bluuebunny/crossref_metadata_2025 huggingface dataset:
How 217 Pediatric Intensivists Manage Anemia at PICU Discharge: Online Responses to an International Survey*
Authors: Demaret Pierre , Karam Oliver , Labreuche, BST Julien , Chiusolo Fabrizio , Mayordomo Colunga Juan , Erickson Simon , Nellis Marianne E. , Perez Marie-Hélène , Ray Samiran , Tucci Marisa , Willems Ariane , Duhamel Alain , Lebrun Frédéric , Loeckx Isabelle , Mulder André , Leteurtre Stéphane
Published: March 2020

Objective:

To describe the management of anemia at PICU discharge by pediatric intensivists.

Design:

Self-administered, online, scenario-based survey.

Setting:

PICUs in Australia/New Zealand, Europe, and North America.

Subjects:

Pediatric intensivists.

Interventions:

None.

Measurements and Main Results:

Respondents were asked to report their decisions regarding RBC transfusions, iron, and erythropoietin prescription to children ready to be discharged from PICU, who had been admitted for hemorrhagic shock, cardiac surgery, craniofacial surgery, and polytrauma. Clinical and biological variables were altered separately in order to assess their effect on the management of anemia. Two-hundred seventeen responses were analyzed. They reported that the mean (±sem) transfusion threshold was a hemoglobin level of 6.9 ± 0.09 g/dL after hemorrhagic shock, 7.6 ± 0.10 g/dL after cardiac surgery, 7.0 ± 0.10 g/dL after craniofacial surgery, and 7.0 ± 0.10 g/dL after polytrauma (p< 0.001). The most important increase in transfusion threshold was observed in the presence of a cyanotic heart disease (mean increase ranging from 1.80 to 2.30 g/dL when compared with baseline scenario) or left ventricular dysfunction (mean increase, 1.41–2.15 g/dL). One third of respondents stated that they would not prescribe iron at PICU discharge, regardless of the hemoglobin level or the baseline scenario. Most respondents (69.4–75.0%, depending on the scenario) did not prescribe erythropoietin.

Conclusions:

Pediatric intensivists state that they use restrictive transfusion strategies at PICU discharge similar to those they use during the acute phase of critical illness. Supplemental iron is less frequently prescribed than RBCs, and prescription of erythropoietin is uncommon. Optimal management of post-PICU anemia is currently unknown. Further studies are required to highlight the consequences of this anemia and to determine appropriate management.
Motor Function in School-Aged Children With Positional Plagiocephaly or Brachycephaly
Authors: Collett Brent R. , Kartin Deborah , Wallace Erin R. , Cunningham Michael L. , Speltz Matthew L.
Published: March 2020

Objective:

To determine whether children with a history of positional plagiocephaly/brachycephaly (PPB) show persistent deficits in motor development.

Methods:

In a longitudinal cohort study, we completed follow-up assessments with 187 school-aged children with PPB and 149 participants without PPB who were originally enrolled in infancy. Primary outcomes were the Bruininks-Oseretsky Test of Motor Proficiency-Second Edition (BOT-2) composite scores.

Results:

Children with PPB scored lower than controls on the BOT-2. Stratified analyses indicated that differences were restricted to children who had moderate-severe PPB. No consistent differences were observed in children who had mild PPB.

Conclusion:

Children who had moderate-severe PPB in infancy show persistent differences in motor function. We suggest close developmental monitoring and early intervention to address motor deficits.
Management of Oronasal Fistulas in Patients With Cleft Lip and Palate
Authors: Miranda Bruna Lima , Júnior Júlio Leite de Araújo , Paiva Marcos Antônio Farias de , Lacerda Rosa Helena Wanderley , Vieira Alexandre Rezende
Published: March 2020

Background:

The oronasal fistula in cleft patients is one of the complications that can be found after primary surgeries due to a failure of healing of the surgical repair that causes the communication between the oral and nasal cavities. A number of procedures can be implemented to correct the fistula and it is not clear if a particular technique is the best to be recommended.

Objective:

This study aims to systematically analyze the scientific evidence regarding the treatment of oronasal fistulas located in the lingual-alveolar and labial-alveolar regions in patients with cleft lip and palate who have undergone primary surgeries.

Material and Methods:

A bibliographic search of articles published until September 2018 without restricted year and language of publication, in PubMed (Medline), Scopus, Cochrane, Web of science, and BVS databases. The MeSHterms “Fistula,” “Oral Fistula,” and “Cleft Lip” were used, which were related to each other and with other keywords related to the subject of the review through the “OR” and “AND” operators. The quality of the publications was evaluated according to the guidelines of the Methodological Index for Nonrandomized Studies.

Results:

After applying the eligibility criteria, a total of 18 articles were selected for the extraction of data and qualitative analysis.

