bluuebunny/crossref_metadata_2025 huggingface dataset:
Killer Cell Immunoglobulin-Like Receptor Haplotype B Modulates Susceptibility to EBV-Associated Classic Hodgkin Lymphoma
Authors: Jiang Peijia , Nolte Ilja M. , Hepkema Bouke G. , Stulp Marijke , van den Berg Anke , Diepstra Arjan
Published: January 2022

Tumor cells of classic Hodgkin lymphoma (cHL) are derived from antigen presenting B cells that are infected by Epstein Barr virus (EBV) in ~30% of patients. Polymorphic Killer cell immunoglobulin-like receptors (KIRs) expressed on NK cells interact with human leukocyte antigen (HLA) class I and play a key role in immune surveillance against virally infected cells and tumor cells. We investigated the effect of KIR types on cHL susceptibility overall (n=211) and in EBV-stratified subgroups using the Dutch GoNL cohort as controls (n=498). The frequency of the KIR haplotype B subgroup was significantly different between EBV+ and EBV− cHL patients (62% vs. 77%, p=0.04) and this difference was more pronounced in nodular sclerosis (NS) cHL (49% vs. 79%, p=0.0003). The frequency of KIR haplotype B subgroup was significantly lower in EBV+ NS cHL compared to controls (49% vs. 67%, p=0.01). Analyses of known KIR – HLA interaction pairs revealed lower carrier frequencies of KIR2DS2 – HLA-C1 (29% vs. 46%, p=0.03) and KIR2DL2 – HLA-C1 (29% vs. 45%, p=0.04) in EBV+ NS cHL patients compared to controls. Carriers of the KIR haplotype B subgroup are less likely to develop EBV+ NS cHL, probably because of a more efficient control over EBV-infected B cells.
Association Between Sex Hormone Levels and Clinical Outcomes in Patients With COVID-19 Admitted to Hospital: An Observational, Retrospective, Cohort Study
Authors: Beltrame Anna , Salguero Pedro , Rossi Emanuela , Conesa Ana , Moro Lucia , Bettini Laura Rachele , Rizzi Eleonora , D’Angió Mariella , Deiana Michela , Piubelli Chiara , Rebora Paola , Duranti Silvia , Bonfanti Paolo , Capua Ilaria , Tarazona Sonia , Valsecchi Maria Grazia
Published: January 2022

Understanding the cause of sex disparities in COVID-19 outcomes is a major challenge. We investigate sex hormone levels and their association with outcomes in COVID-19 patients, stratified by sex and age. This observational, retrospective, cohort study included 138 patients aged 18 years or older with COVID-19, hospitalized in Italy between February 1 and May 30, 2020. The association between sex hormones (testosterone, estradiol, progesterone, dehydroepiandrosterone) and outcomes (ARDS, severe COVID-19, in-hospital mortality) was explored in 120 patients aged 50 years and over. STROBE checklist was followed. The median age was 73.5 years [IQR 61, 82]; 55.8% were male. In older males, testosterone was lower if ARDS and severe COVID-19 were reported than if not (3.6 vs. 5.3 nmol/L, p =0.0378 and 3.7 vs. 8.5 nmol/L, p =0.0011, respectively). Deceased males had lower testosterone (2.4 vs. 4.8 nmol/L, p =0.0536) and higher estradiol than survivors (40 vs. 24 pg/mL, p = 0.0006). Testosterone was negatively associated with ARDS (OR 0.849 [95% CI 0.734, 0.982]), severe COVID-19 (OR 0.691 [95% CI 0.546, 0.874]), and in-hospital mortality (OR 0.742 [95% CI 0.566, 0.972]), regardless of potential confounders, though confirmed only in the regression model on males. Higher estradiol was associated with a higher probability of death (OR 1.051 [95% CI 1.018, 1.084]), confirmed in both sex models. In males, higher testosterone seems to be protective against any considered outcome. Higher estradiol was associated with a higher probability of death in both sexes.
RETRACTED: Transcriptome Analysis Reveals the Expressed Gene Complement and Acute Thermal Stress Response of Acropora digitifera Endosymbionts
Authors: Ravelo Stephanie Faith , Posadas Niño , Conaco Cecilia
Published: January 2022

Dinoflagellate endosymbionts from the family Symbiodiniaceae form a mutualistic relationship with corals. However, this partnership is vulnerable to temperature stress, which can result in coral bleaching. In this study, we sequenced the metatranscriptome of symbionts (dominated by ITS2 type C3u) associated with the common scleractinian coral, Acropora digitifera, from Bolinao, Pangasinan, northwestern Philippines, to elucidate their genetic complement and stress response mechanisms. The assembled metatranscriptome revealed a rich repertoire of genes for the utilization of nutrients and metabolic exchange with the host, as well as genes that provide protection against cellular damage. Exposure of the algal endosymbionts to 31°C for 12 h induced global changes in the transcriptome profile. While transcripts involved in cell signaling, cytoskeletal organization, and rRNA processing were upregulated, downregulation of transcripts related to translation, proteolysis, lipid storage, and immune response indicate vulnerability to acute thermal stress. Some of these stress responsive transcripts were predicted to be under microRNA (miRNA) regulation. These findings reveal conserved hallmarks of coral-algal symbiosis and provide insights into the genetic potential and acute thermal stress response of a common symbiont of corals in the region.
Sediments as a Source of Iron, Manganese, Cobalt and Nickel to Continental Shelf Waters (Louisiana, Gulf of Mexico)
Authors: Lenstra Wytze K. , van Helmond Niels A. G. M. , Żygadłowska Olga M. , van Zummeren Roosmarijn , Witbaard Rob , Slomp Caroline P.
Published: January 2022

