bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Preradiotherapy Education on Anxiety in Parents of Under-Five Children Undergoing Radiation Therapy for the First Time
Authors: Halemani Kurvatteppa , Kumar Basant
Published: November 2020

Introduction

Radiation or radiotherapy is a kind of cancer treatment where high-intensity rays are used to destroy abnormal cells. It is used for therapeutic as well as diagnostic purpose of various malignant diseases. The purpose of the study is to determine the parent's anxiety on radiotherapy and render valid radiotherapy teaching materials. A case study on Wilms' tumor is used to frame the study for pediatric surgical nurses.

Methods and Material

A longitudinal, single-center, quasi-experimental one-group pretest–posttest research design was adopted. Samples were based on convenient sampling techniques for those who fulfilled the inclusion criteria. Separate instruments were used for demographic information and the anxiety of parents. Data were collected from November 2018 to December 2019.

Result

Demographic characteristics measured by descriptive statistics in 26 patients. Most of the participants were aged between 36 and 45 years (n = 17, 65.4%); participants were fathers (n = 19, 73.1%) who had completed high school or college (n = 23, 88.5%) and parents with one or two children. There were no significant differences in parents' age, gender, and number of children. Most of the children were of preschool age (n = 23, 88.5%) and were male (n = 16, 61.5%) diagnosed with a malignant tumor (n = 18, 69.2%).

For the parents, education and family income were associated with less preoperative anxiety (p = .05). There were no significant differences in variables of the child's gender and type of tumor, whereas younger age was found significant for more anxiety (p = .05). The effectiveness of results showed that the paired t test was −10.25; mean and standard deviation in preintervention and postintervention were 70.61 ± 4.85 versus 54.80 ± 9.26, respectively.

Discussion

The present study finding was supported by previous studies, which imply that educational materials, charts, printed materials, and pamphlets remained highly significant on anxiety scores of parents of under-five children. Hence, the researcher assumed that preradiotherapy education intervention was effective for parents of under-five children.
Diagnostic and Treatment Challenges for Acquired Hemophilia A in Pediatrics: Report of 2 Cases
Authors: Kim Kyu S. , Wong Victor , Thornburg Courtney D. , Yu Jennifer C.
Published: November 2020

Acquired hemophilia A (AHA) occurs rarely in children. We report 2 cases of adolescent females with AHA. The first case underwent bone marrow aspiration/biopsy during workup, which was complicated by bleeding. Bleeding resolved after initiation of therapy with cyclophosphamide and glucocorticoid, but despite the addition of rituximab, she did not achieve complete remission until treatment with intravenous immunoglobulin. In the second case, we observed that a mixing study without incubation will not detect an acquired factor VIII inhibitor, but further workup based on suspicion for AHA led to the correct diagnosis. Both had significant medication toxicity which required treatment modification.
Death and Grieving for Family Caregivers of Loved Ones With Life-Limiting Illnesses in the Era of COVID-19
Authors: Holland Diane E. , Vanderboom Catherine E. , Dose Ann Marie , Moore Derek , Robinson Kelly V. , Wild Ellen , Stiles Carole , Ingram Cory , Mandrekar Jay , Borah Bijan , Taylor Erin , Griffin Joan M.
Published: November 2020

Purpose:

Family caregivers of a loved one with a life-limiting or terminal illness are often overwhelmed by, and underprepared for, their responsibilities. They often need help from family members and friends to provide comprehensive care. When death occurs, funerals and other death-related rituals bring family and communities together to honor the life and mourn the death of a loved one and provide needed support to family and caregivers. These collective rituals are often deeply rooted in culturally-bound values and can facilitate grief and help make sense about loss. Rituals act as bridge-building activities that allow people to organize and appraise emotions, information, and actions after a loss. With the emergence of the coronavirus disease-2019 (COVID-19) pandemic and the recommended restrictions to reduce infection and transmission, family members and caregivers are often faced with weighing options for honored rituals to help them grieve. Grieving during the pandemic has become disorganized. The purpose of this article is to provide case managers and other clinical staff with recommendations on guiding caregivers/families through safety precautions when a loved one dies either because of a life-limiting illness or from COVID-19 during the pandemic using guidelines from the Centers for Disease Control and Prevention (CDC). The authors also present information about complicated grief and ways to support coping with death and suggest safe alternatives to traditional death-related rituals and funerals in a COVID-19 era.

Primary Practice Setting(s):

Primary practice settings include home health care, hospice, hospital discharge planning, case management, and primary care.

Findings/Conclusions:

Precautions necessary in a COVID-19 era may add anxiety and stress to an already difficult situation of caring for loved ones at end-of-life and grieving with their loss. Utilization of CDC guidelines lessens the risk of infection while honoring loved ones' wishes and cultural traditions surrounding death and burial. Recognition of social and spiritual connections that comfort mourners must also be considered.

Implications for Case Management Practice:
Lower-Dose Propofol Use for MRI
Authors: Johnson Kay L. , Cochran Joel , Webb Sally
Published: November 2020

Objective

The aim of the study was to evaluate, in children undergoing procedural sedation for magnetic resonance imaging (MRI) scans, whether lower doses of propofol than previously published permitted a high rate of successful MRI completion, whether lower dosages result in a more rapid recovery, and whether age or behavioral diagnosis increases propofol requirements.