Conclusion:

All publications analyzed in this review reported the fistula treatment at the same surgical time as the bone graft, independently of the donor area, the type of cleft treated and the patient's age at operation. There was no consensus among the studies on the best treatment type for oronasal fistulas located in the alveolar region, and further comparative studies between the existing techniques will be necessary to address this question.
The Role of Staged Cryosurgery and Three-Dimensional Computed Tomography Integrated Navigation System in the Surgical Management of Severe Involvement of Craniofacial Polyostotic Fibrous Dysplasia
Authors: Yildiz Kemalettin , Dündar Tolga Turan , Abdallah Anas , Mehdizade Turan , Güneren Ethem , Canter Halil Ibrahim
Published: March 2020

Fibrous dysplasia (FD) is a developmental bone disorder caused by the hamartamatous proliferation of bone-forming cells. A 29-year-old male patient with diagnosis of FD was admitted to our clinic with the symptoms of severe craniomaxillofacial involvement of FD beginning from last year. Neurological examination revealed diplopia, horizontal nystagmus, conductive hearing loss, and partial vision loss. In his medical history, it was reported that he had undergone intramedullary nailing operation in his left femur due to a pathological fracture approximately 8 years ago in the orthopedics clinic of our institution. The patient underwent 3 consecutive surgeries by our plastic and neurosurgical team. The patient was followed-up in the neuro-intensive care unit between the surgical sessions and 1 week after the last operation. Afterwards, he was transferred to the neurosurgical department. No postoperative complication was detected. The preoperative signs were recovered. During his 6th month follow-up control-visit, all his preoperative symptoms were improved. In addition, the patient was satisfied with his postoperative cosmetic improvement. In conclusion, virtual surgical planning and intraoperative surgical navigation systems can make the challenging cases possible to operate with increasing the safety margin of the surgical procedures for polyostotic FD.
“Ready SIM Go”
Authors: Mednick Lauren , O'Connell Brianna , Graber Kelsey , Roussin Christopher , Weinstock Peter
Published: March 2020

Summary Statement

Changing healthcare systems and efforts to decrease medical costs have resulted in many more patients and caregivers (PCs) needing to manage life-sustaining therapies on their own. Given the potential for underpreparedness to result in increased morbidity and mortality, developing safe and efficient homecare training methods for PCs is essential. Medical simulation with PCs is an underused tool, which has the potential to decrease anxiety and increase preparedness through opportunities for repeated practice of medical procedures within a safe, controlled environment. This article describes the development of a hospital-based simulation service line for PCs, leveraging lessons learned from training for 250 patients and 450 caregivers in 14 different departments and subspecialties, and explains adaptations of standard simulation methods necessary for safe and effective use of simulation with this unique population. Process blueprint, examples of specific programs, as well as feedback from participants and clinicians are included.
Association of Knowledge and Presence of Pelvic Floor Disorders and Participation in Pelvic Floor Exercises: A Cross-sectional Study
Authors: Goodridge Sophia Delpe , Chisholm Leah P. , Heft Jessica , Hartigan Siobhan , Kaufman Melissa , Dmochowski Roger R. , Stewart Thomas , Reynolds William Stuart
Published: March 2020

Introduction

Women’s baseline knowledge of pelvic floor exercises (PFEs) and pelvic floor disorders (PFDs) is not well established, as is their knowledge regarding PFE and participation in such exercise. The aim of our study was to assess baseline PFD and PFE knowledge and to determine if knowledge in any way influenced participation in PFEs.

Methods

This was an institutional review board–approved, cross-sectional survey administered to women 18 years or older. We included all women who completed the survey, of which 3733 met the criteria. A survey-based questionnaire was used to query lower urinary tract symptoms, PFD, knowledge, and frequency of participation in PFEs.

Results

Of those who responded, the mean incontinence knowledge score was 9.2 ± 2.6, whereas the mean score for pelvic organ prolapse (POP) knowledge was 6.8 ± 3.6. Of the respondents, 92.5% reported being familiar with Kegel exercises. The majority of respondents reported that they did not participate in PFEs (57.4%). Those with POP were more likely to do daily PFEs than those without POP, 34.8% versus 16.4% (P < 0.001). Stress urinary incontinence did not influence frequency of performing PFEs.

Conclusions

Our study demonstrated that while baseline knowledge of POP and incontinence knowledge were high in this patient population, the majority of participants did not participate in PFE. Participants with POP were more likely to partake in daily PFE. A gap exists between knowledge and willingness to participate in PFE. Bridging this gap may be significantly impactful for women’s health.
Risk Factors and Impact of Perioperative Prophylaxis on the Risk of Extended-spectrum β-Lactamase–producing Enterobacteriaceae–related Infection Among Carriers Following Liver Transplantation
Authors: Logre Elsa , Bert Frédéric , Khoy-Ear Linda , Janny Sylvie , Giabicani Mikhaël , Grigoresco Bénédicte , Toussaint Amélie , Dondero Fédérica , Dokmak Safi , Roux Olivier , Francoz Claire , Soubrane Olivier , Durand François , Paugam-Burtz Catherine , Weiss Emmanuel
Published: March 2020

Background.

Extended-spectrum β-lactamase–producing Enterobacteriaceae (ESBL-E) carriage is frequent among liver transplant (LT) recipients, thereby fostering a large empirical carbapenem prescription. However, ESBL-E infections occur in only 10%–25% of critically ill patients with rectal colonization. Our aim was to identify risk factors for post-LT ESBL-E infection in colonized patients. The effect of perioperative antimicrobial prophylaxis (AP) was also analyzed in patients with prophylaxis lasting <48 hours and without proven intraoperative infection.

Methods.

Retrospective study from a prospective database including patients with a positive ESBL-E rectal screening transplanted between 2010 and 2016.

