bluuebunny/crossref_metadata_2025 huggingface dataset:
Innovation Through Heterochrony: An Amphioxus Perspective on Telencephalon Origin and Function
Authors: Lacalli Thurston
Published: June 2021

Heterochrony has played a key role in the evolution of invertebrate larval types, producing “head larvae” in diverse taxa, where anterior structures are accelerated and specialized at the expense of more caudal ones. For chordates, judging from amphioxus, the pattern has been more one of repeated acceleration of adult features so that they function earlier in development, thus converting the ancestral larva, whether it was a head larva or not, into something progressively more chordate-like. Recent molecular data on gene expression patterns in the anterior nerve cord of amphioxus point to a similar process being involved in the origin of the telencephalon. As vertebrates evolved, a combination of acceleration and increasing egg size appears here to have allowed the development of a structure that would originally have emerged only gradually in the post-embryonic phase of the life history to be compressed into embryogenesis. The question then is what, in functional terms, makes the telencephalon so important to the survival of post-embryonic ancestral vertebrates that this was adaptively advantageous. A better understanding of the function this brain region performs in amphioxus may help provide the answer.
Sublingual Bacterial Vaccination Reduces Recurrent Infections in Patients With Autoimmune Diseases Under Immunosuppressant Treatment
Authors: Sánchez-Ramón Silvia , Fernández-Paredes Lidia , Saz-Leal Paula , Diez-Rivero Carmen M. , Ochoa-Grullón Juliana , Morado Concepción , Macarrón Pilar , Martínez Cristina , Villaverde Virginia , de la Peña Antonia Rodríguez , Conejero Laura , Hernández-Llano Keyla , Cordero Gustavo , Fernández-Arquero Miguel , Gutierrez Benjamin Fernández- , Candelas Gloria
Published: June 2021

Introduction

Conventional or biologic disease-modifying anti-rheumatic drugs (DMARDs) are the mainstay of treatment for systemic autoimmune disease (SAD). Infectious complications are a major concern in their use.

Objective

To evaluate the clinical benefit of sublingual mucosal polybacterial vaccines (MV130 and MV140), used to prevent recurrent respiratory and urinary tract infections, in patients with SAD and secondary recurrent infections following conventional or biologic DMARDs.

Methods

An observational study in SAD patients with recurrent respiratory tract infections (RRTI) and/or recurrent urinary tract infections (RUTI) was carried out. All patients underwent mucosal (sublingual) vaccination with MV130 for RRTI or with MV140 for RUTI daily for 3 months. Clinical evaluation was assessed during 12 months of follow-up after the first dose, i.e., 3 months under treatment and 9 months once discontinued, and compared with the previous year.

Results

Forty-one out of 55 patients completed 1-year follow-up. All patients were on either conventional or biologic DMARDs. A significant decrease in the frequency of RUTI (p<0.001), lower respiratory tract infections (LRTI) (p=0.009) and upper respiratory tract infections (URTI) (p=0.006) at 12-mo with respect to the previous year was observed. Antibiotic prescriptions and unscheduled medical visits decreased significantly (p<0.020) in all groups. Hospitalization rate also declined in patients with RRTI (p=0.019). The clinical benefit demonstrated was concomitant to a significant increase in both anti-S. pneumoniaeIgA and IgG antibodies following MV130 vaccination.

Conclusions

Sublingual polybacterial vaccines prevent recurrent infections in patients with SAD under treatment with immunosuppressant therapies, supporting a broad non-specific anti-infectious effect in these patients.
Epitope Classification and RBD Binding Properties of Neutralizing Antibodies Against SARS-CoV-2 Variants of Concern
Authors: Deshpande Ashlesha , Harris Bethany D. , Martinez-Sobrido Luis , Kobie James J. , Walter Mark R.
Published: June 2021

