bluuebunny/crossref_metadata_2025 huggingface dataset:
Open forensic science*
Authors: Chin Jason M , Ribeiro Gianni , Rairden Alicia
Published: May 2019

The mainstream sciences are experiencing a revolution of methodology. This revolution was inspired, in part, by the realization that a surprising number of findings in the bioscientific literature could not be replicated or reproduced by independent laboratories. In response, scientific norms and practices are rapidly moving towards openness. These reforms promise many enhancements to the scientific process, notably improved efficiency and reliability of findings. Changes are also underway in the forensic. After years of legal-scientific criticism and several reports from peak scientific bodies, efforts are underway to establish the validity of several forensic practices and ensure forensic scientists perform and present their work in a scientifically valid way.

In this article, the authors suggest that open science reforms are distinctively suited to addressing the problems faced by forensic science. Openness comports with legal and criminal justice values, helping ensure expert forensic evidence is more reliable and susceptible to rational evaluation by the trier of fact. In short, open forensic science allows parties in legal proceedings to understand and assess the strength of the case against them, resulting in fairer outcomes. Moreover, several emerging open science initiatives allow for speedier and more collaborative research.
Percutaneous Peripheral Nerve Stimulation for the Treatment of Chronic Pain Following Amputation
Authors: Cohen Steven P , Gilmore Christopher A , Rauck Richard L , Lester Denise D , Trainer Robert J , Phan Thomas , Kapural Leonardo , North James M , Crosby Nathan D , Boggs Joseph W
Published: May 2019

Introduction

Chronic pain and reduced function are significant problems for Military Service members and Veterans following amputation. Peripheral nerve stimulation (PNS) is a promising therapy, but PNS systems have traditionally been limited by invasiveness and complications. Recently, a novel percutaneous PNS system was developed to reduce the risk of complications and enable delivery of stimulation without surgery.

Materials and Methods

Percutaneous PNS was evaluated to determine if stimulation provides relief from residual and phantom limb pain following lower-extremity amputation. PNS leads were implanted percutaneously to deliver stimulation to the femoral and/or sciatic nerves. Patients received stimulation for up to 60 days followed by withdrawal of the leads.

Results

A review of recent studies and clinical reports found that a majority of patients (18/24, 75%) reported substantial (≥50%) clinically relevant relief of chronic post-amputation pain following up to 60 days of percutaneous PNS. Reductions in pain were frequently associated with reductions in disability and pain interference.

Conclusions

Percutaneous PNS can durably reduce pain, thereby enabling improvements in quality of life, function, and rehabilitation in individuals with residual or phantom limb pain following amputation. Percutaneous PNS may have additional benefit for Military Service members and Veterans with post-surgical or post-traumatic pain.
PatchSearch: a web server for off-target protein identification
Authors: Rey Julien , Rasolohery Inès , Tufféry Pierre , Guyon Frédéric , Moroy Gautier
Published: May 2019

The large number of proteins found in the human body implies that a drug may interact with many proteins, called off-target proteins, besides its intended target. The PatchSearch web server provides an automated workflow that allows users to identify structurally conserved binding sites at the protein surfaces in a set of user-supplied protein structures. Thus, this web server may help to detect potential off-target protein. It takes as input a protein complexed with a ligand and identifies within user-defined or predefined collections of protein structures, those having a binding site compatible with this ligand in terms of geometry and physicochemical properties. It is based on a non-sequential local alignment of the patch over the entire protein surface. Then the PatchSearch web server proposes a ligand binding mode for the potential off-target, as well as an estimated affinity calculated by the Vinardo scoring function. This novel tool is able to efficiently detects potential interactions of ligands with distant off-target proteins. Furthermore, by facilitating the discovery of unexpected off-targets, PatchSearch could contribute to the repurposing of existing drugs. The server is freely available at http://bioserv.rpbs.univ-paris-diderot.fr/services/PatchSearch.
Surgical Treatment of Intraneural Ganglion Cysts of the Ulnar Nerve at the Elbow: Long-Term Follow-up of 9 Cases
Authors: Wu Peng , Xu Sudan , Cheng Biao , Chen Lin , Xue Chao , Ge Heng’an , Yu Cong
Published: May 2019

BACKGROUND

Intraneural ganglion (IG) cysts have been considered curiosities and their pathogenesis remains controversial.

OBJECTIVE

To clarify ulnar nerve at the elbow (UNE) pathogenesis and long-term surgical outcomes by presenting 9 rare cases of IG of the UNE.

METHODS

Surgical treatment of IG was performed. Clinical symptoms, physical examinations, and electromyogram were evaluated pre- and postoperatively. At least 4 yr of follow-up was performed.

RESULTS

The Tinel's sign became negative and local elbow pain disappeared in all 9 patients after surgery, and the average visual analog scale/score dropped from 4.9 (3-8) to 0 (0-0) after 6.2 d (2-10) on average. Two patients retained positive Froment test, “claw hand” and paresthesias with the 2-point discrimination much different from the contralateral little finger. Postoperative the UK Medical Research Council muscle strength score (MRC) grades of the flexor carpi ulnaris and the flexor digitorum profundus muscle of the fourth and fifth digits recovered to M4-M5 from M0-M2 in all 9 patients. The postoperative MRC grades of the third to fourth lumbrical muscles, the interossei, and the hypothenar recovered to M3-M5 from M0-M2 in 7 patients. Cystic articular branch (CAB) was found in all 9 patients intraoperatively. No symptomatic recurrence of IG was seen. The mean motor nerve conduction velocity of ulnar nerve across the elbow recovered from 5.3 to 41.2 m/s.

