bluuebunny/crossref_metadata_2025 huggingface dataset:
MYC Alteration by Chromothripsis Event in Aggressive High-Grade B-Cell Lymphoma Negative by Conventional Fluorescence In Situ Hybridization Analysis: A Case Report
Authors: Sukhanova Madina , Van Slambrouck Charles , Yap Kai Lee , Smith Sonali M. , Gurbuxani Sandeep , Venkataraman Girish
Published: January 2022

Double-hit and double-expressor phenotypes in lymphomas are characterized by activation of the expression of the MYC and BCL2 genes through diverse mechanisms including chromosomal translocations and amplifications. Herein, we report a high-grade B-cell lymphoma in a patient with evidence for a chromothripsis event (via chromosomal microarray methodology) at chromosome 8, resulting in a focal copy number gain of the MYC locus, not detected by conventional fluorescence in situ hybridization for MYC despite strong MYC expression by immunohistochemical analysis. Chromosome analysis from the biopsy was not successful because of an extensive tissue necrosis. Chromothripsis is suggested as another mechanism for the activation of MYC in non-Hodgkin lymphoma, resulting in aggressive disease course, and this case underscores the need for chromosomal microarray testing in select cases to identify aggressive biology.
Unusual Presentation of Myeloid Sarcoma in a Patient With Usher Syndrome
Authors: Barron Cynthia Reyes , Crane Genevieve Marie
Published: January 2022

A 45-year-old woman with Usher syndrome, associated congenital deafness, progressive blindness due to retinitis pigmentosa, and latent autoimmune diabetes presented to the emergency department with malaise, dizziness, and pelvic pain following removal of an intrauterine device. A posterior vaginal wall mass was found on examination. Laboratory values demonstrated anemia, thrombocytopenia, and an elevated white blood cell count, raising concern for infection and potential onset of diabetic ketoacidosis. This prompted a peripheral blood smear review, which showed 60% monocytic blasts. A subsequent vaginal mass biopsy showed a myeloid sarcoma. Molecular studies demonstrated an NPM1 mutation in exon 12 without FLT3 mutation or internal tandem duplication. While a diagnosis of acute myeloid leukemia with mutated NPM1 was considered, cytogenetics revealed a complex karyotype with evidence of clonal evolution, consistent with acute myeloid leukemia with myelodysplasia-related changes. In addition to an unusual presentation of myeloid sarcoma, this case posed significant questions regarding management and pursuit of hematopoietic stem cell transplantation. Usher syndrome is genetically and clinically heterogeneous. While it is not known to be associated with increased risk of malignancy, mutation of genes associated with Usher syndrome has been identified in acute leukemia. Our case raises the question as to whether potential germline predisposition should be considered in a patient with a previously unassociated congenital syndrome.
Tips and Tricks for Facial Toxin Injections with Illustrated Anatomy
Authors: Swift Arthur , Green Jeremy B. , Hernandez Claudia A. , Aguilera Shino Bay , Fagien Steven , Gold Michael H. , Casabona Gabriela , Frank Konstantin , Nikolis Andreas , Cotofana Sebastian
Published: January 2022

Learning Objectives:

After studying this article, the participant should be able to: 1. Recognize facial muscle contraction direction and muscle morphology based on skin surface movements and facial rhytides. 2. Classify different muscle contraction patterns and target respectively with the recommended dosage and injection technique. 3. Apply the presented injection techniques to the patients’ individual anatomy with greater precision and without affecting adjacent muscles or causing other adverse events.

Facial muscular anatomy has recently gained increased attention, with new investigative methodologies and new injection techniques arising on the market. These recent advancements have increased our understanding about the functional anatomy of facial muscles and have changed the way health care professionals see and understand their interplay during various facial expressions and in determining facial shape. This new anatomical understanding of facial muscles and their interaction has resulted in superior neuromodulator treatment outcomes with fewer side effects and with increased precision. The latter is of greatest importance, as all facial muscles act as a unit and connect with each other. It is therefore paramount to target during neuromodulator treatments only the muscle responsible for the aesthetic effect desired and not other adjacent muscles, which can have different or even antagonistic effects. Conventional anatomy was previously limited to two-dimensional explanations of muscle locations without incorporating their detailed action or their three-dimensional location of extent. The “new” anatomy incorporates those novel concepts and, once understood, will help health care providers to understand better and to “read” the underlying muscular anatomy based on the wrinkle status and based on the change in skin surface landmarks based on the actions of the underlying musculature. The following article summarizes tips and tricks, pearls and pitfalls, and dos and don’ts during facial neuromodulator injections along with a guide toward adverse event management and patient outcome assessment with special focus on the underlying anatomy.
Extensor Pollicis Brevis Transosseous Tenodesis Technique for Treatment of Acquired Metacarpophalangeal Hyperextension Deformity of the Thumb: A Preliminary Report
Authors: Hernández-Cortés Pedro , Hernández-Peregrina Pedro , Pajares-López Miguel , Cigna Emanuele , Sánchez-Montesinos Indalecio , Roda Olga
Published: January 2022