Severe acute respiratory syndrome coronavirus-2 (SAR-CoV-2) causes coronavirus disease 2019 (COVID19) that is responsible for short and long-term disease, as well as death, in susceptible hosts. The receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) protein binds to cell surface angiotensin converting enzyme type-II (ACE2) to initiate viral attachment and ultimately viral pathogenesis. The SARS-CoV-2 S RBD is a major target of neutralizing antibodies (NAbs) that block RBD - ACE2 interactions. In this report, NAb-RBD binding epitopes in the protein databank were classified as C1, C1D, C2, C3, or C4, using a RBD binding profile (BP), based on NAb-specific RBD buried surface area and used to predict the binding epitopes of a series of uncharacterized NAbs. Naturally occurring SARS-CoV-2 RBD sequence variation was also quantified to predict NAb binding sensitivities to the RBD-variants. NAb and ACE2 binding studies confirmed the NAb classifications and determined whether the RBD variants enhanced ACE2 binding to promote viral infectivity, and/or disrupted NAb binding to evade the host immune response. Of 9 single RBD mutants evaluated, K417T, E484K, and N501Y disrupted binding of 65% of the NAbs evaluated, consistent with the assignment of the SARS-CoV-2 P.1 Japan/Brazil strain as a variant of concern (VoC). RBD variants E484K and N501Y exhibited ACE2 binding equivalent to a Wuhan-1 reference SARS-CoV-2 RBD. While slightly less disruptive to NAb binding, L452R enhanced ACE2 binding affinity. Thus, the L452R mutant, associated with the SARS-CoV-2 California VoC (B.1.427/B.1.429-California), has evolved to enhance ACE2 binding, while simultaneously disrupting C1 and C2 NAb classes. The analysis also identified a non-overlapping antibody pair (1213H7 and 1215D1) that bound to all SARS-CoV-2 RBD variants evaluated, representing an excellent therapeutic option for treatment of SARS-CoV-2 WT and VoC strains.
Potential Micro-Plastics Dispersal and Accumulation in the North Sea, With Application to the MSC Zoe Incident
Authors: van der Molen Johan , van Leeuwen Sonja M. , Govers Laura L. , van der Heide Tjisse , Olff Han
Published: June 2021

The fate and effects of microplastics in the marine environment are an increasingly important area of research, policy and legislation. To manage and reduce microplastics in the seas and oceans, and to help understand causes and effects, we need improved understanding of transport patterns, transit times and accumulation areas. In this paper, we use a particle tracking model to investigate the differences in dispersal and accumulation of microplastics with different properties (floating and sinking) in the North Sea. In these simulations, particles were released with a uniform horizontal distribution, and also from rivers at rates proportional to the river runoff. The results showed that floating particles can accumulate temporarily on salinity fronts and in gyres, and are deposited predominantly on west-facing beaches. Sinking particles moved more slowly and less far, accumulated in deeper areas associated with fine sediments, and were deposited more on west- and north-facing beaches. The model was also applied to the MSC Zoe incident of 1 January 2019, in which 342 containers were lost north of the Dutch Wadden islands in the southern North Sea, tracking two types of microplastics with similar properties (∼5mm floating HDPE pellets and ∼0.6mm sinking PS grains) to identify release locations and potential accumulation areas. We used field observations collected by a citizen science initiative (waddenplastic.nl) to constrain the model results. For these simulations, particles were released along the ship’s trajectory and at locations on the trajectory where debris was found. The simulations of the MSC Zoe incident showed that over 90% of floating (∼5mm) HDPE pellets beached within 3–7 weeks, and predominantly on the more eastern Dutch Wadden Islands in agreement with the field observations, and that most of the sinking (∼0.6mm) PS grains were still at sea after 6 weeks, and a large proportion may have been deposited on German shores. The work is relevant to Descriptor 10 (Marine Litter) of the EU Marine Strategy Framework Directive.
A New Collection Tool-Kit to Sample Microplastics From the Marine Environment (Sediment, Seawater, and Biota) Using Citizen Science
Authors: Paradinas Lola M. , James Neil A. , Quinn Brian , Dale Andrew , Narayanaswamy Bhavani E.
Published: June 2021

