bluuebunny/crossref_metadata_2025 huggingface dataset:
Symbolic Solidarity or Virtue Signaling? A Critical Discourse Analysis of the Public Statements Released by Academic Medical Organizations in the Wake of the Killing of George Floyd
Authors: Brown Allison , Auguste Emmanuelle , Omobhude Favour , Bakana Naomie , Sukhera Javeed
Published: January 2022

Purpose

Many academic medical organizations issued statements in response to demand for collective action against racial injustices and police brutality following the murder of George Floyd in May 2020. These statements may offer insight into how medical schools and national organizations were reflecting on and responding to these incidents. The authors sought to empirically examine the initial statements published by academic medical organizations in response to societal concerns about systemic, anti-Black racism.

Method

The authors searched for initial public statements released by a sample of academic medical organizations in Canada and the United States between May 25 and August 31, 2020. They assembled an archive with a purposive sample of 45 statements, including those issued by 35 medical schools and 10 national organizations. They analyzed the statements using Fairclough’s 3-dimensional framework for critical discourse analysis (descriptive, interpretive, explanatory), which is a qualitative approach to systematically analyzing language and how it reflects and shapes social practice.

Results

Many statements used formal and analytical language and reflected hierarchical thinking and power differentials between statement producers and consumers. The authors identified several tensions in the statements between explicit messaging and implied ideologies (e.g., self-education vs action to address racism), and they found a lack of critical reflection and commitment to institutional accountability to address anti-Black racism in academic medicine. The authors also found that many statements minimized discussions of racism and de-emphasized anti-Black racism as well as portrayed anti-Black racism as outside the institution and institutional accountability.

Conclusions

This research offers insight into how 45 academic medical organizations initially responded following the murder of George Floyd. Many of these statements included self-exculpatory and nonracist discursive strategies. While these statements may have been well intentioned, organizations must move beyond words to transformative action to abolish institutional racism in academic medicine.
Impact of an Innovative Endowed Chair Program on Medical Educator Recipients
Authors: Chin-Hong Peter , Loeser Helen , Peterson Alissa , Ramachandran Rageshree , O’Sullivan Patricia S.
Published: January 2022

Purpose

Rarely do faculty members receive endowed chairs as recognition for their work as educators. In addition to the title, endowed chairholders have traditionally received discretionary income to pursue value-added work. This study assessed the impact on recipients of receiving an endowed chair for education.

Method

The authors conducted a qualitative thematic analysis between 2018 and 2020, interviewing University of California, San Francisco, School of Medicine chairholders who had completed at least one 5-year term. Authors double-coded all transcripts, reconciled codes, applied social cognitive career theory during analysis, and identified themes through an iterative consensus-building approach.

Results

Twenty-three of 24 (96%) eligible faculty members from 16 departments participated. Themes identified were symbolism, resources, education and educator credibility, development, and impact. The chair was a symbol that brought recognition, indicated quality, and amplified visibility and status within the institution and externally. Receiving an endowed chair conferred credibility on recipients and empowered them in the educational domain. The resources allowed chairholders the flexibility to undertake activities that were of value to them, to mentees, and to the organization. Holding the chair facilitated professional development for self and others. Chair recipients reported impact that persisted long after their term(s) concluded. A model of impact emerged, suggesting that simply possessing the chair title led to visibility and gravitas, which, combined with resources, allowed the holder to leverage opportunities in education.

Conclusions

The endowed chair is an important strategy for career development in education for the chairholder and enhances the position of education institutionally. Having a plan sharpens the focus on activities, results, and impact.
Educational Outcomes of a 4-Year MD–MPH Dual-Degree Program: High Completion Rates and Higher Likelihood of Primary Care Residency
Authors: Taylor Barbara S. , Mazurek Paulina H. , Gutierrez Stephanie , Tyson Joshua , Futrell Selina , Jackson Jeff , Hanson Joshua , Valerio Melissa A.
Published: January 2022

Purpose

In 2007, University of Texas Health Science Center Houston School of Public Health at San Antonio (UTHealth SPH) and UT Health San Antonio Long School of Medicine (LSOM) designed and implemented a 4-year dual MD and Master of Public Health (MPH) program. Dual MD–MPH programs wherein students can receive both degrees within 4 years are unique, and programmatic evaluation may have generalizable implications for accredited MD–MPH programs.

Method

Demographic information was collected from UTHealth SPH and LSOM student data. The primary outcome variable was MD–MPH program completion in 4 years. Comprehensive Basic Science Examination (CBSE) scores, United States Medical Licensing Examination Step 1 and Step 2 scores, and successful primary care residency match data were compared between MD–MPH and MD-only students. Family medicine, internal medicine, obstetrics–gynecology, and pediatrics were considered primary care residencies, and an analysis excluding obstetrics–gynecology was also conducted.

Results

Of 241 MD–MPH students enrolled 2007–2017, 66% were women, 22% Hispanic, and 10% African American. Four-year MD–MPH program completion occurred for 202 (93% of eligible) students; 9 (4.1%) received MD only, 3 (1.4%) received MPH only; and 4 (1.8%) received neither. MD–MPH students’ median CBSE score was 2 points lower than for MD-only students (P = .035), but Step 1 and 2 scores did not differ. Primary care residency match was more likely compared with MD-only students, both including and excluding obstetrics–gynecology (odds ratio [OR]: 1.75; 95% confidence interval [CI]: 1.31, 2.33; and OR: 1.36; 95% CI: 1.02, 1.82, respectively).

