bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiologist-supervised Transfer Learning
Authors: Hurt Brian , Rubel Meagan A. , Masutani Evan M. , Jacobs Kathleen , Hahn Lewis , Horowitz Michael , Kligerman Seth , Hsiao Albert
Published: October 2021

Purpose:

To assess the potential of a transfer learning strategy leveraging radiologist supervision to enhance convolutional neural network-based (CNN) localization of pneumonia on radiographs and to further assess the prognostic value of CNN severity quantification on patients evaluated for COVID-19 pneumonia, for whom severity on the presenting radiograph is a known predictor of mortality and intubation.

Materials and Methods:

We obtained an initial CNN previously trained to localize pneumonia along with 25,684 radiographs used for its training. We additionally curated 1466 radiographs from patients who had a computed tomography (CT) performed on the same day. Regional likelihoods of pneumonia were then annotated by cardiothoracic radiologists, referencing these CTs. Combining data, a preexisting CNN was fine-tuned using transfer learning. Whole-image and regional performance of the updated CNN was assessed using receiver-operating characteristic area under the curve and Dice. Finally, the value of CNN measurements was assessed with survival analysis on 203 patients with COVID-19 and compared against modified radiographic assessment of lung edema (mRALE) score.

Results:

Pneumonia detection area under the curve improved on both internal (0.756 to 0.841) and external (0.864 to 0.876) validation data. Dice overlap also improved, particularly in the lung bases (R: 0.121 to 0.433, L: 0.111 to 0.486). There was strong correlation between radiologist mRALE score and CNN fractional area of involvement (ρ=0.85). Survival analysis showed similar, strong prognostic ability of the CNN and mRALE for mortality, likelihood of intubation, and duration of hospitalization among patients with COVID-19.

Conclusions:

Radiologist-supervised transfer learning can enhance the ability of CNNs to localize and quantify the severity of disease. Closed-loop systems incorporating radiologists may be beneficial for continued improvement of artificial intelligence algorithms.
Accuracy of Intentional Change of Frontal Ramal Inclination From Virtual to Actual Orthognathic Surgery Using Computer-Aided Design and Computer-Aided Manufacturing-Made Customized Metal Plates
Authors: Woo Min-Ho , Youn Sungbin , Woo Jae Man , Baek Seung-Hak , Choi Jin-Young
Published: October 2021

Objective:

To evaluate the accuracy of intentional change of the frontal ramal inclination (FRI) from virtual to actual orthognathic surgery.

Materials and Methods:

A total of 16 patients who underwent orthognathic surgery for correction of facial asymmetry and took cone-beam computed tomography 2 to 3 weeks before surgery (T0) and 3 days after surgery (T1A) were selected. After reorientation of cone-beam computed tomography, the digital imaging and communications in medicine data was converted to StereoLithography format for the merging with dental cast scan using R2GATE software (MegaGen Implant, Daegu, Republic of Korea). During virtual surgery using Geomagic Freeform Plus software (3D Systems, Rock Hill, SC), bilateral FRI discrepancy was corrected (T1V) and 3D-printed surgical wafers and customized metal plates were manufactured using 3D printer (Meg-printer II, MegaGen Implant, Daegu, Republic of Korea) and computer numerical control milling machine (ARDEN, TPS Korea Ltd., Gwangju, Republic of Korea) accordingly. During surgery, FRI correction was done using surgical guide and customized plates. The difference between preoperative and virtually corrected FRI (Δ T1V — T0) and the difference between preoperative and actually surgically corrected FRI (Δ T1A — T0) were measured, and the achieved FRI correction in percentage ([Δ T1A — T0]/[Δ T1V — T0] × 100) was calculated.

Results:

The mean absolute value of virtual FRI correction (Δ T1V — T0) and actual FRI correction (Δ T1A - T0) were 3.0° and 2.9°, respectively (n = 32). In the increased (medial rotation) FRI group, mean virtual and actual correction amount were 3.2° and 2.8° (n = 17), whereas in the decreased (lateral rotation) group, mean virtual and actual correction amount were –2.7° and –3.1°, respectively (n = 15). No statistically significant difference between virtual and actual measurements were present in either group. The mean achievement rate was 102.8%. Tendency of undercorrection (91.2%) in the increased FRI group and overcorrection (116.0%) in the decreased FRI group were noted.

Discussion:

With virtual planning and computer-aided design and computer-aided manufacturing-made customized plates, it is possible to correct FRI during orthognathic surgery of patients with facial asymmetry.
How to Distinguish Solitary Neurofibroma From Neurofibromatosis Type 1
Authors: Guo Chengrui , Zhou Lucia , Sun Yi , Hu Xiaojie
Published: October 2021

Neurofibroma is a benign tumor originating from Schwann cells. It is diagnosed as a symptom of neurofibromatosis type 1 (NF1) or solitary neurofibroma. Neurofibromatosis type 1 belongs to a class of hereditary diseases, whereas solitary neurofibroma is not. Presence of germline NF1 gene mutations can be used to distinguish the 2 conditions. However, due to false negative results in gene tests, NF1 may be misdiagnosed as solitary neurofibroma. This calls for development of more accurate diagnostic methods. The authors report 2 patients with neurofibroma who required surgery and fertility consulting. using primary cell culture and next-generation sequencing experiments, the authors found NF1 mutation in neurofibroma Schwann cells. But this mutation was not exit in peripheral blood, hence demonstrate this NF1 mutation was somatic rather than germline. These results confirmed the diagnosis of solitary neurofibroma rather than NF1. The presented method is, therefore, suitable for fertility consultation and diagnosis of solitary neurofibroma patient.
Unusual Mandibular Distraction Complication in Two Neonatal Pierre Robin Sequence Patients
Authors: Morovic Carmen Gloria , Torres Javier , Jorquera Claudia
Published: October 2021