Microplastics (plastic particles ≤ 5 mm) have been studied extensively in coastal areas around the world in several habitats. Nevertheless, understanding and explaining the temporal and spatial occurrence and dynamics of microplastics is challenging. For the first time, three environmental variables were studied at six locations at the same time for each season over a year, along the North and West coasts of Scotland. Surface water was collected with a pole water sampler from the shore whilst beach sediment was sampled using glass jars, and mussels were the target organism collected. Concentrations of microplastics ranged from 0 to 6 ± 1.50 particles per l of surface water. In beach sediment, microplastics concentrations ranged from 0 to 0.37 ± 0.12 particles per g.dw, whilst for mussels it ranged from 0 to 23.81 particles per g.ww. This study was designed to determine the presence of microplastics as well as extend the temporal and geographical scales. We developed a simple, cost-effective and practical tool-kit to collect microplastics from the coastal environment and engaged the public in scientific research. The tool-kit was designed to take into account the latest recommendations for sampling each environmental substrate, whilst being practical for citizen scientists to use. This research demonstrates that using a semi-structured to structured project with a defined sampling approach including the participation of the public with local knowledge can be an effective way to monitor microplastics in the marine environment along the Scottish coastline. This approach, can be adapted to other projects monitoring microplastics to increase the use of citizen science in projects, allowing more studies to take place, more samples to be collected, and a greater understanding of the occurrence and the potential impact of microplastics in the environment.
The Distribution Pattern of Marine Bivalve Death Assemblage From the Western Margin of Bay of Bengal and Its Oceanographic Determinants
Authors: Chattopadhyay Devapriya , Sarkar Deepjay , Bhattacherjee Madhura
Published: June 2021

The global pattern of shallow marine biodiversity is constructed primarily using the data from extra-tropical sites. A severe knowledge gap in the shallow benthic diversity exists for the tropical Indian Ocean, especially along the coastline of peninsular India. Latitudinal biodiversity gradient (LBG)—a poleward decrease in diversity, even though accepted as a pervasive global pattern, often differs from regional trends. Although several oceanographic variables are known to influence regional patterns, their relative effect in shaping the shallow benthic community in tropical seas remains unclear. The east coast of India bordering the Bay of Bengal (BoB) presents a 2,500 km stretch (8–22°N) of tropical coastline with a spatial variation in oceanographic parameters including freshwater mixing, primary productivity, temperature, and shelf area. Here, we documented the marine bivalve distribution using spatially-temporally averaged beach samples and evaluated their relationship with the oceanographic variables. Our data reveal the existence of a highly diverse fauna, comparable to other tropical shallow marine sites. Overall species composition reflects a typical assemblage of the Indian Ocean, dominated by Veneridae but shows an uncharacteristically low proportion of Tellinidae and Lucinidae. The latitudinal variation in diversity shows a mid-latitude drop at around 14°N—a pattern inconsistent with the prediction of latitudinal biodiversity gradient (LBG). The functional groups are dominated by infauna (65%), unattached groups (69%), and suspension feeders (87%). There is only a slight difference in species composition between southern and the northern sites pointing to a predominantly continuous circulation and considerable mixing within the BoB. Productivity range, shelf area, and salinity emerge as best predictors of the species richness. All environmental variables together explain the species composition across the latitudinal bins satisfactorily. The species composition of the east coast shows no distinct nature in comparison to the Indo-Malayan biodiversity hotspot; the proximity to this hotspot and biological exchange with it may have contributed to the high diversity of the east coast fauna. Our study highlights the complex interplay between multiple oceanographic variables in determining the distribution and diversity of tropical shallow marine benthos at a regional scale generating biodiversity patterns that are at odds with global trends such as LBG.
Polyblend Nanofibers to Regenerate Gingival Tissue: A Preliminary In Vitro Study
Authors: Canciani Elena , Gagliano Nicoletta , Paino Francesca , Amler Evžen , Divin Radek , Denti Luca , Henin Dolaji , Fiorati Andrea , Dellavia Claudia
Published: June 2021

Aim: The regeneration of small periodontal defects has been considered an important divide and challenging issue for dental practitioners. The aim of this preliminary in vitro study was to analyze the effects of polycaprolactone (PCL) nanofibers enriched with hyaluronic acid and vitamin E vs. nude nanofibers on gingival fibroblasts activity, an innovative graft for periodontal soft tissue regeneration purposes.