Conclusions

The 4-year MD–MPH program retains and graduates a socioeconomically and racial/ethnically diverse group of students with a 93% success rate. MD–MPH graduates were more likely to pursue primary care residency than non-dual-degree students, which may have implications for addressing population health disparities.
Femoroacetabular impingement in the unpinned contralateral hip in patients with primary unilateral slipped capital femoral epiphysis: preliminary radiographic outcomes
Authors: Kwiatkowska Magdalena , Kwiatkowski Marcin , Czubak-Wrzosek Maria , Czubak Jarosław , Tyrakowski Marcin
Published: January 2022

The study evaluated femoroacetabular impingement (FAI) in the unpinned contralateral hip in patients with unilateral slipped capital femoral epiphysis (SCFE) and verified initial age, posterior sloping angle (PSA) and center-edge angle (CEA) as predictors of FAI in the contralateral hip. 152 patients with unilateral SCFE with a mean index age of 13.2 years (8.2–17.2 years) were enrolled retrospectively into the study. Mean follow-up was 8 years (3–14 years). PSA and CEA were measured on initial radiographs of the unaffected hip. Alpha-angle and CEA were measured on radiographs taken at the last follow-up to identify FAI. Four groups of patients were distinguished: (1) no FAI (10 patients, 17.54%); (2) CAM-type FAI (41 patients, 71.9%); (3) pincer-type FAI (3 patients, 5.26%) and (4) mixed-type FAI (13 patients, 22.8%). The mean PSA was 12.1°, 12°, 16.8°, 11.9° for groups 1, 2, 3 and 4, respectively, with no significant difference (P = 0.65). The mean initial CEA for groups 1, 2, 3 and 4 was 34.4°, 35.5°, 42° and 42° respectively, with significant differences between groups 1 versus 4 (P = 0.034) and 2 versus 4 (P = 0.009). Conclusions are as follows: 1. Radiographic features of FAI were present in 85.1% of unpinned contralateral hips in patients with unilateral SCFE. 2. 71.9% of unpinned contralateral hips developed CAM deformity. 3. CEA can be used in predicting pincer-type FAI in the contralateral hip in unilateral SCFE. 4. PSA and age revealed negligible value in predicting FAI.
The role of lipotoxicity in cardiovascular disease
Authors: Li Chuanbao , Liu Huiruo , Xu Feng , Chen Yuguo
Published: January 2022

Fatty acids are the primary fuel for cardiac muscle. The physiological equilibrium of lipid uptake and oxidation may aid in the prevention of excessive lipid accumulation. Several pathological states, such as myocardial ischemia, obesity, and insulin resistance, are routinely associated with disorders of lipid metabolism. There is growing evidence that certain types of lipids trigger cardiac lipotoxicity and ultimately heart failure. This review focuses on recent advances in the pathogenesis of lipotoxic cardiomyopathy and the treatment prospects for the repair of cardiac damage caused by lipotoxicity.
Cannabinoid drugs against chemotherapy-induced adverse effects: focus on nausea/vomiting, peripheral neuropathy and chemofog in animal models
Authors: Bagues Ana , López-Tofiño Yolanda , Llorente-Berzal Álvaro , Abalo Raquel
Published: January 2022

Although new drugs are being developed for cancer treatment, classical chemotherapeutic agents are still front-line therapies, despite their frequent association with severe side effects that can hamper their use. Cannabinoids may prevent or palliate some of these side effects. The aim of the present study is to review the basic research which has been conducted evaluating the effects of cannabinoid drugs in the treatment of three important side effects induced by classical chemotherapeutic agents: nausea and vomiting, neuropathic pain and cognitive impairment. Several published studies have demonstrated that cannabinoids are useful in preventing and reducing the nausea, vomits and neuropathy induced by different chemotherapy regimens, though other side effects can occur, such as a reduction of gastrointestinal motility, along with psychotropic effects when using centrally-acting cannabinoids. Thus, peripherally-acting cannabinoids and new pharmacological options are being investigated, such as allosteric or biased agonists. Additionally, due to the increase in the survival of cancer patients, there are emerging data that demonstrate an important cognitive deterioration due to chemotherapy, and because the cannabinoid drugs have a neuroprotective effect, they could be useful in preventing chemotherapy-induced cognitive impairment (as demonstrated through studies in other neurological disorders), but this has not yet been tested. Thus, although cannabinoids seem a promising therapeutic approach in the treatment of different side effects induced by chemotherapeutic agents, future research will be necessary to find pharmacological options with a safer profile. Moreover, a new line of research awaits to be opened to elucidate their possible usefulness in preventing cognitive impairment.
Endothelial cell loss associated with minimally invasive glaucoma surgery
Authors: Seah Ivan , Sng Chelvin C.A. , Ang Marcus
Published: January 2022

Purpose of review

Minimally invasive glaucoma surgery (MIGS) represents a safer, albeit moderately effective surgical option for intraocular pressure control. However, the CyPass Micro-Stent (Alcon Laboratories) was withdrawn from the market in 2018 as the COMPASS-XT study demonstrated greater cornea endothelial cell (CEC) loss in patients who received the CyPass Micro-Stent with phacoemulsification compared with phacoemulsification alone. This led to the increased attention on MIGS-associated CEC loss and thus, this review will summarise the recent, available evidence on MIGS-associated CEC loss.