The Pierre Robin sequence (PRS) is characterized by the triad of micrognathia, glossoptosis, and airway obstruction. Conservative management in Pierre Robin sequence consists of nasogastric tube feeding and positioning of the neonate (prone or lateral position) that facilitates the anterior position of the tongue or the application of continuous positive nasal pressure. In case of failure of this treatment, emergency tracheostomy and/or mandibular distraction must be performed.

Mandibular distraction is a standard technique used by craniofacial surgeons to achieve an anteroposterior horizontal lengthening of the mandibular body, correcting the posterior position of the base of the tongue and thus retropharyngeal enlargement of the airway.

The authors present 2 clinical cases of hypertrophy of the sublingual salivary glands with the use of mandibular distractors in SPR patients with severe airway obstruction.
Endoscopic Resection of a Rare Chondromyxoid Fibroma From the Nasal Septum
Authors: Wang Yunxiu , Cao Zhiwei , Gu Zhaowei
Published: October 2021

Chondromyxoid fibroma is a rare benign tumor mostly found in the metaphysis of long bones. In rare cases, it develops in unusual locations. We report a case of chondromyxoid fibroma from the nasal septum. Endoscopic surgery was performed with the patient under general anesthesia. A plasma knife was used to ablate the tumor. No recurrence was noted at the 4-year follow-up. The advantages of endoscopic surgery include direct observation, improved visibility and magnification, reduced intraoperative trauma, and fewer postoperative complications. The advantages of the plasma knife include its ability to separate and ablate the tumor simultaneously while effectively reducing bleeding and maintaining the visibility of the surgical field.
Promoting parental education of infants hospitalized in a children's hospital in Tabriz, Iran: a best practice implementation project
Authors: Kabiri Neda , Hajebrahimi Sakineh , Alizadeh Gisoo , Azimzadeh Solmaz , Dehkhoda Nahid , Talebpour Amin
Published: October 2021

Introduction:

Parents of infants admitted to hospital have high information needs. A good educational program will improve the outcomes and communication needs of these parents. Results from some studies have shown that patient education in Iran is inappropriate and should be improved.

Objectives:

The aim of this evidence implementation project was to evaluate the current practice and implement the best practice related to promoting patient education in a children's hospital in Tabriz, Iran.

Methods:

A clinical audit was undertaken using the Joanna Briggs Institute Practical Application of Clinical Evidence System tool. Eight audit criteria that represent the best practice recommendations for patient education were used. A baseline audit was conducted followed by implementing multiple strategies, and the project was finalized with a follow-up audit to determine a change in practice.

Results:

Significant improvements in the follow-up audit in comparison with the baseline audit were as follows: evaluation of patient learning has been undertaken to determine met and unmet needs (from 65 to 77%); patients’ learning needs, readiness to learn, and their learning style have been assessed before the implementation of an educational initiative (from 55 to 66%); and educational resources in different formats (e.g., written handouts, brochures, and links to online materials) are available in the ward (from 33 to 77%). Strategies that were implemented to achieve change in practice included conducting workshops and conferences, determining a trained nurse as responsible for educating parents, training in discharge time, the presentation of educational films daily, conducting group training, and installing related posters in the department and patient's room. The other five criteria were less compliant with best practice in the follow-up audit rather than the baseline audit; however, all of them except one (Criterion 3) were still up to 75% compliant, which is considered excellent by the audit team.

Conclusion:

The follow-up audit results indicated an improvement in providing parental education. It can be concluded that these interventions can facilitate the implementation of evidence into clinical practice.
Inference of Electrical Stimulation Sensitivity from Recorded Activity of Primate Retinal Ganglion Cells
Authors: Madugula Sasidhar S. , Vilkhu Ramandeep , Shah Nishal P. , Grosberg Lauren E. , Kling Alexandra , Gogliettino Alex R. , Nguyen Huy , Hottowy Paweł , Sher Alexander , Litke Alan M. , Chichilnisky E.J.
Published: October 2021

High-fidelity electronic implants can in principle restore the function of neural circuits by precisely activating neurons via extracellular stimulation. However, direct characterization of the individual electrical responses of a large population of target neurons, in order to precisely control their activity, is often difficult or impossible. A potential solution is to leverage biophysical principles to infer sensitivity to electrical stimulation from features of spontaneous electrical activity, which can be recorded relatively easily. Here, this approach is developed and its potential value for vision restoration is tested quantitatively using large-scale high-density stimulation and recording from primate retinal ganglion cells (RGCs)ex vivo. Electrodes recording larger spikes from a given cell exhibited lower stimulation thresholds, with distinct trends for somas and axons, across cell types, retinas, and eccentricities. Thresholds for somatic stimulation increased with distance from the axon initial segment. The dependence of spike probability on injected current was inversely related to threshold, and was substantially steeper for axonal than somatic compartments, which could be identified by recorded electrical signatures. Dendritic stimulation was largely ineffective for eliciting spikes. These findings were quantitatively reproduced with biophysical simulations, and confirmed in tests on human RGCs. The inference of stimulation sensitivity from recorded electrical features was tested in simulated visual reconstruction, and revealed that the approach could significantly improve the function of future high-fidelity retinal implants.
(–)-Epicatechin alters reactive oxygen and nitrogen species production independent of mitochondrial respiration in human vascular endothelial cells
Authors: Sadler Daniel G. , Barlow Jonathan , Draijer Richard , Jones Helen , Thijssen Dick H. J. , Stewart Claire E.
Published: October 2021