Methods

After institutional review board approval, we retrospectively reviewed the pediatric sedation team's sedation database of children receiving propofol infusion for MRI scans between 2007 and 2016. Data collected included propofol induction dose (in milligrams per kilogram), propofol infusion dose (in micrograms per kilogram per hour), total propofol dose (in milligrams per kilogram and in milligrams per kilogram per hour), and the number of administered ancillary sedative medications. Additional data included the American Society of Anesthesiologist status, sedation duration, recovery duration, and successful completion of MRI. Dosing data were also stratified by age.

Results

A total of 2354 patients met inclusion criteria. Eight percent of patients received propofol infusion alone, 79% received midazolam before their propofol induction, and 13% received a combination of propofol and other drugs. Mean induction dose was 2.2 + 0.9 mg/kg, mean infusion dose was 93.5 + 29.0 μg/kg per minute, and total mean dose was 9.0 + 3.0 mg/kg per hour. Mean recovery time was 44 minutes, and 99.3% of the scans were completed with good images. We noted an increase requirement in the mean induction dose and total dose in children younger than 1 year.

Conclusions

Propofol infusion doses lower than commonly reported permit successful completion of scans and similar recovery times in a single institution. Younger children require more propofol for successful procedural sedation.
Influence of dapivirine vaginal ring use on cervicovaginal immunity and functional microbiome in adolescent girls
Authors: Farr Zuend Christina , Noël-Romas Laura , Hoger Sarah , McCorriser Stuart , Westmacott Garrett , Marrazzo Jeanne , Hillier Sharon L. , Dezzutti Charlene , Squires Kathleen , Bunge Katherine E. , Burgener Adam
Published: November 2020

Objective:

The antiretroviral-based dapivirine vaginal ring reduced HIV risk among women in phase III clinical trials. However, limited data exists on the impact of dapivirine on the vaginal microenvironment in adolescents.

Design:

A comprehensive metaproteomics approach was used to assess host proteome and microbiome changes in cervicovaginal mucus with dapivirine ring use in adolescents enrolled in the MTN-023/IPM 030 (MTN-023) trial.

Methods:

Participants were randomized 3 : 1 to use dapivirine or placebo vaginal rings monthly for 6 months. Cervicovaginal samples from a subset of 35 participants (8 placebo, 27 dapivirine) were analyzed.

Results:

Mass spectrometry analysis identified 405 human and 2467 bacterial proteins belonging to 15 unique genera. The host proteome belonged to many functional pathways primarily related to inflammation. When stratified by study treatment arm, 18 (4.4%) and 28 (6.9%) human proteins were differentially abundant (adjusted P < 0.05) between baseline and follow-up in the placebo and dapivirine arms, respectively. The vaginal microbiome was predominantly composed of Lactobacillus, Gardnerella, and Prevotella. Although bacterial taxa did not differ by arm or change significantly, Lactobacillus crispatus increased (P < 0.001) and Lactobacillus iners decreased (P < 0.001) during the 6-month follow-up. There were no significant differences in bacterial functions by arm or time in the trial. Protected vaginal sex significantly associated with decreased neutrophil inflammatory biomarkers and may be associated with changes in bacterial taxa and metabolism.

Conclusion:

Condom use may associate with differences to inflammation and bacterial function but dapivirine ring use does not, thereby supporting the mucosal safety profile of this vaginal ring for adolescents.
A Novel Design of V-shaped Radial Forearm Free Flap Facilitates the Direct Closure of Donor Site Wound
Authors: Li Hao , Xu Wenguang , Wang Yuxin , Liu Zhe , Cao Yazhou , Han Wei
Published: November 2020

The radial forearm free flap (RFFF) is one of the commonly used flaps in the repair of head and neck soft tissue defects, especially small and medium-sized defects. The free skin grafts from abdomen are usually used to repair the RFFF donor site wound. This study aims to design a novel V-shaped RFFF, hoping that it might facilitate the direct closure of the forearm donor site wound. From August to December in 2019, 20 patients with oral cancers received radical surgeries, and V-shaped RFFFs were designed to repair the soft defects and the forearm donor site wound was directly closed. The patients were followed up for 6 months to assess the final outcome of repair. The results showed that the pre-designed V-shaped RFFF met the needs of soft tissue defect repair, with the size ranging from 24 cm2 to 30 cm2. Fifteen patients with tongue cancers and four with buccal cancers had satisfactory repair results, and only one patient with buccal cancer had mild limitation of mouth opening. There were 3 patients with a small area of ischemia. The mean postoperative hospital stay was 13.85 ± 1.09 days. In 5 patients, wrist tilt motility decreased compared with that before surgery. The postoperative influence score of wrist exercise on daily life was 2.75 ± 0.44 points. In conclusion, the V-shaped RFFF can meet the needs of small and medium-sized defect repair. This novel design can directly close the forearm donor site wound, which avoids surgical trauma to secondary donor site, and significantly reduces related complications.
Perioperative Outcomes of Rectovaginal Fistula Repair Based on Surgical Approach: A National Contemporary Analysis
Authors: Raju Rubin , Linder Brian J. , Bews Katherine A. , Tappy Erryn , Habermann Elizabeth B. , Occhino John A.
Published: November 2020

Objective

To compare the perioperative outcomes of transvaginal/perineal and abdominal approaches to rectovaginal fistula (RVF) repair using a national multicenter cohort.

