bluuebunny/crossref_metadata_2025 huggingface dataset:
Outpatient Cervical Ripening
Authors: McDonagh Marian , Skelly Andrea C. , Tilden Ellen , Brodt Erika D. , Dana Tracy , Hart Erica , Kantner Shelby N. , Fu Rongwei , Hermesch Amy C.
Published: March 2021

OBJECTIVE:

To assess the comparative effectiveness and potential harms of cervical ripening in the outpatient compared with the inpatient setting, or different methods of ripening in the outpatient setting alone.

DATA SOURCES:

Searches for articles in English included MEDLINE, EMBASE, CINAHL, Cochrane Library, ClinicalTrials.gov, and reference lists (up to August 2020).

METHODS OF STUDY SELECTION:

Using predefined criteria and DistillerSR software, 10,853 citations were dual-reviewed for randomized controlled trials (RCTs) and cohort studies of outpatient cervical ripening using prostaglandins and mechanical methods in pregnant women at or beyond 37 weeks of gestation.

TABULATION, INTEGRATION, AND RESULTS:

Using prespecified criteria, study data abstraction and risk of bias assessment were conducted by two reviewers, random-effects meta-analyses were conducted and strength of evidence was assessed. We included 30 RCTs and 10 cohort studies (N=9,618) most generalizable to women aged 25–30 years with low-risk pregnancies. All findings were low or insufficient strength of evidence and not statistically significant. Incidence of cesarean delivery was not different for any comparison of inpatient and outpatient settings, or comparisons of different methods in the outpatient setting (most evidence available for single-balloon catheters and dinoprostone). Harms were inconsistently reported or inadequately defined. Differences were not found for neonatal infection (eg, sepsis) with outpatient compared with inpatient dinoprostone, birth trauma (eg, cephalohematoma) with outpatient compared with inpatient single-balloon catheter, shoulder dystocia with outpatient dinoprostone compared with placebo, maternal infection (eg, chorioamnionitis) with outpatient compared with inpatient single-balloon catheters or outpatient prostaglandins compared with placebo, and postpartum hemorrhage with outpatient catheter compared with inpatient dinoprostone. Evidence on misoprostol, hygroscopic dilators, and other outcomes (eg, perinatal mortality and time to vaginal birth) was insufficient.

CONCLUSION:

In women with low-risk pregnancies, outpatient cervical ripening with dinoprostone or single-balloon catheters did not increase cesarean deliveries. Although there were no clear differences in harms when comparing outpatient with inpatient cervical ripening, the certainty of evidence is low or insufficient to draw definitive conclusions.

SYSTEMATIC REVIEW REGISTRATION:

PROSPERO, CRD42020167406.
Rotational Composite Flap Technique for Primary Incomplete Cleft Nose Deformity
Authors: Rossell-Perry Percy
Published: March 2021

Background:

Nasal deformities accompanying unilateral incomplete cleft lip have minor skeletal and soft tissue deficiencies compared with deformities associated with unilateral complete cleft lip. Extended dissection and surgical incisions (often required for nasal deformities in complete cleft lip) are not recommended to address deformities accompanying incomplete cleft lip. The purpose of this study is to describe an innovative method involving a rotational composite flap for nasal repair in patients with unilateral cleft lip.

Methods:

Since 2016, 49 consecutive patients with unilateral incomplete cleft lip have undergone primary anatomical repair of accompanying nasal deformities. The technique involves a skin incision along the marginal and intercartilaginous borders to create a V-shaped composite flap consisting of vestibular skin and alar cartilage. Rotational mobilization of the composite flap creates a triangular raw surface laterally, which is closed by advancement of the vestibular skin.

Results:

This innovative method, which is based on the use of a rotational composite vestibular flap, achieves proper symmetry of the repaired nose.

Conclusion:

The herein described composite flap rhinoplasty is a good surgical option, which provides a good overall nasal symmetry in patients with nasal deformities accompanying unilateral incomplete cleft lip.
The Laterally Extended Paramedian Forehead Flap for Nasal Reconstruction: The Delay Technique Revisited
Authors: Itani Yoshihito , Yotsuyanagi Takatoshi , Yamauchi Makoto , Sugai Asuka , Kato Shinji , Yamashita Ken , Isogai Noritaka
Published: March 2021

Background:

Problems with poor circulation often occur when a large defect or a distant region, such as the apex of the nose, is covered with a paramedian forehead flap. Delay technique increases the safety of reconstruction procedures, but it has been used less frequently because a 2-stage surgery is necessary, and various other flaps and techniques have been developed.

Method:

We performed the delay technique of paramedian forehead flap at the same time as tumor resection. For the flap, a narrow pedicle of about 1-cm was prepared on the supratrochlear artery and vein, and the incision was extended toward the lateral side conforming to the defect morphology, and a paramedian forehead flap with a design consistent with the esthetic unit containing the defect was prepared. The region below the flap was dissected to create the flap bipedicle, and surgery was completed.

Result:

This procedure was used in 4 patients with malignant tumor of the external nose, and the flap survived perfectly in all patients. The postoperative esthetic outcome was also found to be good.