Continental shelf sediments are a key source of trace metals to the ocean. In this study, we investigate the impact of sedimentary processes on water column concentrations of iron (Fe), manganese (Mn), cobalt (Co), and nickel (Ni) at five stations on the Louisiana continental shelf and slope, Gulf of Mexico. The highest trace metal concentrations were observed close to the seafloor at the most nearshore shelf station (water depth of 16 m), with most of the metals present in particulate form. This enrichment in the bottom water is likely the combined effect of input of trace metals in suspended matter from the Mississippi/Atchafalaya Rivers and, for Mn, Co, and Ni, benthic release from the shelf sediments. While particulate matter was the dominant carrier of Fe and Mn in bottom waters in the shelf and slope regions, Co and Ni were nearly exclusively present in dissolved form. Hence, lateral transport of Co and Ni in shelf waters is decoupled from that of Fe and Mn. Concentrations of particulate and dissolved trace metals in the water column generally decreased from the shelf to the slope, while those in the sediment increased. This suggests an increased retention of metals deposited on the sediment with distance from the coast, linked to the decrease in organic matter input and associated reductive sediment processes. The offshore decline in sediment trace metal mobilization is likely typical for river-dominated continental margins where most organic matter is deposited close to the coast.
High-Resolution Dynamics of Hydrogen Peroxide on the Surface of Scleractinian Corals in Relation to Photosynthesis and Feeding
Authors: Ousley Sara , de Beer Dirk , Bejarano Sonia , Chennu Arjun
Published: January 2022

We developed and used a microsensor to measure fast (<1 s) dynamics of hydrogen peroxide (H2O2) on the polyp tissue of two scleractinian coral species (Stylophora pistillata and Pocillopora damicornis) under manipulations of illumination, photosynthesis, and feeding activity. Our real-time tracking of H2O2 concentrations on the coral tissue revealed rapid changes with peaks of up to 60 μM. We observed bursts of H2O2 release, lasting seconds to minutes, with rapid increase and decrease of surficial H2O2 levels at rates up to 15 μM s–1. We found that the H2O2 levels on the polyp surface are enhanced by oxygenic photosynthesis and feeding, whereas H2O2 bursts occurred randomly, independently from photosynthesis. Feeding resulted in a threefold increase of baseline H2O2 levels and was accompanied by H2O2 bursts, suggesting that the coral host is the source of the bursts. Our study reveals that H2O2 levels at the surface of coral polyps are much higher and more dynamic than previously reported, and that bursts are a regular feature of the H2O2 dynamics in the coral holobiont.
Effect of ZrSiO4 Concentration on the Microstructure and Corrosion Resistance of MAO Coatings Formed on AZ91 Magnesium Alloy
Authors: Li Tianlu , Chen Guorui , Xiang Mingzhe , Zhao Yun , Chen Minfang
Published: January 2022

As a metallic material with lightweight and high specific strength, magnesium alloy has excellent application prospects. However, the rapid corrosion rate and localized corrosion behavior of magnesium alloys limit the practical application in the automobile industry. In this study, to improve the corrosion resistance of AZ91 alloy, the film of different concentrations containing zirconium (AZR0, AZR5, AZR10, AZR15) was prepared on the surface of AZ91 alloy by micro-arc oxidation technology in the Na2SiO3-Na3PO4 system. Furthermore, the influence of electrolyte composition on the corrosion resistance of the MAO film was systematically investigated. The experimental results revealed that the ZrSiO4 particles added in the electrolyte could enter into the MAO film and ZrSiO4 particles were also decomposed into ZrO2 and Mg2Zr5O11 in the process of micro-arc oxidation. More importantly, the formation of micro-cracks and other defects in the film could be reduced after this process. The addition of 15 g l−1 ZrSiO4 in the electrolyte was contributed to the best comprehensive properties of MAO-processed AZ91 specimens, including improved Vickers hardness of 167.16 Hv, Young’s modulus of 652 MPa, and enhanced corrosion resistance (RP = 9.82 × 105 Ω cm2). This approach could provide the approach for developing Mg-based materials with high anticorrosion in industrial fields.
The Xiangya Ocular Tumor Bank: A Disease-Specific Biobank for Advancing Translational Research Into Ocular Tumors
Authors: Gao Zhaolin , Tan Jia , Wang Sha , Yu Haiyang , Zhou Ziyu , Zhang Yun , Zhou Mushi , Xia Xiaobo , Yao Fei , Huang Jufang
Published: January 2022

