimate a root between Fungi and all other eukaryotes, or between Opisthokonta and all other eukaryotes, and reject alternative roots from the literature. Based on further analysis of genome size we propose Opisthokonta + others as the most likely root.

Impact summary

Finding the root of the eukaryotic tree of life is critical for the field of comparative biology as it allows us to understand the timing and mode of evolution of characters across the evolutionary history of eukaryotes. But this is one of the most challenging questions in evolutionary biology because the age (~1.8 billion years), diversity and complexity of eukaryotes challenge phylogenomic methods. This study evaluates the root using reconciliation of gene trees and species trees instead of the more common approach of analyzing concatenated genes. The dataset used in this study is bigger and more taxonomically inclusive than the dataset of any previous study about the eukaryotic root, and supports a root at or within Opisthokonta (e.g. animals and fungi). Finally, we explicitly test alternative hypotheses from the literature, and again find support for an Opisthokonta root.
Sequence-unrelated long noncoding RNAs converged to modulate the activity of conserved epigenetic machineries across kingdoms
Authors: Fonouni-Farde Camille , Christ Aurélie , Blein Thomas , Ramírez-Prado Juan Sebastián , Legascue María Florencia , Latrasse David , Moison Michaël , Lucero Leandro , Ferrero Lucía , Gonzalez Daniel , Benhamed Moussa , Quadrana Leandro , Crespi Martin , Ariel Federico
Published: February 2021

RNA-DNA hybrid (R-loop)-associated long noncoding RNAs (lncRNAs), including the Arabidopsis lncRNAAUXIN-REGULATED PROMOTER LOOP(APOLO), are emerging as important regulators of three-dimensional chromatin conformation and gene transcriptional activity. Here, we showed that in addition to the PRC1-component LIKE-HETEROCHROMATIN PROTEIN 1 (LHP1),APOLOinteracts with the methylcytosine-binding protein VARIANT IN METHYLATION 1 (VIM1), a conserved homolog of the mammalian DNA methylation regulator UBIQUITIN-LIKE CONTAINING PHD AND RING FINGER DOMAINS 1 (UHRF1). TheAPOLO-VIM1-LHP1 complex directly regulates the transcription of the auxin biosynthesis geneYUCCA2by dynamically determining DNA methylation and H3K27me3 deposition over its promoter during the plant thermomorphogenic response. Strikingly, we demonstrated that the lncRNAUHRF1 Protein Associated Transcript(UPAT), a direct interactor of UHRF1 in humans, can be recognized by VIM1 and LHP1 in plant cells, despite the lack of sequence homology betweenUPATandAPOLO. In addition, we showed that increased levels ofAPOLOorUPAThamper VIM1 and LHP1 binding toYUCCA2promoter. Collectively, our results uncover a new mechanism in which a plant lncRNA coordinates Polycomb action and DNA methylation, and reveal that evolutionary unrelated lncRNAs may exert similar functions across kingdoms.
A cytofluorimetric analysis of aSaccharomyces cerevisiaepopulation cultured in a fed-batch bioreactor
Authors: Palomba Emanuela , Tirelli Valentina , de Alteriis Elisabetta , Landi Carmine , Mazzoleni Stefano , Sanchez Massimo
Published: February 2021

The yeastSaccharomyces cerevisiaeis a reference model system and one of the widely used microorganisms in many biotechnological processes. In industrial yeast applications, combined strategies aim to maximize biomass/product yield, with the fed-batch culture being one of the most frequently used. Flow cytometry (FCM) is widely applied in biotechnological processes and represents a key methodology to monitor cell population dynamics. We propose here an application of FCM in the analysis of yeast cell cycle along the time course of a typical S.cerevisiaefed-batch culture. We used two different dyes, SYTOX Green and SYBR Green, with the aim to better define each stage of cell cycle during S.cerevisiaefed-batch culture. The results provide novel insights in the use of FCM cell cycle analysis for the real-time monitoring ofS. cerevisiaebioprocesses.
Seasonal dynamics are the major driver of microbial diversity and composition in intensive freshwater aquaculture
Authors: Marmen Sophi , Fadeev Eduard , Al Ashhab Ashraf , Benet-Perelberg Ayana , Naor Alon , Patil Hemant J. , Cytryn Eddie , Viner-Mozzini Diti , Sukenik Assaf , Lalzar Maya , Sher Daniel
Published: February 2021

Aquaculture facilities such as fishponds are one of the most anthropogenically impacted freshwater ecosystems. The high fish biomass reared in aquaculture is associated with an intensive input into the water of fish-feed and fish excrements. This nutrients load may affect the microbial community in the water, which in turn can impact the fish health. To determine to what extent aquaculture practices and natural seasonal cycles affect the microbial populations, we characterized the microbiome of an inter-connected aquaculture system at monthly resolution, over three years. The system comprised two fishponds, where fish are grown, and a “control” operational water reservoir in which fish are not actively stocked. Clear natural seasonal cycles of temperature and inorganic nutrients concentration, as well as recurring cyanobacterial blooms during summer, were observed in both the fishponds and the reservoir. The structure of the aquatic bacterial communities in the system, characterized using 16S rRNA sequencing, was explained primarily by the natural seasonality, whereas aquaculture-related parameters had only a minor explanatory power. However, the cyanobacterial blooms were characterized by different cyanobacterial clades dominating at each fishpond, possibly in response to distinct nitrogen and phosphate ratios. In turn, nutrient ratios may have been by the magnitude of fish feed input. Taken together, our results show that, even in strongly anthropogenically impacted aquatic ecosystems, the structure of bacterial communities is mainly driven by the natural seasonality, with more subtle effects if aquaculture-related factors.

Highlights

We present three years of monthly microbiome data from an aquaculture facility.

The microbiome changes seasonally, likely driven by temperature and rainwater runoff.

Summer blooms of toxin-producing cyanobacteria are repeatedly observed.

Fish food may impact microbiome through changes in nutrient ratios.