Methods: Nanofibers were produced in PCL (NF) or PCL enriched with hyaluronic acid and vitamin E (NFE) by electrospinning technique. NF and NFE were stereologically and morphologically characterized by scanning electron microscope (SEM), and composition was analyzed by infrared spectroscopy. Human fibroblasts were obtained from one gingival tissue fragment (HGF) and then seeded on NF, NFE, and plastic (CT). Cell adhesion and morphology were evaluated using SEM at 24 h and cell viability after 24, 48, and 72 h by alamarBlue® assay. Gene expression for COL-I, LH2b, TIMP-1, PAX, and VNC was analyzed by real-time RT-PCR in samples run in triplicate and GAPDH was used as housekeeping gene. Slot blot analysis was performed and immunoreactive bands were revealed for MMP-1 and COL-I. YAP and p-YAP were analyzed by Western blot and membranes were reprobed by α-tubulin. Statistical analysis was performed.

Results: IR spectrum revealed the presence of PCL in NF and PCL and vitamin E and hyaluronic acid in NFE. At 24 h, HGF adhered on NF and NFE conserving fibroblast like morphology. At 72 h from seeding, statistically significant differences were found in proliferation of HGF cultured on NF compared to NFE. Expression of genes (LH2b, TIMP-1, and MMP-1) and proteins (COL-I) related to collagen turnover revealed a reduction of COL-1 secretion in cells cultured on NF and NFE compared to CT; however, NFE stimulated cross-linked collagen deposition. Mechanosensor genes (PAX, VNC, and YAP) were upregulated in HGF on NF while they were decreased in cells grown on NFE.

Conclusion: Preliminary data suggest that PCL-enriched nanofibers could represent a support to induce HGF proliferation, adhesion, collagen cross-linking, and to reduce collagen degradation, therefore favoring collagen deposition in gingival connective tissue.
Graft Failure in Patients With Hematological Malignancies: A Successful Salvage With a Second Transplantation From a Different Haploidentical Donor
Authors: Sun Yu-Qian , Wang Yu , Wang Feng-Rong , Yan Chen-Hua , Cheng Yi-Fei , Chen Yu-Hong , Zhang Yuan-Yuan , Han Ting-Ting , Han Wei , Suo Pan , Xu Lan-Ping , Zhang Xiao-Hui , Liu Kai-Yan , Huang Xiao-Jun
Published: June 2021