Recent findings

Prospective clinical trials and retrospective observational studies published between 2011 and 2021 reported a wide range of 12 month CEC loss from ‘insignificant’, and up to 14.6%, for phacoemulsification combined with various MIGS procedures. Recent clinical trials over the same time period reported CEC loss of 12.8–15.2% associated with phacoemulsification alone.

Apart from the CyPass Micro-Stent clinical trial, no other studies on combined phacoemulsification with MIGS that is ‘phaco-plus’ procedures have reported a higher short-term CEC loss compared with phacoemulsification alone. However, studies that specifically examine postprocedural CEC loss following phacoemulsification compared to ’phaco-plus’ procedures over a longer follow-up period are required.
Nandrolone-Induced Tumor Progression in Hormone-Sensitive Prostate Cancer
Authors: Goyal Shikha , Madan Renu , Kumar Narendra , Kumar Rajender
Published: January 2022

Hormone-sensitive prostate cancer responds favorably to testosterone suppression induced by GnRH analogs or antagonists. This effect may theoretically be countered by anabolic steroids. We describe a patient of a recurrent hormone-sensitive prostate cancer who was on salvage androgen deprivation therapy with degarelix and developed rapid progression after over-the-counter nandrolone injections.
OMENS+ Classification Correlations Analysis of Craniofacial Microsomia in China: The Relationship Between Macrostomia and Mandibular Hypoplasia
Authors: Kim Byeong Seop , Chen Xiaojun , Chen Chingyu , Chong Chio Hou , Yan Ying Jie , Han Wenqing , Sun Mengzhe , Yang Xianxian , Xu Hai Song , Zhang Yan , Chai Gang
Published: January 2022

Macrostomia is arare congenital craniofacial deformity that influences the appearance and function of patients. In most cases, it coexists with craniomaxillofacial deformities such as craniofacial microsomia (CFM). This study aimed to analyze the relationship between macrostomia and mandibular hypoplasia so as to facilitate the early detection and diagnosis of children with CFM. It included 236 patients diagnosed with CFM. All underwent facial expression analysis, multi-angle photography, computed tomography, and three-dimensional reconstruction of soft and hard tissues. The clinical classification was performed according to OMENS+. Spearman (rank) correlation analysis was used to analyze the relationship between the severity of macrostomia (C1 and C2) and the degree of mandibular involvement (M1, M2a, M2b, and M3), and the correlation among the components of OMENS+. Of the 80 cases of macrostomia (34%) reported, 72 cases (90%) were C1 and 8 (10%) were C2. The analysis of OMENS+ revealed significant correlations among OMENS+ components. Also, a high correlation was observed between macrostomia (C) and hypoplasia of the mandible (M) (P = 0.002). Macrostomia was closely related to mandibular hypoplasia among children diagnosed with CFM. These results suggested that patients with macrostomia, who might also have craniofacial malformations caused by other first branchial arch anomalies, should be comprehensively physically examined for other syndromes.
Effective connectivity determines the critical dynamics of biochemical networks
Authors: Manicka Santosh , Marques-Pita Manuel , Rocha Luis M.
Published: January 2022

Living systems comprise interacting biochemical components in very large networks. Given their high connectivity, biochemical dynamics are surprisingly not chaotic but quite robust to perturbations—a feature C.H. Waddington named canalization. Because organisms are also flexible enough to evolve, they arguably operate in acriticaldynamical regime between order and chaos. The established theory of criticality is based on networks of interacting automata where Boolean truth values model presence/absence of biochemical molecules. The dynamical regime is predicted using network connectivity and node bias (to be on/off) as tuning parameters. Revising this to account for canalization leads to a significant improvement in dynamical regime prediction. The revision is based oneffective connectivity, a measure of dynamical redundancy that buffers automata response to some inputs. In both random and experimentally validated systems biology networks, reducing effective connectivity makes living systems operate in stable or critical regimes even though the structure of their biochemical interaction networks predicts them to be chaotic. This suggests that dynamical redundancy may be naturally selected to maintain living systems near critical dynamics, providing both robustness and evolvability. By identifying how dynamics propagates preferably via effective pathways, our approach helps to identify precise ways to design and control network models of biochemical regulation and signalling.
Decision rules for determining terrestrial movement and the consequences for filtering high-resolution global positioning system tracks: a case study using the African lion (Panthera leo)
Authors: Gunner Richard M. , Wilson Rory P. , Holton Mark D. , Hopkins Phil , Bell Stephen H. , Marks Nikki J. , Bennett Nigel C. , Ferreira Sam , Govender Danny , Viljoen Pauli , Bruns Angela , van Schalkwyk O. Louis , Bertelsen Mads F. , Duarte Carlos M. , van Rooyen Martin C. , Tambling Craig J. , Göppert Aoife , Diesel Delmar , Scantlebury D. Michael
Published: January 2022