Results.

Among the 749 patients transplanted, 100 (13.3%) were colonized with an ESBL-E strain. Thirty-nine (39%) patients developed an infection related to the same ESBL-E (10 pulmonary, 11 surgical site, 13 urinary, 5 bloodstream) within 11 postoperative days in median. Klebsiella pneumoniae carriage, model for end-stage liver disease ≥25, preoperative spontaneous bacterial peritonitis prophylaxis, and antimicrobial exposure during the previous month were independent predictors of ESBL-E infection. We propose a colonization to infection risk score built on these variables. The prevalence of infection for colonization to infection score of 0, 1, 2, and ≥3 were 7.4%, 26.3%, 61.9%, and 91.3%, respectively. Of note, the incidence of post-LT ESBL-E infection was lower in case of perioperative AP targeting colonizing ESBL-E (P = 0.04).

Conclusions.

Thirty-nine percentage of ESBL-E carriers develop a related infection after LT. We identified predictors for ESBL-E infection in carriers that may help in rationalizing carbapenem prescription. Perioperative AP targeting colonizing ESBL-E may be associated with a reduced risk of post-LT ESBL-E infections.
The Impact of Portal Vein Thrombosis on Liver Transplant Outcomes: Does Grade or Flow Rate Matter?
Authors: Rizzari Michael D. , Safwan Mohamed , Sobolic Michael , Kitajima Toshihiro , Collins Kelly , Yoshida Atsushi , Abouljoud Marwan , Nagai Shunji
Published: March 2020

Background.

Portal vein thrombosis (PVT) makes the technical aspect of liver transplantation challenging and also affects outcomes. Our aim was to study impact of PVT grade and postreperfusion portal flow on posttransplant outcomes.

Methods.

Patients who underwent transplantation with PVT between January 2007 and May 2017 were selected (n = 126). Data on grade of PVT and portal vein flow were collected. Patients were classified into 2 groups; low grade (Yerdel Grade I, n = 73) and high grade (Yerdel Grade II or III, n = 53). Using portal flow rate, patients were divided into high flow (≥1000 mL/min, n = 95) and low flow (<1000 mL/min, n = 31). Additional analyses of flow by graft weight and complications were performed.

Results.

Postoperatively, incidence of biliary strictures were significantly greater in high-grade PVT compared with low grade (P= 0.02). Incidence of postoperative portal vein thrombosis was higher in low flow after reperfusion compared with high flow (P= 0.02), as was bile leak (P= 0.02). On identifying factors associated with graft loss, moderate to severe ascites preoperatively, high PVT grade and bile leak were associated with worse graft survival. Subanalysis performed combining grade and flow showed that low grade, high flow had the highest graft survival while high grade, low flow had the lowest (P= 0.006). High-grade PVT with low flow also appeared to be an independent risk factor for biliary complications (P= 0.01).

Conclusions.

In conclusion, biliary complications, especially strictures are more common in high-grade PVT and graft survival is worse in high-grade PVT and low portal flow.
Adding Insult on Injury: Immunogenic Role for Donor-derived Cell-free DNA?
Authors: Dholakia Shamik , De Vlaminck Iwijn , Khush Kiran K.
Published: March 2020

Donor-derived cell-free DNA (dd-cfDNA) in the blood circulation is an early marker of injury in solid organ transplantation. Here, we review recent evidence that indicates that dd-cfDNA may itself be a trigger of inflammation, thereby adding insult on injury. Early unresolving molecular allograft injury measured via changes in dd-cfDNA may be an early warning sign and may therefore enable stratification of patients who are at risk of subsequent allograft injury. Considering dd-cfDNA as a continuous and clinically significant biomarker opens up the potential for new management strategies, therapeutics, and ways to quantify interventions by considering the immunological potential of dd-cfDNA.
Factor Consistency of Neuropsychological Test Battery Versions in the NACC Uniform Data Set
Authors: Culhane Jessica E. , Chan Kwun C.G. , Teylan Merilee A. , Chen Yen-Chi , Mock Charles , Gauthreaux Kathryn , Kukull Walter A.
Published: March 2020

The proprietary neuropsychological tests (Form C1) of the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set were replaced with nonproprietary versions (Form C2) chosen to closely model their proprietary counterparts. Correlations between analogous test pairs as measured in previous work were good (0.68-0.78), but it is unclear whether the paired tests represent the same set of common factors of cognition or if important factors specific to C1 or C2 only exist. The authors performed multiple factor analysis to analyze correlated C1 and C2 data. They included participants who completed both neuropsychological batteries within 1 year with no change in cognitive status. They found that the C1 and C2 neuropsychological test pairs are strongly related and are represented by the same principal factors. These findings support the use of the C2 test results in conjunction with C1 in longitudinal analyses of NACC data.
Identifying Adaptive and Maladaptive Behaviors Following a Diagnosis of Mild Cognitive Impairment
Authors: Gibson Allison , Bardach Shoshana H. , Jicha Gregory A.
Published: March 2020

Introduction:

Individual reactions to a diagnosis of mild cognitive impairment (MCI) can vary in a wide range of both adaptive and maladaptive responses. Understanding such reactions to diagnosis is important to maximize adaptive responses that can promote continued independence.