Hyperextension deformity of the metacarpophalangeal joint of the thumb causes pain and loss of function. Although many treatments have been proposed, none of them are universally accepted as ideal. The authors report a study of 12 symptomatic hyperextension deformities of the thumb metacarpophalangeal joint in 10 patients who underwent surgical correction. The purpose of this study was to describe a new technique of tenodesis of the thumb metacarpophalangeal joint using the extensor pollicis brevis tendon. The technique consists of extensor pollicis brevis tenotomy at the wrist and tendon transfer through two bone tunnels to the palmar aspect of the metacarpophalangeal joint before metacarpal fixation with a flexor tenodesis effect. Correction of hyperextension and range of motion were assessed. Functional changes were evaluated by Quick Disabilities of the Arm, Shoulder, and Hand score, pain visual analogue scale, Kapandji opposition scheme, and pinch strength. The Wilcoxon test was used for statistical analysis. Mean preoperative and postoperative metacarpophalangeal joint hyperextension deformities were +50.83 ± 5.57 degrees and −17.91 ± 7.82 degrees, respectively. Thumb opposition improved by one point on Kapandji’s scheme. Mean perceived pain decreased from 7.66 to 1.16. On average, the Quick Disabilities of the Arm, Shoulder, and Hand score was reduced by 34.4 points and pinch strength increased by 50.42 percent. The authors found that extensor pollicis brevis transosseous tenodesis is a safe and minimally invasive method for successfully correcting the functionality and cosmetic appearance of metacarpophalangeal joint hyperextension deformities in posttraumatic and trapeziometacarpal osteoarthritis cases. The patients retained functional active flexion, even in deformities greater than 40 degrees.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Perforating Fat Injections for Chronic Plantar Fasciitis: A Randomized, Crossover Clinical Trial
Authors: Gusenoff Beth R. , Minteer Danielle , Gusenoff Jeffrey A.
Published: January 2022

Plantar fasciitis affects 2 million patients per year. Ten percent of cases are chronic, with thickened plantar fascia. Treatment may lead to prolonged recovery, foot instability, and scar. The authors hypothesized that perforating fat injections would decrease plantar fascia thickness, reduce pain, and improve quality of life. Adults with plantar fascia greater than 4 mm for whom standard treatment had failed were included in a prospective, randomized, crossover pilot study. Group 1 (intervention) was followed for 12 months. Group 2 was observed for 6 months, injected, and then followed for 6 months. Validated patient reported outcome measures, ultrasound, and complications were assessed. Group 1 had nine female patients and group 2 had five patients. A total of 2.6 ± 1.6 ml of fat was injected per foot at one to two sites. In group 1, plantar fascia thickness decreased from screening at 6 and 12 months (p < 0.05). Group 2 had decreased plantar fascia thickness from screening to 6 months after injection (p < 0.05). Group 1 had pain improvements at 6 and 12 months compared with screening (p < 0.01). Group 2 reported no pain difference after injections (p > 0.05). Group 1 had improved activities of daily living and sports activity at 6 and 12 months compared with screening (p < 0.003). Group 2 noted increased sports activity 6 months after injection compared with screening (p < 0.03). In conclusion, perforating fat injections for chronic plantar fasciitis demonstrate significant improvement in pain, function, and plantar fascia thickness.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, II.
Diversity in Plastic Surgery Authorship: A 14-Year Analysis of 2688 Articles Published in Plastic and Reconstructive Surgery
Authors: Gunderson Kirsten A. , Edalatpour Armin , Wood Kasey Leigh , Nkana Zeeda H. , Bentz Michael L. , Afifi Ahmed M.
Published: January 2022

Background:

Publication in peer-reviewed journals is a duty and privilege. It is essential to the advancement of evidence-based medicine and often used as a proxy for academic achievement, contributing to decisions around promotion in academia. Within plastic surgery, authors have historically been male surgeons affiliated with academic institutions, lacking representation of women, private practice, medical students, and international collaboration. This study analyzes differences in authors’ gender, practice affiliation, degree of education, and international collaboration in articles published in Plastic and Reconstructive Surgery, which was chosen as the representative journal given its high impact factor (3.946) and consistent ranking as the number one journal in plastic surgery worldwide.

Methods:

A list of Breast, Cosmetic, and Hand/Peripheral Nerve articles published between 2006 and 2019 was compiled from the online archive of Plastic and Reconstructive Surgery. Demographic author characteristics were recorded, and statistical analyses were performed to identify trends over time.

Results:

A total of 2688 articles were analyzed. The proportion of articles written by female authors in the Breast category, authors in private practice with academic affiliation in the Cosmetic section, and U.S. collaboration with other countries increased over time (p = 0.038, p = 0.029, p < 0.001, respectively). First authors with bachelor’s, master’s, and doctorate degrees have also been contributing increasingly.

Conclusions:

This analysis revealed increasing demographic heterogeneity of authors in Plastic and Reconstructive Surgery over time, with increasing contributions from women, surgeons in private practice with academic affiliation, medical students, and international collaborations. The Journal is capturing contributions from an increasingly diverse authorship, consistent with the changing demographics of plastic surgeons.
Wealth Management and Retirement
Authors: Turin Sergey Y. , Fine Peter , Fine Neil
Published: January 2022