CONCLUSION

A unifying articular theory is responsible for the pathogenesis of IG of UNE and disconnection of the CAB would prevent recurrence. The long-term outcome is good after surgical treatment of IG of UNE.
Comparison of the In Vitro Susceptibility of Ceftolozane-Tazobactam With the Cumulative Susceptibility Rates of Standard Antibiotic Combinations When Tested Against Pseudomonas aeruginosa From ICU Patients With Bloodstream Infections or Pneumonia
Authors: Shortridge Dee , Pfaller Michael A , Arends S J Ryan , Raddatz Janet , DePestel Daryl D , Flamm Robert K
Published: May 2019

Background

Pseudomonas aeruginosa remains an important cause of hospital-acquired infections in the United States and is frequently multidrug-resistant (MDR). The Infectious Diseases Society of America guidelines recommend empiric combination therapy that includes an antipseudomonal β-lactam with an aminoglycoside or fluoroquinolone likely to cover ≥95% of P. aeruginosa infections in seriously ill patients at risk of having an MDR pathogen. Ceftolozane is an antipseudomonal cephalosporin, combined with the β-lactamase inhibitor tazobactam. Ceftolozane-tazobactam is approved for treatment of complicated urinary tract infections and complicated intra-abdominal infections. A phase 3 clinical trial for the treatment of hospital-acquired pneumonia including ventilator-associated pneumoniae was recently completed. We compared the in vitro susceptibility rate of ceftolozane-tazobactam with the cumulative susceptibility rates of antibiotic combinations commonly used against P. aeruginosa.

Methods

Isolates were collected from intensive care unit patients hospitalized in 32 US hospitals from 2011 to 2017. The susceptibilities of 1543 P. aeruginosa isolates from bloodstream infections (198 isolates, 12.8%) or pneumonia (1345 isolates, 87.2%) were determined for ceftolozane-tazobactam and comparators.

Results

The most active antimicrobials were colistin (99.4% susceptible), amikacin (98.1% susceptible), and ceftolozane-tazobactam (96.5% susceptible). The susceptibilities to other antipseudomonal β-lactams and fluoroquinolones were <84%. A cumulative susceptibility of ≥95% was reached for cefepime, ceftazidime, meropenem, and piperacillin-tazobactam only in combination with amikacin due to the lower susceptibilities of gentamicin, ciprofloxacin, and levofloxacin. Monotherapies that exceeded 95% were ceftolozane-tazobactam, amikacin, and colistin.

Conclusions

Ceftolozane-tazobactam monotherapy is likely to be active against more isolates than a combination of another β-lactam and a fluoroquinolone or gentamicin for serious P. aeruginosa infections.
Factors Associated With Ventriculoperitoneal Shunt Placement in Patients With Cryptococcal Meningitis
Authors: Baddley John W , Thompson George R , Riley Kristen O , Moore Mary K , Moser Stephen A , Pappas Peter G
Published: May 2019

Objective

Increased intracranial pressure (ICP) is an important complication of cryptococcal meningitis (CM) and impacts morbidity and mortality. Factors associated with permanent ventriculoperitoneal (VP) shunt placement are poorly characterized.

Method

We conducted a retrospective cohort study of patients with CM at the University of Alabama at Birmingham from 1996 through 2015. Characteristics of patients at time of CM diagnosis who did and did not receive a VP shunt were compared with use of the 2-group chi-square test or Fisher exact test for categorical variables and the 2-group t test for continuous variables. Stepwise logistic regression analysis was used to determine predictors of shunt placement.

Results

Of 422 patients with cryptococcosis, 257 (60.9%) had CM. Mean age was 47.7 years, 71.6% were male, and 44.4% were African American. The most common underlying conditions were HIV (42.4%), solid organ transplantation (29.6%), and corticosteroid use (34.2%). Forty-four (17.1%) received a VP shunt a median of 17 days (range, 1–320 days) post-diagnosis. By multivariable analysis, baseline opening pressure >30 cm H2O (OR, 9.4; 95% CI, 3.0, 28.8; P < .0001), being a normal host (OR, 6.3; 95% CI, 1.5, 26.1; P = .011) and hydrocephalus (OR, 4.9, 95% CI, 1.3, 17.9); P = .017) were associated with increased odds of shunting (Table 2). In contrast, age (OR, 0.96; 95% CI, 0.92, 0.99; P = .037) and male gender (OR, 0.18; 95% CI, 0.06, 0.55; P = .023) were associated with decreased odds of shunting.

Conclusions

Identification of factors at time of CM diagnosis associated with need for permanent VP shunt placement may allow for earlier, more aggressive treatment and potentially improve outcomes associated with increased ICP from cryptococcal meningitis.
Vein of Galen Malformations: The Texas Children's Hospital Experience in the Modern Endovascular Era
Authors: Wagner Kathryn M , Ghali Michael G Z , Srinivasan Visish M , Lam Sandi , Johnson Jeremiah , Chen Stephen , Kan Peter
Published: May 2019

BACKGROUND

Vein of Galen malformations (VOGM) comprise nearly a third of pediatric cerebrovascular anomalies, with potentially devastating neurological and systemic complications. Advances in endovascular therapies have dramatically improved outcomes compared to historical surgical treatments, and neurosurgeons are an essential component of the multidisciplinary critical care team.

OBJECTIVE

To retrospectively review pediatric patients with VOGM treated at Texas Children's Hospital (TCH), a quaternary referral center, over 15 yr, and present lessons learned in treating children with modern endovascular techniques.