Methods

The American College of Surgeons National Surgical Quality Improvement Program database was utilized to identify women undergoing RVF repair from 2005 to 2016. Emergent cases and those with concomitant bowel diversion were excluded. Baseline patient demographics, procedure characteristics, 30-day postoperative complications, return to the operating room, and readmission were evaluated. Baseline characteristics were compared across surgical approach. Multivariable logistic regression models identified preoperative characteristics independently associated with postoperative complications.

Results

A total of 2288 women underwent RVF repair: 1560 (68.2%) via transvaginal/perineal approach and 728 (31.8%) via abdominal approach. Patients undergoing transvaginal/perineal repair were significantly younger (median age, 46 years vs 63 years), with lower American Society for Anesthesiologist (ASA) scores, and less frequency of diabetes mellitus, dyspnea, severe chronic obstructive pulmonary disease, hypertension, disseminated cancer, and bleeding disorders (all P < 0.01). Those undergoing abdominal repair had higher rates of major complications (25.8% vs 8.7%), minor complications (13.5% vs 6.3%), and readmission (13.2% vs 7.8%). On multivariable analyses, ASA Class 3/4, disseminated cancer, and hematocrit <30% (P < 0.01) were associated with major complications in both groups.

Conclusions

Patients undergoing RVF repair via abdominal approach were older with more comorbidities and had higher postoperative complications rates, likely secondary to underlying differences in the treated populations. Irrespective of surgical approach, ASA class, disseminated cancer, and preoperative anemia were associated with higher postoperative morbidity. This may enhance preoperative counseling and allow for careful patient selection.
Mesenteric lymphadenopathy in COVID-19 infection (Jammu and Kashmir sign) as a presenting sign in adult: case report
Authors: Wani Imtiaz , Tantray Hanief M. , Agha Nadeem , Rashid Masood , Lone Wasim , Younus Umar , Khan Nawab , Ashraf Samina , Pandith Samiullah , Jan Tariq
Published: November 2020

Introduction:

Mesenteric lymphadenopathy in an adult with gastrointestinal COVID-19 infection is a very rare. Ultrasonography is helpful in the diagnosis of mesenteric lymphadenopathy in COVID-19 infection.

Presentation of Case:

A 33-year-old man presented with recurrent abdominal pain of 5 days duration. Ultrasonography and computed tomography of abdomen documented findings of the diffuse mesenteric lymphadenopathy, mostly on the left upper abdomen followed by right upper abdomen. Real time-polymerase chain reaction for SARS-CoV-2 was found reactive. Patient was managed by the local protocol and had regression of mesenteric lymphadenopathy.

Discussion:

This is a first kind of case report where an adult patient having gastrointestinal COVID-19 infection presented with mesenteric lymphadenopathy only and named as the “Jammu and Kashmir sign (JK sign) in COVID-19 infection.”

Conclusion:

Mesenteric lymphadenopathy in an adult with COVID-19 infection is very rare. This may be the only presenting sign in gastrointestinal COVID-19 infection.
Maraviroc, celastrol and azelastine alter Chlamydia trachomatis development in HeLa cells
Authors: Kuratli Jasmin , Leonard Cory Ann , Nufer Lisbeth , Marti Hanna , Schoborg Robert , Borel Nicole
Published: November 2020

Introduction

. Chlamydia trachomatis (Ct) is an obligate intracellular bacterium, causing a range of diseases in humans. Interactions between chlamydiae and antibiotics have been extensively studied in the past.

Hypothesis/Gap statement: Chlamydial interactions with non-antibiotic drugs have received less attention and warrant further investigations. We hypothesized that selected cytokine inhibitors would alter Ct growth characteristics in HeLa cells.

Aim. To investigate potential interactions between selected cytokine inhibitors and Ct development in vitro.

Methodology. The CCR5 receptor antagonist maraviroc (Mara; clinically used as HIV treatment), the triterpenoid celastrol (Cel; used in traditional Chinese medicine) and the histamine H1 receptor antagonist azelastine (Az; clinically used to treat allergic rhinitis and conjunctivitis) were used in a genital in vitro model of Ct serovar E infecting human adenocarcinoma cells (HeLa).

Results. Initial analyses revealed no cytotoxicity of Mara up to 20 µM, Cel up to 1 µM and Az up to 20 µM. Mara exposure (1, 5, 10 and 20 µM) elicited a reduction of chlamydial inclusion numbers, while 10 µM reduced chlamydial infectivity. Cel 1 µM, as well as 10 and 20 µM Az, reduced chlamydial inclusion size, number and infectivity. Morphological immunofluorescence and ultrastructural analysis indicated that exposure to 20 µM Az disrupted chlamydial inclusion structure. Immunofluorescence evaluation of Cel-incubated inclusions showed reduced inclusion sizes whilst Mara incubation had no effect on inclusion morphology. Recovery assays demonstrated incomplete recovery of chlamydial infectivity and formation of structures resembling typical chlamydial inclusions upon Az removal.