The purpose of this publication is to introduce basic financial planning concepts and highlight their use in creating a retirement savings plan. These tools may help young surgeons set their financial targets and create a plan to meet them, whereas surgeons later in their careers may reflect on their choices and implement adjustments, or be inspired to pass on the lessons they learned to the next generation. This publication is limited by design and should be thought of as a primer, not a comprehensive treatise. The topic of personal financial management is as vague as it is broad, and there are many concepts and situations that are outside the scope of this publication. Unique goals, income and expense streams, and risk tolerances necessitate individualized solutions, but there are fundamental concepts listed below that are more universally applicable. The discussion is tailored to the high income stream that plastic surgeons can expect, albeit one that starts relatively late in their careers compared to nonphysician colleagues. There are three foundational principles the reader should take away: having a plan is crucial in achieving any financial goal; starting any savings/investment endeavors as early as possible is as or more important than the amount of capital committed to them; and lastly, individual investors (professional and amateur) have consistently demonstrated an inability to consistently do better than the market over the long run.
Salegentibacter lacus sp. nov. and Salegentibacter tibetensis sp. nov., isolated from hypersaline lakes on the Tibetan Plateau
Authors: Lu Huibin , Gao Peixin , Phurbu Dorji , Wu Qinglong L. , Xing Peng
Published: January 2022

Two Gram-stain-negative, catalase- and oxidase-positive, rod-shaped and non-motile strains (LM13ST and JZCK2T) were isolated from hypersaline lakes in China. The colonies of both strains were yellow-pigmented and convex. Both strains could grow at 4–34 °C, pH 6.5–9.0 and with 1.0–13.0 % (w/v) NaCl. Comparisons based on 16S rRNA gene sequences showed that strains LM13ST and JZCK2T share less than 98.3 % similarity with species of the genus

Salegentibacter

. The phylogenetic tree reconstructed based on 16S rRNA gene sequences also showed that

Salegentibacter

species are the most closely related neighbours of strains LM13ST and JZCK2T. The sequenced draft genome sizes of strains LM13ST and JZCK2T are 4.06 and 4.22 Mbp with G+C contents of 37.0 and 37.8 mol%, respectively. The phylogenomic tree reconstructed using the Up-to-date Bacterial Core Gene set pipeline also demonstrated that both strains belong to the genus

Salegentibacter

. The calculated pairwise average nucleotide identity values and digital DNA–DNA hybridization values between strains LM13ST and JZCK2T and

Salegentibacter

species were less than 86.4 and 32.0 %, respectively. The respiratory quinone in both strains was MK-6. Their major fatty acids were iso-C12 : 0, iso-C14 : 0, C15 : 1
 ω10c, iso-C15 : 0, anteiso-C15 : 0, iso-C16 : 0 and C17 : 1
 ω10c. Their major polar lipids included phosphatidylethanolamine, one unidentified lipid and one unidentified aminolipid, but strain LM13ST also contained one more unidentified aminolipid, one more unidentified lipid and one unidentified phospholipid. Combining the above descriptions, strains LM13ST and JZCK2T should represent two independent novel species of the genus

Salegentibacter

, for which the names Salegentibacter lacus sp. nov. (type strain LM13ST=GDMCC 1.2643T=KCTC 82861T) and Salegentibacter tibetensis sp. nov. (type strain JZCK2T=GDMCC 1.2621T=KCTC 82862T) are proposed.
The promiscuous and highly mobile resistome of Acinetobacter baumannii
Authors: Hernández-González Ismael L , Mateo-Estrada Valeria , Castillo-Ramirez Santiago
Published: January 2022

Antimicrobial resistance (AR) is a major global threat to public health. Understanding the population dynamics of AR is critical to restrain and control this issue. However, no study has provided a global picture of the whole resistome of

Acinetobacter baumannii

, a very important nosocomial pathogen. Here we analyse 1450+ genomes (covering >40 countries and >4 decades) to infer the global population dynamics of the resistome of this species. We show that gene flow and horizontal transfer have driven the dissemination of AR genes in

A. baumannii

. We found considerable variation in AR gene content across lineages. Although the individual AR gene histories have been affected by recombination, the AR gene content has been shaped by the phylogeny. Furthermore, many AR genes have been transferred to other well-known pathogens, such as

Pseudomonas aeruginosa

or

Klebsiella pneumoniae

. Despite using this massive data set, we were not able to sample the whole diversity of AR genes, which suggests that this species has an open resistome. Our results highlight the high mobilization risk of AR genes between important pathogens. On a broader perspective, this study gives a framework for an emerging perspective (resistome-centric) on the genomic epidemiology (and surveillance) of bacterial pathogens.
Integrating Math Modeling, Coding, and Biology in a CURE Lab
Authors: Dale Renee , Craig Stewart
Published: January 2022

The development of mathematical and quantitative skills is increasingly critical for biology students. Literacy in coding, statistics, and mathematical modeling enables students to engage in systems-thinking and the analysis of large data sets. Here we present a flexible tool illustrating concepts in mathematical modeling, coding, and biology for integration into both traditional ‘cookbook’ and inquiry-driven labs for freshmen biology students. We developed simple and complex mathematical models of potato catechol oxidase, a popular system to teach enzyme kinetics in undergraduate biology labs. We integrated both models into a freely-available web app for simulation and parameter estimation. The models are usable even if experimental details are unknown or poorly controlled, so that even novice students can work through the problem. We illustrate this by estimating the kinetic parameters of catechol oxidase in the complex model using data obtained from two sections of a course-based undergraduate research experience (CURE) freshman biology lab. Worksheets with questions motivating model building and simulation comprehension are provided. The effect of these exercises on students’ opinions of math, biology, and coding are evaluated using pre- and post-test surveys and student feedback. Our results show that these tools illustrate enzyme kinetics mathematically, students are not intimidated by the degree of math or coding involved, and in some cases are interested to do more, despite being unaware of the focus of the lab when signing up.
miniTurbo-based interactomics of two plasma membrane-localized SNARE proteins in Marchantia polymorpha
Authors: Melkonian Katharina , Stolze Sara Christina , Harzen Anne , Nakagami Hirofumi
Published: January 2022

Marchantia polymorpha is a model liverwort and its overall low genetic redundancy is advantageous for dissecting complex pathways. Proximity-dependent in vivo biotin-labelling methods have emerged as powerful interactomics tools in recent years. However, interactomics studies applying proximity labelling are currently limited to angiosperm species in plants.