The pathogenesis and etiology of various ocular tumors remain largely unclear, limiting the development of diagnostic and treatment approaches for such tumors. Tissue samples from patients are also valuable resource to elucidate mechanisms underlying tumorigenesis. Here we present the early phase setup of an ocular tumor biobank at Xiangya Hospital. Blood and tissue samples along with associated clinical data were obtained from patients who underwent surgery in the Department of Ophthalmology of Xiangya Hospital from December 1, 2018 to January 31, 2020. Standardized operating protocols were developed for the collection, transportation, processing and preservation of ocular tumor samples. A total of 92 clinical cases suffered from 21 types of eye tumors and several undiagnosed eye diseases were covered. A total of 846 samples were preserved in the ocular tumor biobank, including 356 blood samples (42.1%), 324 plasma samples (38.3%), and 166 tissue samples (19.6%). Using the clinical data, we analyzed the prevalence of malignant ocular tumors in association with variables of age, gender, tumors' location and size, and presenting complaints of lump and proptosis. The factors predictive of malignant ocular tumors, included gender (B = 1.599; P = 0.025) and the symptom of proptosis (B = −2.534; P = 0.001). Overall, the setup of clinically-based ophthalmologic biobank could support pathological and translational research into ocular tumors.
Angiotensin Converting Enzyme Activity in Anti-TNF-Treated Rheumatoid Arthritis and Ankylosing Spondylitis Patients
Authors: Soós Boglárka , Fagyas Miklós , Horváth Ágnes , Végh Edit , Pusztai Anita , Czókolyová Monika , Csongrádi Alexandra , Hamar Attila , Pethő Zsófia , Bodnár Nóra , Kerekes György , Hodosi Katalin , Szekanecz Éva , Szamosi Szilvia , Szántó Sándor , Szűcs Gabriella , Papp Zoltán , Szekanecz Zoltán
Published: January 2022

Introduction

Angiotensin-converting enzyme (ACE) and ACE2 have been implicated in the regulation of vascular physiology. Elevated synovial and decreased or normal ACE or ACE2 levels have been found in rheumatoid arthritis (RA). Very little is known about the effects of tumor necrosis factor α (TNF-α) inhibition on ACE or ACE2 homeostasis. In this study, we assessed the effects of one-year anti-TNF therapy on ACE and ACE2 production in RA and ankylosing spondylitis (AS) in association with other biomarkers.

Patients and Methods

Forty patients including 24 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 16 AS patients treated with ETN were included in a 12-month follow-up study. Serum ACE levels were determined by commercial ELISA, while serum ACE2 activity was assessed using a specific quenched fluorescent substrate. Ultrasonography was performed to determine flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and arterial pulse-wave velocity (PWV) in all patients. In addition, CRP, rheumatoid factor (RF) and ACPA were also measured. All assessments were performed at baseline and 6 and 12 months after treatment initiation.

Results

Anti-TNF therapy increased ACE levels in the full cohort, as well as in the RA and AS subsets. ACE2 activity increased in the full cohort, while the ACE/ACE2 ratio increased in the full cohort and in the RA subset (p < 0.05). Uni- and multivariable regression analyses determined associations between ACE or ACE/ACE2 ratios at different time points and disease duration, CRP, RF, FMD and IMT (p < 0.05). ACE2 activity correlated with CRP. The changes of ACE or ACE2 over 12 months were determined by treatment together with either RF or FMD (p < 0.05).

Conclusions

Anti-TNF treatment may increase ACE and ACE2 in the sera of RA and AS patients. ACE and ACE2 may be associated with disease duration, markers of inflammation and vascular pathophysiology. The effects of TNF inhibition on ACE and ACE2 may reflect, in part, the effects of these biologics on the cardiovascular system.
Acute Respiratory Distress Syndrome Caused by Human Adenovirus in Adults: A Prospective Observational Study in Guangdong, China
Authors: Wu Zhan , Zhang Rong , Liu Dongdong , Liu Xuesong , Zhang Jierong , Zhang Zhihui , Chen Sibei , He Weiqun , Li Yimin , Xu Yonghao , Liu Xiaoqing
Published: January 2022

Background

Viral causes of acute respiratory distress syndrome (ARDS) are mostly limited to influenza. However, adenovirus has been emerging as a cause of ARDS with a high mortality rate and described in adults are rare.

Methods

We conducted a prospective, single-center observational study of viral pneumonia with ARDS and confirmed adenovirus-associated ARDS in adults at our quaternary referral institution between March 2019 and June 2020. We prospectively analyzed clinical characteristics, laboratory test results, radiological characteristics, viral load from nasopharyngeal swabs and endotracheal aspirates, treatments, and outcomes for the study participants.

Results

The study enrolled 143 ARDS patients, including 47 patients with viral pneumonia-related ARDS, among which there were 14 adenovirus-associated ARDS patients, which accounted for 29.79% of the viral pneumonia-related ARDS cases. Among the adenovirus-associated ARDS patients, 78.57% were men with a mean age of 54.93 ± 19.04 years, younger than that of the non-adenovirus associated ARDS patients. Adenovirus-associated ARDS patients had no specific clinical characteristics, but they presented with decrease in the number of CD3+CD4+ T cells and higher serum creatinine during the early stage. The viral load and the positivity rate in the lower respiratory tract were higher than that of the upper respiratory tract in the patients with adenovirus-associated ARDS. All patients required invasive mechanical ventilation treatment. The average time from shortness of breath to the application of invasive ventilation was 24 h. Ten patients (71.43%) complicated by acute kidney injury, while 13 patients (71.43%) in the non-adenovirus associated ARDS group (P = 0.045). Additionally, 85.71% of the 14 adenovirus-associated ARDS patients survived. No significant differences were detected between the two groups regarding duration of ventilation, length of ICU stay and mortality.