Methods:

In this pilot study, the Aging and Memory Quality of Life survey was developed to facilitate an understanding of adaptive and maladaptive behaviors results from a diagnosis of MCI. The Aging and Memory Quality of Life was administered to 45 individuals diagnosed with MCI and 45 cognitively normal participants serving as control subjects matched for age, sex, and education. Study partners were surveyed to collect corroborating and or discrepant observer responses.

Results:

Inconsistent with study partners’ reporting, MCI subjects may be underreporting physical limitations, and overreporting medication compliance. MCI subjects identified challenges to managing financial affairs.

Discussion:

Developing strategies to circumvent the development of maladaptive behaviors could significantly reduce morbidity and mortality in MCI patients.
Incrimination of Aedes aegypti and Aedes albopictus as vectors of dengue virus serotypes 1, 2 and 3 from four states of Northeast India
Authors: Chetry Sumi , Patgiri Saurav Jyoti , Bhattacharyya Dibya Ranjan , Dutta Prafulla , Kumar N. Pradeep
Published: March 2020

Dengue is an important vector borne disease with a great public health concern worldwide. Northeast India has experienced dengue almost every year for a decade. As studies on dengue vectors from this region are limited, we undertook an investigation to detect natural infection of the dengue virus (DENV) in potential dengue vectors of this region. AdultAedesmosquitoes which were collected were subjected to RT-PCR for detection of infecting dengue serotype. Minimum infection rate was also determined for each positive pool. Out of the total 6229 adultAedesmosquitoes collected,Aedes aegypti(63.3 %) was abundant in comparison toAedes albopictus(36.7 %). These specimens (515 mosquito pools) were subjected to RT-PCR for detection of DENV-1, 2, 3 and 4. RT-PCR revealed the existence of DENV in both male as well as female mosquito pools suggesting natural transovarial transmission of DENV in this region. A total of 54 pools tested were positive for DENV-1, 2, 3 serotypes. This study revealed the occurence of DENV in both the potential dengue vectors from this region along with evidence of transovarial transmission which helps in persistence of the virus in nature.
Genomic surveillance of Escherichia coli ST131 identifies local expansion and serial replacement of subclones
Authors: Ludden Catherine , Decano Arun Gonzales , Jamrozy Dorota , Pickard Derek , Morris Dearbhaile , Parkhill Julian , Peacock Sharon J. , Cormican Martin , Downing Tim
Published: March 2020

Escherichia coli

sequence type 131 (ST131) is a pandemic clone that is evolving rapidly with increasing levels of antimicrobial resistance. Here, we investigated an outbreak of

E. coli

ST131 producing extended spectrum β-lactamases (ESBLs) in a long-term care facility (LTCF) in Ireland by combining data from this LTCF (n=69) with other Irish (n=35) and global (n=690) ST131 genomes to reconstruct the evolutionary history and understand changes in population structure and genome architecture over time. This required a combination of short- and long-read genome sequencing, de novo assembly, read mapping, ESBL gene screening, plasmid alignment and temporal phylogenetics. We found that Clade C was the most prevalent (686 out of 794 isolates, 86 %) of the three major ST131 clades circulating worldwide (A with fimH41, B with fimH22, C with fimH30), and was associated with the presence of different ESBL alleles, diverse plasmids and transposable elements. Clade C was estimated to have emerged in c. 1985 and subsequently acquired different ESBL gene variants (bla

CTX-M-14
vs bla

CTX-M-15
). An ISEcp1-mediated transposition of the bla

CTX-M-15
gene further increased the diversity within Clade C. We discovered a local clonal expansion of a rare C2 lineage (C2_8) with a chromosomal insertion of bla

CTX-M-15
at the mppA gene. This was acquired from an IncFIA plasmid. The C2_8 lineage clonally expanded in the Irish LTCF from 2006, displacing the existing C1 strain (C1_10), highlighting the potential for novel ESBL-producing ST131 with a distinct genetic profile to cause outbreaks strongly associated with specific healthcare environments.
Genomic epidemiology and population structure of Neisseria gonorrhoeae in Norway, 2016–2017
Authors: Alfsnes Kristian , Eldholm Vegard , Olsen Anne Olaug , Brynildsrud Ola Brønstad , Bohlin Jon , Steinbakk Martin , Caugant Dominique A.
Published: March 2020

This study presents the nationwide epidemiology of

Neisseria gonorrhoeae

, using whole-genome sequencing of all culture-positive cases, which comprise roughly 40 % of all cases of gonorrhea reported in Norway from 2016 to 2017. Isolates were assigned to sequence types and Bayesian analysis clusters and variation in genes coding for antibiotic resistance was linked to phenotypic resistance data. The study also included isolates taken from the same patients from different anatomical sites at one or more time points. Comparing these isolates allows for observation of patterns of infections, i.e. multiple reinfections of genetically related clones vs. reinfections of genetically distant clones, and quantification of the genomic variation of closely related isolates from samples taken from a patient within the same day. Demographically, the patients in the study could be split into two groups; one group of patients from the capital with a high proportion of men who have sex with men (MSM), and another consisting of young adults with transmission primarily between males and females from outside the capital. Some clusters of

N. gonorrhoeae

were restricted to one of these two demographic groups. Pairwise comparison of multiple isolates from the same patients revealed that most were reinfected with different clones. Observations of frequent reinfections in patients is a concern and should be taken into account in the development of improved information and treatment guidelines.
Human leukocyte antigen susceptibility map for SARS-CoV-2
Authors: Nguyen Austin , David Julianne K. , Maden Sean K. , Wood Mary A. , Weeder Benjamin R. , Nellore Abhinav , Thompson Reid F.
Published: March 2020

Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen [HLA] A, B, and C) may affect susceptibility to and severity of severe acute respiratory syndrome 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We execute a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across 145 HLA -A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explore the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome is successfully sampled and presented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (1). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting it could enable cross-protective T-cell based immunity. Finally, we report global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic.