METHODS

Charts from TCH were retrospectively reviewed for the past 15 yr. Patients with diagnosis including “Vein of Galen,” “Vein of Galen malformation,” “Vein of Galen aneurysmal malformation,” or any abbreviations (ie, VOG, VOGM, VOGAM) were reviewed. Presentation, imaging, treatment specifics, and clinical outcomes were reported.

RESULTS

There were 18 patients with VOGM managed at TCH from 2002 to 2018 with a total of 29 embolizations. Seventeen were performed with a single embolisate (NBCA or Onyx), and 12 with a combination. A dual lumen balloon catheter was used as an adjunct in 3 embolizations. Complications occurred in 5 embolizations (24%), including hemorrhage, embolisate migration, and femoral vessel occlusion. Surviving patients were followed for a mean of 38 mo, with 12 having normal or near-normal neurological development.

CONCLUSION

VOGM can present with a myriad of neurological and systemic symptoms, potentially in extremis. Neurosurgical involvement in these cases is critical, as urgent treatment can be lifesaving. Patients may require multiple treatment sessions using a variety of endovascular tools and techniques.
Women’s Political Representation in a Hybrid and Patriarchal Regime: Evidence from Singapore
Authors: Tam Waikeung
Published: May 2019

This article investigates women’s political representation in a hybrid and patriarchal regime—Singapore. Specifically, it examines whether female legislators in Singapore put more emphasis on women’s rights and traditional women’s concerns than male legislators. We answer this question through conducting content analyses of the questions raised by legislators at the plenary meetings during the 10th–12th Parliaments of Singapore (2002–2015). Our results demonstrate that female legislators in Singapore were more likely to provide substantive representation on women’s interests than male legislators. Besides gender, this study shows that legislators’ political affiliation crucially affected the likelihood of them to represent traditional women’s concerns but not women’s rights. Opposition legislators were more likely than People’s Action Party legislators to ask questions on traditional women’s concerns. Finally, legislators’ ethnicity mattered, given that ethnic minority legislators (Malay, Indian and Eurasian legislators) were more likely to raise questions on women’s rights and traditional women’s concerns (except environment) than Chinese legislators.
Does community engaged Carnegie status matter for county health rankings in the United States?
Authors: Apatu Emma , Stallings-Smith Sericea , Alvarez Elizabeth , Anderson Laura , Spaulding Aaron
Published: May 2019

Background

Community engagement is commonly used to address social inequities. The Carnegie Foundation offers an optional designation for which U.S. colleges and universities may apply to facilitate better educational outcomes through the institutionalization of community engagement. This study is the first to examine the relationship between Carnegie community engaged status and community health outcomes.

Methods

Ordinal logistic regression was conducted to investigate the association between the presence of a community engaged institution and county health outcomes, including health behaviors, clinical care relating to access and quality, social and economic factors, and physical environment from the 2016 Robert Wood Johnson County Health Rankings and 2015 New England Resource Center for Higher Education Community engaged list. We examined 820 U.S. counties containing a university or college, 240 of which had a community engaged designation.

Results

Findings indicated that the presence of a community-engaged institution was positively associated with Clinical Care (OR = 1.99; 95% CI: 1.09, 3.64). Other county health factors were not similarly associated.

Conclusions

Our findings suggest that community engagement status may be most relevant for achieving better access and quality of clinical care. More research is needed to explore this association in the U.S. and internationally.
Fluorodeoxyglucose positron emission tomography/computed tomography in the diagnosis, assessment of disease activity and therapeutic response in relapsing polychondritis
Authors: Sharma Aman , Kumar Rajender , MB Adarsh , Naidu G S R S N K , Sharma Vikas , Sood Apurva , Dhir Varun , Verma Roshan , Singh Harmandeep , Bhattacharya Anish , Jain Sanjay , Mittal Bhagwant Rai
Published: May 2019

Objective

To evaluate 18F-fluorodeoxyglucose (FDG) PET/CT in the assessment of disease activity, extent of the disease and response to therapy in relapsing polychondritis.

Methods

Twenty-five patients (9 men, 16 women) with a mean age of 38.2 years (s.d. 13.7; range 18–62), diagnosed to have relapsing polychondritis according to Damiani and Levine’s modification of McAdam’s criteria, who underwent PET/CT examination were included. Ten patients underwent a second PET/CT examination after therapy or during follow-up. Clinical symptoms and auxiliary examination findings were recorded. PET/CT findings were reviewed and correlated with the clinical symptoms.

Results

The major symptoms were aural pain (n = 21), nasal pain (n = 10), stridor (n = 5), cough (n = 9), fever (n = 8) and laryngeal tenderness (n = 8). The initial PET/CT was positive in 23/25 patients. PET/CT revealed involvement of auricular (n = 14), nasal (n = 8), laryngeal (n = 7), tracheobronchial (n = 6) and Eustachian (n = 3) cartilages with a mean maximum standardized uptake value (SUVmax) of 4.1 (s.d. 2.5; range 1.7–12.7). Fair correlation of aural/nasal pain/stridor with FDG avidity of cartilage involvement on PET/CT was noted. The key finding was detection of asymptomatic large airway involvement in seven patients (28%). Re-examination PET in 10 patients revealed complete therapeutic response (n = 5), partial response (n = 1), stable disease (n = 1), progressive disease (n = 1) and disease recurrence (n = 2).