Here, we established and evaluated a miniTurbo-based interactomics method in M. polymorpha using MpSYP12A and MpSYP13B, two plasma membrane- localized SNARE proteins, as baits.

We show that our method yields a manifold of potential interactors of MpSYP12A and MpSYP13B compared to a co-immunoprecipitation approach. Our method could capture specific candidates for each SNARE.

We conclude that a miniTurbo-based method is a feasible tool for interactomics in M. polymorpha and potentially applicable to other model bryophytes. Our interactome dataset on MpSYP12A and MpSYP13B will be a useful resource to elucidate the evolution of SNARE functions.
T cell response to intact SARS-CoV-2 includes coronavirus cross-reactive and variant-specific components
Authors: Jing Lichen , Wu Xia , Krist Maxwell P. , Hsiang Tien-Ying , Campbell Victoria L. , McClurkan Christopher L. , Favors Sydney M. , Hemingway Lawrence A. , Godornes Charmie , Tong Denise Q. , Selke Stacy , LeClair Angela C. , Pyo Chu-Woo , Geraghty Daniel E. , Laing Kerry J. , Wald Anna , Gale Michael , Koelle David M.
Published: January 2022

SARS-CoV-2 provokes a brisk T cell response. Peptide-based studies exclude antigen processing and presentation biology and may influence T cell detection studies. To focus on responses to whole virus and complex antigens, we used intact SARS-CoV-2 and full-length proteins with DC to activate CD8 and CD4 T cells from convalescent persons. T cell receptor (TCR) sequencing showed partial repertoire preservation after expansion. Resultant CD8 T cells recognize SARS-CoV-2-infected respiratory cells, and CD4 T cells detect inactivated whole viral antigen. Specificity scans with proteome-covering protein/peptide arrays show that CD8 T cells are oligospecific per subject and that CD4 T cell breadth is higher. Some CD4 T cell lines enriched using SARS-CoV-2 cross-recognize whole seasonal coronavirus (sCoV) antigens, with protein, peptide, and HLA restriction validation. Conversely, recognition of some epitopes is eliminated for SARS-CoV-2 variants, including spike (S) epitopes in the alpha, beta, gamma, and delta variant lineages.
Post-COVID-19 Memory Complaints: Prevalence and Associated Factors
Authors: Ahmed Mashrur , Roy Simanta , Chowdhury Sreshtha , Iktidar Mohammad Azmain , Akhter Sharmin , Khairul Islam A. M. , Hossain Hawlader Mohammad Delwer
Published: January 2022

Introduction

Memory complaints resulting from COVID-19 may have a significant impact on the survivors’ quality of life. Unfortunately, there is insufficient information available on memory loss and its relationship to COVID-19. Therefore, the purpose of this research was to determine the prevalence of memory complaints in post-COVID-19 patients and to find potential contributing factors.

Method

A cross-sectional survey was conducted on 401 individuals who had previously been diagnosed with COVID-19 at four COVID testing centers situated across Bangladesh. The MAC-Q questionnaire was used to evaluate memory. A binary logistic regression model was fit to study the variables related to memory complaints, with a p-value of <0.05 deemed statistically significant.

Result

Memory complaints was prevalent in 19.2% of the post-COVID patients. Individual predictor analysis revealed that among the treatment modalities, steroids and antibiotics were associated with impaired memory. Multiple logistic regression showed that individuals who recovered from COVID-19 within six to twelve months were more likely to have memory deficits. Even though age, sex, oxygen demand, and hospitalization were not linked with memory complaints, rural residents exhibited more significant memory complaints than urban residents.

Conclusion

Nearly one-fifth of the COVID-19 patients suffer from various degrees of memory complaints within one year. However, no association was found between COVID-19 severity to memory complaints.
Systemic adverse effects induced by the BNT162b2 vaccine are associated with higher antibody titers from 3 to 6 months after vaccination
Authors: Koike Ryousuke , Sawahata Michiru , Nakamura Yosikazu , Nomura Yushi , Katsube Otohiro , Hagiwara Koichi , Niho Seiji , Masuda Norihiro , Tanaka Takaaki , Sugiyama Kumiya
Published: January 2022

Objective

We aimed to determine the relationship between vaccine-related adverse effects and antibody (Ab) titers from 3 to 6 months after the second dose of the BNT162b2 coronavirus disease 2019 (COVID-19) mRNA vaccine (Pfizer/BioNTech) in Japan.

Methods

We enrolled 378 healthcare workers (255 women, 123 men) whose Ab titers 3 and 6 months after the second dose were analyzed in our previous study and whose characteristics and adverse effects were collected previously using a structured self-report questionnaire.