Introduction

Vascular endothelial dysfunction is characterised by lowered nitric oxide (NO) bioavailability, which may be explained by increased production of reactive oxygen species (ROS), mitochondrial dysfunction and altered cell signalling. (-)-Epicatechin (EPI) has proven effective in the context of vascular endothelial dysfunction, but the underlying mechanisms associated with EPI’s effects remain unclear.

Objective(s)

Our aim was to investigate whether EPI impacts reactive oxygen and nitrogen species (RONS) production and mitochondrial function of human vascular endothelial cells (HUVECs). We hypothesised that EPI would attenuate ROS production, increase NO bioavailability, and enhance indices of mitochondrial function.

Methods

HUVECs were treated with EPI (0-20 µM) for up to 48 h. Mitochondrial and cellular ROS were measured in the absence and presence of antimycin A (AA), an inhibitor of the mitochondrial electron transport protein complex III, favouring ROS production. Genes associated with mitochondrial remodelling and the antioxidant response were quantified by RT-qPCR. Mitochondrial bioenergetics were assessed by respirometry and signalling responses determined by western blotting.

Results

Mitochondrial superoxide production without AA was increased 32% and decreased 53% after 5 and 10 µM EPI treatment vs. CTRL (P<0.001). With AA, only 10 µM EPI increased mitochondrial superoxide production vs. CTRL (25%, P<0.001). NO bioavailability was increased by 45% with 10 µM EPI vs. CTRL (P=0.010). However, EPI did not impact mitochondrial respiration. NRF2 mRNA expression was increased 1.5- and 1.6-fold with 5 and 10 µM EPI over 48 h vs. CTRL (P=0.015 and P=0.001, respectively). Finally, EPI transiently enhanced ERK1/2 phosphorylation (2.9 and 3.2-fold over 15 min and 1 h vs. 0 h, respectively; P=0.035 and P=0.011).

Conclusion(s)

EPI dose dependently alters RONS production of HUVECs but does not impact mitochondrial respiration. The induction of NRF2 mRNA expression with EPI might relate to enhanced ERK1/2 signalling, rather than RONS production. In humans, EPI may improve vascular endothelial dysfunction via alteration of RONS and activation of cell signalling.
IntAct: a non-disruptive internal tagging strategy to study actin isoform organization and function
Authors: van Zwam M.C. , Dhar A. , Bosman W. , van Straaten W. , Weijers S. , Seta E. , Joosten B. , Palani S. , van den Dries K.
Published: October 2021

Actin plays a central role in many cell biological processes including division and motility. Mammals have six, highly conserved actin isoforms with nonredundant biological functions, yet the molecular basis of isoform specificity remains elusive due to a lack of tools. Here, we describe the development of IntAct, an internal tagging strategy to study actin isoform function in fixed and living cells. We first identified a residue pair in β-actin that permits non-disruptive tag integration. Next, we used knock-in cell lines to demonstrate that the expression and filament incorporation of IntAct β-actin is indistinguishable from wildtype. Furthermore, IntAct β-actin remains associated with actin-binding proteins profilin, cofilin and formin family members DIAPH1 and FMNL2 and can be targeted in living cells. To demonstrate the usability of IntAct for actin isoform investigations, we also generated IntAct γ-actin cells and show that actin isoform specific distribution remains unaltered in human cells. Moreover, introduction of tagged actin variants in yeast demonstrated an expected variant-dependent incorporation into patches and filaments. Together, our data indicate that IntAct is a versatile tool to study actin isoform localization, dynamics and molecular interactions.
Safety Monitoring of mRNA Vaccines Administered During the Initial 6 Months of the U.S. COVID-19 Vaccination Program: Reports to Vaccine Adverse Events Reporting System (VAERS) and v-safe
Authors: Rosenblum Hannah G. , Gee Julianne M. , Liu Ruiling , Marquez Paige L. , Zhang Bicheng , Strid Penelope , Abara Winston E. , McNeil Michael M. , Myers Tanya R. , Hause Anne M. , Su John R. , Baer Bethany , Menschik David , Markowitz Lauri E. , Shimabukuro Tom T. , Shay David K.
Published: October 2021

Background

In December 2020, two mRNA-based COVID-19 vaccines were authorized for use in the United States. Vaccine safety was monitored using the Vaccine Adverse Event Reporting System (VAERS), a passive surveillance system, and v-safe, an active surveillance system.

Methods

VAERS and v-safe data during December 14, 2020—June 14, 2021 were analyzed. VAERS reports were categorized as non-serious, serious, or death; reporting rates were calculated. Rates of reported deaths were compared to expected mortality rates by age. Proportions of v-safe participants reporting local and systemic reactions or health impacts the week following doses 1 and 2 were determined.