Conclusions:

This procedure does not increase the frequency of surgery, circulation in the flap is maintained, the flap pedicle on the supratrochlear artery can be made narrow, and flap thinning can be performed from the beginning. Coverage of an extensive defect is possible because a large flap can be excised, and satisfactory esthetic appearance can be obtained by matching with the esthetic unit. The delay technique for various flaps (not limited to forehead flap alone) should be considered an effective technique for the current treatment of malignant tumors.
A New Approach in the Correction of the Midcheek Groove: The Liquid Malar-lift Technique
Authors: Bagci Bulent
Published: March 2021

The liquid malar-lift technique describes an approach to correct the midcheek groove by injecting monophasic cross-linked hyaluronic acid into the deep medial cheek fat, deep lateral cheek fat, and the superficial fat compartments, that is the superficial medial cheek fat and superficial middle cheek fat, respectively. The selective volume loss in the deep fat compartments of the face with aging is restored with the liquid malar-lift technique, and the midcheek groove is corrected in harmony with the patient’s unique facial anatomy.
Hydrosurgical Debridement Allows Effective Wound Bed Preparation of Pressure Injuries: A Prospective Case Series
Authors: Matsumine Hajime , Giatsidis Giorgio , Takagi Mika , Kamei Wataru , Shimizu Mari , Takeuchi Masaki
Published: March 2021

Background:

Pressure injuries (PIs) are common in hospitalized patients, with incidence exceeding 50% in high-risk patients. Immobilization causes a prolonged compression of vascular networks in tissues overlying bony prominences, leading to ischemia and ulceration. Traditionally, PIs are treated with a combination of surgical debridement and reconstruction. This approach can be invasive for debilitated patients who cannot tolerate prolonged surgeries and extensive tissue resection. Hydrosurgery uses high-pressure irrigation to low-invasively debride and cleanse wounds; its use has shown positive outcomes in burn and chronic wounds care. Here, we hypothesize that hydrosurgery allows low-invasive yet effective wound bed preparation in truncal PIs.

Methods:

We conducted a single-center, prospective, uncontrolled case series. Inclusion criteria for this study were presence of a truncal PI (stage III or IV) and an American Society of Anesthesiologists physical status of ≥2 (no exclusion criteria). Measured outcomes included duration of hydrosurgery, postsurgical local (dehiscence, infection, seroma) or systemic complications in the first 30 days, and PI recurrence rate (6-month follow-up).

Results:

Seven patients (3 sacral, 2 greater trochanteric, and 2 ischial tuberosity PIs) were enrolled for this study. Average duration of hydrosurgery was 12 minutes (±3.1). No local or systemic complications were observed at a 30-day follow-up (0/7, 0%). All flaps (6/7, 86%) and graft (1/7, 14%) reconstructions successfully survived, and no PI recurrence was reported within a 6-month follow-up (0/7, 0%).

Conclusions:

Hydrosurgery seems to allow safe, low-invasive, and effective wound bed preparation in truncal PIs. Larger controlled trials are needed to confirm this preliminary evidence, to guide its broader adoption for improved care of high-risk patients with PIs.
Keystone Flap Type IIIB: A New Variation for Coverage of Defects at Joint Regions
Authors: Bauer Benedikt A. , Christen Samuel , Spiegl Matthias K. F. , Müller Daniel Andreas , Grünert Jörg G.
Published: March 2021

Soft tissue defect reconstruction at joint regions is a challenging problem due to the sparse excessive tissue and late complication of constrigent scar formation. Priorly irradiated tissue, often the case in sarcoma patients, is especially problematic. The keystone design perforator island flap is safe and reliable. We now present a new keystone flap design, which is particularly suitable for the reconstruction of large soft tissue defects at joint regions. It provides a cutaneous component without the need for a skin graft and therefore minimizes the risk of contracture. Donor site morbidity is negligible. Furthermore, it offers a favorable aesthetic result compared to other flaps, eg, a muscular flap. We propose a new keystone flap design as an extension of Behan's classification, the Keystone flap type IIIb.
A Case of Traumatic Intractable Leg Ulcer with Lymphorrhea Diagnosed Using ICG Lymphography
Authors: Osada Atsuyoshi , Yamaki Takashi , Kamei Wataru , Yamamoto Yusuke , Sakurai Hiroyuki
Published: March 2021

We report a case of traumatic lower extremity ulcers with lymphorrhea in a 37-year-old woman. She presented intractable ulcers without lymphedema for nearly 6 months after a traumatic injury. She was treated conservatively for 6 months at a referral hospital. Unfortunately, during conservative treatment, cellulitis was developed. Even though the inflammation resolved, the ulcer did not heal. We suspected persistent lymphorrhea as the cause of refractory ulcer, and for that reason, we performed indocyanine green lymphography. The lymphatic vessel damage site was identified; also, a collateral lymphatic vessel connected toward the central side was recognized. The lymph fluid drainage site was selectively ligated. The lymphorrhea and ulcers healed 1 month after ligation. Ulcers with lymphorrhea can be persistent and refractory to treatment. Indocyanine green lymphography can be a feasible diagnostic technique. It can identify the site of leakage and is thus useful for treatment. There are fewer reports on the evaluation of lymphorrhea with video presentation. Here, we report a case with video presentation.
Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment
Authors: Zhou Yadi , Xu Jielin , Hou Yuan , Leverenz James B. , Kallianpur Asha , Mehra Reena , Liu Yunlong , Yu Haiyuan , Pieper Andrew A. , Jehi Lara , Cheng Feixiong
Published: March 2021

Background

Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive interventions.