Conclusion. These observations indicate that distinct mechanisms might be involved in potential interactions of the drugs evaluated herein and highlight the need for continued investigation of the interaction of commonly used drugs with

Chlamydia

and its host.
Network-based Virus-Host Interaction Prediction with Application to SARS-CoV-2
Authors: Du Hangyu , Chen Feng , Liu Hongfu , Hong Pengyu
Published: November 2020

COVID-19, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has quickly become a global health crisis since the first report of infection in December of 2019. However, the infection spectrum of SARS-CoV-2 and its comprehensive protein-level interactions with hosts remain unclear. There is a massive amount of under-utilized data and knowledge about RNA viruses highly relevant to SARS-CoV-2 and their hosts’ proteins. More in-depth and more comprehensive analyses of that knowledge and data can shed new insight into the molecular mechanisms underlying the COVID-19 pandemic and reveal potential risks. In this work, we constructed a multi-layer virus-host interaction network to incorporate these data and knowledge. A machine learning-based method, termed Infection Mechanism and Spectrum Prediction (IMSP), was developed to predict virus-host interactions at both protein and organism levels. Our approach revealed five potential infection targets of SARS-CoV-2, which deserved public health attention, and eight highly possible interactions between SARS-CoV-2 proteins and human proteins. Given a new virus, IMSP can utilize existing knowledge and data about other highly relevant viruses to predict multi-scale interactions between the new virus and potential hosts.
Neuroanatomical abnormalities in a nonhuman primate model of congenital Zika virus infection
Authors: Seelke Adele M. H. , Beckman Danielle , Bennett Jeffrey , Dougherty Paige , Van Rompay Koen K. A. , Keesler Rebekah I. , Pesavento Patricia A. , Coffey Lark L. , Morrison John H. , Bliss-Moreau Eliza
Published: November 2020

Zika virus (ZIKV) infection of pregnant women can cause major congenital neuronal abnormalities. In the present study, we evaluated neuropathological consequences of fetal ZIKV exposure in rhesus macaques, a highly translatable animal model for human neural development. Quantitative neuroanatomical analyses of the nearly full-term brains of fetuses infected with ZIKV at gestational days 50, 64, and 90, and three procedure-matched sham-inoculated controls were carried out. Whole tissue sections across a complete cerebral hemisphere were evaluated using immunohistochemical and neuroanatomical staining techniques to detect virus localization, identify affected cell types and evaluate gross neuroanatomical abnormalities. None of the subjects were microcephalic. Immunohistochemical staining revealed the presence of ZIKV in the frontal lobe, which contained activated microglia and showed increased apoptosis of immature neurons. ZIKV-infected animals exhibited macrostructural changes within the occipital lobe, including a reduction in gyrification as well as a higher proportion of white matter. Finally, the ZIKV-infected subjects had abnormalities throughout the visual pathway, including disorganization within the lateral geniculate nucleus (LGN) and primary visual cortex (V1). Regional differences tracked with the temporal patterns of the developing brain and likely reflect the neural progenitor cell tropism ZIKV exhibits – painting a picture of inflammatory processes related to viral infiltration sweeping through the cortex, followed by a wave of cell death resulting in morphological changes. These findings may help explain why some infants born with normal sized heads during the ZIKV epidemic manifest developmental challenges as they age, and ultimately may contribute to developing effective treatments and interventions.

One sentence summary

Macaque fetuses infected with Zika virus show both macro- and micro-scale neuropathological abnormalities, including decreased gyrencephality, relative increases in cortical white matter, activation of glia, and increased apoptosis.
Neuromesodermal Progenitors Advance Network Formation of Spinal Neurons and Support Cells in Neural RibbonsIn Vitroand Unprotected Survival in a Rat Subacute Contusion Model
Authors: Olmsted Zachary T. , Stigliano Cinzia , Scimemi Annalisa , Marzullo Brandon , Wolfe Tatiana , Cibelli Jose , Horner Philip J. , Paluh Janet L.
Published: November 2020

Improved human stem cell interventions to treat CNS trauma requires continued expansion ofin vitromodels and delivery platforms to fill gaps in analysis and treatment. Transplanted neural stem cells (NSCs) face unique, multi-faceted challenges beyond survival that include differentiation, maturation, and integration into a complex cytokine-releasing microenvironment that impinges on a multipotent cell type. Alternate strategies to transplant neurons and neuronal networks deserve reevaluation, particularly since novel differentiation protocols mimicking region-specific developmental and positional cues have recently emerged. To investigate transplantation of neurons and their early networks, we generatein vitroneural ribbons containing spinal neurons and support cells anatomically matched for cervical spinal cord injury (SCI). These glutamate-responsive, electrically-active neural ribbons apply a new hiPSC differentiation strategy transiting through neuromesodermal progenitors (NMps) to derive developmentally relevant spinal motor neurons (SMNs), interneurons (INs), and oligodendrocyte progenitor cells (OPCs). Bioinformatic profiling validates region-specific identities. Neurons and neuronal networks are functionally evaluated for action potential firing, calcium signaling, population activity, and synaptogenesis. NMp-derived neurons survivein vivowithin the subacute phase hemi-contusion injury cavity when delivered either as free suspension or as encapsulated networks of pre-formed CNS cytoarchitectures. Delivery as encapsulated networks further supports survival of lower cell numbers and rapid graft penetration into host tissue. Neural network ribbons therefore provide a novel intermediary approach between cell suspensions and complex organoids for investigating network formation and early transplantation events with hiPSC-derived neurons, providing flexibility to rapidly tune cell type(s), cell ratios, and traceable biomarkers.