Findings

During the analytic period, 298,792,852 doses of mRNA vaccines were administered in the United States. VAERS processed 340,522 reports; 92·1% were non-serious; 6·6%, serious, non-death; and 1·3%, death. Over half of 7,914,583 v-safe participants self-reported local and systemic reactogenicity, more frequently after dose 2. Injection-site pain, fatigue, and headache were commonly reported during days 0–7 following vaccination. Reactogenicity was reported most frequently one day after vaccination; most reactions were mild. More reports of being unable to work or do normal activities occurred after dose 2 (32·1%) than dose 1 (11·9%); <1% of participants reported seeking medical care after vaccination. Rates of deaths reported to VAERS were lower than expected background rates by age group.

Interpretation

Safety data from >298 million doses of mRNA COVID-19 vaccine administered in the first 6 months of the U.S. vaccination program show the majority of reported adverse events were mild and short in duration.
Hotmelt tissue adhesive with supramolecularly-controlled sol-gel transition for preventing postoperative abdominal adhesion
Authors: Nishiguchi Akihiro , Ichimaru Hiroaki , Ito Shima , Nagasaka Kazuhiro , Taguchi Tetsushi
Published: October 2021

Postoperative adhesion is a serious and frequent complication, but there is currently no reliable anti-adhesive barrier available due to low tissue adhesiveness, undesirable chemical reactions, and poor operability. Here, we report a single-syringe hotmelt tissue adhesive to prevent postoperative abdominal adhesions. Through the augmentation of intermolecular hydrogen bonding by conjugation of the ureidopyrimidinone unit to tendon-derived gelatin, the sol-gel transition behavior of gelatin was supramolecularly-controlled, which provided a hotmelt tissue adhesive that dissolves upon warming over 40 °C and glues at 37 °C. This functionalization improved the key features necessary for an anti-adhesive barrier, including bulk mechanical strength, tissue adhesive properties, underwater stability, and anti-adhesive property. This hotmelt tissue adhesive with excellent tissue adhesiveness, biocompatibility, and operability has enormous potential to prevent postoperative complications.
Plant secondary metabolite diversity reflects both phylogeny and ecological adaptation
Authors: Pierce Simon , Guo Wen-Yong , Cerabolini Bruno. E.L. , Negreiros Daniel , Faoro Franco , Magoga Giulia , Montagna Matteo , Fernandes G. Wilson , Spada Alberto
Published: October 2021

A phylogenetic framework explaining plant secondary metabolite diversity is lacking, but metabolite classes could represent adaptations to habitat resource availability. We test the hypothesis that primary adaptive strategies (competitors, C; stress-tolerators, S; ruderals, R) are associated, respectively, with nitrogenous metabolites synthesized in persistent organs (alkaloids), nitrogen-lacking aromatic terpenes and phenolics, and nitrogenous compounds prevalent in reproductive tissues (cyanogenic glucosides and glucosinolates). A matrix was compiled of 1019 species for which secondary metabolite pathways and CSR strategies are known. Accounting for phylogenetic relatedness and native biomes, we found that most phytochemical pathways did not correlate with strategy axes, but certain key associations were evident. C-selection was positively associated with amino acid-derived phenylpropanoids (low phylogenetic relatedness; λ <0.5) and pyrrolizidine alkaloids and galloyl derivatives (high λ), and negatively with N-lacking linear monoterpenes (low λ). Nitrogenous cyanogenic glucosides positively correlated with R-selection (low λ). Terpenoids were widely distributed, but correlated positively with S- and negatively with R-selection (low λ). Twenty-six correlations between phytochemicals and biomes (low λ) were evident. Most secondary metabolite synthesis pathways are widespread, reflecting common roles and obligate defence, and strong phylogenetic effects are often evident. However, the character of phytochemical/adaptive strategy associations agrees with ecological theory and thus reflects adaptation.
Transcriptome Dynamics of Floral Organs Approaching Blooming in the Flowering Cherry (Cerasus × yedoensis) Cultivar ‘Somei-Yoshino’
Authors: Shirasawa Kenta , Esumi Tomoya , Itai Akihiro , Isobe Sachiko
Published: October 2021

To gain insights into the genetic mechanisms underlying blooming and petal movement in flowering cherry (Cerasus × yedoensis), we performed time-course RNA-seq analysis of the floral buds and open-flowers of the most popular flowering cherry cultivar, ‘Somei-Yoshino’. Independent biological duplicate samples of floral buds and open-flowers were collected from ‘Somei-Yoshino’ trees grown at three different locations in Japan. RNA-seq reads obtained from floral bud and open-flower samples collected in the current study (in 2019) and in a previous study (in 2017) were aligned against the genome sequence of ‘Somei-Yoshino’ to quantify gene transcript levels. Clustering analysis of RNA-seq reads revealed dynamic changes in the transcriptome, with genes in seven modules predominantly expressed at specific time points, ranging from 5 weeks before flowering to 2 weeks after flowering. Based on the identified gene modules and Gene Ontology (GO) terms enriched at different floral stages, we speculate that the genetic mechanisms underlying petal movement and flower opening in cherry involve the processes of development, cell wall organization, reproduction, and metabolism, which are executed by genes encoding transcription factors, phytohormones, transporters, and polysaccharide metabolic enzymes. Furthermore, we propose a method for cherry bloom forecasting, based on gene expression levels at different time points before flowering as RNA markers.
The molecular chaperone DNAJB6 provides surveillance of FG-Nups and is required for interphase nuclear pore complex biogenesis
Authors: Elsiena Kuiper E. F. , Gallardo Paola , Bergsma Tessa , Mari Muriel , Musskopf Maiara Kolbe , Kuipers Jeroen , Giepmans Ben N. G. , Steen Anton , Veenhoff Liesbeth M. , Kampinga Harm H. , Bergink Steven
Published: October 2021