Methods

In this study, we conducted a network-based, multimodal genomics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9 based genetic assay results, and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer’s disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2.

Results

We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSGandFURIN) and antiviral defense genes (LY6E,IFITM2,IFITM3, andIFNAR1) was significantly elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Notably, individuals with the AD risk alleleAPOEE4/E4 displayed reduced levels of antiviral defense genes compared toAPOEE3/E3 individuals.

Conclusion

Our results suggest significant mechanistic overlap between AD and COVID-19, strongly centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions.
Scaling down the microbial loop: data-driven modelling of growth interactions in a diatom-bacterium co-culture
Authors: Daly Giulia , Perrin Elena , Viti Carlo , Fondi Marco , Adessi Alessandra
Published: March 2021

An intricate set of interactions characterizes marine ecosystems. One of the most important is represented by the so-called microbial loop, which includes the exchange of dissolved organic matter (DOM) from phototrophic organisms to heterotrophic bacteria. Here, it can be used as the major carbon and energy source. Arguably, this interaction is one of the foundations of the entire ocean food-web. Carbon fixed by phytoplankton can be redirected to bacterial cells in two main ways; either i) bacteria feed on dead (eventually lysed) phytoplankton cells or ii) DOM is actively released by phytoplankton cells (a widespread process that may result in up to 50% of the fixed carbon leaving the cell). In this work, we have set up a co-culture of the model diatomPhaeodactylum tricornutumand the model chemoheterotrophic bacteriumPseudoalteromonas haloplanktisTAC125 and used this system to study the interactions between these two representatives of the microbial loop. We show that the bacterium can indeed thrive on diatom-derived carbon and that this growth can be sustained by both diatom dead cells and diatom-released compounds. These observations were formalized in a network of putative interactions betweenP. tricornutumandP. haloplanktisand implemented in a mathematical model that reproduces the observed co-culture dynamics, suggesting that our hypotheses on the interactions occurring in this two-player system can accurately explain the experimental data.
Chronic inflammation in ulcerative colitis causes long term changes in gobletcell function
Authors: Singh Varsha , Johnson Kelli , Yin Jianyi , Lee Sunny , Lin Ruxian , Yu Helen , In Julie G. , Foulke-Abel Jennifer , Zachos Nicholas
Published: March 2021

Objective

One of the features of ulcerative colitis (UC) is a defect in the protective mucus layer. This has been attributed to a reduced number of goblet cells (GC). However, it is not known whether abnormal GC mucus secretion also contributes to the reduced mucus layer. Our aims were to test the hypothesis that GC secretion was abnormal in UC with the changes persistent in colonoids even in the absence of immune cells.

Design

Colonoids were established from intestinal stem cells of healthy subjects (HS) and from patients with UC (inactive and active sites). Colonoids were maintained as undifferentiated (UD) or induced to differentiate (DF) and studied as 3D or monolayers on Transwell filters. Total RNA was extracted for quantitative real-time PCR analysis. Carbachol and PGE2mediated stimulation followed by examination of mucus layer by MUC2 IF/confocal microscopy and TEM were performed.

Results

Colonoids derived from patients with UC can be propagated over many passages; however, they exhibit a reduced rate of growth and TEER compared with colonoids from HS. Differentiated UC colonoid monolayers form a thin and non-continuous mucus layer. UC colonoids have increased expression of secretory lineage markers: ATOH1 and SPDEF, including MUC2 positive GCs and ChgA positive enteroendocrine cells but failed to secrete mucin when exposed to the cholinergic agonist carbachol and PGE2, which caused increased secretion in HS. Exposure to TNF-α (5days), reduced the number of GC with a greater percentage decrease in UC colonoids compared to HS.

Conclusions

Abnormal mucus layer in UC is due to long term changes in epithelial cells that lead to abnormal mucus secretion as well as effects of the inflammatory environment to reduce the number of GC. This continued defect in GC mucus secretion may be involved in UC recurrence.
Mechanical bistability of the mesoderm epithelium facilitates mesoderm invagination duringDrosophilagastrulation
Authors: Guo Hanqing , Swan Michael , He Bing
Published: March 2021

Apical constriction driven by non-muscle myosin II (“myosin”) provides a well-conserved mechanism to mediate epithelial folding. It remains unclear how contractile forces near the apical surface of a cell sheet drive out-of-the-plane bending of the sheet and whether myosin contractility is required throughout folding. By optogenetic-mediated acute inhibition of myosin, we find that duringDrosophilamesoderm invagination, myosin contractility is critical to prevent tissue relaxation during the early, “priming” stage of folding but is dispensable for the actual folding step after the tissue passes through a stereotyped transitional configuration. The binary response suggests that the mesoderm is mechanically bistable during gastrulation. Combined modeling analysis and experimental measurements suggest that the observed mechanical bistability may arise from apicobasal shrinkage of the surrounding ectoderm, which promotes mesoderm invagination by facilitating a buckling transition. Our results suggest thatDrosophilamesoderm invagination requires a joint action of local myosin contractility and mechanical bistability of the epithelium to trigger epithelial buckling.
Elimination of GPI2 suppresses glycosylphosphatidylinositol GlcNAc transferase activity and alters GPI glycan modification inTrypanosoma brucei
Authors: Jenni Aurelio , Knüsel Sebastian , Nagar Rupa , Benninger Mattias , Häner Robert , Ferguson Michael A. J. , Roditi Isabel , Menon Anant K. , Bütikofer Peter
Published: March 2021