Conclusion

Adenovirus infection is an important cause of virus-related ARDS. The positivity rate of adenovirus infection in lower respiratory tract secretions was higher than that in upper respiratory tract secretions in these patients. Age, lower CD3+CD4+ T cells, and high serum creatinine may be were associated with adenovirus induce ARDS in adults required mechanical ventilation. Early identification and intervention to prevent disease progression are essential for reducing the mortality rate in these patients.
The Effects of Donor-Recipient Age and Sex Compatibility in the Outcomes of Deep Anterior Lamellar Keratoplasties
Authors: Ong Hon Shing , Chiam Nathalie , Htoon Hla Myint , Kumar Ashish , Arundhati Anshu , Mehta Jodhbir S.
Published: January 2022

Purpose

Corneal transplantations are the commonest allogenic transplant surgeries performed worldwide. Transplantable grade donor cornea is a finite resource. There is thus an impetus for eye banks to optimize the use of each harvested cornea, and clinicians to minimize the risks of graft rejection and failure. With better survival and lower rejection rates, anterior lamellar keratoplasty has gained popularity as an alternative technique to full-thickness penetrating keratoplasty, for the treatment of corneal stromal diseases. This study evaluated the effects of donor-recipient age- and sex-matching on the outcomes of eyes that had undergone deep anterior lamellar keratoplasty (DALK) surgeries.

Design

Observational cross-sectional study (national corneal graft registry data).

Subjects

All DALK surgeries performed in a tertiary ophthalmic hospital over an 11-year period.

Methods

To analyse the effects of donor-recipient sex-matching, transplantations were classified as “presumed H-Y incompatible” (male donor to female recipient) or “presumed H-Y compatible” (all other donor-recipient sex combinations). For age-matching, differences in donor and recipient ages were calculated. Cox proportional hazards regressions were used to evaluate the influence of donor-recipient sex-matching and age-matching on graft failure and rejection.

Main Outcome Measures

Rates of graft failure and rejection within each group.

Results

401 eyes were included. 271 (67.6%) transplants were presumed H-Y compatible. 29 (7.2%) grafts failed and 9 (2.2%) grafts rejected. There were trends of lower hazard ratios (HRs) in graft failure and rejection in the presumed H-Y compatible group [HRs: 0.59 (95% CI 0.20–1.77,p= 0.34) and 0.93 (95% CI 0.22–3.89,p= 0.926), respectively]. Median difference in age between recipients and donors was 15.0 years (IQR −2.8–34.3). The HRs of graft failure and rejection were not influenced by donor-recipient age [HRs per 1-year increase in age difference: 0.995 (95% CI 0.98–1.01,p= 0.483) and 1.01 (95% CI 0.99–1.03,p= 0.394), respectively].

Conclusion

In eyes that had undergone DALK surgeries, no significant influence of donor-recipient sex- or age-matching on graft rejection and failure was observed. Without strong evidence and the limitations of obtaining sample sizes required for an adequately powered study, the benefits of sex- and age-matching of donors and recipients during graft allocation for DALK surgeries is currently inconclusive.
Code-Free Development and Deployment of Deep Segmentation Models for Digital Pathology
Authors: Pettersen Henrik Sahlin , Belevich Ilya , Røyset Elin Synnøve , Smistad Erik , Simpson Melanie Rae , Jokitalo Eija , Reinertsen Ingerid , Bakke Ingunn , Pedersen André
Published: January 2022

Application of deep learning on histopathological whole slide images (WSIs) holds promise of improving diagnostic efficiency and reproducibility but is largely dependent on the ability to write computer code or purchase commercial solutions. We present a code-free pipeline utilizing free-to-use, open-source software (QuPath, DeepMIB, and FastPathology) for creating and deploying deep learning-based segmentation models for computational pathology. We demonstrate the pipeline on a use case of separating epithelium from stroma in colonic mucosa. A dataset of 251 annotated WSIs, comprising 140 hematoxylin-eosin (HE)-stained and 111 CD3 immunostained colon biopsy WSIs, were developed through active learning using the pipeline. On a hold-out test set of 36 HE and 21 CD3-stained WSIs a mean intersection over union score of 95.5 and 95.3% was achieved on epithelium segmentation. We demonstrate pathologist-level segmentation accuracy and clinical acceptable runtime performance and show that pathologists without programming experience can create near state-of-the-art segmentation solutions for histopathological WSIs using only free-to-use software. The study further demonstrates the strength of open-source solutions in its ability to create generalizable, open pipelines, of which trained models and predictions can seamlessly be exported in open formats and thereby used in external solutions. All scripts, trained models, a video tutorial, and the full dataset of 251 WSIs with ~31 k epithelium annotations are made openly available at https://github.com/andreped/NoCodeSeg to accelerate research in the field.
Genomic and Virological Characterization of SARS-CoV-2 Variants in a Subset of Unvaccinated and Vaccinated U.S. Military Personnel
Authors: Smith Darci R. , Singh Christopher , Green Jennetta , Lueder Matthew R. , Arnold Catherine E. , Voegtly Logan J. , Long Kyle A. , Rice Gregory K. , Luquette Andrea E. , Miner Haven L. , Glang Lindsay , Bennett Andrew J. , Miller Robin H. , Malagon Francisco , Cer Regina Z. , Bishop-Lilly Kimberly A.
Published: January 2022