Biogenesis of nuclear pore complexes (NPCs) includes the formation of the permeability barrier composed of phenylalanine-glycine-rich nucleoporins (FG-Nups) that regulate the selective passage/crossing of biomolecules. The FG-Nups are intrinsically disordered and prone to liquid-liquid phase separate1,2 and aggregate when isolated3. It has remained largely unclear how FG-Nups are protected from making inappropriate interactions during NPC biogenesis. We found that DNAJB6, a molecular chaperone of the heat shock protein network, formed foci next to NPCs. The number of these foci decreases upon removal of proteins involved in the early steps of interphase NPC biogenesis. Reversely, when this process is stalled in the last steps, the number of DNAJB6-containing foci increases and they could be identified as herniations at the nuclear envelope (NE). Immunoelectron tomography showed that DNAJB6 localizes inside the lumen of the herniations arising at NPC biogenesis intermediates. Interestingly, loss of DNAJB6 results in annulate lamellae, which are structures containing partly assembled NPCs associated with disturbances in NPC biogenesis. We find that DNAJB6 binds to FG-Nups and can prevent the aggregation of the FG-region of several FG-Nups in cells and in vitro. Together, our data show that DNAJB6 provides quality control during NPC biogenesis and is the first molecular chaperone that is involved in the surveillance of native intrinsically disordered proteins, including FG-Nups.
Neurocomputational mechanisms of affected beliefs
Authors: Müller-Pinzler Laura , Czekalla Nora , Mayer Annalina V , Schröder Alexander , Stolz David S , Paulus Frieder M , Krach Sören
Published: October 2021

The feedback people receive on their behavior shapes the process of belief formation and self-efficacy in mastering a given task. However, the neural and computational mechanisms of how the subjective value of these beliefs, and the corresponding affect, bias the learning process remain unclear. We investigated these mechanisms during the learning of self-efficacy beliefs using fMRI, pupillometry, and computational modeling, and by analyzing individual differences in affective experience. Biases in the formation of self-efficacy beliefs were associated with affect, pupil dilation, and neural activity within the anterior insula, amygdala, ventral tegmental area/ substantia nigra, and mPFC. Specifically, neural and pupil responses map the valence of the prediction errors in correspondence with individuals’ experienced affect and learning bias during belief formation. Together with the functional connectivity dynamics of the anterior insula within this network, our results hint at neural and computational mechanisms that integrate affect into the process of belief formation.
Multi-label topic classification for COVID-19 literature annotation using an ensemble model based on PubMedBERT
Authors: Tian Shubo , Zhang Jinfeng
Published: October 2021

The BioCreative VII Track 5 calls for participants to tackle the multi-label classification task for automated topic annotation of COVID-19 literature. In our participation, we evaluated several deep learning models built on PubMedBERT, a pre-trained language model, with different strategies addressing the challenges of the task. Specifically, multi-instance learning was used to deal with the large variation in the lengths of the articles, and focal loss function was used to address the imbalance in the distribution of different topics. We found that the ensemble model performed the best among all the models we have tested. Test results of our submissions showed that our approach was able to achieve satisfactory performance with an F1 score of 0.9247, which is significantly better than the baseline model (F1 score: 0.8678) and the mean of all the submissions (F1 score: 0.8931).
Differential Vulnerability of Anterior Cingulate Cortex Cell-Types to Diseases and Drugs
Authors: Smail Marissa A. , Chandrasena Sapuni S. , Zhang Xiaolu , Reddy Vineet , Kelley Craig , Herman James P. , Sherif Mohamed , McCullumsmith Robert E. , Shukla Rammohan
Published: October 2021

In psychiatric disorders, mismatches between disease-states and therapeutic strategies are highly pronounced, largely because of unanswered questions regarding specific vulnerabilities of different cell-types and therapeutic responses. Which cellular events (housekeeping or salient) are most affected? Which cell-types succumb first to challenges, and which exhibit the strongest response to drugs? Are these events coordinated between cell-types? How does the disease-state and drug affect this coordination? To address these questions, we analyzed single-nucleus-RNAseq (sn-RNAseq) data from the human anterior cingulate cortex—a region involved in many psychiatric disorders. Density index, a metric for quantifying similarities and dissimilarities across functional profiles, was employed to identify common (housekeeping) or salient functional themes across all cell-types. Cell-specific signatures were integrated with existing disease and drug-specific signatures to determine cell-type-specific vulnerabilities, druggabilities, and responsiveness. Clustering of functional profiles revealed cell-types jointly participating in these events. SST and VIP interneurons were found to be most vulnerable, whereas pyramidal neurons were least vulnerable. Overall, the disease-state is superficial layer-centric, largely influences cell-specific salient themes, strongly impacts disinhibitory neurons, and influences astrocyte interaction with a subset of deep-layer pyramidal neurons. Drug activities, on the other hand, are deep layer-centric and involve activating a distinct subset of deep-layer pyramidal neurons to circumvent the disinhibitory circuit malfunctioning in the disease-state. These findings demonstrate a novel application of sn-RNAseq data to explain drug and disease action at a systems level, suggests a targeted drug development and reevaluate various postmortem-based findings.
Ormyrus labotus Walker (Hymenoptera: Ormyridae): another generalist that should not be a generalist is not a generalist
Authors: Sheikh Sofia I. , Ward Anna K.G. , Zhang Y. Miles , Davis Charles K. , Zhang Linyi , Egan Scott P. , Forbes Andrew A.
Published: October 2021