The biosynthesis of glycosylphosphatidylinositol (GPI) membrane protein anchors is initiated in the endoplasmic reticulum by transfer of GlcNAc from the sugar nucleotide UDP-GlcNAc to phosphatidylinositol. The reaction is catalyzed by GPI GlcNAc transferase, a multi-subunit complex comprising the catalytic subunit Gpi3/PIG-A, as well as at least five other subunits including the hydrophobic protein Gpi2 which is essential for activity in yeast and mammals, but whose function is not known. Here we exploitedTrypanosoma brucei(Tb), an early diverging eukaryote and important model organism, to investigate the function of Gpi2. We generated trypanosomes that lack TbGPI2 and found that in TbGPI2-null parasites (i) GPI GlcNAc transferase activity is reduced but not lost, in contrast with the situation in yeast and human cells, (ii) the GPI GlcNAc transferase complex persists, but its architecture is affected, with loss of at least the TbGPI1 subunit, and (iii) the GPI anchors of the major surface proteins are underglycosylated when compared with their wild-type counterparts, indicating the importance of TbGPI2 for reactions that are expected to occur in the Golgi apparatus. Additionally, TbGPI2-null parasites were unable to perform social motility, a form of collective migration on agarose plates. Immunofluorescence microscopy localized TbGPI2 to the endoplasmic reticulum as expected, but also to the Golgi apparatus, suggesting that in addition to its expected function as a subunit of the GPI GlcNAc transferase complex, TbGPI2 may have an enigmatic non-canonical role in Golgi-localized GPI anchor modification in trypanosomes.
Ciliary Hedgehog signaling regulates cell survival to build the facial midline
Authors: Abrams Shaun , Reiter Jeremy F.
Published: March 2021

Craniofacial defects are among the most common phenotypes caused by ciliopathies, yet the developmental and molecular etiology of these defects is poorly understood. We investigated multiple mouse models of human ciliopathies (includingTctn2, Cc2d2aandTmem231mutants)and discovered that each displays hypotelorism, a narrowing of the midface. As early in development as the end of gastrulation,Tctn2mutants displayed reduced activation of the Hedgehog (HH) pathway in the prechordal plate, the head organizer. This prechordal plate defect preceded a reduction of HH pathway activation andShhexpression in the adjacent neurectoderm. Concomitant with the reduction of HH pathway activity,Tctn2mutants exhibited increased cell death in the neurectoderm and facial ectoderm, culminating in a collapse of the facial midline. Enhancing HH signaling by decreasing the gene dosage of a negative regulator of the pathway,Ptch1,decreased cell death and rescued the midface defect in bothTctn2andCc2d2amutants. These results reveal that ciliary HH signaling mediates communication between the prechordal plate and the neurectoderm to provide cellular survival cues essential for development of the facial midline.
Population-specific genome graphs improve high-throughput sequencing data analysis: A case study on the Pan-African genome
Authors: Tetikol H. Serhat , Narci Kubra , Turgut Deniz , Budak Gungor , Kalay Ozem , Arslan Elif , Demirkaya-Budak Sinem , Dolgoborodov Alexey , Jain Amit , Kabakci-Zorlu Duygu , Brown Richard , Semenyuk Vladimir , Davis-Dusenbery Brandi
Published: March 2021

Graph-based genome reference representations have seen significant development, motivated by the inadequacy of the current human genome reference to represent the diverse genetic information from different human populations and its inability to maintain the same level of accuracy for non-European ancestries. While there have been many efforts to develop computationally efficient graph-based toolkits for NGS read alignment and variant calling, methods to curate genomic variants and subsequently construct genome graphs remains an understudied problem that inevitably determines the effectiveness of the overall bioinformatics pipeline. In this study, we discuss obstacles encountered during graph construction and propose methods for sample selection based on population diversity, graph augmentation with structural variants and resolution of graph reference ambiguity caused by information overload. Moreover, we present the case for iteratively augmenting tailored genome graphs for targeted populations and demonstrate this approach on the whole-genome samples of African ancestry. Our results show that population-specific graphs, as more representative alternatives to linear or generic graph references, can achieve significantly lower read mapping errors and enhanced variant calling sensitivity, in addition to providing the improvements of joint variant calling without the need of computationally intensive post-processing steps.
Changes in HIV Treatment Differentiated Care Utilization During the COVID-19 Pandemic in Zambia
Authors: Jo Youngji , Rosen Sydney , Sy Karla Therese L , Phiri Bevis , Huber Amy N , Mwansa Muya , Shakwelele Hilda , Haimbe Prudence , Mwenechanya Mpande M , Mulenga Priscilla Lumano , Nichols Brooke E
Published: March 2021

Background

Differentiated service delivery (DSD) models aim to lessen the burden of HIV treatment on patients and providers in part by reducing requirements for facility visits and extending dispensing intervals. With the advent of the COVID-19 pandemic, minimizing patient contact with healthcare facilities and other patients, while maintaining treatment continuity and avoiding loss to care, has become more urgent, resulting in efforts to increase DSD uptake. We assessed the extent to which DSD coverage and antiretroviral treatment (ART) dispensing intervals have changed during the COVID-19 pandemic in Zambia.