The combined use of global positioning system (GPS) technology and motion sensors within the discipline of movement ecology has increased over recent years. This is particularly the case for instrumented wildlife, with many studies now opting to record parameters at high (infra-second) sampling frequencies. However, the detail with which GPS loggers can elucidate fine-scale movement depends on the precision and accuracy of fixes, with accuracy being affected by signal reception. We hypothesized that animal behaviour was the main factor affecting fix inaccuracy, with inherent GPS positional noise (jitter) being most apparent during GPS fixes for non-moving locations, thereby producing disproportionate error during rest periods. A movement-verified filtering (MVF) protocol was constructed to compare GPS-derived speed data with dynamic body acceleration, to provide a computationally quick method for identifying genuine travelling movement. This method was tested on 11 free-ranging lions (Panthera leo) fitted with collar-mounted GPS units and tri-axial motion sensors recording at 1 and 40 Hz, respectively. The findings support the hypothesis and show that distance moved estimates were, on average, overestimated by greater than 80% prior to GPS screening. We present the conceptual and mathematical protocols for screening fix inaccuracy within high-resolution GPS datasets and demonstrate the importance that MVF has for avoiding inaccurate and biased estimates of movement.
Design of arbitrarily shaped acoustic cloaks through partial differential equation-constrained optimization satisfying sonic-metamaterial design requirements
Authors: Cominelli Sebastiano , Quadrelli Davide E. , Sinigaglia Carlo , Braghin Francesco
Published: January 2022

We develop an optimization framework for the design of acoustic cloaks, with the aim of overcoming the limitations of usual transformation-based cloaks in terms of microstructure complexity and shape arbitrarity of the obstacle. This is achieved by recasting the acoustic cloaking design as a nonlinear optimal control problem constrained by a linear elliptic partial differential equation. In this setting, isotropic material properties’ distributions realizing the cloak take the form of control functions and a system of the first-order optimality conditions is derived accordingly. Such isotropic media can then be obtained in practice with simple hexagonal lattices of inclusions in water. For this reason, the optimization problem is directly formulated to consider suitable partitions of the control domain. Two types of inclusions are analysed, and long-wavelength homogenization is used to define the feasible set of material properties that is employed as a constraint in the optimization problem. In this manner, we link the stage of material properties optimization with that of microstructure design, aiming at finding the optimal implementable solution. The resulting cloak is numerically tested via coupled structural/acoustic simulations. As a further test benchmark, a concave target and the silhouette of a ship are considered other than the usual axisymmetric cloak.
Evolutionary modularity, integration and disparity in an accretionary skeleton: analysis of venerid Bivalvia
Authors: Edie Stewart M. , Khouja Safia C. , Collins Katie S. , Crouch Nicholas M. A. , Jablonski David
Published: January 2022

Modular evolution, the relatively independent evolution of body parts, may promote high morphological disparity in a clade. Conversely, integrated evolution via stronger covariation of parts may limit disparity. However, integration can also promote high disparity by channelling morphological evolution along lines of least resistance—a process that may be particularly important in the accumulation of disparity in the many invertebrate systems having accretionary growth. We use a time-calibrated phylogenetic hypothesis and high-density, three-dimensional semilandmarking to analyse the relationship between modularity, integration and disparity in the most diverse extant bivalve family: the Veneridae. In general, venerids have a simple, two-module parcellation of their body that is divided into features of the calcium carbonate shell and features of the internal soft anatomy. This division falls more along developmental than functional lines when placed in the context of bivalve anatomy and biomechanics. The venerid body is tightly integrated in absolute terms, but disparity appears to increase with modularity strength among subclades and ecologies. Thus, shifts towards more mosaic evolution beget higher morphological variance in this speciose family.
Functionally distinct tree species support long-term productivity in extreme environments
Authors: Delalandre Léo , Gaüzère Pierre , Thuiller Wilfried , Cadotte Marc , Mouquet Nicolas , Mouillot David , Munoz François , Denelle Pierre , Loiseau Nicolas , Morin Xavier , Violle Cyrille
Published: January 2022

Despite evidence of a positive effect of functional diversity on ecosystem productivity, the importance of functionally distinct species (i.e. species that display an original combination of traits) is poorly understood. To investigate how distinct species affect ecosystem productivity, we used a forest-gap model to simulate realistic temperate forest successions along an environmental gradient and measured ecosystem productivity at the end of the successional trajectories. We performed 10 560 simulations with different sets and numbers of species, bearing either distinct or indistinct functional traits, and compared them to random assemblages, to mimic the consequences of a regional loss of species. Long-term ecosystem productivity dropped when distinct species were lost first from the regional pool of species, under the harshest environmental conditions. On the contrary, productivity was more dependent on ordinary species in milder environments. Our findings show that species functional distinctiveness, integrating multiple trait dimensions, can capture species-specific effects on ecosystem productivity. In a context of an environmentally changing world, they highlight the need to investigate the role of distinct species in sustaining ecosystem processes, particularly in extreme environmental conditions.
Positive-to-negative behavioural responses suggest hedonic evaluation in treefrog mate choice
Authors: Höbel Gerlinde , Rodríguez Rafael L.
Published: January 2022