The emergence of SARS-CoV-2 variants complicates efforts to control the COVID-19 pandemic. Increasing genomic surveillance of SARS-CoV-2 is imperative for early detection of emerging variants, to trace the movement of variants, and to monitor effectiveness of countermeasures. Additionally, determining the amount of viable virus present in clinical samples is helpful to better understand the impact these variants have on viral shedding. In this study, we analyzed nasal swab samples collected between March 2020 and early November 2021 from a cohort of United States (U.S.) military personnel and healthcare system beneficiaries stationed worldwide as a part of the Defense Health Agency's (DHA) Global Emerging Infections Surveillance (GEIS) program. SARS-CoV-2 quantitative real time reverse-transcription PCR (qRT-PCR) positive samples were characterized by next-generation sequencing and a subset was analyzed for isolation and quantification of viable virus. Not surprisingly, we found that the Delta variant is the predominant strain circulating among U.S. military personnel beginning in July 2021 and primarily represents cases of vaccine breakthrough infections (VBIs). Among VBIs, we found a 50-fold increase in viable virus in nasal swab samples from Delta variant cases when compared to cases involving other variants. Notably, we found a 40-fold increase in viable virus in nasal swab samples from VBIs involving Delta as compared to unvaccinated personnel infected with other variants prior to the availability of approved vaccines. This study provides important insight about the genomic and virological characterization of SARS-CoV-2 isolates from a unique study population with a global presence.
A Patients' Perspective Towards the Injection Devices for Humira® and Imraldi® in a Nationwide Switching Program
Authors: Karlsdottir Kristin , Gunnarsdottir Anna I. , Grondal Gerdur , Love Thorvardur J. , Stefansdottir Elinborg , Davidsdottir Loa G. , Thorleifsdottir Ragna H. , Gudbjornsson Bjorn
Published: January 2022

Objective

Due to a tender process in Iceland, all patients on Humira® were switched nationwide to its biosimilar Imraldi® in March 2019. The study aimed to explore the patient's perspective of the Humira® and Imraldi® injection devices.

Methods

A standard telephone interview was carried out among patients with inflammatory arthritis, inflammatory bowel disease and psoriasis, who underwent this nationwide switching program a few months earlier.

Results

The response rate was 84.5% (n = 198). The average age was 50.8 years, and 53.5% were female. The patients self-administered the drugs in 96% of the cases. The majority (90.5%) stated that they received individualized instruction on using the Humira® pen, compared to 18.2% who accepted instruction in the case of the Imraldi® pen. Almost half (46.6%) of the patients found it more difficult to use the Imraldi® pen than the Humira® pen, while only 12.5% found the Imraldi® pen easier to use. Firstly, these differences were due to more painful insertion of the needle (62.2%) and secondly, due to the experience, the injection process was different (63.0%).

Conclusion

Patients with inflammatory disorders who have been treated regularly with adalimumab preferred the Humira® injection device over the Imraldi® device, according to our results. After all, these injection devices' structure and content are not the same, although both contain the same active ingredient, i.e. adalimumab. Our results highlight the importance of thorough information, not only with an information letter but also with the possibilities for individualized introduction in planning switching to biosimilars.
Aquatic Macrophytes Are Associated With Variation in Biogeochemistry and Bacterial Assemblages of Mountain Lakes
Authors: DeWolf Ella Ide , Calder William John , Harrison Joshua Grant , Randolph Gregory Donald , Noren Benjamin Edward , Weinig Cynthia
Published: January 2022

In aquatic systems, microbes likely play critical roles in biogeochemical cycling and ecosystem processes, but much remains to be learned regarding microbial biogeography and ecology. The microbial ecology of mountain lakes is particularly understudied. We hypothesized that microbial distribution among lakes is shaped, in part, by aquatic plant communities and the biogeochemistry of the lake. Specifically, we investigated the associations of yellow water lilies (Nuphar polysepala) with the biogeochemistry and microbial assemblages within mountain lakes at two scales: within a single lake and among lakes within a mountain range. We first compared the biogeochemistry of lakes without water lilies to those colonized to varying degrees by water lilies. Lakes with >10% of the surface occupied by water lilies had lower pH and higher dissolved organic carbon than those without water lilies and had a different microbial composition. Notably, cyanobacteria were negatively associated with water lily presence, a result consistent with the past observation that macrophytes outcompete phytoplankton and can suppress cyanobacterial and algal blooms. To examine the influence of macrophytes on microbial distribution within a lake, we characterized microbial assemblages present on abaxial and adaxial water lily leaf surfaces and in the water column. Microbial diversity and composition varied among all three habitats, with the highest diversity of microbes observed on the adaxial side of leaves. Overall, this study suggests that water lilies influence the biogeochemistry and microbiology of mountains lakes.
Urinary Tract Infection Etiological Profiles and Antibiotic Resistance Patterns Varied Among Different Age Categories: A Retrospective Study From a Tertiary General Hospital During a 12-Year Period
Authors: Huang Lei , Huang Chenwei , Yan Yan , Sun Liying , Li Haixia
Published: January 2022

Background

Urinary tract infections (UTIs) are among the most common infections worldwide. With continuing trends of antibiotic resistance, the etiological distribution and antibiotic susceptibility surveillance are of great importance for empirical antimicrobial therapy. The risk factors and clinical circumstances of UTI among different age categories varied; thus, the pathogens and antimicrobial susceptibilities of UTI may also change with age. The aim of this study was to compare the etiological profiles and antibiotic resistance patterns of UTIs sorted by different age categories from a tertiary general hospital during a 12-year period.

Methods

All positive urine culture results from non-repetitive UTI patients in our hospital from January 2009 to December 2020 were collected retrospectively. The microbial distribution and antibiotic resistance rates were analyzed by WHONET 5.6 software. The etiological profiles sorted by different age categories (newborn, pediatric, adult, and geriatric) and antibiotic resistance rates of the top five pathogens were analyzed.