IMPORTANCE

Individual genetic variation may help to explain different immune responses to a virus across a population. In particular, understanding how variation in HLA may affect the course of COVID-19 could help identify individuals at higher risk from the disease. HLA typing can be fast and inexpensive. Pairing HLA typing with COVID-19 testing where feasible could improve assessment of viral severity in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination.
The formal demography of kinship II: Multistate models, parity, and sibship
Authors: Caswell Hal
Published: March 2020

Background

Recent kinship models focus on the age structures of kin as a function of the age of the focal individual. However, variables in addition to age have important impacts. Generalizing age-specific models to multistate models including other variables is an important and hitherto unsolved problem.

Objectives

Our aim is to develop a multistate kinship model, classifying individuals jointly by age and other criteria (generically, “stages”).

Methods

We use the vec-permutation method to create multistate projection matrices including age- and stage-dependent survival, fertility, and transitions. These matrices operate on block-structured population vectors that describe the age×stage structure of each kind of kin, at each age of a focal individual.

Results

The new matrix formulation is directly comparable to, and greatly extends, the recent age-classified kinship model of Caswell (2019a). As an application, we derive a model that includes age and parity. We obtain, for all types of kin, the joint age×parity structure, the marginal age and parity structures, and the (normalized) parity distributions, at every age of the focal individual. We show how to use the age×parity distributions to calculate the distributions of sibship sizes of kin.

As an example, we apply the model to Slovakia (1960–2014). The results include a dramatic shift in the parity distribution as the frequency of low-parity kin increased and that of high-parity kin decreased.

Contribution

The new model extends the formal demographic analysis of kinship to age×stage-classified models. In addition to parity, other stage classifications, including marital status, maternal age effects, and sex are now open to analysis.
The motor neuron-like cell line NSC-34 and its parent cell line N18TG2 have glycogen that is degraded under cellular stress
Authors: Pfeiffer-Guglielmi Brigitte , Jansen Ralf-Peter
Published: March 2020

Brain glycogen has a long and versatile history: Primarily regarded as an evolutionary remnant, it was then thought of as an unspecific emergency fuel store. A dynamic role for glycogen in normal brain function has been proposed later but exclusively attributed to astrocytes, its main storage site. Neuronal glycogen had long been neglected, but came into focus when sensitive technical methods allowed quantification of glycogen at low concentration range and the detection of glycogen metabolizing enzymes in cells and cell lysates. Recently, an active role of neuronal glycogen and even its contribution to neuronal survival could be demonstrated. Our studies continue these investigations on the function and regulation of neuronal glycogen metabolism. We demonstrate the presence of an active glycogen metabolism in the neuronal cell lines NSC-34 and N18TG2 and the mobilization of the glycogen stores under hypoxia, oxidative and acidic metabolic stress. The key enzyme in glycogen degradation is glycogen phosphorylase. Neurons express only the brain isoform (GPBB) that is supposed to be activated primarily by the allosteric activator AMP and less by covalent phosphorylation via the cAMP cascade. Our results indicate that neuronal glycogen is not degraded upon hormone action but by factors lowering the energy charge of the cells directly.
Variable expression quantitative trait loci analysis of breast cancer risk variants
Authors: Wiggins George , Black Michael A , Dunbier Anita , Merriman Tony R , Pearson John , Walker Logan C
Published: March 2020

Genome wide association studies (GWAS) have identified more than 180 variants associated with breast cancer risk, however the underlying functional mechanisms and biological pathways which confer disease susceptibility remain largely unknown. As gene expression traits are under genetic regulation we hypothesise that differences in gene expression variability may identify causal breast cancer susceptibility genes. We performed variable expression quantitative trait loci (veQTL) analysis using tissue-specific expression data from the Genotype-Tissue Expression (GTEx) Common Fund Project. veQTL analysis identified 70 associations (p< 5×10−8) consisting of 60 genes and 27 breast cancer risk variants, including 55 veQTL that were observed in breast tissue only. Pathway analysis of genes associated with breast-specific veQTL revealed an enrichment of four genes (CYP11B1, CYP17A1 HSD3B2andSTAR) involved in the C21-steroidal biosynthesis pathway that converts cholesterol to breast-related hormones (e.g. oestrogen). Each of these four genes were significantly more variable in individuals homozygous for rs11075995 (A/A) breast cancer risk allele located in theFTOgene, which encodes an RNA demethylase. The A/A allele was also found associated with reduced expression ofFTO, suggesting an epi-transcriptomic mechanism may underlie the dysregulation of genes involved in hormonal biosynthesis leading to an increased risk of breast cancer. These findings provide evidence that genetic variants govern high levels of expression variance in breast tissue, thus building a more comprehensive insight into the underlying biology of breast cancer risk loci.
The length of lipoteichoic acid polymers controlsStaphylococcus aureuscell size and envelope integrity
Authors: Hesser Anthony R. , Matano Leigh M. , Vickery Christopher R. , Wood B. McKay , Santiago Ace George , Morris Heidi G. , Do Truc , Losick Richard , Walker Suzanne
Published: March 2020