Sexual competition hinges on the ability to impress other conspecifics, to drive them away or attract them. In such cases, the selective environment may be hedonic or affective in nature, as it consists of the evaluations of the individuals making the decisions. This may contribute to the power of sexual selection because evaluations may range from positive to negative rather than simply from positive to neutral. Selection due to mate choice may therefore be stronger than currently appreciated. Further, change in preferred mate types can occur simply by changes (flips) in the evaluation of similar display features, adding to the dynamism of sexual selection as well as its strength. We tested the hypothesis of positive-to-negative behavioural responses in mate choice with a playback experiment using two treefrog species with ‘mirror image’ structures in their advertisement and aggressive calls. Female treefrog responses ranged from approach to evasion, and the presence of an aversive stimulus tainted evaluation of an attractive stimulus. Further, females in the two species showed flips in approach/evasion of stimuli with comparable signal structure. These results suggest that hedonic evaluation may have an important role in mate choice and showcase how mechanistic analysis can help understand evolutionary processes.
Mitochondrial DNA content in eggs as a maternal effect
Authors: Kim Sin-Yeon , Chiara Violette , Álvarez-Quintero Náyade , Velando Alberto
Published: January 2022

The transmission of detrimental mutations in animal mitochondrial DNA (mtDNA) to the next generation is avoided by a high level of mtDNA content in mature oocytes. Thus, this maternal genetic material has the potential to mediate adaptive maternal effects if mothers change mtDNA level in oocytes in response to their environment or body condition. Here, we show that increased mtDNA abundance in mature oocytes was associated with fast somatic growth during early development but at the cost of increased mortality in three-spined sticklebacks. We also examined whether oocyte mtDNA and sperm DNA damage levels have interacting effects because they can determine the integrity of mitochondrial and nuclear genes in offspring. The level of oxidative DNA damage in sperm negatively affected fertility, but there was no interacting effect of oocyte mtDNA abundance and sperm DNA damage. Oocyte mtDNA level increased towards the end of the breeding season, and the females exposed to warmer temperatures during winter produced eggs with increased mtDNA copies. Our results suggest that oocyte mtDNA level can vary according to the expected energy demands for offspring during embryogenesis and early growth. Thus, mothers can affect offspring development and viability through the context-dependent effects of oocyte mtDNA abundance.
Parasite co-infection: an ecological, molecular and experimental perspective
Authors: Venter Frank , Matthews Keith R. , Silvester Eleanor
Published: January 2022

Laboratory studies of pathogens aim to limit complexity in order to disentangle the important parameters contributing to an infection. However, pathogens rarely exist in isolation, and hosts may sustain co-infections with multiple disease agents. These interact with each other and with the host immune system dynamically, with disease outcomes affected by the composition of the community of infecting pathogens, their order of colonization, competition for niches and nutrients, and immune modulation. While pathogen-immune interactions have been detailed elsewhere, here we examine the use of ecological and experimental studies of trypanosome and malaria infections to discuss the interactions between pathogens in mammal hosts and arthropod vectors, including recently developed laboratory models for co-infection. The implications of pathogen co-infection for disease therapy are also discussed.
Reef environments shape microbial partners in a highly connected coral population
Authors: Kriefall N. G. , Kanke M. R. , Aglyamova G. V. , Davies S. W.
Published: January 2022

Evidence is mounting that composition of microorganisms within a host can play an essential role in total holobiont health. In corals, for instance, studies have identified algal and bacterial taxa that can significantly influence coral host function and these communities depend on environmental context. However, few studies have linked host genetics to algal and microbial partners across environments within a single coral population. Here, using 2b-RAD sequencing of corals and metabarcoding of their associated algal (ITS2) and bacterial (16S) communities, we show evidence that reef zones (locales that differ in proximity to shore and other environmental characteristics) structure algal and bacterial communities at different scales in a highly connected coral population (Acropora hyacinthus) in French Polynesia. Fore reef (FR) algal communities in Mo'orea were more diverse than back reef (BR) communities, suggesting that these BR conditions constrain diversity. Interestingly, in FR corals, host genetic diversity correlated with bacterial diversity, which could imply genotype by genotype interactions between these holobiont members. Our results illuminate that local reef conditions play an important role in shaping unique host–microbial partner combinations, which may have fitness consequences for dispersive coral populations arriving in novel environments.
ASGR1 is a candidate receptor for SARS-CoV-2 that promotes infection of liver cells
Authors: Yang Xinyi , Zhu Yuqi , Zhao Xiaying , Liu Jun , Xun Jiangna , Yuan Songhua , Chen Jun , Pan Hanyu , Yang Jinlong , Wang Jing , Liang Zhimin , Shen Xiaoting , Liang Yue , Lin Qinru , Liang Huitong , Li Min , Lu Hongzhou , Zhu Huanzhang
Published: January 2022

Backgroud & Aims

Currently, the COVID-19 pandemic, caused by SARS-CoV-2 infection, represents a serious public health problem worldwide. Although it has been shown that ACE2 serves as the main receptor for SARS-CoV-2 entry into host cells, studies have shown that ACE2 is expressed at extremely low levels in various tissues, especially in some organs where virus particles have been found, such as the heart and liver. Therefore, these organs potentially express additional SARS-CoV-2 receptors that have not yet been discovered.