Several recent reappraisals of supposed generalist parasite species have revealed hidden complexes of species, each with considerably narrower host ranges. Parasitic wasps that attack gall-forming insects on plants have life history strategies that are thought to promote specialization, and though many species are indeed highly specialized, others have been described as generalist parasites. Ormyrus labotus Walker (Hymenoptera: Ormyridae) is one such apparent generalist, with rearing records spanning more than 65 host galls associated with a diverse set of oak tree species and plant tissues. We pair a molecular approach with morphology, host ecology, and phenological data from across a wide geographic sample to test the hypothesis that this supposed generalist is actually a complex of several more specialized species. We find 16–18 putative species within the morphological species O. labotus, each reared from only 1–6 host gall types, though we identify no single unifying axis of specialization. We also find cryptic habitat specialists within two other named Ormyrus species. Our study suggests that caution should be applied when considering host ranges of parasitic insects described solely by morphological traits, particularly given their importance as biocontrol organisms and their role in biodiversity and evolutionary studies.
Extrinsic motivators drive children’s cooperation to conserve forests
Authors: Bowie Aleah , Tan Jingzhi , Zhou Wen , White Philip , Stoinski Tara , Su Yanjie , Hare Brian
Published: October 2021

Forests are essential common-pool resources. It is increasingly critical to nurture a lifelong concern for forest health both locally and globally. Here, in two experiments, we demonstrate that school age children (6-18 yrs. old; N>1000;) of three nationalities (China, D. R. Congo and U.S.) do not have levels of intrinsic motivation to allow for successful cooperation in common-pool goods games requiring them to maintain a forest. We instead find that the size, timing, and certainty of receiving individual payoffs from cooperation significantly boost the odds of successful conservation efforts. We also provide evidence that the experience of playing this game increases longer term motivation to conserve forests. Results have implications for designing policy and curriculum to encourage collective action for forest conservation.

One Sentence Summary

Extrinsic motivation boosts concern for forests among children and adolescents in the United States, China, and the Democratic Republic of the Congo.
Categorization of prophage genes in Bacillus subtilis 168 and assessing their relative importance through RNA-seq gene expression analysis
Authors: Ng Wenfa
Published: October 2021

Bacteriophage evolves to control the population of fast-growing bacterial cells, without which explosion in bacterial population may induce unimaginable harm to diverse ecosystems. But, bacteriophage also “hide” in bacterial genomes when nutritional and environmental circumstances are unfavourable. This involves the integration of phage genome into the host genome at appropriate genomic loci in a process known as lysogeny. This work sought to delineate the prophages present in the annotated genome of Bacillus subtilis 168, and assess their relative importance through RNA-seq expression analysis. Firstly, examination of the annotated genome of the model Gram-positive bacterium revealed five distinct prophage regions: SPBeta, prophage 6, PBSX, prophage 3 region, and prophage 1 region. All prophage regions contain host genes, which suggests that host transposase activity have swapped in host genes for phage genes in the prophage genome. Given the significant number of phage genes that have been swapped into each of the prophage genome, all prophage regions are deemed to be defective. BLAST analysis further highlighted that many of the prophages in B. subtilis are extinct given that they do not have ancestral or daughter brethren. However, RNA-seq transcriptome analysis of B. subtilis turned out an interesting paradox indicative of the important role that host transposase have in swapping in host promoters for prophage genes. Specifically, a significant number of prophage genes are highly expressed, which is implausible given that phage genes should be transcriptionally silent. The result and phenomenon further suggests the relative facile nature in which host promoters could be swapped in for phage genes, which is indicative of presence of genomic motifs in prophage genome recognizable by host transposase. Existence of such sequence motifs is thus indicative of possible co-evolution of transposase and phages where transposases were originally a part of the phage genome, which latter “jumped out” into the host genome to aid the swapping in of host genes into the prophage genome for augmenting prophage genetic repertoire in the face of changing environmental conditions. Overall, it is not uncommon for bacterial species to harbour multiple prophages. But, lysogeny may not be a viable option for long-term preservation of prophage genetic repertoire given that host transposase would inevitable swap in host genes at random locations in the prophage genome.
A hyper-immunogenic and slow-growing fungal strain induces a murine granulomatous response to cryptococcal infection
Authors: Telzrow Calla L. , Righi Shannon Esher , Castro-Lopez Natalia , Campuzano Althea , Brooks Jacob T. , Carney John M. , Wormley Floyd L. , Alspaugh J. Andrew
Published: October 2021