The opportunistic pathogenStaphylococcus aureusis protected by a cell envelope that is crucial for viability. In addition to peptidoglycan, lipoteichoic acid (LTA) is an especially important component of theS. aureuscell envelope. LTA is an anionic polymer anchored to a glycolipid in the outer leaflet of the cell membrane. It was known that deleting the gene for UgtP, the enzyme that makes this glycolipid anchor, causes cell growth and division defects. InBacillus subtilis, growth abnormalities from the loss ofugtPhave been attributed to the absence of the encoded protein, not to loss of its enzymatic activity. Here, we show that growth defects inS. aureus ugtPdeletion mutants are due to the long, abnormal LTA polymer that is produced when the glycolipid anchor is missing from the outer leaflet of the membrane. Dysregulated cell growth leads to defective cell division, and these phenotypes are corrected by mutations in the LTA polymerase,ltaS, that reduce polymer length. We also show thatS. aureusmutants with long LTA are sensitized to cell wall hydrolases, beta-lactam antibiotics, and compounds that target other cell envelope pathways. We conclude that control of LTA polymer length is important forS. aureusphysiology and promotes survival under stressful conditions, including antibiotic stress.

IMPORTANCE

Methicillin-resistantStaphylococcus aureus(MRSA) is a common cause of community- and hospital-acquired infections and is responsible for a large fraction of deaths caused by antibiotic-resistant bacteria.S. aureusis surrounded by a complex cell envelope that protects it from antimicrobial compounds and other stresses. Here we show that controlling the length of an essential cell envelope polymer, lipoteichoic acid, is critical for controllingS. aureuscell size and cell envelope integrity. We also show that genes involved in LTA length regulation are required for resistance to beta-lactam antibiotics in MRSA. The proteins encoded by these genes may be targets for combination therapy with an appropriate beta-lactam.
Proteome comparison between natural desiccation-tolerant plants and drought-protectedCaspicum annuumplants byMicrobacteriumsp. 3J1
Authors: García-Fontana C , Vilchez JI , Manzanera M
Published: March 2020

Desiccation-tolerant plants are able to survive for extended periods of time in the absence of water. The molecular understanding of the mechanisms used by these plants to resist droughts can be of great value for the improvement of tolerance of sensitive plants with agricultural interest. This understanding is especially relevant in an environment that tends to increase the number and intensity of droughts. The combination of certain microorganisms with drought-sensitive plants can improve their tolerance to water scarcity. One of these bacteria isMicrobacteriumsp. 3J1, an actinobacteria able to protect pepper plants from drought. In this study we describe the proteome of the interaction ofMicrobacteriumsp. 3J1 with pepper plants during droughts. We also compare this proteome with the proteome found in desiccation-tolerant plants. In addition, we studied the proteome ofMicrobacteriumsp. 3J1 subjected to drought to analyze its contribution to the plant-microbe interaction. We describe those mechanisms shared by desiccation-tolerant plants and sensitive plants protected by microorganisms focusing on protection against oxidative stress, and production of compatible solutes, plant hormones, and other more specific proteins.

IMPORTANCE

Maintaining agricultural production under greater number and intensity of droughts is one of the main global challenges. Some plants can survive in the absence of water for extended periods of time. The molecular understanding of the mechanisms used by these plants to resist droughts is of great interest for the development of new strategies to face this challenge. Some microorganisms protect sensitive plants to some extent from droughts.Microbacteriumsp. 3J1, is an actinobacteria able to protect pepper plants from drought. In this study we describe the different protein profile under drought used by the plant during the interaction with the microorganism and compare it with the one presented by desiccation-tolerant plants and with the one presented byMicrobacteriumsp. 3J1 to analyze its contribution to the plant-microbe interaction. We describe those mechanisms focusing on protection against oxidative stress, and production of compatible solutes, plant-hormones, and other more specific proteins.
Toxoplasmicidalin vitroeffect of dehydroepiandrosterone on Toxoplasma gondii extracellular tachizoytes
Authors: Muñiz-Hernández Saé , de León Carmen T. Gómez , Nophal Angélica Luna , Domínguez-Ramírez Lenin , Patrón-Soberano Olga-Araceli , Nava-Castro Karen E , Ostoa-Saloma Pedro , Morales-Montor Jorge
Published: March 2020