Methods & Results

Here, by a genome-wide CRISPR-Cas9 activation library screening, we found that ASGR1 promoted SARS-CoV-2 infection of 293T cells. In Huh-7 and HepG2 cell lines, simultaneous knock out ofACE2andASGR1prevented SARS-CoV-2 pseudovirus infection. In the immortalized THLE-2 hepatocyte cell line and primary liver parenchymal cells, both of which hardly express ACE2, SARS-CoV-2 could successfully establish an infection. After treatment with ASGR1 antibody, the infection rate significantly reduced. This suggests that SARS-CoV-2 infects liver cells mainly through an ASGR1-dependent mechanism. Finally, we also found that the soluble ASGR1 could not only prevent the SARS-CoV-2 pseudovirus, which binds to the ASGR1 receptors, from infecting host liver cells, but also had a protective effect on those expressing ACE2, indicating that administration of soluble ASGR1 protein may represent a new treatment approach.

Conclusions

Colletively, these findings indicate that ASGR1 is a candidate receptor for SARS-CoV-2 that promotes infection of liver cells.

Lay Summary

We show that ASGR1 is a candidate receptor for SARS-CoV-2 to infect liver cells.
Artificial Intelligence in laryngeal endoscopy: Systematic Review and Meta-Analysis
Authors: Żurek Michał , Rzepakowska Anna , Jasak Kamil , Niemczyk Kazimierz
Published: January 2022

Background

Early and proper diagnosis of laryngeal lesions is necessary to begin treatment of the patient as soon as possible with the possibility of preserve organ functions. Imaging examinations are oft aided by artificial intelligence (AI) to improve quality and facilitate appropriate diagnosis. The aim of the study is to investigate of the diagnostic utility of AI in laryngeal endoscopy.

Methods

Five electronic databases (PubMed, Embase, Cochrane, Scopus, Web of Science) were searched for studies published before October 15, 2021 implementing artificial intelligence (AI) enhanced models assessing images of laryngeal lesions taken during laryngeal endoscopy. Outcomes were analyzed in terms of accuracy, sensitivity and specificity.

Results

All 13 included studies presented overall low risk of bias. The overall accuracy of AI models was very high (from 0.806 to 0.997) and the number of images used to build and evaluate the models ranged from 120 to 24,667. The accuracy was significantly higher in studies using larger database. The pooled sensitivity and specificity for identification of healthy laryngeal tissue (8 studies) was 0.91 (95% CI: 0.83-0.98) and 0.97 (95% CI: 0.96-0.99), respectively. The same values for differentiation between benign and malignant lesions (7 studies) were 0.91 (95% CI: 0.86-0.96) and 0.95 (95% CI: 0.90-0.99), respectively. The analysis was extended to a comparison of sensitivity and specificity of AI models assessing Narrow Band Imaging (3 studies) and white light endoscopy images (4 studies). The results were similar for both methods, no subgroup effect was revealed (p = 0.406 for sensitivity and p = 0.817 for specificity).

Conclusions

In assessing images of laryngeal lesions, AI demonstrates extraordinarily high accuracy, sensitivity, and specificity. AI enhanced diagnostic tools should be introduced into everyday clinical work. The performance of AI diagnoses increases efficacy with the size of the image database when using similar standards for evaluating images. The multicentre cooperation should concentrate on creation of huge database of laryngeal lesions images and implement their sharing, which allows building AI modes with the best performance, based on vast amount of images for learning and testing.
NestedBD: Bayesian Inference of Phylogenetic Trees From Single-Cell DNA Copy Number Profile Data Under a Birth-Death Model
Authors: Liu Yushu , Edrisi Mohammadamin , Ogilvie Huw A. , Nakhleh Luay
Published: January 2022

Copy number aberrations (CNAs) are ubiquitous in many types of cancer. Inferring CNAs from cancer genomic data could help shed light on the initiation, progression, and potential treatment of cancer. While such data have traditionally been available via “bulk sequencing”, the more recently introduced techniques for single-cell DNA sequencing (scDNAseq) provide the type of data that makes CNA inference possible at the single-cell resolution.

In this paper, we introduce a new birth-death evolutionary model of CNAs as well as a Bayesian method, NestedBD, for the inference of evolutionary trees (topologies and branch lengths with relative mutation rates) from single-cell data under this model. We assessed the accuracy of our method on both simulated and biological data and compared it to the accuracy of two standard phylogenetic tools, namely neighbor-joining and maximum parsimony (MP). We show through simulations that our method infers more accurate topologies and branch lengths. We also studied the ancestral state reconstruction accuracy with the birth-death evolutionary model and found it outperformed MP. Finally, running all three methods on a colorectal cancer data set, we observed that among all three methods, only the phylogeny inferred by NestedBD clearly separated the primary tumor cells from the metastatic ones, providing a more plausible history of the tumor cells.
Neuroanatomical correlates of polygenic risk for Parkinson’s Disease
Authors: Abbasi Nooshin , Tremblay Christina , Rajimehr Reza , Yu Eric , Markello Ross D , Shafiei Golia , Khatibi Nina ,   The ENIGMA-Parkinson’s study, Jahanshad Neda , Thompson Paul M. , Gan-Or Ziv , Misic Bratislav , Dagher Alain
Published: January 2022