Many successful pathogens cause latent infections, remaining dormant within the host for years but retaining the ability to reactivate to cause symptomatic disease. The human opportunistic pathogen Cryptococcus neoformans is a ubiquitous yeast that establishes latent pulmonary infections in immunocompetent individuals upon fungal inhalation from the environment. These latent infections are frequently characterized by granulomas, or foci of chronic inflammation, that contain dormant cryptococcal cells. Immunosuppression causes these granulomas to break down and release viable fungal cells that proliferate, disseminate, and eventually cause lethal cryptococcosis. This course of C. neoformans dormancy and reactivation is understudied due to limited models, as chronic pulmonary granulomas do not typically form in most mouse models of cryptococcal infection. Here, we report that a previously characterized Cryptococcus-specific gene which is required for host-induced cell wall remodeling, MAR1, inhibits murine granuloma formation. Specifically, the mar1Δ loss-of-function mutant strain induces mature pulmonary granulomas at sites of infection dormancy in mice. Our data suggest that the combination of reduced fungal burden and increased immunogenicity of the mar1Δ mutant strain stimulates a host immune response that contains viable fungi within granulomas. Furthermore, we find that the mar1Δ mutant strain has slow growth and hypoxia resistance phenotypes, which may enable fungal persistence within pulmonary granulomas. Together with the conventional primary murine infection model, latent murine infection models will advance our understanding of cryptococcal disease progression and define fungal features important for persistence in the human host.
Intrahost-diversity of influenza A virus in upper and lower respiratory tract derived samples from a college community
Authors: Sapoval Nicolae , de Mesquita P. Jacob Bueno , Liu Yunxi , Wang Roger , Liu Tian Rui , Garza Josie , Williams Torrey , Cadiz Carmelli , Tan Gene S. , Van Bakel Harm , Elworth R. A. Leo , Grantham Michael L. ,   EMIT Investigators, Milton Donald K. , Treangen Todd J.
Published: October 2021

Motivation

Influenza is a rapidly mutating RNA virus responsible for annual epidemics causing substantial morbidity, mortality, and economic loss. Characterizing influenza virus mutational diversity and evolutionary processes within and between human hosts can provide tools to help track and understand transmission events. In this study we investigated possible differences between the intrahost genomic content of influenza virus in upper respiratory swabs and exhaled aerosols thought to be enriched for virus from the lower respiratory tract.

Results

We examined the sequences of specimens collected from influenza A virus (IAV) infected college community members from December 2012 through May 2013. We analyzed four types of IAV samples (fine ≤5 µm aerosols (N=38), coarse >5µm aerosols (N=27), nasopharyngeal (N=53), and oropharyngeal swabs (N=47)) collected from 42 study participants with 60 sampling instances. Eighteen (42.9%) participants had data from four sample types (nasopharyngeal swab, oropharyngeal swab, coarse aerosol, fine aerosol) included in the analysis, 10 (23.8%) had data from 3 sample types, 10 (23.8%) had data from 2 sample types, and 4 (9.5%) had data from one type of sample included in the analysis. We found that 481 (53.3%) consensus single nucleotide polymorphisms are shared by all sample types and 600 (66.5%) are shared by at least three different sample types. We observed that within a single patient consensus and non-consensus single nucleotide variants are shared across all sample types. Finally, we inferred a phylogenetic tree using consensus sequences and found that samples derived from a single patient are monophyletic.

Conclusions

Single nucleotide polymorphisms did not differentiate between samples with varying origin along the respiratory tree. We found that signatures of variation in non-consensus intrahost single nucleotide variants are host and sample, but not site specific. We conclude that the genomic information available does not allow us to discern a transmission route. Future investigation into whether any site-specific mutational signatures emerge over a longer period of infection, for example in immunocompromised hosts, can be interesting from the virus evolution perspective.
Signal Intensity Normalization of Multispectal Magnetic Resonance Images Obtained with Clinical Sequences
Authors: Brier Matthew R. , Xiang Biao , Li Zhuocheng , Naismith Robert T. , Yablonskiy Dmitriy , Cross Anne H. , Benzinger Tammie L. S. , Snyder Abraham Z.
Published: October 2021

Assessment of intrinsic tissue integrity is commonly accomplished via quantitative relaxometry or other specialized imaging, which requires sequences and analysis procedures not routinely available in clinical settings. We detail an alternative technique for extraction of quantitative tissue biomarkers based on intensity normalization of T1- and T2-weighted images. We develop the theoretical underpinnings of this approach and demonstrate its utility in imaging of multiple sclerosis.
RNA sensing via LGP2 is essential for the induction of a type I IFN response in ADAR1 deficiency
Authors: Stok Jorn E. , Oosenbrug Timo , ter Haar Laurens R. , Gravekamp Dennis , Bromley Christian P. , Zelenay Santiago , Reis e Sousa Caetano , van der Veen Annemarthe G.
Published: October 2021