Methods

We used patient data from Zambia’s electronic medical record system (SmartCare) for 737 health facilities, representing about 3/4 of all ART patients nationally, to compare the numbers and proportional distributions of patients enrolled in DSD models in the six months before and six months after the first case of COVID-19 was diagnosed in Zambia in March 2020. Segmented linear regression was used to determine whether the introduction of COVID-19 into Zambia further accelerated the increase in DSD scale-up.

Results

Between September 2019 and August 2020, 181,317 patients aged 15+ (81,520 and 99,797 from September 1, 2019 to March 1, 2020 and from March 1 to August 31, 2020, respectively) enrolled in DSD models in Zambia. Overall participation in all DSD models increased over the study period, but uptake varied by model. The rate of acceleration increased in the second period for home ART delivery (152%), ≤2-month fast-track (143%), and 3-month MMD (139%). There were significant decelerations in the increase in enrolment for 4-6-month fast-track (−28%) and ‘other’ models (−19%).

Conclusions

Participation in DSD models for stable ART patients in Zambia increased after the advent of COVID-19, but dispensing intervals diminished. Eliminating obstacles to longer dispensing intervals, including those related to supply chain management, should be prioritized to achieve the expected benefits of DSD models and minimize COVID-19 risk.
Symptoms of COVID-19 in a population-based cohort study
Authors: Khan Sana M. , Farland Leslie V. , Austhof Erika , Bell Melanie L. , Catalfamo Collin J. , Chen Zhao , Cordova-Marks Felina , Ernst Kacey C. , Garcia-Filion Pamela , Heslin Kelly M. , Hoskinson Joshua , Jehn Megan L , Joseph Emily C.S. , Kelley Connor P. , Klimentidis Yann , Carroll Stephanie Russo , Kohler Lindsay N. , Pogreba-Brown Kristen , Jacobs Elizabeth T.
Published: March 2021

Accurate diagnosis of potential SARS-CoV-2 infections by symptoms is one strategy for continuing global surveillance, particularly in low-resource communities. We conducted a prospective, population-based cohort study, the Arizona CoVHORT, among Arizona residents to elucidate the symptom profile of laboratory-confirmed COVID-19 participants(16.2%) compared to laboratory-confirmed negative(22.4%) and untested general population participants(61.4%). Among the 1514 study participants, those who were COVID-19 positive were more likely to be Hispanic(33.5%) and more likely to report obesity > 30 kg/m2(34.7%) compared to COVID-19 negative participants(19.2%; 31.0%) and untested CoVHORT participants(13.8%; 23.8%). Of the 245 laboratory-confirmed COVID-19 cases, 15.0% reported having had no symptoms. Of those that did report symptoms, the most commonly-reported first symptoms were sore throat(19.0%), headache(15.5%), cough(12.7%), runny nose/cold-like symptoms(12.1%), and fatigue(12.0%). In adjusted logistic regression models, COVID-19 positive participants were more likely than negative participants to experience loss of taste and smell(OR:35.7; 95% CI 18.4-69.5); bone or nerve pain(OR:17.9; 95% CI 6.7-47.4), vomiting(OR:10.8; 95% CI 3.1-37.5), nausea(OR:10.5; 95% CI 5.5-19.9), and headache(OR:8.4; 95% CI 5.6-12.8). When comparing confirmed COVID-19 cases with confirmed negative or untested participants, the pattern of symptoms that discriminates SARS-CoV-2 infection from those arising from other potential circulating pathogens may differ from general reports of symptoms among cases alone.
Rotavirus A Genome Segments Show Distinct Segregation and Codon Usage Patterns
Authors: Hoxie Irene , Dennehy John J.
Published: March 2021

Reassortment of the Rotavirus A (RVA) 11-segment dsRNA genome may generate new genome constellations that allow RVA to expand its host range or evade immune responses. Reassortment may also produce phylogenetic incongruities and weakly linked evolutionary histories across the 11 segments, obscuring reassortant-specific epistasis and changes in substitution rates. To determine the co-segregation patterns of RVA segments, we generated time-scaled phylogenetic trees for each of the 11 segments of 789 complete RVA genomes isolated from mammalian hosts and compared the segments’ geodesic distances. We found that segments 4 (VP4) and 9 (VP7) occupied significantly different treespaces from each other and from the rest of the genome. By contrast, segments 10 and 11 (NSP4 and NSP5/6) occupied nearly indistinguishable treespaces, suggesting strong co-segregation. Host-species barriers appeared to vary by segment, with segment 9 (VP7) presenting the least conservation by host species. Bayesian skyride plots were generated for each segment to compare relative genetic diversity among segments over time. All segments showed a dramatic decrease in diversity around 2007 coinciding with the introduction of RVA vaccines. To assess selection pressures, codon adaptation indices and relative codon deoptimization indices were calculated with respect to common host genomes. Codon usage varied by segment with segment 11 (NSP5) exhibiting significantly higher adaptation to host genomes. Furthermore, RVA codon usage patterns appeared optimized for expression in humans and birds relative to the other hosts examined, suggesting that translational efficiency is not a barrier in RVA zoonosis.
Evolutionary genomics of socially polymorphic populations ofPogonomyrmex californicus
Authors: Errbii Mohammed , Ernst Ulrich R. , Lajmi Aparna , Privman Eyal , Gadau Jürgen , Schrader Lukas
Published: March 2021