Results

Median age was 44 years. While injection-site symptoms occurred with almost equal frequency between the first and second doses, systemic adverse effects, such as general fatigue and fever, were significantly more frequent after the second dose than after the first. Multivariate analysis showed that fever was significantly correlated with female sex for the second dose (odds ratio [OR], 2.139; 95% confidence interval [95%CI], 1.185–3.859), older age for the first dose (OR, 0.962; 95%CI, 0.931–0.994) and second dose (OR, 0.957; 95%CI, 0.936–0.979), and dyslipidemia for the first dose (OR, 8.750; 95%CI, 1.814–42.20). Age-adjusted Ab titers at 3 months after vaccination were 23.7% and 23.4% higher in patients with fever than in those without fever after first and second dose, respectively. In addition, age-adjusted Ab titers at 3 and 6 months after the second dose were respectively 21.7% and 19.3% higher in the group with anti-inflammatory agent use than in the group without anti-inflammatory agent use.

Conclusion

Participants with systemic adverse effects tend to have higher Ab titers from 3 to 6 months after the second dose of the BNT162b2 vaccine. Our results may encourage vaccination, even among people with vaccine hesitancy related to relatively common systemic adverse effects.
Should healthcare workers with SARS-CoV-2 household exposures work? A Cohort Study
Authors: Quach Caroline , Blanchard Ana C. , Lamarche Josée , Audy Nathalie , Lamarre Valérie
Published: January 2022

Importance

Due to high community transmission of the Omicron variant, healthcare workers (HCWs) have been increasingly reporting household exposures to confirmed COVID-19 cases. Quebec (Canada) provincial guidelines required to quarantine these HCWs. Facing the risk of staffing shortages, our hospital decided to allow them to work.

Objective

To evaluate the risk for HCWs, who were household contacts, to become positive for COVID-19 by RT-PCR and evaluate the risk of nosocomial COVID-19 transmission.

Design

Cohort of HCWs with a history of household exposure to a confirmed case of COVID-19.

Setting

CHU Sainte-Justine, a tertiary care mother and child center in Montreal (QC) Canada

Participants

Consecutive HCWs who contacted OHS between December 20, 2021 and January 17, 2022 for a history of household exposure to COVID-19.

Exposure

Confirmed case of COVID-19 in the household

Main outcome and measures

The main outcome was a positive RT-PCR for SARS-CoV-2. Outbreaks and nosocomial cases were identified through daily analysis of COVID-19 cases, by sector and part of the usual Infection Prevention and Control surveillance process.

Results

Overall, 237 of 475 (50%) HCWs who declared a known household contact with a confirmed COVID-19 case remained negative. Of those who became positive, 196 (82.4%) were positive upon initial testing and were quarantined. Only 42 (15%) of 279 HCWs who were allowed to work became positive, a median of 4 days after the initial test. The absence of symptoms at initial evaluation (OR 3.8, 95% CI 2.5-5.7) and having received a third vaccine dose more than 7 days before (OR 1.88, 95% CI 1.3 – 2.8) were associated with an increased odds of remaining negative. There was no outbreak among HCWs and no nosocomial transmission to patients from a HCW that was allowed to work, while a known household contact.

Conclusion and relevance

Measures taken to protect the health care environment from COVID-19 must be cautiously balanced with the risk of staffing shortage. Allowing vaccinated asymptomatic HCWs who are known household contacts of confirmed COVID-19 cases to work is likely a safe alternative, when staff shortage is anticipated.
Early alveolar epithelial cell necrosis is a potential driver of COVID-19-induced acute respiratory distress syndrome
Authors: Tojo Kentaro , Yamamoto Natsuhiro , Tamada Nao , Mihara Takahiro , Abe Miyo , Nishii Mototsugu , Takeuchi Ichiro , Goto Takahisa
Published: January 2022

Acute respiratory distress syndrome (ARDS) with COVID-19 is aggravated by hyperinflammatory responses even after the peak of viral load has passed; however, its underlying mechanisms remain unclear. In the present study, analysis of the alveolar tissue injury markers and epithelial cell death markers in patients with COVID-19 revealed that COVID-19-induced ARDS was characterized by alveolar epithelial necrosis at an early disease stage. Serum levels of HMGB-1, one of DAMPs released from necrotic cells, were also significantly elevated in these patients. Further analysis using mouse model mimicking COVID-19-induced ARDS showed that the alveolar epithelial cell necrosis involved two forms of programmed necrosis, namely necroptosis and pyroptosis. Finally, the neutralization of HMGB-1 attenuated alveolar tissue injury in the mouse model. Collectively, necrosis, including necroptosis and pyroptosis, is the predominant form of alveolar epithelial cell death at an early disease stage and subsequent release of DAMPs is a potential driver of COVID-19-induced ARDS.
FMSClusterFinder: A new tool for detection and identification of clusters of sequential motifs with varying characteristics inside genomic sequences
Authors: Hejazi Mohammad Mahdi , Golabi Faegheh , Bahrami Mohsen , Kahroba Houman , Hejazi Mohammad Saeid
Published: January 2022

This paper describes FMSClusterFinder, a new tool and algorithm for identification and detection of clusters of sequential blocks inside the DNA and RNA subject sequences. Gene expression and genomic groups’ performance is under the control of functional elements cooperating with each other as clusters. The functional motifs or blocks are often comparably short, degenerate and are located within varying distances from each other. Since functional motifs mostly act in relation to each other as clusters, finding such clusters of blocks is an effective approach to identify functional groups and their function and structure, which represents the need for development of new corresponding tools.