RNA editing by the enzyme Adenosine Deaminase Acting on RNA 1 (ADAR1) is an important mechanism by which cells avoid innate immune responses to some endogenous RNAs. In ADAR1-deficient cells, unedited self RNAs can form base-paired structures that resemble viral RNAs and inadvertently activate antiviral innate immune pathways that lead to the induction of type I interferon (IFN). Rare mutations in ADAR1 cause Aicardi-Goutières Syndrome (AGS), a severe childhood autoinflammatory syndrome that is characterized by chronic and excessive type I IFN production and developmental delay. Conversely, ADAR1 dysfunction and consequent type I IFN production helps restrict tumor growth and potentiates the activity of some chemotherapy drugs. Induction of type I IFN in ADAR1-deficient cells is thought to be due to triggering of the cytosolic RIG-I-like receptor (RLR), MDA5, by unedited self RNAs. Here, we show that another RLR, LGP2, also has an essential role. We demonstrate that ADAR1-deficient human cells fail to mount a type I IFN response in the absence of LGP2 and this involves the canonical function of LGP2 as an RNA sensor and facilitator of MDA5-dependent signaling. Further, we show that the sensitivity of tumor cells to ADAR1 loss requires the presence of LGP2. Finally, we find that type I IFN induction in tumor cells depleted of ADAR1 and treated with some chemotherapeutics is fully dependent on the expression of LGP2. These findings highlight a central role for LGP2 in self RNA sensing with important clinical implications for the treatment of AGS as well as for the potential application of ADAR1-directed anti-tumor therapy.
Hand and face somatotopy shown using MRI-safe vibrotactile stimulation with a novel Soft Pneumatic Actuator (SPA)-Skin interface
Authors: Kikkert Sanne , Sonar Harshal A. , Freund Patrick , Paik Jamie , Wenderoth Nicole
Published: October 2021

The exact somatotopy of the human facial representation in the primary somatosensory cortex (S1) remains debated. One reason that progress has been hampered is due to the methodological challenge of how to apply automated vibrotactile stimuli to face areas in a manner that is: 1) reliable despite differences in the curvatures of face locations; and 2) MR-compatible and free of MR-interference artefacts when applied in the MR head-coil. Here we overcome this challenge by using soft pneumatic actuator (SPA) technology. SPAs are made of a soft silicon material and can be in- or deflated by means of airflow, have a small diameter, and are flexible in structure, enabling good skin contact even on curved body surfaces (as on the face). To validate our approach, we first mapped the well-characterised S1 finger layout using this novel device and confirmed that tactile stimulation of the fingers elicited characteristic somatotopic finger activations in S1. We then used the device to automatically and systematically deliver somatosensory stimulation to different face locations. We found that the forehead representation was least distant from the representation of the hand. Within the face representation, we found that the lip representation is most distant from the forehead representation, with the chin represented in between. Together, our results demonstrate that this novel MR compatible device produces robust and clear somatotopic representational patterns using vibrotactile stimulation through SPA-technology.
Cancer/Testis genes are predictive of breast tumor subtypes
Authors: Laisné Marthe , Benlamara Sarah , Nicolas André , Djerroudi Lounes , Gupta Nikhil , Daher Diana , Ferry Laure , Kirsh Olivier , Philippe Claude , Okada Yuki , Cristofari Gael , Meseure Didier , Vincent-Salomon Anne , Ginestier Christophe , Defossez Pierre-Antoine
Published: October 2021

Breast cancer is the most prevalent type of cancer in women worldwide. Within breast tumors, the basal-like subtype has the worst prognosis and no dedicated therapy, therefore new tools to understand, detect, and treat these tumors are needed. Certain germline genes are re-expressed in tumors, and constitute the Cancer/Testis genes; their misexpression has diagnostic and therapeutic applications. Here, we designed a new approach to examine Cancer/ Testis gene misexpression in breast tumors. We identify several new markers in Luminal and HER-2 positive tumors, some of which predict response to chemotherapy. We then use machine learning to identify the 2 Cancer/Testis genes most associated with basal-like breast tumors: HORMAD1 and CT83. We show that these genes are expressed by tumor cells but not the microenvironment, and that they are not expressed by normal breast progenitors, in other words their activation occurs de novo. We find these genes are epigenetically repressed by DNA methylation, and that their activation upon DNA demethylation is irreversible, providing a memory of past epigenetic disturbances. Basal-like tumors expressing both genes have a poorer outcome than tumors expressing either gene alone or neither gene. Therefore, these findings suggest a potential synergistic effect between Cancer/Testis genes in basal breast tumors; these findings have consequences for the understanding, diagnosis, and therapy of the breast tumors with the worse outcomes.
First evidence towards chemical self-recognition in a gecko
Authors: Szabo Birgit , Ringler Eva
Published: October 2021

Self-recognition is the ability to recognise stimuli originating from oneself. Humans and most great apes show evidence of true self-recognition in the mirror test. They use their reflection to remove a mark that is only visible in the mirror. Not all animals, however, rely primarily on vision. In lizards, chemical cues are important in social interactions. A number of lizard species show chemical self-recognition but it has never been investigated in a gecko species. Here, we test the tokay gecko (Gekko gecko) a territorial species with parental care on their ability to discriminate their own skin and faecal chemicals from those of same-sex, unfamiliar conspecifics. Geckos show a higher response rate towards chemicals from unfamiliar individuals compared to self-produced chemicals and a water control. Lizards showed self-directed behaviour, responded stronger to skin chemicals and females responded more than males. Our study provides first evidence towards self-recognition and for a social function of chemical present on faeces in tokay geckos but further tests are needed to confirm true self-recognition. Tokay geckos are an excellent model species to investigate individual recognition to demonstrate more sophisticated social cognitive abilities than have previously been attributed to reptiles.