Social insects vary considerably in their social organization both between and within species. In the California harvester ant,Pogonomyrmex californicus(Buckley 1867), colonies are commonly founded and headed by a single queen (haplometrosis, primary monogyny). However, in some populations in California (USA), unrelated queens cooperate not only during founding (pleometrosis) but throughout the life of the colony (primary polygyny). The genetic architecture and evolutionary dynamics of this complex social niche polymorphism (haplometrosis vs pleometrosis) have remained unknown. Here, we provide a first analysis of its genomic basis and evolutionary history using population genomics comparing individuals from a haplometrotic population to those from a pleometrotic population. We discovered a recently evolved (< 200 k years), 8 Mb non-recombining region segregating with the observed social niche polymorphism. This region shares several characteristics with supergenes underlying social polymorphisms in other socially polymorphic ant species. However, we also find remarkable differences from previously described social supergenes. Particularly, four additional genomic regions not in linkage with the supergene show signatures of a selective sweep in the pleometrotic population. Within these regions, we find for example genes crucial for epigenetic regulation via histone modification (chameau) and DNA methylation (Dnmt1). These results suggest that social morph in this species is a polygenic trait involving a potential young supergene. Further studies targeting haplo- and pleometrotic individuals from a single population are however required to conclusively resolve whether these genetic differences underlie the alternative social phenotypes or have emerged through genetic drift.
Fast ATP-dependent Subunit Rotation in Reconstituted FoF1-ATP Synthase Trapped in Solution
Authors: Heitkamp Thomas , Börsch Michael
Published: March 2021

FoF1-ATP synthases are ubiquitous membrane-bound, rotary motor enzymes that can catalyze ATP synthesis and hydrolysis. Their enzyme kinetics are controlled by internal subunit rotation, by substrate and product concentrations, by mechanical inhibitory mechanisms, but also by the electrochemical potential of protons across the membrane. Single-molecule Förster resonance energy transfer (smFRET) has been used to detect subunit rotation within FoF1-ATP synthases embedded in freely diffusing liposomes. We now report that kinetic monitoring of functional rotation can be prolonged from milliseconds to seconds by utilizing an Anti-Brownian electrokinetic trap (ABEL trap). These extended observation times allowed us to observe fluctuating rates of functional rotation for individual FoF1-liposomes in solution. Broad distributions of ATP-dependent catalytic rates were revealed. The buildup of an electrochemical potential of protons was confirmed to limit the maximum rate of ATP hydrolysis. In the presence of ionophores or uncouplers, the fastest subunit rotation speeds measured in single reconstituted FoF1-ATP synthases were 180 full rounds per second. This was much faster than measured by biochemical ensemble averaging, but not as fast as the maximum rotational speed reported previously for isolated single F1complexes uncoupled from the membrane-embedded Focomplex. Further application of ABEL trap measurements should help resolve the mechanistic causes of such fluctuating rates of subunit rotation.

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Figure 1.
The Central Importance of Hub Proteins in a Disease-Gene Network Model: A New Paradigm of Chronic Myeloid Leukemia Disease Study
Authors: Rahman K M Taufiqur , Islam Md. Fahmid , Saha Sanjib , Billah Md. Morsaline
Published: March 2021

Background

The network biology of disease-gene association provides a holistic framework to decipher the intrinsic complexity of disease signaling pathways into cellular communication level. Different types of studies including large-scale genome-wide association, multifactor dimensional reduction analysis, whole genome, or exome-based sequencing strategies of diseases are striving to connect genes to diseases. Indeed, these approaches have had some accomplishments, but the cellular communication level needs a more streamlining outcome to understand the mechanistic impact of context. The higher-order combination of disease-gene interaction has a great potential to decipher the intricateness of diseases. The molecular interaction pattern of diseases at the genomic and proteomic level offers a revolutionized platform not only to understand the complexity of particular disease modules and pathways but also leading towards design novel therapeutics.

Results

The enrichment and topology analysis was performed by JEPETTO a plugin of Cytoscape software. We identified the chronic myeloid leukemia (CML) disease signaling pathways that appeared first in the ranking order based on XD-score among the bone, breast, and colon genes set and second at kidney and liver. This result validates the highest proximity between CML and five cancerous tissue gene set clusters. The topology analysis also supports the results while (p<0.0001) is considered to be extremely significant between CML and fives cancerous tissues genes set. Enrichment analysis identified thatabl-gene acts as an overlapping node which is the major gene for inducing various mutations in CML. Amazingly, we identified 56 common path expansion/added genes among these five cancerous tissues which can be considered the direct cofactors of CML disease. By relative node degree, resolution, possible ligand, stoichiometry, Q-mean, and Z-score analysis we found 11 hubs proteins like SMAD3, GRB2, TP53, SMAD4, RB1, HDAC1, RAF1, ABL1, SHC1, TGFBR1, RELA which can be regarded for further drug target identification.