Conclusion

FDG PET/CT is a useful tool for the assessment of the disease activity and extent. It identified activity in clinically inaccessible sites that are of clinical significance. It is also useful in assessing treatment response and finding relapse.
INGESTION AND INHALATION DOSES DUE TO INTAKE OF RADON IN DRINKING WATER SAMPLES OF AMRITSAR PROVINCE, PUNJAB, INDIA
Authors: Sharma Sumit , Kumar Ajay , Mehra Rohit , Kaur Ranbir
Published: May 2019

In the present investigation, the ingestion and inhalation dosage for the particular body organs in light of the intake of radon through ground water utilised by the occupants have been assessed in the different villages of the Upper Bari Doab region of Amritsar province, India using an electrostatic collection type radon monitor (RAD7) analyzer with RAD-H2O accessory. The mean radon activity level in water was seen to be 8.34 ± 2.99 Bql−1. The newborn children have higher radiation dosage than the other age groups because of their high dosage transformation factors. However, the radiation dosage received by all different age groups significantly less than the UNSCEAR and WHO suggested a level of 100 μSv y−1. The annual effective dosage for the diverse body organs because of the intake of radon was moreover ascertained and found the maximum dosage for lungs than other organs. The radiation dosage received by bronchial epithelium by the means of inhalation was likewise high when contrasted with that by stomach walls through ingestion.
RADIATION DOSE DISTRIBUTION OF A PLAIN RADIOGRAPHY ROOM AND COMPUTED TOMOGRAPHY ROOM IN A VETERINARY HOSPITAL
Authors: Chen Kuan-Sheng , Chou Ying-Hsiang , Wu Ruey-Shyuan , Lee Wei-Ming , Tyan Yeu-Sheng , Chen Tou-Rong
Published: May 2019

Thermoluminescent dosemeters (TLDs) were attached to the walls of a plain radiography room and a computed tomography (CT) room, control rooms and corridors to measure the radiation dose. The types of animals scanned and scan parameters were analysed. Dogs and cats accounted for the largest proportion of animals, a combined total of 96.0%. Distributions of tube voltage and tube current-time product are presented. In the CT room, the dose at the angle of the gantry opening was higher than that on either side of the gantry. The study developed equations that may be useful to assess the dose for staff standing in radiography rooms. The personal annual doses for the controlled and uncontrolled areas were lower than the recommended dose limit. The annual doses for personnel and nonworkers were also within the acceptable level for radiation safety.
The Effect of Fossil Sampling on the Estimation of Divergence Times with the Fossilized Birth–Death Process
Authors: O’Reilly Joseph E , Donoghue Philip C J
Published: May 2019

Timescales are of fundamental importance to evolutionary biology as they facilitate hypothesis tests of historical evolutionary processes. Through the incorporation of fossil occurrence data, the fossilized birth–death (FBD) process provides a framework for estimating divergence times using more paleontological data than traditional node calibration approaches have allowed. The inclusion of more data can refine evolutionary timescale estimates, but for many taxonomic groups it is computationally infeasible to include all available fossil occurrence data. Here, we utilize both empirical data and a simulation framework to identify approaches to subsampling fossil occurrence data that result in the most accurate estimates of divergence times. To achieve this we assess the performance of the FBD-Skyline model when implementing multiple approaches to incorporating subsampled fossil occurrence data. Our results demonstrate that it is necessary to account for all available fossil occurrence data to achieve the most accurate estimates of clade age. We show that this can be achieved if an empirical Bayes approach, accounting for fossil sampling through time, is applied to the FBD process. Random subsampling of occurrence data can lead to estimates of clade age that are incompatible with fossil evidence if no control over the affinities of fossil occurrences is enforced. Our results call into question the accuracy of previous divergence time studies incorporating the FBD process that have used only a subsample of all available fossil occurrence data.
Dual role of Miro protein clusters in mitochondrial cristae organisation and ER-Mitochondria Contact Sites
Authors: Modi Souvik , López-Doménech Guillermo , Halff Elise F. , Covill-Cooke Christian , Ivankovic Davor , Melandri Daniela , Arancibia-Cárcamo Lorena , Burden Jemima J. , Lowe Alan R. , Kittler Josef T.
Published: May 2019

Mitochondrial Rho (Miro) GTPases localize to the outer mitochondrial membrane and are essential machinery for the regulated trafficking of mitochondria to defined subcellular locations. However, their sub-mitochondrial localization and relationship with other critical mitochondrial complexes remains poorly understood. Here, using super-resolution fluorescence microscopy, we report that Miro proteins form nanometer-sized clusters along the mitochondrial outer membrane in association with the Mitochondrial Contact Site and Cristae Organizing System (MICOS). Using knockout mouse embryonic fibroblasts (MEF) we show that Miro1 and Miro2 are required for normal mitochondrial cristae architecture and endoplasmic reticulum-mitochondria contacts sites (ERMCS). Further, we show that Miro couples MICOS to TRAK motor protein adaptors to ensure the concerted transport of the two mitochondrial membranes and the correct distribution of cristae on the mitochondrial membrane. The Miro nanoscale organization, association with MICOS complex and regulation of ERMCS reveal new levels of control of the Miro GTPases on mitochondrial functionality.
How thermophilic Gram-positive organisms perform extracellular electron transfer: characterization of the cell surface terminal reductase OcwA
Authors: Costa N.L. , Hermann B. , Fourmond V. , Faustino M. , Teixeira M. , Einsle O. , Paquete C.M. , Louro R.O.
Published: May 2019

Extracellular electron transfer is the key process underpinning the development of bioelectrochemical systems for the production of energy or added-value compounds. Thermincola potens JR is a promising Gram-positive bacterium to be used in these systems because it is thermophilic. In this paper we describe the structural and functional properties of the nonaheme cytochrome OcwA, which is the terminal reductase of this organism. The structure of OcwA, determined at 2.2Å resolution shows that the overall-fold and organization of the hemes are not related to other metal reductases and instead are similar to that of multiheme cytochromes involved in the biogeochemical cycles of nitrogen and sulfur. We show that, in addition to solid electron acceptors, OcwA can also reduce soluble electron shuttles and oxyanions. These data reveal that OcwA can take the role of a respiratory ‘swiss-army knife’ allowing this organism to grow in environments with rapidly changing availability of terminal electron acceptors without the need for transcriptional regulation and protein synthesis.