Results

A total of 13,308 non-repetitive UTI patients were included in our study. Enterococcus faecium was dominant in newborn (45%, n = 105), and replaced by Escherichia coli in pediatric (34%, n = 362), adult (43%, n = 3,416), and geriatric (40%, n = 1,617), respectively. The etiological profiles of different age categories were divergent, sorted by genders (male and female) and ward types (outpatient, inpatient, ICU, and emergency). E. coli, Klebsiella pneumoniae, Enterococcus faecalis, E. faecium, and Pseudomonas aeruginosa were the top five pathogens in all age categories. The resistance rates of cefoperazone–sulbactam and piperacillin–tazobactam in E. coli were low in all age categories. The resistance rates of other cephalosporins, carbapenems, and fluoroqinolones in K. pneumoniae were higher in geriatric patients overall. E. faecium was more resistant than E. faecalis in all age categories. Multidrug resistance increased with age, which was more serious in geriatric patients.

Conclusion

The UTI etiological profiles and antibiotic resistance patterns varied among different age categories, especially in pediatric and geriatric patients; thus, a different antibiotic therapy for various age categories should be considered when initiating empirical antimicrobial therapies.
Plant Natural Products as Antimicrobials for Control of Streptomyces scabies: A Causative Agent of the Common Scab Disease
Authors: Gutierrez Justin , Bakke Amanda , Vatta Maritza , Merrill A. Rod
Published: January 2022

The common scab disease caused by Streptomyces scabies, a soil-dwelling Gram-positive bacterium, is an economically important disease of potatoes and other tuber crops. The lack of effective treatments against this disease accounts for large economic losses globally. Plant extracts were screened to find several that effectively inhibited Streptomyces scabies growth in culture. Seven tinctures showed the greatest inhibition of S. scabies growth by reducing pathogen growth in culture by 75% or more. These extracts were myrrh, garlic, cayenne, barberry, frankincense, wild indigo root, and lavender. Myrrh extract from Commiphora myrrha, a resin made from tree sap, showed strong antibacterial activity by reducing the growth of S. scabies to 13% of the control. Additionally, a flavonoid library was screened to identify several compounds that were effective to control the pathogen growth. The flavonoids that showed the greatest inhibition of Streptomyces scabies growth were sophoraflavanone G, jaceosidin, baicalein, and quercetin. Minimum inhibitory concentrations for the effective flavonoids were calculated to be 6.8 ± 0.4 μM, 100.0 ± 2.1 μM, 202.9 ± 5.3 μM, and 285.2 ± 6.8 μM, respectively. The mean lethal doses for these flavonoids against Streptomyces scabies were 2.0 ± 0.1 μM, 22.6 ± 0.5 μM, 52.9 ± 1.3 μM, and 37.8 ± 1.0 μM, respectively. A live/dead assay showed complete cell death in the presence of sophoraflavanone G indicative of a bactericidal mechanism for flavonoid action on Streptomyces scabies. Scanning electron and transmission electron microscopy imaging showed damaged cell membrane morphologies when Streptomyces scabies was exposed to these flavonoids. Mycelia appeared as flat and deflated structures with contents seen as spewing from branching hyphae with numerous holes and tears in the membrane structure indicative of cell death. Sophoraflavanone G showed the greatest potency and potential as a natural antibiotic from the library of tested flavonoids. These results suggest that these plant compounds act on the pathogen through a bactericidal mechanism involving cell membrane destabilization and disruption leading to cell death.
Integrated Analysis Reveals the Characteristics and Effects of SARS-CoV-2 Maternal–Fetal Transmission
Authors: Huang Ziliang , Xia Shuting , Mei Shiqiang , Wen Yanzi , Liu Jialiu , Dong Chengzhi , Chen Wenxin , Yu Peijie , Qu Lianghu , Luo Yanmin , Zheng Lingling
Published: January 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has caused a pandemic of coronavirus disease 2019 (COVID-19) and is threatening global health. SARS-CoV-2 spreads by air with a transmission rate of up to 15%, but the probability of its maternal–fetal transmission through the placenta is reported to be low at around 3.28%. However, it is still unclear that which tissues and developmental periods hold higher risks and what the underlying molecular mechanisms are. We conducted an integrated analysis of large-scale transcriptome and single-cell sequencing data to investigate the key factors that affect SARS-CoV-2 maternal–fetal transmission as well as the characteristics and effects of them. Our results showed that the abundance of cytomegalovirus (CMV) and Zika virus (ZIKV) infection-associated factors in the placenta were higher than their primarily infected tissues, while the expression levels of SARS-CoV-2 binding receptor angiotensin-converting enzyme II (ACE2) were similar between lung and placenta. By contrast, an important SARS-CoV-2 infection-associated factor, type II transmembrane serine protease (TMPRSS2), was poorly expressed in placenta. Further scRNA-Seq analysis revealed that ACE2 and TMPRSS2 were co-expressed in very few trophoblastic cells. Interestingly, during the embryonic development stages, the abundance of ACE2 and TMPRSS2 was much higher in multiple embryonic tissues than in the placenta. Based on our present analysis, the intestine in 20th week of embryonic development was at a high risk of SARS-CoV-2 infection. Additionally, we found that during the fetal development, ACE2 and TMPRSS2 were enriched in pathogen infection-associated pathways and may involve in the biological processes related to T-cell activation. In conclusion, our present study suggests that though the placenta provides a good physical barrier against SARS-CoV-2 infection for healthy fetal development, multiple embryonic tissues are under risks of the virus infection, which may be adversely affected once infected prenatally. Therefore, it is necessary to enhance maternal care to prevent the potential impact and harm of SARS-CoV-2 maternal–fetal transmission.
Molecular Architecture of the Antiophidic Protein DM64 and its Binding Specificity to Myotoxin II From Bothrops asper Venom
Authors: Soares Barbara S. , Rocha Surza Lucia G. , Bastos Viviane A. , Lima Diogo B. , Carvalho Paulo C. , Gozzo Fabio C. , Demeler Borries , Williams Tayler L. , Arnold Janelle , Henrickson Amy , Jørgensen Thomas J. D. , Souza Tatiana A. C. B. , Perales Jonas , Valente Richard H. , Lomonte Bruno , Gomes-Neto Francisco , Neves-Ferreira Ana Gisele C.
Published: January 2022