Significance Statement

In the two decades since human stem cell technologies have emerged, the challenge has remained to improve the developmentally relevant derivation of therapeutic cells. The ability to now generate anatomically matched neurons for SCI necessitates a re-evaluation of these cells and their networksin vitroandin vivo. In this study, we apply developmental cues via neuromesodermal progenitors to generate spinal neurons from hiPSCs. Genetic and functional evaluation of these cells asin vitroneuronal networks, due to their capacity to survive and graft effectively within the rat subacute contusion cavity, offer novel approaches for customizing SCI transplantation. This work demonstrates a strategy to develop transplantable, chemically-responsive networks linkingin vitromodels with injury customization towards improvedin vivooutcomes.
Maternal nutritional stress alters sperm competence in male mice offspring leading to reduced fertility
Authors: Muranishi Yuki , Parry Laurent , Vachette-Dit-Martin Mélanie , Saez Fabrice , Coudy-Gandilhon Cécile , Sauvanet Pierre , Volle David , Tournayre Jérémy , Bottari Serge , Carpentiero Francesca , Escoffier Jessica , Bruhat Alain , Maurin Anne-Catherine , Averous Julien , Arnoult Christophe , Fafournoux Pierre , Jousse Céline
Published: November 2020

Infertility represents a growing burden worldwide, with one in seven couples presenting difficulties conceiving. Amongst these, 10-15% of the men have idiopathic infertility that does not correlate with any defect in the classical sperm parameters measured. In the present study, we used a mouse model to investigate the effects of maternal undernutrition on fertility in male progeny. Our results indicate that mothers fed on a low protein diet during gestation and lactation produce male offspring with normal sperm morphology, concentration and motility but exhibiting an overall decrease of fertility when they reach adulthood. Particularly, sperm from these offspring show a remarkable lower capacity to fertilize oocytes when copulation occurs early in the estrus cycle relative to ovulation, due to an altered sperm capacitation.

Our data demonstrate for the first time that maternal nutritional stress can have long-term consequences on the reproductive health of male progeny by affecting sperm physiology, especially capacitation, with no observable impact on spermatogenesis and classical quantitative and qualitative sperm parameters. Moreover, our experimental model could be of major interest to study, explain, and ultimately treat certain categories of infertilities.
Sustained pupil responses are modulated by predictability of auditory sequences
Authors: Milne Alice , Zhao Sijia , Tampakaki Christina , Bury Gabriela , Chait Maria
Published: November 2020

The brain is highly sensitive to auditory regularities and exploits the predictable order of sounds in many situations, from parsing complex auditory scenes, to the acquisition of language. To understand the impact of stimulus predictability on perception, it is important to determine how the detection of predictable structure influences processing and attention. Here we use pupillometry to gain insight into the effect of sensory regularity on arousal. Pupillometry is a commonly used measure of salience and processing effort, with more perceptually salient or perceptually demanding stimuli consistently associated with larger pupil diameters.

In two experiments we tracked human listeners’ pupil dynamics while they listened to sequences of 50ms tone pips of different frequencies. The order of the tone pips was either random, contained deterministic (fully predictable) regularities (experiment 1, n = 18, 11 female) or had a probabilistic regularity structure (experiment 2, n = 20, 17 female). The sequences were rapid, preventing conscious tracking of sequence structure thus allowing us to focus on the automatic extraction of different types of regularities. We hypothesized that if regularity facilitates processing by reducing processing demands, a smaller pupil diameter would be seen in response to regular relative to random patterns. Conversely, if regularity is associated with heightened arousal and attention (i.e. engages processing resources) the opposite pattern would be expected. In both experiments we observed a smaller sustained (tonic) pupil diameter for regular compared with random sequences, consistent with the former hypothesis and confirming that predictability facilitates sequence processing.

Significance statement

The brain is highly sensitive to auditory regularities. To appreciate the impact that detecting predictability has on perception, we need to better understand how a predictable structure influences processing and attention. We recorded listeners’ pupil responses to sequences of tones that followed either a predictable or unpredictable pattern, as the pupil can be used to implicitly tap into these different cognitive processes. We found that the pupil showed a smaller sustained diameter to predictable sequences, indicating that predictability eased processing rather than boosted attention. The findings suggest that the pupil response can be used to study the automatic extraction of regularities, and that the effects are most consistent with predictability helping the listener to efficiently process upcoming sounds.
LongTron: Automated Analysis of Long Read Spliced Alignment Accuracy
Authors: Wilks Christopher , Schatz Michael C.
Published: November 2020

Motivation

Long read sequencing has increased the accuracy and completeness of assemblies of various organisms’ genomes in recent months. Similarly, spliced alignments of long read RNA sequencing hold the promise of delivering much longer transcripts of existing and novel isoforms in known genes without the need for error-prone transcript assemblies from short reads. However, low coverage and high-error rates potentially hamper the widespread adoption of long-read spliced alignments in annotation updates and isoform-level expression quantifications.

Results

Addressing these issues, we first develop a simulation of error modes for both Oxford Nanopore and PacBio CCS spliced-alignments. Based on this we train a Random Forest classifier to assign new long-read alignments to one of two error categories, a novel category, or label them as non-error. We use this classifier to label reads from the spliced-alignments of the popular aligner minimap2, run on three long read sequencing datasets, including NA12878 from Oxford Nanopore and PacBio CCS, as well as a PacBio SKBR3 cancer cell line. Finally, we compare the intron chains of the three long read alignments against individual splice sites, short read assemblies, and the output from the FLAIR pipeline on the same samples.

Our results demonstrate a substantial lack of precision in determining exact splice sites for long reads during alignment on both platforms while showing some benefit from postprocessing. This work motivates the need for both better aligners and additional post-alignment processing to adjust incorrectly called putative splice-sites and clarify novel transcripts support.