Importance

Thermophilic Gram-positive organisms were recently shown to be a promising class of organisms to be used in bioelectrochemical systems for the production of electrical energy. These organisms present a thick peptidoglycan layer that was thought to preclude them to perform extracellular electron transfer (i.e. exchange catabolic electrons with solid electron acceptors outside of the cell). In this manuscript we describe the structure and functional mechanisms of the multiheme cytochrome OcwA, the terminal reductase of the Gram-positive bacterium Thermincola potens JR found at the cell surface of this organism. The results presented here show that this protein is unrelated with terminal reductases found at the cell surface of other electroactive organisms. Instead, OcwA is similar to terminal reductases of soluble electron acceptors. Our data reveals that terminal oxidoreductases of soluble and insoluble substrates are evolutionarily related, providing novel insights into the evolutionary pathway of multiheme cytochromes.
Aversive Learning Increases Release Probability of Olfactory Sensory Neurons
Authors: Bhattarai Janardhan P. , Schreck Mary , Moberly Andrew H. , Luo Wenqin , Ma Minghong
Published: May 2019

Predicting danger from previously associated sensory stimuli is essential for survival. Contributions from altered peripheral sensory inputs are implicated in this process, but the underlying mechanisms remain elusive. Here we use the mammalian olfactory system to investigate such mechanisms. Primary olfactory sensory neurons (OSNs) project their axons directly to the olfactory bulb (OB) glomeruli where their synaptic release is subject to local and cortical influence and neuromodulation. Pairing optogenetic activation of a single glomerulus with foot shock in mice induces freezing to the light stimulation alone during fear retrieval. This is accompanied by an increase in OSN release probability and a reduction in GABAB receptor expression in the conditioned glomerulus. Furthermore, freezing time is positively correlated with the release probability of OSNs in fear conditioned mice. These results suggest that aversive learning increases peripheral olfactory inputs at the first synapse, which may contribute to the behavioral outcome.
Single-cell analyses reveal aberrant pathways for megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets
Authors: Psaila Bethan , Wang Guanlin , Meira Alba Rodriguez , Heuston Elisabeth F. , Li Rong , O’Sullivan Jennifer , Sousos Nikolaos , Anderson Stacie , Senis Yotis , Weinberg Olga K. , Calicchio Monica L. ,   NIH Intramural Sequencing Center, Iskander Deena , Royston Daniel , Milojkovic Dragana , Roberts Irene , Bodine David M. , Thongjuea Supat , Mead Adam J.
Published: May 2019

Myelofibrosis is a severe myeloproliferative neoplasm characterised by increased numbers of abnormal bone marrow megakaryocytes that induce progressive fibrosis, destroying the hematopoietic microenvironment. To determine the cellular and molecular basis for aberrant megakaryopoiesis in myelofibrosis, we performed high-throughput single-cell transcriptome profiling of 50,538 hematopoietic stem/progenitor cells (HSPCs), single-cell proteomics, genomics and functional assays. We identified an aberrant pathway for direct megakaryocyte differentiation from the earliest stages of hematopoiesis in myelofibrosis and associated aberrant molecular signatures, including surface antigens selectively expressed byJAK2-mutant HSPCs. Myelofibrosis megakaryocyte progenitors were heterogeneous, with distinct expression of fibrosis and proliferation-associated genes and putative therapy targets. We validated the immunoglobulin receptor G6B as a promisingJAK2-mutant clone-specific antigen warranting further development as an immunotherapy target. Our study paves the way for selective targeting of the myelofibrosis clone and more broadly illustrates the power of single-cell multi-omics to discover tumor-specific therapeutic targets and mediators of tissue fibrosis.
Categorical Assignment of Pulmonary Embolism is a Simple and More Accurate Indicator of Right Ventricular Dysfunction and Short Team Mortality
Authors: Chen Yu Lin , Wright Colin , Pietropaoli Anthony P. , Elbadawi Ayman , Delehanty Joseph , Barrus Bryan , Gosev Igor , Trawick David , Patel Dhwani , Cameron Scott J.
Published: May 2019