Parkinson ‘s Disease (PD) is heritable, however how genetic risk confers vulnerability remains mostly unknown. Here we use genetic and neuroimaging measures from 20,000 healthy adults from the UK Biobank to show that PD polygenic risk score (PRS) is associated with cortical thinning in a pattern that resembles cortical atrophy seen in PD. Conversely, PD PRS is associated with a global increase in cortical surface area. We also show that the genetically determined cortical thinning profile overlaps with the expression of genes associated with synaptic signaling, is dependent on anatomical connectivity and on regional expression of the most significant PD risk genes. Despite identical PRS distributions in males and females, only males show the associated brain features, possibly explaining the sex disparity in PD. We discuss potential mechanisms linking genetic risk to cortical thickness and surface area, and suggest that the divergent effects may reflect separate routes of genetic vulnerability.
EXTRACELLULAR MATRIX REMODELING IN ATOPIC DERMATITIS HARNESSES THE ONSET OF AN ASTHMATIC PHENOTYPE AND IS A POTENTIAL CONTRIBUTOR TO THE ATOPIC MARCH
Authors: Graff Patrick , Wilzopolski Jenny , Voss Anne , Blimkie Travis M. , Weiner January , Kershaw Olivia , Panwar Preety , Hackett Tillie , Brömme Dieter , Loyal Lucie , Thiel Andreas , Beule Dieter , Hancock Robert E.W. , Gruber Achim D. , Bäumer Wolfgang , Hedtrich Sarah
Published: January 2022

The development of atopic dermatitis (AD) in infancy, and subsequent allergic rhinitis, food allergies, and asthma in later childhood, is known as the atopic march. The mechanism is largely unknown, yet the course of disease indicates the contribution of inter-epithelial crosstalk, through to the onset of inflammation in the skin and progression to another mucosal epithelium.

Here, we investigated if and how skin-lung epithelial crosstalk could contribute to the development of the atopic march. First, we emulated this inter-epithelial crosstalk through indirect co-culture of bioengineered atopic-like skin disease models and three-dimensional bronchial epithelial models triggering an asthma-like phenotype in the latter. A subsequent secretome analysis identified throm-bospondin-1, CD44, complement factor C3, fibronectin, and syndecan-4 as potentially relevant skin-derived mediators. As these mediators are extracellular matrix (ECM)-related proteins, we then studied the involvement of the ECM, unveiling distinct proteomic, transcriptomic, and ultrastructural differences in atopic samples. The latter indicated ECM remodeling triggering the release of the above-mentioned mediators. In addition to pro-inflammatory effects in lung tissue, the ECM mediators also exert distinct effects on CD4+ T cells. In vivo mouse data showed that exposure to these mediators over seven days dysregulated activated circadian clock genes which have been previously discussed in the context of atopic diseases and asthma development.

We hypothesize the existence of a skin-lung axis that could contribute to the atopic march driven by skin ECM remodeling.

One Sentence Summary

Atopic skin harbors the progression of atopic diseases to lung tissue through a skin-lung axis that contributes to the atopic march via extracellular matrix remodeling.
SUMO/deSUMOylation of the BRI1 brassinosteroid receptor modulates plant growth responses to temperature
Authors: Naranjo-Arcos Maria , Srivastava Moumita , Bhardwarj Mansi , Sadanandom Ari , Vert Grégory
Published: January 2022

Brassinosteroids (BRs) are a class of steroid molecules perceived at the cell surface that act as plant hormones. The BR receptor BRI1 offers a model to understand receptor-mediated signaling in plants and the role of post-translational modifications. Here we identify SUMOylation as a new modification, targeting BRI1 to regulate its activity. BRI1 is SUMOylated in planta on two lysine residues and the levels of BRI1-SUMO conjugates are controlled by the Desi3a SUMO protease. We demonstrate that BRI1 is deSUMOylated at elevated temperature by Desi3a, leading to increased BRI1 interaction with the negative regulator of BR signaling BIK1 and enhancing BRI1 endocytosis. Loss of Desi3a or BIK1 results in increased response to temperature elevation, indicating that BRI1 deSUMOylation acts as a safety mechanism necessary to keep temperature responses in check. Altogether, our work establishes BRI1 deSUMOylation as a molecular crosstalk mechanism between temperature and BR signaling, allowing plants to translate environmental inputs into growth response.

SIGNIFICANCE STATEMENT

The brassinosteroid (BR) receptor BRI1 provides a paradigm for understanding receptor-mediated signaling in plants and contribution of post-translational modifications. Here, we show that BRI carries SUMO modifications in planta on two intracellular lysine residues and that temperature elevation triggers BRI1 deSUMOylation mediated by the Desi3a SUMO protease. Importantly, BRI1 deSUMOylation leads to downregulation of BR signaling via increased BRI1 interaction with the BIK1 negative regulator and increased BRI1 endocytosis. Loss of BRI1 deSUMOylation in desi3a mutants boosts plant responses to heat, indicating that BRI1 deSUMOylation acts as a brake to keep temperature responses in check. Our study uncovers a new post-translational modification targeting BRI1 and sheds light on its functional outcome for environmentally-controlled plant growth.
Nirmatrelvir, an orally active Mpro inhibitor, is a potent inhibitor of SARS-CoV-2 Variants of Concern
Authors: Rai Devendra K. , Yurgelonis Irina , McMonagle Patricia , Rothan Hussin A. , Hao Li , Gribenko Alexey , Titova Elizabeth , Kreiswirth Barry , White Kris M. , Zhu Yuao , Anderson Annaliesa S. , Cardin Rhonda D.
Published: January 2022