Toxoplasmosis is a zoonotic disease caused by the apicomplexa protozoan parasiteToxoplasma gondii. This disease is a health burden, mainly in pregnant women and immunocompromised individuals, in whom they can cause death. Despite advances in the medical area, nowadays there are no new drugs to treat toxoplasmosis. The standard therapy to toxoplasmosis has not had progress for last seven decades; it is a combination of sulfadiazine-pyrimethamine (S-P); which is co-administered with folic acid due to the adverse effects of the drug. Several studies have shown that the conventional treatment has limited effectiveness and severe adverse effects. Thus, the search of better treatments with greater efficacy and without the adverse effects becomes relevant. In the current work we demonstrate for the first time the parasiticidal effect of dehydroepiandrosterone (DHEA), a steroid hormone produced by many mammals, on extracellular tachyzoites (the infective stage ofT. gondii). In vitro treatment with DHEA reduces the viability of extracellular tachyzoites, and both the active and passive invasion processes. The ultrastructural analysis of treated parasites showed that DHEA alters the cytoskeleton structures, leading in the lost of the organelle structure and organization, as well as, the lost of the cellular shape. On a molecular level, we observed an important reduction of the expression of several proteins that are essential for the motility and virulence of parasites when they were exposed to DHEA. These results suggest that DHEA could be used as an alternative treatment against toxoplasmosis.
Auditory-Vestibulomotor Temporal Processing and Crossmodal Plasticity for Musical Rhythm in the Early Blind
Authors: Phillips-Silver Jessica , VanMeter John W. , Rauschecker Josef P.
Published: March 2020

The auditory dorsal stream (ADS) is a cortical brain network responsible for sensorimotor control and integration, including spatiotemporal processing. Although spatiotemporal movement of the head and body involves input from the vestibular system, and despite the wealth of evidence for the strong coupling between the vestibular and visual systems, very little is known about how vestibular information is integrated with auditory-motor inputs in the ADS. There is also no evidence addressing to what extent auditory-vestibulomotor integration is affected by early visual deprivation. Using functional magnetic resonance imaging and motion capture technology we show that in a task of sensorimotor temporal processing (‘feeling the beat’), the ADS includes an extension to parietoinsular vestibular cortex (PIVC) and to subcortical regions including basal ganglia and vestibular cerebellum. This circuit is engaged after sensorimotor synchronization training, during beat recognition, and is preserved in the early blind. The strength of activation of PIVC in the early blind correlates with a measure of lifetime physical spatial activity, suggesting that experience with vestibular stimulation via physical spatial activities might compensate for any negative effects of early blindness, and thus reinforcing the potential beneficial effects of mobility training. Finally, rhythmic entrainment provides an effective tool for studying auditory-vestibulomotor integration and music appreciation, and for developing music- and movement-based interventions for early blind individuals.
Activity-dependent tuning of intrinsic excitability in mouse and human neurogliaform cells
Authors: Chittajallu R. , Auville K. , Mahadevan V. , Lai M. , Hunt S. , Calvigioni D. , Pelkey K.A. , Zaghloul K.A. , McBain C.J.
Published: March 2020

The ability to modulate the efficacy of synaptic communication between neurons constitutes an essential property critical for normal brain function. Animal models have proved invaluable in revealing a wealth of diverse cellular mechanisms underlying varied plasticity modes. However, to what extent these processes are mirrored in humans is largely uncharted thus questioning their relevance to human circuit function. In this study, we focus on neurogliaform cells, a specialized form of neuron that possess physiological features enabling them to impart a widespread inhibitory influence on neural activity. We demonstrate that this prominent neuronal subtype, embedded in both mouse and human neural circuits, undergo remarkably similar activity-dependent modulation manifesting as epochs of enhanced intrinsic excitability. In principle, these evolutionary conserved plasticity routes likely tune the extent of neurogliaform cell mediated inhibition thus constituting canonical circuit mechanisms relevant for human cognitive processing and behavior.
Molecular Scale Spatio-Chemical Control of the Activating-Inhibitory Signal Integration in NK Cells
Authors: Toledo Esti , Le Saux Guillaume , Li Long , Rosenberg Maor , Keidar Yossi , Bhingardive Viraj , Edri Avishay , Hadad Uzi , Di Primo Carmelo , Buffeteau Thierry , Smith Ana-Sunčana , Porgador Angel , Schvartzman Mark
Published: March 2020

The role of the spatial juxtaposition between activating and inhibitory receptors in cytotoxic lymphocytes has been strongly debated in the context of the inhibition of immune signaling. The challenge in addressing this problem was so far a lack of experimental tools which can simultaneously manipulate different signaling molecules. Here, we circumvent this challenge by introducing a nanoengineered multifunctional cell niche, in which activating and inhibitory ligands are positioned with molecular-scale variability and control, and applied it to elucidate the role of the spatial juxtaposition between ligands for NKG2D and KIR2DL1 – activating and inhibitory receptors in Natural Killer (NK) cells – in KIR2DL1-mediated inhibition of NKG2D signaling. We realized the niche by a nanopatterning of nanodots of different metals with molecular scale registry in one lithographic step, followed by a novel ternary functionalization of the fabricated bi-metallic pattern and its background to with three distinct biochemical moieties. We found, that within the probed range, the 40 nm gap between the activating and inhibitory ligands provided an optimal inhibition condition. Supported by theoretical modeling and simulations we interpret these findings as a consequence of the size and conformational flexibility of the ligands in their spatial interaction. Our findings provide an important insight onto the spatial mechanism of the inhibitory immune checkpoints, whose understanding is both fundamentally important, and essential for the rational design of future immunotherapies. Furthermore, our approach is highly versatile and paves the way to numerous complex molecular platforms aimed at revealing molecular mechanisms through which receptors integrate their signals.
Temporal environmental variation imposes differential selection on genomic and ecological traits of virtual plant communities
Authors: Leidinger Ludwig , Cabral Juliano Sarmento
Published: March 2020