Availability and implementation

Source code for the random forest implemented in python is available athttps://github.com/schatzlab/LongTronunder the MIT license. The modified version of GffCompare used to construct Table 3 and related is here:https://github.com/ChristopherWilks/gffcompare/releases/tag/0.11.2LT

Supplementary Information

Supplementary notes and figures are available online.
The unfolded protein response links tumor aneuploidy to local immune dysregulation
Authors: Xian Su , Searles Stephen , Sahani Paras , Waller T. Cameron , Jepsen Kristen , Carter Hannah , Zanetti Maurizio
Published: November 2020

Aneuploidy is a chromosomal abnormality associated with poor prognosis in many cancer types. Here we tested the hypothesis that the unfolded protein response (UPR) links mechanistically aneuploidy and local immune dysregulation. Using a single somatic copy-number alteration (SCNA) score inclusive of whole-chromosome, arm and focal chromosome alterations in a pan-cancer analysis of 9,375 samples in The Cancer Genome Atlas (TCGA) database, we found an inverse correlation with a cytotoxicity (CYT) score across disease stages. Co-expression patterns of UPR genes changed substantially between SCNAlowand SCNAhighgroups. Pathway activity scores showed increased activity by multiple branches of the UPR in response to aneuploidy. The PERK branch showed the strongest association with a reduced CYT score. The conditioned medium of aneuploid cells transmitted XBP1 splicing and caused IL-6 and Arginase1 transcription in receiver bone marrow-derived macrophages. We propose the UPR as a mechanistic link between aneuploidy and immune dysregulation in the tumor microenvironment.

Statement of Significance

Aneuploidy accumulates over the life of a tumor and is associated with poor prognosis. Tumor progression is also associated with a progressive immune dysregulation. To explain these complex and concurrent disorders we tested the hypothesis that the unfolded protein could represent the link between aneuploidy and a dysregulation of local immunity favoring tumor progression.
Distributed Representation of Taste Quality by Second-Order Gustatory Neurons inDrosophila
Authors: Snell Nathaniel J. , Fisher John D. , Hartmann Griffin G. , Talay Mustafa , Barnea Gilad
Published: November 2020

Sweet and bitter compounds excite different sensory cells and drive opposing behaviors. It is commonly thought that the neural circuits linking taste sensation to behavior conform to a labeled-line architecture, but inDrosophila, evidence for labeled lines beyond first-order neurons is lacking. To address this, we devisedtrans-Tango(activity), a strategy for calcium imaging of second-order gustatory projection neurons based ontrans-Tango, a genetic transsynaptic tracing technique. We found distinct projection neuron populations that respond to sweet and bitter tastants. However, the bitter-responsive population was also activated by water alone. We further discovered that bitter tastants evoke activity upon both stimulus onset and offset. Bitter offset responses are exhibited by both first- and second-order gustatory neurons, but these responses are distributed among multiple types of projection neurons in the second order. These findings suggest a more complex coding scheme for gustatory information than can be explained by a labeled line model.
ASCL1 represses a latent osteogenic program in small cell lung cancer in multiple cells of origin
Authors: Olsen Rachelle R. , Kastner David W. , Ireland Abbie S. , Groves Sarah M. , Pozo Karine , Whitney Christopher P. , Guthrie Matthew R. , Wait Sarah J. , Soltero Danny , Witt Benjamin L. , Quaranta Vito , Johnson Jane E. , Oliver Trudy G.
Published: November 2020

ASCL1 is a neuroendocrine-lineage-specific oncogenic driver of small cell lung cancer (SCLC), highly expressed in a significant fraction of tumors. However, ~25% of human SCLC are ASCL1-low and associated with low-neuroendocrine fate and high MYC expression. Using genetically-engineered mouse models (GEMMs), we show that alterations inRb1/Trp53/Mycin the mouse lung induce an ASCL1+state of SCLC in multiple cells of origin. Genetic depletion of ASCL1 in MYC-driven SCLC dramatically inhibits tumor initiation and progression to the NEUROD1+subtype of SCLC. Surprisingly, ASCL1 loss converts tumors to a SOX9+mesenchymal/neural-crest-stem-like state that can differentiate into RUNX2+bone tumors. ASCL1 represses SOX9 expression, as well as WNT and NOTCH developmental pathways, consistent with human gene expression data. Together, SCLC demonstrates remarkable cell fate plasticity with ASCL1 repressing the emergence of non-endodermal stem-like fates that have the capacity for bone differentiation.
Structure of the RPAP3:TRBP interaction reveals an involvement of the HSP90/R2TP chaperone complex in dsRNA pathways
Authors: Abel Yoann , Charron Christophe , Bourguignon-Igel Valérie , Quinternet Marc , Chagot Marie-Eve , Verheggen Céline , Branlant Christiane , Bertrand Edouard , Manival Xavier , Charpentier Bruno , Rederstorff Mathieu
Published: November 2020