New variants of SARS-CoV-2 with potential for enhanced transmission, replication, and immune evasion capabilities continue to emerge causing reduced vaccine efficacy and/or treatment failure. As of January 2021, the WHO has defined five ‘variants of concern’ (VOC): B.1.1.7 (Alpha, α), B.1.351 (Beta, β), P.1 (Gamma, γ), B.1.617.2 (Delta, δ), and B.1.1.529 (Omicron, o). To provide a therapeutic option for the treatment of COVID-19 and variants, Nirmatrelvir, the antiviral component of PAXLOVID™, an oral outpatient treatment recently authorized for conditional or emergency use treatment of COVID-19, was developed to inhibit SARS-CoV-2 replication. Nirmatrelvir (PF-07321332) is a specific inhibitor of coronavirus main protease (Mpro, also referred to as 3CLpro), with potent antiviral activity against several human coronaviruses, including SARS-CoV-2, SARS-CoV, and MERS (Owen et al, Science 2021. doi: 10.1126/science.abl4784). Here, we evaluated PF-07321332 against the five SARS-CoV-2 VOC (α, β, γ, δ,, o) and two Variants of Interest or VOI, C.37 (λ) and B.1.621 (μ), using qRT-PCR in VeroE6 cells lacking the P-glycoprotein (Pgp) multidrug transporter gene (VeroE6 P-gp knockout cells). Nirmatrelvir potently inhibited USA-WA1/2020 strain, and α, β, γ, λ, δ, μ, and o variants in VeroE6 P-gp knockout cells with mean EC50 values 38.0 nM, 41.0 nM, 127.2 nM, 24.9 nM, 21.2 nM, 15.9 nM, 25.7 nM and 16.2 nM, respectively. Sequence analysis of the Mpro encoded by the variants showed ~100% identity of active site amino acid sequences, reflecting the essential role of Mpro during viral replication leading to ability of Nirmatrelvir to exhibit potent activity across all the variants.
Systematic histone H4 replacement inArabidopsis thalianareveals a role for H4R17 in regulating flowering time
Authors: Corcoran Emma Tung , LeBlanc Chantal , Tsang Mia Arias , Sarkiss Anthony , Hu Yuzhao , Pedmale Ullas V. , Jacob Yannick
Published: January 2022

Despite the broad array of roles for epigenetic mechanisms on regulating diverse processes in eukaryotes, no experimental system for the direct assessment of histone function is currently available in plants. In this work, we present the development of a genetic strategy inArabidopsis thalianain which modified H4 transgenes can completely replace the expression of endogenous histone H4. Using this strategy, we established a collection of plants expressing different H4 point mutants targeting residues that may be post-translationally modifiedin vivo. To demonstrate the utility of this new H4 mutant collection, we screened it to uncover substitutions in H4 that alter flowering time. We identified different mutations in the tail (H4R17A) and the globular domain (H4R36A, H4R39K, H4R39A, and H4K44A) of H4 that strongly accelerate the floral transition. Furthermore, we found a conserved regulatory relationship between H4R17 and the ISWI chromatin remodeling complex in plants. Similar to other biological systems, H4R17 regulates nucleosome spacing via ISWI. Overall, this work provides a large set of H4 mutants to the plant epigenetics community that can be used to systematically assess histone H4 function inA. thalianaand a roadmap to replicate this strategy for studying other histone proteins in plants.
Central tolerance is impaired in the middle-aged thymic environment
Authors: Lancaster Jessica N. , Keatinge-Clay Damaris L. , Srinivasan Jayashree , Li Yu , Selden Hilary J. , Nam Seohee , Richie Ellen R. , Ehrlich Lauren I. R.
Published: January 2022

One of the earliest hallmarks of immune aging is thymus involution, which not only reduces the number of newly generated and exported T cells, but also alters the composition and organization of the thymic microenvironment. Thymic T-cell export continues into adulthood, yet the impact of thymic involution on the quality of newly generated T-cell clones is not well established. Notably, the number and proportion of medullary thymic epithelial cells (mTECs) and expression of tissue restricted antigens (TRAs) decline with age, suggesting the involuting thymus may not promote efficient central tolerance. Here, we demonstrate that the middle-aged thymic environment does not support rapid motility of medullary thymocytes, potentially diminishing their ability to scan antigen presenting cells that display the diverse self-antigens that induce central tolerance. Consistent with this possibility, thymic slice assays reveal that the middle-aged thymic environment does not support efficient negative selection or regulatory T cell (Treg) induction of thymocytes responsive to either TRAs or ubiquitous self-antigens. This decline in central tolerance is not universal, but instead impacts lower-avidity self-antigens that are either presented at low levels or bind to TCRs with moderate affinities. Additionally, the decline in thymic tolerance by middle-age is accompanied by both a reduction in mTECs and hematopoietic antigen presenting cell subsets that cooperate to drive central tolerance. Thus, age-associated changes in the thymic environment result in impaired central tolerance against moderate avidity self-antigens, potentially resulting in export of increasingly autoreactive naive T cells, with a deficit of Treg counterparts by middle age.