DM64 is a toxin-neutralizing serum glycoprotein isolated from Didelphis aurita, an ophiophagous marsupial naturally resistant to snake envenomation. This 64 kDa antitoxin targets myotoxic phospholipases A2, which account for most local tissue damage of viperid snakebites. We investigated the noncovalent complex formed between native DM64 and myotoxin II, a myotoxic phospholipase-like protein from Bothrops asper venom. Analytical ultracentrifugation (AUC) and size exclusion chromatography indicated that DM64 is monomeric in solution and binds equimolar amounts of the toxin. Attempts to crystallize native DM64 for X-ray diffraction were unsuccessful. Obtaining recombinant protein to pursue structural studies was also challenging. Classical molecular modeling techniques were impaired by the lack of templates with more than 25% sequence identity with DM64. An integrative structural biology approach was then applied to generate a three-dimensional model of the inhibitor bound to myotoxin II. I-TASSER individually modeled the five immunoglobulin-like domains of DM64. Distance constraints generated by cross-linking mass spectrometry of the complex guided the docking of DM64 domains to the crystal structure of myotoxin II, using Rosetta. AUC, small-angle X-ray scattering (SAXS), molecular modeling, and molecular dynamics simulations indicated that the DM64-myotoxin II complex is structured, shows flexibility, and has an anisotropic shape. Inter-protein cross-links and limited hydrolysis analyses shed light on the inhibitor’s regions involved with toxin interaction, revealing the critical participation of the first, third, and fifth domains of DM64. Our data showed that the fifth domain of DM64 binds to myotoxin II amino-terminal and beta-wing regions. The third domain of the inhibitor acts in a complementary way to the fifth domain. Their binding to these toxin regions presumably precludes dimerization, thus interfering with toxicity, which is related to the quaternary structure of the toxin. The first domain of DM64 interacts with the functional site of the toxin putatively associated with membrane anchorage. We propose that both mechanisms concur to inhibit myotoxin II toxicity by DM64 binding. The present topological characterization of this toxin-antitoxin complex constitutes an essential step toward the rational design of novel peptide-based antivenom therapies targeting snake venom myotoxins.
Molecular Docking and Dynamics Studies to Explore Effective Inhibitory Peptides Against the Spike Receptor Binding Domain of SARS-CoV-2
Authors: Biswas Suvro , Mahmud Shafi , Mita Mohasana Akter , Afrose Shamima , Hasan Md. Robiul , Sultana Shimu Mst. Sharmin , Saleh Md. Abu , Mostafa-Hedeab Gomaa , Alqarni Mohammed , Obaidullah Ahmad J. , Batiha Gaber El-Saber
Published: January 2022

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a pandemic due to the high transmission and mortality rate of this virus. The world health and economic sectors have been severely affected by this deadly virus, exacerbated by the lack of sufficient efficient vaccines. The design of effective drug candidates and their rapid development is necessary to combat this virus. In this study, we selected 23 antimicrobial peptides from the literature and predicted their structure using PEP-FOLD 3.5. In addition, we docked them to the SARS-CoV-2 spike protein receptor-binding domain (RBD) to study their capability to inhibit the RBD, which plays a significant role in virus binding, fusion and entry into the host cell. We used several docking programs including HDOCK, HPEPDOCK, ClusPro, and HawkDock to calculate the binding energy of the protein-peptide complexes. We identified four peptides with high binding free energy and docking scores. The docking results were further verified by molecular dynamics (MD) simulations to characterize the protein-peptide complexes in terms of their root-mean-square fluctuation (RMSF), root-mean-square deviation (RMSD), radius of gyration (Rg), solvent-accessible surface area (SASA), and hydrogen bond formation. Allergenicity and toxicity predictions suggested that the peptides we identified were non-allergenic and non-toxic. This study suggests that these four antimicrobial peptides could inhibit the RBD of SARS-CoV-2. Future in vitro and in vivo studies are necessary to confirm this.
Pan-Cancer Analysis Reveals the Multidimensional Expression and Prognostic and Immunologic Roles of VSTM2L in Cancer
Authors: Zhang Shuyi , Xiong Hailin , Yang Jiahui , Yuan Xia
Published: January 2022