Several risk stratification tools are available to predict short-term mortality in patients with acute pulmonary embolism (PE). Right ventricular (RV) dysfunction, which is common to intermediate and high risk PE, is an independent predictor of mortality and may be a faster and simpler way to assess patient risk in acute care settings. We evaluated 571 patients presenting with acute PE as the primary diagnosis, stratifying them by the Pulmonary Embolism Severity Index (PESI), by the BOVA score, orcategoricallyas low risk (no RV dysfunction by imaging), intermediate risk (RV dysfunction by imaging), or high risk PE (RV dysfunction by imaging with sustained hypotension). Using imaging data to firstly define the presence of RV dysfunction, and plasma cardiac troponin T (cTnT) and NT-proBNP as additional evidence for myocardial strain, we evaluated the PESI and BOVA scoring systems compared to categorical assignment of PE as low risk, submassive, and massive PE. Cardiac biomarkers poorly distinguished between PESI classes and BOVA stages in patients with acute PE. Cardiac TnT and NT-proBNP easily distinguished low risk from submassive PE with an area under the curve (AUC) of 0.84 (95% C.I. 0.73 – 0.95, p< 0.0001), and 0.88 (95% C.I. 0.79-0.97, p< 0.0001), respectively, and low risk from massive PE with an area under the curve (AUC) of 0.89 (95% C.I. 0.78 – 1.00, p< 0.0001), and 0.89 (95% C.I. 0.82-0.95, p< 0.0001), respectively. Predicted short-term mortality by PESI score or BOVA stage was lower than the observed mortality for submassive PE by a two-fold order of magnitude. These data suggest the presence of RV dysfunction in the context of acute PE is sufficient for the purposes of risk stratification, while more complicated risk stratification algorithms may under-estimate short-term mortality risk.
TrkB Agonist LM22A-4 Increases Oligodendroglial Populations During Myelin Repair in the Brain
Authors: Nguyen Huynh TH , Wood Rhiannon J , Prawdiuk Alexa R , Furness Sebastian GB , Xiao Junhua , Murray Simon S , Fletcher Jessica L
Published: May 2019

The neurotrophin, brain-derived neurotrophic factor (BDNF) promotes central nervous system (CNS) myelination during development and after injury. This is achieved via activation of oligodendrocyte-expressed tropomyosin-related kinase (Trk) B receptors. However, while administration of BDNF has shown beneficial effects, BDNF itself has a poor pharmacokinetic profile. Here, we compare two TrkB-targeted BDNF-mimetics, the structural-mimetic, tricyclic dimeric peptide-6 (TDP6) and the non-peptide small molecule TrkB agonist LM22A-4 in the cuprizone model of central demyelination in female mice. Both mimetics promoted remyelination, increasing myelin sheath thickness and oligodendrocyte densities after one-week recovery. Importantly, LM22A-4 exerts these effects in an oligodendroglial TrkB-dependent manner. However, analysis of TrkB signaling by LM22A-4 suggests rather than direct activation of TrkB, LM22A-4 exerts its effects via indirect transactivation of Trk receptors. Overall, these studies support the therapeutic strategy to selectively targeting TrkB activation to promote remyelination in the brain.
Interactions between motor thalamic field potentials and single unit spiking predict behavior in rats
Authors: Gaidica Matt , Hurst Amy , Cyr Christopher , Leventhal Daniel K.
Published: May 2019

The thalamus plays a central role in generating circuit-level neural oscillations believed to coordinate brain activity over large spatiotemporal scales. Such thalamic influences are well-documented for sleep rhythms and in sensory systems, but the relationship between thalamic activity, motor circuit local field potential (LFP) oscillations, and behavior is unknown. We recorded wideband motor thalamic (Mthal) electrophysiology as healthy rats performed a two-alternative forced choice task. The power of delta (1−4 Hz), beta (13−30 Hz), low gamma (30−70 Hz), and high gamma (70−200 Hz) oscillations were strongly modulated by task performance. As in cortex, delta phase predicted beta/low gamma power and reaction time. Furthermore, delta phase differentially predicted spike timing in functionally distinct populations of Mthal neurons, which also predicted task performance and beta power. These complex relationships suggest mechanisms for commonly observed LFP-LFP and spike-LFP interactions, as well as subcortical influences on motor output.
Unique spatial integration in mouse primary visual cortex and higher visual areas
Authors: Murgas Kevin A. , Wilson Ashley M. , Michael Valerie , Glickfeld Lindsey L.
Published: May 2019

Neurons in the visual system integrate over a wide range of spatial scales. This diversity is thought to enable both local and global computations. To understand how spatial information is encoded across the mouse visual system, we use two-photon imaging to measure receptive fields in primary visual cortex (V1) and three downstream higher visual areas (HVAs): LM (lateromedial), AL (anterolateral) and PM (posteromedial). We find significantly larger receptive field sizes and less surround suppression in PM than in V1 or the other HVAs. Unlike other visual features studied in this system, specialization of spatial integration in PM cannot be explained by specific projections from V1 to the HVAs. Instead, our data suggests that distinct connectivity within PM may support the area’s unique ability to encode global features of the visual scene, whereas V1, LM and AL may be more specialized for processing local features.
In vivoimaging of myonuclei during spontaneous muscle contraction reveals non-uniform nuclear mechanical dynamics inNesprin/klarmutants
Authors: Lorber Dana , Rotkopf Ron , Volk Talila
Published: May 2019

Muscle contractions produce reiterated cytoplasmic mechanical variations, which impact the nuclear membrane and potentially influence nuclear mechanotransduction. It is unclear, however, whether the mechanical dynamics of individual myonuclei changes during each contractile wave, and whether mutants whose connection to the cytoskeleton is impaired are subjected to different mechanical input.