The presented web application finds clusters of sequential blocks, with even altering sequences and located in varying distances from each other inside the subject sequences, simultaneously. Additionally, the blocks could be searched with user defined constant or varying characteristics such as: a) different levels of similarity, b) varying minimum number of blocks required to build up the query cluster, c) different types of sequence (degenerate or standard) and d) one or multiple alternative sequences for each block. FMSClusterFinder is available freely at http://fmsclusterfinder.fmsbiog.com.
Diet outweighs genetics in shaping gut microbiomes in Asian honeybee
Authors: Su Qinzhi , Tang Min , Hu Jiahui , Tang Junbo , Zhang Xue , Li Xingan , Niu Qingsheng , Zhou Xuguo , Luo Shiqi , Zhou Xin
Published: January 2022

Background

The gut microbiome is a crucial element that facilitates a host’s adaptation to a changing environment. Host-specificity often coincides with distinctions in gut microbes, suggesting a co-evolution of the holobionts. However, it is unclear how gut microbiota shared by a common host ancestor would co-diversify with hosts and eventually become distinct among sister hosts. In this context, understanding the evolutionary pathway of gut microbiomes of the same host species could provide insight on how holobionts co-adapt along environmental gradients. Specifically, we ask which factor, nature or nurture, i.e., genetics or diets, contributes more to the shaping of gut microbiome, along with host diversification and range expansion.

Results

We compared and analyzed the gut microbiomes of 99 Asian honeybees, Apis cerana, from genetically diverged populations covering 13 provinces across China. Bacterial composition varied significantly across populations at phylotype, sequence-discrete population (SDP), and strain levels, but with extensive overlaps, indicating the diversity of microbial community among A. cerana populations is driven by nestedness. Taken together, genetics exhibited tangential impacts, while pollen diets were significantly correlated with both the composition and function of gut microbiome. Core bacteria, Gilliamella and Lactobacillus Firm-5, showed antagonistic turnovers and contributed to the enrichment in carbohydrate transport and metabolism. By feeding and inoculation bioassays, we confirmed that the variations in pollen polysaccharide composition contributed to the trade-off of these core bacteria.

Conclusions

Progressive change, i.e., nestedness, is the foundation of gut microbiome evolution in the Asian honeybee. Such a transition during the co-diversification of gut microbiomes is shaped primarily by environmental factors, diets in general, pollen polysaccharide in particular.
Relation between the number of peaks and the number of reciprocal sign epistatic interactions
Authors: Saona Raimundo , Kondrashov Fyodor A. , Khudiakova Ksenia A.
Published: January 2022

Empirical essays of fitness landscapes suggest that they may be rugged, that is having multiple fitness peaks. Such fitness landscapes, those that have multiple peaks, necessarily have special local structures, called reciprocal sign epistasis ([14]). Here, we investigate the quantitative relationship between the number of fitness peaks and the number of reciprocal sign epistatic interactions. Previously it has been shown ([14]) that pairwise reciprocal sign epistasis is a necessary but not sufficient condition for the existence of multiple peaks. Applying discrete Morse theory, which to our knowledge has never been used in this context, we extend this result by giving the minimal number of reciprocal sign epistatic interactions required to create a given number of peaks.
Single-molecule nanopore dielectrophoretic trapping of α-Synuclein with lipid membranes
Authors: Wu Jinming , Yamashita Tohru , Hamilton Andrew D. , Thompson Sam , Luo Jinghui
Published: January 2022

The lipid-α-Synuclein (α-Syn) interaction plays a crucial role in the pathogenesis of Parkinson’s disease. Here, we trap α-Syn at a conjunction of an α-hemolysin (αHL) single nanopore-lipid to investigate the folding and unfolding kinetics of α-Syn in a lipidic environment. The hybridized α-Syn is generated through a reaction between a 5’-thiol-modified nucleotide oligo (dC30) and the α-Syn mutant (A140C). Owing to an applied voltage, single-molecule hybridized α-Syn can be trapped at the single nanopore. The trapping events are associated with dielectrophoretic force. The folding and unfolding events of α-Syn can be observed at the pore-membrane junction through interpretation of blockade current amplitudes and dwell time. This can be related to the protein quaternary structure influenced by the α-Syn-membrane interaction, allowing further analysis of α-Syn conformational dynamics. We studied how disease associated metal ions (Cu2+, Zn2+) modulate folding and unfolding of α-Syn at the interface of the membranes and pore, and how α-helical peptidomimetics stabilize the helical conformation of α-Syn in the presence of a membrane. These studies aid our understanding of the complexity of the interaction of α-Syn, lipid membranes and metal ions, and in using peptidomimetics, a new strategy against α-Syn toxicity and aggregation is advanced.
Impaired ERK MAPK activation in mature osteoblasts enhances bone formation via the mTOR pathway
Authors: Kim Jung-Min , Yang Yeon-Suk , Hong Jaehyoung , Chaugule Sachin , Chun Hyonho , van der Meulen Marjolein C. H. , Xu Ren , Greenblatt Matthew B. , Shim Jae-Hyuck
Published: January 2022