Immunotherapy can improve survival in a variety of cancers by modulating the interaction between tumors and the tumor immune microenvironment (TIME). V-set and transmembrane domain containing 2 like (VSTM2L) regulates interleukin (IL)-4 signaling pathway—which involves immune-related factors—and has been linked to some cancers. However, the expression profile and prognostic significance of VSTM2L in different cancers as well as its relationship to the TIME are not known. This study investigated the pan-cancer expression profile, prognostic value, and immunologic relevance of VSTM2L. VSTM2L expression in different cancers was analyzed using the Cancer Cell Line Encyclopedia (CCLE), Human Protein Atlas (HPA), Tumor Immune Estimation Resource (TIMER), The Cancer Genome Atlas (TCGA), and Genotype–Tissue Expression (GTEx) portal. We examined the association between VSTM2L expression and clinical outcomes by Kaplan–Meier and Cox regression analyses using TCGA and Kaplan–Meier Plotter, and the results were validated in a Gene Expression Omnibus cohort. The correlations between VSTM2L expression and immune cell infiltration, immunomodulators, tumor mutation burden (TMB), microsatellite instability (MSI), and immune and stromal scores across cancers were analyzed using TCGA, TIMER, and Tumor–Immune System Interactions and Drugbank databases (TISIDB). The results showed that VSTM2L expression varied across cancers and its aberrant expression was associated with clinical outcomes: upregulation of VSTM2L was positively associated with advanced stage and reduced overall survival (OS), disease-specific survival (DSS), progression-free interval (PFI), and disease-free interval (DFI) in stomach adenocarcinoma (STAD); and its upregulation was associated with early-stage disease and improved OS, DSS, PFI, and DFI in kidney renal papillary cell carcinoma (KIRP). VSTM2L expression level was correlated with immune cell infiltration, expression of immunomodulators, TMB, MSI, and immune and stromal scores in multiple cancers. In conclusion, VSTM2L has prognostic value in various cancers and can predict both poor (STAD) and good (KIRP) outcomes. The relationship between VSTM2L expression and immune markers suggests a role in modulating the TIME.
Online Machine Learning for Accelerating Molecular Dynamics Modeling of Cells
Authors: Zhang Ziji , Zhang Peng , Han Changnian , Cong Guojing , Yang Chih-Chieh , Deng Yuefan
Published: January 2022

We developed a biomechanics-informed online learning framework to learn the dynamics with ground truth generated with multiscale modeling simulation. It was built on Summit-like supercomputers, which were also used to benchmark and validate our framework on one physiologically significant modeling of deformable biological cells. We generalized the century-old equation of Jeffery orbits to a new equation of motion with additional parameters to account for the flow conditions and the cell deformability. Using simulation data at particle-based resolutions for flowing cells and the learned parameters from our framework, we validated the new equation by the motions, mostly rotations, of a human platelet in shear blood flow at various shear stresses and platelet deformability. Our online framework, which surrogates redundant computations in the conventional multiscale modeling by solutions of our learned equation, accelerates the conventional modeling by three orders of magnitude without visible loss of accuracy.
Membrane-Bound Configuration and Lipid Perturbing Effects of Hemagglutinin Subunit 2 N-Terminus Investigated by Computer Simulations
Authors: Michalski Michal , Setny Piotr
Published: January 2022

Hemagglutinin (HA) mediated fusion of influenza virus envelope with host lipid membrane is a critical step warrantying virus entry to the cell. Despite tremendous advances in structural biology methods, the knowledge concerning the details of HA2 subunit insertion into the target membrane and its subsequent bilayer perturbing effect is still rather limited. Herein, based on a set of molecular dynamics simulations, we investigate the structure and interaction with lipid membrane of the N-terminal HA2 region comprising a trimer of fusion peptides (HAfps) tethered by flexible linkers to a fragment of coiled-coil stem structure. We find that, prior to insertion into the membrane, HAfps within the trimers do not sample space individually but rather associate into a compact hydrophobic aggregate. Once within the membrane, they fold into tight helical hairpins, which remain at the lipid-water interface. However, they can also assume stable, membrane-spanning configurations of significantly increased membrane-perturbing potential. In this latter case, HAfps trimers centre around the well-hydrated transmembrane channel-forming distinct, symmetric assemblies, whose wedge-like shape may play a role in promoting membrane curvature. We also demonstrate that, following HAfps insertion, the coiled-coil stem spontaneously tilts to almost membrane-parallel orientation, reflecting experimentally observed configuration adopted in the course of membrane fusion by complete HA2 units at the rim of membrane contact zones.
Agomelatine Prevents Amyloid Plaque Deposition, Tau Phosphorylation, and Neuroinflammation in APP/PS1 Mice
Authors: Yang Xiao-bo , Zu Heng-bing , Zhao Yong-fei , Yao Kai
Published: January 2022

Agomelatine, an agonist of melatonergic MT1 and MT2 receptors and a selective 5-hydroxytryptamine 2C receptor antagonist, is widely applied in treating depression and insomnia symptoms in several neurogenerative diseases. However, the neuroprotective effect of agomelatine in Alzheimer’s disease (AD) is less known. In this study, a total of 30 mice were randomly divided into three groups, namely, wild type (WT), APP/PS1, and agomelatine (50 mg/kg). After 30 days, the Morris water maze was performed to test the cognitive ability of mice. Then, all mice were sacrificed, and the hippocampus tissues were collected for ELISA, Western blot, and immunofluorescence analysis. In this study, we found that agomelatine attenuated spatial memory deficit, amyloid-β (Aβ) deposition, tau phosphorylation, and neuroinflammation in the hippocampus of APP/PS1 mice. Further study demonstrated that agomelatine treatment upregulated the protein expression of DHCR24 and downregulated P-Akt, P-mTOR, p-p70s6k, Hes1, and Notch1 expression. In summary, our results identified that agomelatine could improve cognitive impairment and ameliorate AD-like pathology in APP/PS1 mice via activating DHCR24 signaling and inhibiting Akt/mTOR and Hes1/Notch1 signaling pathway. Agomelatine may become a promising drug candidate in the therapy of AD.