MicroRNAs silence mRNAs by guiding the RISC complex. RISC assembly requires cleavage of pre-miRNAs by Dicer, assisted by TRBP or PACT, and the transfer of miRNAs to AGO proteins. The R2TP complex is an HSP90 cochaperone involved in the assembly of ribonucleoprotein particles. Here, we show that the R2TP component RPAP3 binds TRBP but not PACT. Specifically, the RPAP3-TPR1 domain interacts with the TRBP-dsRBD3 and the 1.5 Å resolution crystal structure of this complex is presented. We identify key residues involved in the interaction and show that binding of TRBP to RPAP3 or Dicer is mutually exclusive. In contrast, RPAP3 can simultaneously bind TRBP and HSP90. Interestingly, AGOs and Dicer are sensitive to HSP90 inhibition and TRBP becomes sensitive in absence of RPAP3. These data indicate that the HSP90/R2TP chaperone is an important cofactor of proteins involved in dsRNA pathways.
Genetically-identified cell types in avian pallium mirror core principles of excitatory and inhibitory neurons in mammalian cortex
Authors: Spool Jeremy A. , Macedo-Lima Matheus , Scarpa Garrett , Morohashi Yuichi , Yazaki-Sugiyama Yoko , Remage-Healey Luke
Published: November 2020

In vertebrates, advanced cognitive abilities are associated with a highly developed telencephalic pallium. In mammals, the six-layered neocortex of the pallium is composed of excitatory neurons and inhibitory interneurons, organized across layers into microcircuits. These organizational principles are proposed to support efficient, high-level information processing. Comparative perspectives across vertebrates provide a lens to understand what common features of pallium are important for complex cognition. For non-mammalian vertebrates that exhibit complex cognitive abilities, such as birds, the physiology of identified pallial cell types and their circuit organization are largely unresolved. Using viral tools to target excitatory vs. inhibitory neurons in the zebra finch auditory association pallium, we systematically tested predictions derived from mammalian neocortex. We identify two segregated neuronal populations that exhibit profound physiological and computational similarities with mammalian excitatory and inhibitory neocortical cells. Specifically, despite dissimilarities in gross architecture, avian association pallium exhibits neocortex-typical coding principles, and inhibitory-dependent cortical synchrony, gamma oscillations, and local suppression. Our findings suggest parallel evolution of physiological and network roles for pallial cell types in amniotes with substantially divergent pallial organization.
Swimming, fast and slow: strategy and survival of bacterial predators in response to chemical cues
Authors: Carlson M , Seyler S L , Pressé S
Published: November 2020

Bdellovibrio bacteriovorusis a predatory bacterium that preys upon gram-negative bacteria. As such,B. bacteriovorushas the potential to control antibiotic-resistant pathogens and biofilm populations. To survive and reproduce,B. bacteriovorusmust locate and infect a host cell. However, in the temporary absence of prey, it is largely unknown howB. bacteriovorusmodulate their motility patterns in response to physical or chemical environmental cues to optimize their energy expenditure. To investigateB. bacteriovorus’predation strategy, we track and quantify their motion by measuring speed distributions and velocity autocorrelations as a function of starvation time. An initial unimodal speed distribution, relaxing to that expected for pure diffusion at long times, may be expected. Instead, we observe a complex, non-Brownian, search strategy as evidenced by distinctly bimodal speed distributions. That is, for an increasing amount of time over whichB. bacteriovorusis starved, we observe a progressive re-weighting from a fast mode to a slow mode in the speed distribution obtained over consecutive frames. By contrast to its predator,B. bacteriovorus’prey,Escherichia coliexhibits almost immediate decrease to a speed expected from passive diffusion following resuspension from rich to poor media. Distributions of trajectory-averaged speeds forB. bacteriovorusare largely unimodal, indicating nontrivialswitchingbetween fast and slow swimming modes within individual observed trajectories rather than there being distinct fast and slow populations. We also find thatB. bacteriovorus’slow speed mode is not merely caused by the diffusion of inviable bacteria as subsequent spiking experiments show that bacteria can be resuscitated and bimodality restored. Indeed, starvedB. bacteriovorusmay modulate the frequency and duration of active swimming as a means of balancing energy consumption and procurement. Our results are evidence of a nontrivial predation strategy, which contrasts with the comparatively simple search pattern of its prey, in response to environmental cues.

SIGNIFICANCE

Bdellovibrio bacteriovorusis a predatory bacterium that is poised to help control gram-negative bacterial populations in environmental and clinical settings. In order to locate its prey in solution,B. bacteriovorusmust expend energy in order to fight hydrodynamic drag. This raises the question as to howB. bacteriovorusshould expend its energy reserves in the absence of chemical cues from its prey. Here, we show thatB. bacteriovorusadapts its motility to minimize energy expenditure (due to fighting drag in swimming) upon prolonged starvation by exploiting two modes of motility. This is in sharp contrast to its prey,E. coli, which shows little active motility under starvation conditions.
Impact of conscious awareness on pupillary response to faces
Authors: Yang Yung-Hao , Liao Hsin-I , Furukawa Shigeto
Published: November 2020

Pupillary response reflects not only ambient light changes but also top-down factors. Nevertheless, it remains inconclusive whether the conscious awareness modulates the pupillary response. We investigated pupillary responses to faces under different conscious conditions using continuous flash suppression (CFS). In Experiment 1 and 2, we used a breaking-CFS procedure in which participants had to detect the face from suppression. Results showed that the pupil constricted more to upright faces than to inverted faces before the face was detected, suggesting that pupillary responses reflect face processing entering consciousness. In Experiment 3 and 4, we used a fixed duration-CFS procedure with both objective performance and subjective reports. Different pupillary responses were observed only when the participant was aware of the face. These findings imply that the conscious awareness is critical for modulating autonomic neural circuits of the pupillary function. The corresponding pupillary responses may reflect dynamic processes underlying conscious awareness.
Chirality-dependent anti-inflammatory effect of glutathione after spinal cord injury
Authors: Kim Seong Jun , Ko Wan-Kyu , Han Gong Ho , Lee Daye , Lee Yuhan , Sheen Seung Hun , Hong Je Beom , Sohn Seil
Published: November 2020