The reaction of species to changing conditions determines how community composition will change functionally — not only by (temporal) species turnover, but also by trait shifts within species. For the latter, selection from standing variation has been suggested to be more efficient than acquiring new mutations. Yet, studies on community trait composition and trait selection largely focus on phenotypic variation in ecological traits, whereas the underlying genomic traits remain relatively understudied despite evidence of their role to standing variation. Using a genome-explicit, niche- and individual-based model, we address the potential interactions between genomic and ecological traits shaping communities under an environmental selective forcing, namely temporal variation. In this model, all ecological traits are explicitly coded by the genome. For our experiments, we initialized 90 replicate communities, each with ca. 350 initial species, characterized by random genomic and ecological trait combinations, on a 2D spatially-explicit landscape with two orthogonal gradients (temperature and resource use). We exposed each community to two contrasting scenarios: without (i.e. static environments) and with temporal variation. We then analyzed emerging compositions of both genomic and ecological traits at the community, population and genomic levels. Communities in variable environments were species poorer than in static environments, populations more abundant and genomes had a higher numbers of genes. The surviving genomes (i.e. those selected by variable environments) coded for enhanced environmental tolerance and smaller biomass, which resulted in faster life cycles and thus also in increased potential for evolutionary rescue. Even under the constant environmental filtering presented by temporal environmental variation, larger, more linked genomes allowed selection of increased variation in dispersal abilities. Our results provide clues to how sexually-reproducing diploid plant communities might react to increased environmental variation and highlights the importance of genomic traits and their interaction with ecological traits for eco-evolutionary responses to changing climates.
Segment-Specific Optogenetic Stimulation inDrosophila melanogasterwith Linear Arrays of Organic Light-Emitting Diodes
Authors: Murawski Caroline , Pulver Stefan R. , Gather Malte C.
Published: March 2020

Optogenetics allows light-driven, non-contact control of neural systems, but light delivery remains challenging, in particular when fine spatial control of light is required to achieve local specificity. Here, we employ organic light-emitting diodes (OLEDs) that are micropatterned into linear arrays to obtain precise optogenetic control inDrosophila melanogasterlarvae expressing the light-gated activator CsChrimson and the inhibitor GtACR2 within their peripheral sensory system. Our method allows confinement of light stimuli to within individual abdominal segments, which facilitates the study of larval behaviour in response to local sensory input. We show controlled triggering of specific crawling modes and find that targeted neurostimulation in abdominal segments switches the direction of crawling. More broadly, our work demonstrates how OLEDs can provide tailored patterns of light for photo-stimulation of neuronal networks, with future implications ranging from mapping neuronal connectivity in cultures to targeted photo-stimulation with pixelated OLED implantsin vivo.
Methylation Data Processing Protocol & Comparison of Blood and Cerebral Spinal Fluid Following Aneurysmal Subarachnoid Hemorrhage
Authors: Arockiaraj Annie I. , Liu Dongjing , Shaffer John R. , Koleck Theresa A. , Crago Elizabeth A. , Weeks Daniel E. , Conley Yvette P.
Published: March 2020

One challenge in conducting DNA methylation-based epigenome-wide association studies (EWAS) is the appropriate cleaning and quality-checking of the methylation values to minimize biases and experimental artifacts, while simultaneously retaining potential biological signals. These issues are compounded in studies that include multiple tissue types, and/or tissues for which reference data are unavailable to assist in adjusting for cell-type mixture, for example cerebral spinal fluid (CSF). For our study that evaluated blood and CSF taken from aneurysmal subarachnoid hemorrhage (aSAH) patients, we developed a protocol to clean and quality-check genome-wide methylation levels and compared the methylomic profiles of the two tissues to determine whether blood is a suitable surrogate for CSF. CSF samples were collected from 279 aSAH patients longitudinally during the first 14 days of hospitalization, and a subset of 88 of these patients also provided blood samples within the first two days. Quality control (QC) procedures included identification and exclusion of poor performing samples and low-quality probes, functional normalization, and correction for cell-type heterogeneity via surrogate variable analysis (SVA). Significant differences in rates of poor sample performance was observed between blood (1.1% failing QC) and CSF (9.12% failing QC; p = 0.003). Functional normalization increased the concordance of methylation values among technical replicates in both CSF and blood. Likewise, SVA improved the asymptotic behavior of the test of association in a simulated EWAS under the null hypothesis. To determine the suitability of blood as a surrogate for CSF, we calculated the correlation of adjusted methylation values between blood and CSF globally and by genomic regions. Overall, mean correlation (r < 0.26) was low, suggesting that blood is not a suitable surrogate for global methylation in CSF. However, differences in the magnitude of the correlation were observed by genomic region (CpG island, shore, shelf, open sea; p < 0.001 for all) and orientation with respect to nearby genes (3’ UTR, transcription start site, exon, body, 5’ UTR; p < 0.01 for all). In conclusion, the correlation analysis and QC pipelines indicated that DNA extracted from blood was not, overall, a suitable surrogate for DNA extracted from CSF in aSAH methylomic studies.