Conclusions

Our proposed network analysis reflects on the gene set interaction pattern of disease signaling pathways of humans. The integrated multidrug computational and experimental approaches boost up to improve the novel drug target approach. Besides, such a trove can yield unprecedented insights to lead to an enhanced understanding of potential application both in drug target optimization and for drug dislodging.
Combined Inhibition of SHP2 and CXCR1/2 Promotes Anti-Tumor T Cell Response in NSCLC
Authors: Tang Kwan Ho , Li Shuai , Khodadadi-Jamayran Alireza , Jen Jayu , Han Han , Guidry Kayla , Chen Ting , Hao Yuan , Fedele Carmine , Zebala John , Maeda Dean , Christensen James , Olson Peter , Athanas Argus , Wong Kwok-Kin , Neel Benjamin G.
Published: March 2021

Clinical trials of SHP2 inhibitors (SHP2i) alone and in various combinations are ongoing for multiple tumors with over-activation of the RAS/ERK pathway. SHP2 plays critical roles in normal cell signaling; hence, SHP2is could influence the tumor microenvironment. We found that SHP2i treatment depleted alveolar and M2-like macrophages and promoted B and T lymphocyte infiltration inKras- andEgfr-mutant non-small cell lung cancer (NSCLC). However, treatment also increased intratumor gMDSCs via tumor-intrinsic, NF-kB-dependent production of CXCR2 ligands. Other RAS/ERK pathway inhibitors also induced CXCR2 ligands and gMDSC influx in mice, and CXCR2 ligands were induced in tumors from patients on KRASG12C-inhibitor trials. Combined SHP2(SHP099)/CXCR1/2(SX682) inhibition depleted a specific cluster ofS100a8/9highgMDSCs, generatedKlrg1+ CD8+ effector T cells with a strong cytotoxic phenotype but expressing the checkpoint receptor NKG2A, and enhanced survival inKras-andEgfr-mutant models. Our results argue for testing RAS/ERK pathway/CXCR1/2/NKG2A inhibitor combinations in NSCLC patients.

Statement of Significance

Our study shows that inhibiting the SHP2/RAS/ERK pathway triggers NF-kB-dependent up-regulation of CXCR2 ligands and recruitment of S100A8highgMDSCs, which suppress T cells in NSCLC. Combining SHP2 and CXCR2 inhibitors blocks this gMDSC immigration, resulting in enhanced Th1 polarization, induction of CD8+ KLRG1+ effector T cells with high cytotoxic activity and improved survival in multiple NSCLC models.
Genetic characteristics ofApodemus speciosusat Akiyoshidai Quasi-National Park in Yamaguchi Prefecture
Authors: Imai Hiroyuki , Tanaka Hiroshi , Matsuo Taiki , Seto Miho , Matsuya Sumito , Hyoto Muneyoshi , Kano Kiyoshi , Kusakabe Ken Takeshi
Published: March 2021

abstract

The large Japanese field mouse (Apodemus speciosus) is a small rodent endemic to Japan. The mice have a genetic characteristic in which the number of chromosomes differs between those from western Japan and those from eastern Japan.A. spesiosus, found throughout Japan, is used as a model animal for geogenetics and monitoring of radiation effects of wildlife. In this present study, to elucidate the genetic characteristics of the mice Akiyoshidai Quasi-National Park in Yamaguchi Prefecture, we investigated mitochondrial DNA and chromosome numbers. As a result,A. speciosusfrom Yamaguchi Prefecture were classified into the Honshu-Shikoku-Kyushu group and had a western Japan-type chromosome set of 2n=46; however, some Yamaguchi Prefecture mice formed a genetic cluster in Yamaguchi Prefecture, suggesting that continuous monitoring is needed to reveal the dynamics of genetic diversity.
Application of high dimensional flow cytometry and unsupervised analysis to define the immune cell landscape of early childhood respiratory and blood compartments
Authors: Shanthikumar Shivanthan , Ranganathan Sarath C. , Saffery Richard , Neeland Melanie R.
Published: March 2021

The cellular landscape of the paediatric respiratory system remains largely uncharacterised and as a result, the mechanisms of highly prevalent childhood respiratory diseases remain poorly understood. A major limitation in defining mechanisms of disease has been the availability of tissue samples collected in early life, as well as technologies that permit deep immune analysis from limited sample volumes. In this work, we developed new experimental methods and applied unsupervised analytical tools to profile the local (bronchoalveolar lavage) and systemic (whole blood) immune response in childhood respiratory disease. We quantified and comprehensively phenotyped immune cell populations across blood and lung compartments in young children (under 6 years of age), showed that inflammatory cells in the BAL express higher levels of activation and migration markers relative to their systemic counterparts, and applied new analytical tools to reveal novel tissue-resident macrophage and infiltrating monocyte populations in the paediatric lung. To our knowledge, this is the first description of the use of these methods for paediatric respiratory samples. Combined with matched analysis of the systemic immune cell profile, the application of these pipelines will increase our understanding of childhood lung disease with potential to identify clinically relevant disease biomarkers.
A protease-activatable luminescent biosensor and reporter cell line for authentic SARS-CoV-2 infection
Authors: Gerber Pehuén Pereyra , Duncan Lidia M , Greenwood Edward JD , Marelli Sara , Naamati Adi , Teixeira-Silva Ana , Crozier Thomas WM , Gabaev Ildar , Zhan Jun R , Mulroney Thomas E , Horner Emily C , Doffinger Rainer , Willis Anne E , Thaventhiran James ED , Protasio Anna V , Matheson Nicholas J
Published: March 2021