Emerging evidence supports that osteogenic differentiation of skeletal stem cells (SSCs) is a key determinant of overall bone formation and bone mass. Despite extensive studies showing mitogen-activated protein kinase (MAPK) function in osteoblast differentiation, none of these studies properly show in vivo evidence of impacting post-lineage commitment and subsequent maturation. Here, we describe how the extracellular signal-regulated kinase (ERK) pathway in osteoblasts controls bone formation by suppressing the mechanistic target of rapamycin (mTOR) pathway. We also show that, while ERK inhibition blocks the differentiation of osteogenic precursors when initiated at an early stage, ERK inhibition surprisingly promotes the later stages of osteoblast differentiation. Accordingly, inhibition of the ERK pathway using a small compound inhibitor or conditional deletion of the MAP2Ks Mek1 and Mek2, in mature osteoblasts and osteocytes (Mek1/2Dmp1), markedly increased bone formation due to augmented osteoblast differentiation. Mice with inducible deletion of the ERK pathway in mature osteoblasts (Mek1/2Ocn-Ert) also displayed similar phenotypes, demonstrating that this phenotype reflects continuous postnatal inhibition of late-stage osteoblast maturation. Mechanistically, ERK inhibition increases mitochondrial function and SGK1 phosphorylation via mTOR2 activation, which leads to osteoblast differentiation and production of angiogenic and osteogenic factors to promote bone formation. This phenotype was partly reversed by inhibiting mTOR. Our study uncovers a surprising dichotomy of ERK pathway functions in osteoblasts, whereby ERK activation promotes the early differentiation of osteoblast precursors, but inhibits the subsequent differentiation of committed osteoblasts via mTOR-mediated regulation of mitochondrial function and SGK1.
Mechano-signaling feedback underlies precise inner hair cell patterning in the organ of Corti
Authors: Cohen Roie , Taiber Shahar , Loza Olga , Kasirer Shahar , Woland Shiran , Sprinzak David
Published: January 2022

The mammalian hearing organ, the organ of Corti, is one of the most organized tissues in the mammalian body plan. It contains precisely positioned array of alternating sensory hair cells (HC) and non-sensory supporting cells that emerge during embryonic development from an initially disordered pro-sensory domain. While much is known on the genetics and biochemistry underlying this process, it is still unclear how such precise alternating patterns emerge during embryonic development. Here, we combine live imaging of mouse inner ear explants with hybrid mechano-regulatory models to elucidate the mechanisms underlying the formation of a single row of inner HC (IHC). We show that a narrow strip of initially disordered salt-and-pepper pattern, generated by Notch-mediated lateral inhibition, is dynamically refined by coordinated intercalations, delaminations, and differential adhesion. We identify a new morphological transition, termed ‘hopping intercalation’, that allows nascent IHC to ‘hop’ under the apical plane into their final position. We further show that IHC patterning is associated with boundary localization of the cell adhesion molecules, Nectin-3 and Nectin-1. Our experimental results and modeling support a mechanism for precise patterning based on a feedback between Notch-mediated differentiation and mechanically driven cellular reorganization that is likely relevant for many developmental processes.
Multiomics analysis integrating pyroptosis-related signatures for building a prognostic prediction model in hepatocellular carcinoma
Authors: Huang Jiahao , Li Yan , Chu Ming , Wang Yuedan
Published: January 2022

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide and has a poor prognosis. Pyroptosis, which is programmed cell necrosis mediated by gasdermin, participates in the progression of tumors. Recently, multiple omics analysis has been applied frequently to provide comprehensive and more precise conclusions. However, multiomics analysis combining pyroptosis-related signatures in HCC and their correlations with prognosis remain unclear. Here, we identified 42 pyroptosis genes that were differentially expressed between HCC and normal hepatocellular tissues. According to these differentially expressed genes (DEGs), all HCC cases could be divided into two heterogeneous subtypes. Then, we evaluated the prognostic value of differential pyroptosis-related genes to construct a multigene model using The Cancer Genome Atlas (TCGA) cohort. A 22-gene model was built and classified HCC patients in the TCGA cohort into low-risk and high-risk groups by the least absolute shrinkage and selection operator (LASSO) Cox regression method. HCC patients belonging to the low-risk group had significantly higher survival possibilities than those belonging to the high-risk group (p<0.001). Furthermore, the related genes and two groups were analyzed with multiple omics in different molecular layers. The pyroptosis-related gene model was validated with HCC patients from the Gene Expression Omnibus (GEO) cohort, and the low-risk group in GEO showed increased overall survival (OS) time (P=0.018). The risk score was an independent factor for predicting the OS of HCC patients. In conclusion, pyroptosis-related genes in HCC are correlated with tumor immunity and could be used to predict the prognosis of HCC patients.
Ligand-independent modulation of GIPR signaling by splice variants
Authors: Hang Kaini , Shao Lijun , Zhou Qingtong , Zhao Fenghui , Dai Antao , Cai Xiaoqing , Stevens Raymond C. , Yang Dehua , Wang Ming-Wei
Published: January 2022