To monitor nuclear mechanical dynamicsin vivo, we imaged myonuclei along muscles during multiple spontaneous muscle contractile events, within live and intactDrosophilawild-type orNesprin/klarmutant larvae. The data were subsequently analyzed and quantified aiming to reveal potential changes in the mechanical parameters of nuclear dynamics during muscle contraction in theNesprin/klarmutant. Our results show that all myonuclei in control larvae exhibited comparable dynamics in the course of multiple contractile events. In contrast, myonuclei of homozygous mutant larvae lacking the Nesprin-like geneklardisplayed differential dynamics relative to wild type, and higher variability between myonuclei at distinct positions along individual myofibers. Estimation of the drag force applied on individual myonuclei revealed that force fluctuations in time were considerably higher in theNesprin/klarmutant myonuclei relative to control, reflecting a significant variability in the mechanical dynamics of individual myonuclei during contractile waves. The variable mechanical dynamics along the muscle fiber and the higher variance ofNesprin/klarmutant myonuclei may lead to altered nuclear mechanotransduction. Since mutations inNespringenes lead to devastating muscle and cardiac human diseases, our findings may provide new insight into the mechanism underlying these pathologies.
Neurophysiological alterations in the nucleus reuniens of a mouse model of Alzheimer’s disease
Authors: Walsh D.A. , Brown J.T. , Randall A.D.
Published: May 2019

Transgenic mice that overproduce beta-amyloid (Aβ) peptides exhibit neurophysiological alterations at the cellular, synaptic and network levels. Recently, increased neuronal activity in nucleus reuniens (Re), has been linked to hyperexcitability within hippocampal-thalamo-cortical networks in the J20 mouse model of amyloidopathy. Here in vitro whole-cell patch clamp recordings were used to compare old pathology-bearing J20 mice and wild-type controls to examine whether alterations to the intrinsic electrophysiological properties of Re neurons could contribute to the amyloidopathy-associated Re hyperactivity. A greater proportion of Re neurons displayed a hyperpolarised membrane potential in J20 mice without changes to the incidence or frequency of spontaneous action potential (AP) generation. Passive membrane properties were independent of transgene expression. Re neurons recorded from J20 mice did not exhibit increased AP generation in response to depolarising current stimuli but did exhibit an increased propensity to rebound burst following hyperpolarising current stimuli. This increase in rebound firing does not appear to result from alterations to T-type calcium channels. Finally, in J20 mice there was an ∼8% reduction in spike width, similar to what we and others have reported in CA1 pyramidal neurons from multiple amyloidopathy mice. We conclude that alterations to the intrinsic properties of Re neurons may contribute to the hyperexcitability observed in hippocampal-thalmo-cortical circuits under pathological Aβ load.

Key Points

Alterations in the neurophysiology of hippocampal and cortical neurons has been linked to network hyperexcitability in mouse models of amyloidopathy.

The nucleus reuniens (Re) is part of a cognitive network involving the hippocampal formation and prefrontal cortex. Increased cellular activity in Re has been linked to the generation of hippocampal-thalamo-cortical seizure activity in J20 mice.

Re neurons display hyperpolarised resting membrane potentials in J20 mice. Passive membrane properties are unaffected by transgene expression. Re neurons recorded from J20 mice did not exhibit increased excitability in response to depolarising current stimuli but did exhibit an increased propensity to rebound burst following hyperpolarising current stimuli. This increased rebound firing was not a result of changes in T-type Ca2+ conductances. Finally we observed a decrease in AP width.

These results help us understand how altered Re cellular neurophysiology may contribute to hippocampal-thalamo-cortical hyperexcitability in J20 mice.
Context-Aware Seeds for Read Mapping
Authors: Xin Hongyi , Shao Mingfu , Kingsford Carl
Published: May 2019

Motivation

Most modern seed-and-extend NGS read mappers employ a seeding scheme that requires extracting t non-overlapping seeds in each read in order to find all valid mappings under an edit distance threshold of t. As t grows (such as in long reads with high error rate), this seeding scheme forces mappers to use more and shorter seeds, which increases the seed hits (seed frequencies) and therefore reduces the efficiency of mappers.

Results

We propose a novel seeding framework, context-aware seeds (CAS). CAS guarantees finding all valid mapping but uses fewer (and longer) seeds, which reduces seed frequencies and increases efficiency of mappers. CAS achieves this improvement by attaching a confidence radius to each seed. We prove that all valid mappings can be found if the sum of confidence radii of seeds are greater than t. CAS generalizes the existing pigeonhole-principle-based seeding scheme in which this confidence radius is implicitly always 1. Moreover, we design an efficient algorithm that constructs the confidence radius database in linear time. We experiment CAS with E. coli genome and show that CAS reduces seed frequencies by up to 25.4% when compared with the state-of-the-art pigeonhole-principle-based seeding algorithm, the Optimal Seed Solver.

Availability

https://github.com/Kingsford-Group/CAS_code
Cervical gene delivery of the antimicrobial peptide, Human β-defensin (HBD)-3, in a mouse model of ascending infection-related preterm birth
Authors: Suff Natalie , Karda Rajvinder , Antinao Diaz Juan , Ng Joanne , Baruteau Julien , Perocheau Dany , Taylor Peter W. , Alber Dagmar , Buckley Suzanne M.K. , Bajaj-Elliott Mona , Waddington Simon N. , Peebles Donald
Published: May 2019

Approximately 40% of preterm births are preceded by microbial invasion of the intrauterine space: ascent from the vagina is the most common pathway. Within the cervical canal, antimicrobial peptides and proteins (AMPs) help to constitute a barrier which prevents ascending infection. We investigated whether expression of the AMP, human β-defensin-3 (HBD3), in the cervical mucosa prevented bacterial ascent from the vagina into the uterine cavity of pregnant mice. An adeno-associated virus vector containing both the HBD3 gene and GFP transgene (AAV8 HBD3.GFP) or control (AAV8 GFP), was administered intravaginally into E13.5 pregnant mice. Ascending infection was induced at E16.5 using bioluminescent E.coli (E.coli K1 A192PP-lux2). Bioluminescence imaging showed bacterial ascent into the uterine cavity, cellular events that led to premature delivery and a reduction in pups born alive, compared with uninfected controls. In addition, a significant reduction in uterine bioluminescence in the AAV8 HBD3.GFP-treated mice was observed 24 hours post-E.coli infection, compared to AAV8 GFP treated mice, signifying reduced bacterial ascent in AAV8 HBD3.GFP-treated mice. There was also an increase in the number of living pups in AAV HBD3.GFP-treated mice. We propose that HBD3 may be considered a possible candidate for augmenting cervical innate immunity to prevent ascending infection-related preterm birth.
HCN channel-mediated neuromodulation can control action potential velocity and fidelity in central axons
Authors: Byczkowicz Niklas , Eshra Abdelmoneim , Montanaro Jacqueline , Trevisiol Andrea , Hirrlinger Johannes , Kole Maarten H. P. , Shigemoto Ryuichi , Hallermann Stefan
Published: May 2019

Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels control electrical rhythmicity and excitability in the heart and brain, but the function of HCN channels at subcellular level in axons remains poorly understood. Here, we show that the action potential conduction velocity in both myelinated and unmyelinated central axons can bidirectionally be modulated by HCN channel blockers, cyclic adenosine monophosphate (cAMP), and neuromodulators. Recordings from mice cerebellar mossy fiber boutons show that HCN channels ensure reliable high-frequency firing and are strongly modulated by cAMP (EC50 40 µM; estimated endogenous cAMP concentration 13 µM). In accord, immunogold-electron microscopy revealed HCN2 as the dominating subunit in cerebellar mossy fibers. Computational modeling indicated that HCN2 channels control conduction velocity primarily via altering the resting membrane potential and was associated with significant metabolic costs. These results suggest that the cAMP-HCN pathway provides neuromodulators an opportunity to finely tune energy consumption and temporal delays across axons in the brain.
Area 2 of primary somatosensory cortex encodes kinematics of the whole arm
Authors: Chowdhury Raeed H , Glaser Joshua I , Miller Lee E
Published: May 2019

Abstract

Proprioception, the sense of body position, movement, and associated forces, remains poorly understood, despite its critical role in movement. Most studies of area 2, a proprioceptive area of somatosensory cortex, have simply compared neurons’ activities to the movement of the hand through space. By using motion tracking, we sought to elaborate this relationship by characterizing how area 2 activity relates to whole arm movements. We found that a whole-arm model, unlike classic models, successfully predicted how features of neural activity changed as monkeys reached to targets in two workspaces. However, when we then evaluated this whole-arm model across active and passive movements, we found that many neurons did not consistently represent the whole arm over both conditions. These results suggest that 1) neural activity in area 2 includes representation of the whole arm during reaching and 2) many of these neurons represented limb state differently during active and passive movements.
Huntingtin phosphorylation governs BDNF homeostasis and improves the phenotype of Mecp2 knockout mice
Authors: Ehinger Yann , Bruyère Julie , Panayotis Nicolas , Abada Yah-Se , Borloz Emilie , Matagne Valérie , Scaramuzzino Chiara , Vitet Hélène , Delatour Benoit , Saidi Lydia , Villard Laurent , Saudou Frédéric , Roux Jean-Christophe
Published: May 2019

Mutations in the X-linked MECP2 gene are responsible for Rett syndrome (RTT), a severe neurological disorder for which there is no treatment. Several studies have linked the loss of MeCP2 function to alterations of brain-derived neurotrophic factor (BDNF) levels, but non-specific overexpression of BDNF only partially improves the phenotype of Mecp2-deficient mice. We and others have previously shown that huntingtin (HTT) scaffolds molecular motor complexes, transports BDNF-containing vesicles, and is under-expressed in Mecp2 knock-out brains. Here we demonstrate that promoting HTT phosphorylation at Ser421, either by a phospho-mimetic mutation or inhibition of the phosphatase calcineurin, restores endogenous BDNF axonal transport in vitro in the corticostriatal pathway, increases striatal BDNF availability and synaptic connectivity in vivo, and improves the phenotype and the survival of Mecp2 knockout mice—even though treatments were initiated only after the mice had already developed symptoms. Stimulation of endogenous cellular pathways may thus be a promising approach for the treatment of RTT patients.
A Subset of Olfactory Sensory Neurons Express Forkhead Box J1-Driven eGFP
Authors: Pathak Shivani , Larson Eric D. , Ramakrishnan Vijay R. , Finger Thomas E
Published: May 2019

Forkhead box protein J1 (Foxj1), a member of the forkhead family transcription factors, is a transcriptional regulator of motile ciliogenesis. The nasal respiratory epithelium, but not olfactory epithelium, is lined with FOXJ1-expressing multiciliated epithelial cells with motile cilia. Using a Foxj1-eGFP reporter mouse, we find robust eGFP expression not only in the multi-ciliated cells of the respiratory epithelium, but in a distinctive small subset of olfactory sensory neurons in the olfactory epithelium. These eGFP-positive cells lie at the extreme apical part of the neuronal layer and are most numerous in dorsal-medial regions of olfactory epithelium. Interestingly, we observed a corresponding small number of glomeruli in the olfactory bulb wherein eGFP-labeled axons terminate, suggesting that the population of eGFP+ receptor cells expresses a limited number of olfactory receptors. Similarly, a subset of vomeronasal sensory neurons express eGFP but these distribute throughout the full height of the vomeronasal sensory epithelium. In keeping with this broad distribution of labeled vomeronasal receptor cells, eGFP labeled axons terminate in many glomeruli of the accessory olfactory bulb. These findings suggest that Foxj1-driven eGFP marks a specific population of olfactory and vomeronasal sensory neurons although neither receptor cell population possess motile cilia.