Efforts to define serological correlates of protection against COVID-19 have been hampered by the lack of a simple, scalable, standardised assay for SARS-CoV-2 infection and antibody neutralisation. Plaque assays remain the gold standard, but are impractical for high-throughput screening. In this study, we show that expression of viral proteases may be used to quantitate infected cells. Our assays exploit the cleavage of specific oligopeptide linkers, leading to the activation of cell-based optical biosensors. First, we characterise these biosensors using recombinant SARS-CoV-2 proteases. Next, we confirm their ability to detect viral protease expression during replication of authentic virus. Finally, we generate reporter cells stably expressing an optimised luciferase-based biosensor, enabling viral infection to be measured within 24 h in a 96- or 384-well plate format, including variants of concern. We have therefore developed a luminescent SARS-CoV-2 reporter cell line, and demonstrated its utility for the relative quantitation of infectious virus and titration of neutralising antibodies.

Author summary

Techniques for measuring infection with SARS-CoV-2 in the laboratory are laborious and time-consuming, and different laboratories use different approaches. There is therefore no generally agreed way to quantitate neutralising antibodies against SARS-CoV-2, which block infection with the virus and protect people from COVID-19. In this study, we describe a new way to measure SARS-CoV-2 infection, which is much simpler and faster than existing methods. It relies on the production of a specific protease enzyme by the virus, which is able to cleave and activate an engineered protein biosensor in infected cells. This biosensor emits light in the presence of viral infection, and the amount of light released is used as a readout for the amount of infectious SARS-CoV-2 present. The signal is very sensitive, so the number of infected cells required is very small, and the method can be scaled-up to test many samples at once. In particular, we demonstrate how it can be used to detect different variants of SARS-CoV-2, and quantitate neutralising antibodies against these viruses.
Live Imaging of SARS-CoV-2 Infection in Mice Reveals Neutralizing Antibodies Require Fc Function for Optimal Efficacy
Authors: Ullah Irfan , Prévost Jérémie , Ladinsky Mark S , Stone Helen , Lu Maolin , Anand Sai Priya , Beaudoin-Bussières Guillaume , Symmes Kelly , Benlarbi Mehdi , Ding Shilei , Gasser Romain , Fink Corby , Chen Yaozong , Tauzin Alexandra , Goyette Guillaume , Bourassa Catherine , Medjahed Halima , Mack Matthias , Chung Kunho , Wilen Craig B , Dekaban Gregory A. , Dikeakos Jimmy D. , Bruce Emily A. , Kaufmann Daniel E , Stamatatos Leonidas , McGuire Andrew T. , Richard Jonathan , Pazgier Marzena , Bjorkman Pamela J. , Mothes Walther , Finzi Andrés , Kumar Priti , Uchil Pradeep D.
Published: March 2021

Neutralizing antibodies (NAbs) are effective in treating COVID-19 but the mechanism of immune protection is not fully understood. Here, we applied live bioluminescence imaging (BLI) to monitor the real-time effects of NAb treatment in prophylaxis and therapy of K18-hACE2 mice intranasally infected with SARS-CoV-2-nanoluciferase. We could visualize virus spread sequentially from the nasal cavity to the lungs and thereafter systemically to various organs including the brain, which culminated in death. Highly potent NAbs from a COVID-19 convalescent subject prevented, and also effectively resolved, established infection when administered within three days. In addition to direct Fab-mediated neutralization, Fc effector interactions of NAbs with monocytes, neutrophils and natural killer cells were required to effectively dampen inflammatory responses and limit immunopathology. Our study highlights that both Fab and Fc effector functions of NAbs are essential for optimalin vivoefficacy against SARS-CoV-2.
Motion extrapolation in the flash-lag effect depends on perceived, rather than physical speed
Authors: Yook Jane , Lee Lysha , Vossel Simone , Weidner Ralph , Hogendoorn Hinze
Published: March 2021

In the flash-lag effect (FLE), a flash in spatiotemporal alignment with a moving object is misperceived as lagging behind the moving object. One proposed explanation for this illusion is based on predictive motion extrapolation of trajectories. In this interpretation, the diverging effects of velocity on the perceived position of the moving object suggest that FLE might be based on the neural representation of perceived, rather than physical, velocity. By contrast, alternative explanations based on differential latency or temporal averaging would predict that the FLE does not rely on such a representation of perceived velocity. Here we examined whether the FLE is sensitive to illusory changes in perceived speed that result in changes to perceived velocity, while physical speed is constant. The perceived speed of the moving object was manipulated using revolving wedge stimuli with variable pattern textures (Experiment 1) and luminance contrast (Experiment 2). The motion extrapolation interpretation would predict that the changes in FLE magnitude should correspond to the changes in the perceived speed of the moving object. In the current study, two experiments demonstrated that perceived speed and FLE magnitude increased in the dynamic pattern relative to the static pattern conditions, and that the same effect was found in the low contrast compared to the high contrast conditions. These results showed that manipulations of texture and contrast that are known to alter judgments of perceived speed also modulate perceived position. We interpret this as a consequence of motion extrapolation mechanisms and discuss possible explanations for why we observed no cross-effect correlation.