Glucose-dependent insulinotropic polypeptide receptor (GIPR) is a potential drug target for metabolic disorders. It works with glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) in humans to maintain glucose homeostasis. Unlike the other two receptors, GIPR has at least 7 reported (EMBL-EBI, 2022; NCBI, 2022a, 2022b) splice variants (SVs) with previously undefined functions. To explore their roles in endogenous peptide mediated GIPR signaling, we investigated the outcome of co-expressing each of the four SVs in question with GIPR in terms of ligand binding, cAMP accumulation, Gs activation, β-arrestin recruitment and cell surface localization. The effects of these SVs on intracellular cAMP responses modulated by receptor activity-modifying proteins (RAMPs) were also studied. It was found that while SVs of GIPR neither bound to the hormone nor affected its signal transduction per se, they differentially regulated GIPR-mediated cAMP and β-arrestin responses. Specifically, SV1 and SV4 were preferable to Gs signaling, SV3 was biased towards β-arrestin recruitment, whereas SV2 was inactive on both pathways. In the presence of RAMPs, only SV1 and SV4 synergized the repressive action of RAMP3 on GIP-elicited cAMP production. The results suggest a new form of signal bias that is constitutive and ligand-independent, thereby expanding our knowledge of biased signaling beyond pharmacological manipulation (i.e., ligand specific) as well as constitutive and ligand-dependent (e.g., SV1 of the growth hormone-releasing hormone receptor).
Impact of decision and action outcomes on subsequent decision and action behaviors
Authors: Saleri Lunazzi Clara , Thura David , Reynaud Amélie J.
Published: January 2022

Speed-accuracy tradeoff adjustments in decision-making have been mainly studied separately from those in motor control. In the wild however, animals coordinate their decision and action, freely investing time in choosing versus moving given specific contexts. Recent behavioral studies support this view, indicating that humans trade decision time for movement time to maximize their global rate of reward during experimental sessions. Besides, it is established that choice outcomes impact subsequent decisions. Crucially though, whether and how a decision also influences the subsequent motor behavior, and whether and how a motor error influences the next decision is unknown. Here we address these questions by analyzing trial-to-trial changes of choice and motor behaviors in healthy human participants instructed to perform successive perceptual decisions expressed with reaching movements whose duration was either bounded or unconstrained in separate tasks. Results indicate that after a bad decision, subjects who were not constrained in their action duration decided more slowly and more accurately. Interestingly, they also shortened their subsequent movement duration by moving faster. Conversely, we found that movement errors not only influenced the speed and the accuracy of the following movement, but those of the decision as well. If the movement had to be slowed down, the decision that precedes that movement was accelerated, and vice versa. Together, these results indicate that from one trial to the next, humans are primarily concerned about determining a behavioral duration as a whole instead of optimizing each of the decision and action speed-accuracy trade-offs independently of each other.
A sparse set of spikes corresponding to reliable correlations is highly informative of visual stimulus on single trials
Authors: Levy Maayan , Guo Jeff K. , MacLean Jason N.
Published: January 2022

Spike trains in cortical neuronal populations vary in number and timing trial-to-trial, rendering a viable single trial coding scheme for sensory information elusive. Correlations between pairs of neocortical neurons can be segmented into either sensory or noise according to their stimulus specificity. Here we show that pairs of spikes, corresponding to reliable sensory correlations in imaged populations in layer 2/3 of mouse visual cortex are particularly informative of visual stimuli. This set of spikes is sparse and exhibits comparable levels of trial-to-trial variance relative to the full spike train. Despite this, correspondence of pairs of spikes to a specific set of sensory correlations identifies spikes that carry more information per spike about the visual stimulus than the full set or any other matched set of spikes. Moreover, this sparse subset is more accurately decoded, regardless of the decoding algorithm employed. Our findings suggest that consistent pairwise correlations between neurons, rather than first-order statistical features of spike trains, may be an organizational principle of a single trial sensory coding scheme.
Decoding the IGF1 Signaling Gene Regulatory Network Behind Alveologenesis from A Mouse Model of Bronchopulmonary Dysplasia
Authors: Gao F , Li C , Smith SM , Peinado N , Kohbodi G , Tran E , Loh E , Li W , Borok Z , Minoo P
Published: January 2022

Lung development is precisely controlled by underlying Gene Regulatory Networks (GRN). Disruption of genes in the network can interrupt normal development and cause diseases such as bronchopulmonary dysplasia (BPD)–a chronic lung disease in preterm infants with morbid and sometimes lethal consequences characterized by lung immaturity and reduced alveolarization.

Here, we generated a transgenic mouse exhibiting a moderate severity BPD phenotype by blocking IGF1 signaling in secondary crest myofibroblasts (SCMF) at the onset of alveologenesis. Using approaches mirroring the construction of the model GRN in sea urchin’s development, we constructed the IGF1 signaling network underlying alveologenesis using this mouse model that phenocopies BPD. The constructed GRN, consisting of 43 genes, provides a bird’s-eye view of how the genes downstream of IGF1 are regulatorily connected. The GRN also reveals a mechanistic interpretation of how the effects of IGF1 signaling are transduced within SCMF from its specification genes to its effector genes and then from SCMF to its neighboring alveolar epithelial cells with WNT5A and FGF10 signaling as the bridge. Consistently, blocking WNT5A signaling in mice phenocopies BPD as inferred by the network. A comparative study on human samples suggests that a GRN of similar components and wiring underlies human BPD.

Our network view of alveologenesis is transforming our perspective to understand and treat BPD. This new perspective calls for the construction of the full signaling GRN underlying alveologenesis, upon which targeted therapies for this neonatal chronic lung disease can be viably developed.