Neuroinflammation forms a glial scar following a spinal cord injury (SCI). The injured axon cannot regenerate across the scar, suggesting permanent paraplegia. In this study, we report that d-chiral glutathione (D-GSH) suppresses the inflammatory response after SCI and leads to axon regeneration of the injured spinal cord to a greater extent than l-chiral glutathione (L-GSH). After SCI, axon regrowth in D-GSH-treated rats was significantly increased compared to that in L-GSH-treated rats (***p< 0.001). Secondary damage and motor function were significantly improved in D-GSH-treated rats compared to those outcomes in L-GSH-treated rats (**p< 0.01). Moreover, D-GSH significantly decreased pro-inflammatory cytokines and glial scar via inhibition of the mitogen-activated protein kinase (MAPK) signaling pathway compared to L-GSH (***p< 0.001). In primary cultured macrophages, we found that D-GSH undergoes more intracellular interaction with activated macrophages than L-GSH (***p< 0.001). These findings reveal a potential new regenerative function of chiral GSH in SCI and suggest that chiral GSH has therapeutic potential as a treatment of other diseases.
Neurons in the dorso-central division of zebrafish pallium respond to change in visual numerosity
Authors: Messina Andrea , Potrich Davide , Schiona Ilaria , Sovrano Valeria Anna , Fraser Scott E. , Brennan Caroline H. , Vallortigara Giorgio
Published: November 2020

Non-symbolic number cognition based on an approximate sense of magnitude has been documented in zebrafish. Here we investigated for the first time its neural bases. Zebrafish were habituated to a set of three or nine small dots associated with food reward. During habituation trials, the dots changed in their individual size, position and density maintaining their numerousness and overall surface area. In the dishabituation test, zebrafish faced a change (i) in number (from three to nine or vice versa with the same overall surface), (ii) in shape (with the same overall surface and number), or (iii) in size (with the same shape and number); in a control group (iv) zebrafish faced the same familiar stimuli as during the habituation. Using qPCR to measure modulation of the expression of the immediate early genes c-fos and egr-1 and in-situ hybridization to count egr1-positive cells we found a specific and selective activation of the caudal part of the dorso-central (Dc) division of the zebrafish pallium upon change in numerosity. As pallial regions are implicated in number cognition in mammals and birds, these findings support the existence of an evolutionarily conserved mechanism for approximate magnitude and provide an avenue for exploring the underlying molecular correlates.
Water-mediated interactions determine helix formation of peptides in open nanotubes
Authors: Suvlu Dylan , Thirumalai D. , Rasaiah Jayendran C.
Published: November 2020

Water-mediated interactions (WMIs) play diverse roles in molecular biology. They are particularly relevant in geometrically confined spaces such as the interior of the chaperonin, at the interface between ligands and their binding partners, and in the ribosome tunnel. Inspired in part by the geometry of the ribosome tunnel, we consider confinement effects on the stability of peptides. We describe results from replica exchange molecular dynamics simulations of a system containing a 23-alanine or 23-serine polypeptide confined to non-polar and polar nanotubes in the gas phase and when open to a water reservoir. We quantify the effect of water in determining the preferred conformational states of these polypeptides by calculating the difference in the solvation free energy for the helix and coil states in the open nanotube in the two phases. Our simulations reveal several possibilities. We find that nanoscopic confinement preferentially stabilizes the helical state of polypeptides with hydrophobic side chains, which is explained by the entropic stabilization mechanism proposed on the basis of polymer physics. Polypeptide chains with hydrophilic side chains can adopt helical structures within nanotubes, but helix formation is sensitive to the nature of the nanotube due to WMIs. We elaborate on the potential implications of our findings to the stability of peptides in the ribosome tunnel.
N-Terminus ofDrosophila MelanogasterMSL1 Is Critical for Dosage Compensation
Authors: Babosha Valentin , Klimenko Natalia , Revel-Muroz Anastasia , Tikhonova Evgeniya , Georgiev Pavel , Maksimenko Oksana
Published: November 2020

The male-specific lethal complex (MSL), which consists of five proteins and two non-coding roX RNAs, is involved in the transcriptional enhancement of X-linked genes to compensate for the sex chromosome monosomy inDrosophilaXY males compared with XX females. The MSL1 and MSL2 proteins form the heterotetrameric core of MSL complex and are critical for the specific recruitment of the complex to the high-affinity “entry” sites (HAS) on the X chromosome. In this study, we demonstrated that the N-terminal region of MSL1 is critical for stability and functions of MSL1. Amino acid deletions and substitutions in the N-terminal region of MSL1 strongly affect both the interaction with roX2 RNA and the MSL complex binding to HAS on the X chromosome. In particular, substitution of the conserved N-terminal amino-acids 3-7 in MSL1 (MSL1GS) affects male viability similar to the inactivation of genes encoding roX RNAs. In addition, MSL1GSbinds to promoters such as MSL1WTbut does not co-bind with MSL2 and MSL3 to X chromosomal HAS. However, overexpression of MSL2 partially restores the dosage compensation. Thus, the interaction of MSL1 with roX RNA is critical for the efficient assembly of the MSL complex on HAS of the male X chromosome.