Graft failure (GF) is a fatal complication of allogeneic stem cell transplantation, especially after haploidentical transplantation. The mortality of GF is nearly 100% without an effective salvage method. A second transplantation is usually necessary to save the patient's life. However, there is no standardized regimen, and the outcome is usually disappointing. We report on a prospective single-center study using a reduced-intensity conditioning regimen with different haploidentical donors (HIDs). Patients with GF after the first transplantation were enrolled in a prospective single-arm clinical trial (ClinicalTrials.Gov ID: NCT03717545) at the Peking University Institute of Hematology. The conditioning regimen consisted of fludarabine (30 mg/m2) (days−6 to−2) and cyclophosphamide (1,000 mg/m2/day) (days−5 to−4). Patients underwent a second transplant from a different HID using a granulocyte colony-stimulating factor primed bone marrow and peripheral blood stem cells. The primary outcome was neutrophil engraftment at day 28. The secondary outcomes included platelet engraftment at day 100, transplant-related mortality (TRM) at day 30, TRM at day 100, and overall survival (OS) at 1 year. From March 2018 to June 2020, 13 patients were enrolled in this clinical trial. Of the 13 patients, five had acute myeloid leukemia, five had acute lymphoblastic leukemia, two had myelodysplastic syndromes, and one had a non-Hodgkin lymphoma. The median age at first transplantation was 38 years (range, 8–55 years). As for the first transplantation, 11 patients underwent haploidentical transplantations and two underwent unrelated donor transplantations. At the time of GF, three patients had complete donor chimerism, five had mixed chimerism, and five had complete recipient chimerism. The median time from the first transplantation to the second transplantation was 49 (range 35–120) days. The medians of infused cell doses were as follows: mononuclear cells 7.93 (5.95–12.51) × 108/kg and CD34 + cells 2.28 (0.75–5.57) × 106/kg. All 13 patients achieved neutrophil engraftment after the second transplantation, with a median engraftment time of 11 (range 10–20) days after transplantation. The platelet engraftment rate on day 100 after transplantation was 76.9%. The TRMs at day 30, day 100, and 1-year were 0, 0, and 23.1%, respectively. The OS and disease-free survival at 1-year were 56.6 and 48.4%, respectively. For patients with GF after first transplantation, a second transplantation using a fludarabine/cyclophosphamide regimen from a different HID was a promising salvage option. Further investigation is needed to confirm the suitability of this method.
Analysis of the Impact of Medical Features and Risk Prediction of Acute Kidney Injury for Critical Patients Using Temporal Electronic Health Record Data With Attention-Based Neural Network
Authors: Chen Zhimeng , Chen Ming , Sun Xuri , Guo Xieli , Li Qiuna , Huang Yinqiong , Zhang Yuren , Wu Lianwei , Liu Yu , Xu Jinting , Fang Yuming , Lin Xiahong
Published: June 2021

Acute kidney injury (AKI) is one of the most severe consequences of kidney injury, and it will also cause or aggravate the complications by the fast decline of kidney excretory function. Accurate AKI prediction, including the AKI case, AKI stage, and AKI onset time interval, can provide adequate support for effective interventions. Besides, discovering how the medical features affect the AKI result may also provide supporting information for disease treatment. An attention-based temporal neural network approach was employed in this study for AKI prediction and for the analysis of the impact of medical features from temporal electronic health record (EHR) data of patients before AKI diagnosis. We used the publicly available dataset provided by the Medical Information Mart for Intensive Care (MIMIC) for model training, validation, and testing, and then the model was applied in clinical practice. The improvement of AKI case prediction is around 5% AUC (area under the receiver operating characteristic curve), and the AUC value of AKI stage prediction on AKI stage 3 is over 82%. We also analyzed the data by two steps: the associations between the medical features and the AKI case (positive or inverse) and the extent of the impact of medical features on AKI prediction result. It shows that features, such as lactate, glucose, creatinine, blood urea nitrogen (BUN), prothrombin time (PT), and partial thromboplastin time (PTT), are positively associated with the AKI case, while there are inverse associations between the AKI case and features such as platelet, hemoglobin, hematocrit, urine, and international normalized ratio (INR). The laboratory test features such as urine, glucose, creatinine, sodium, and blood urea nitrogen and the medication features such as nonsteroidal anti-inflammatory drugs, agents acting on the renin–angiotensin system, and lipid-lowering medication were detected to have higher weights than other features in the proposed model, which may imply that these features have a great impact on the AKI case.
Investigation of Coagulation Biomarkers to Assess Clinical Deterioration in SARS-CoV-2 Infection
Authors: Billoir Paul , Alexandre Kevin , Duflot Thomas , Roger Maxime , Miranda Sébastien , Goria Odile , Joly Luc Marie , Demeyere Mathieu , Feugray Guillaume , Brunel Valery , Etienne Manuel , Le Cam Duchez Véronique
Published: June 2021

Since December 2019, a pandemic caused by a new coronavirus has spread to more than 170 countries around the world. Worsening infected patients requiring intensive care unit (ICU) admission associated with 30% of mortality. A part of worsening is induced by hemostasis deregulation. The aim of this study was to investigate the association of coagulation activation in COVID-19 progression. Thirty-five of the 99 patients got clinically worse. The final model of the logistic regression analysis revealed that O2 requirement (RR = 7.27 [1.50–19.31]), monocytes below 0.2G/L (RR = 2.88 [1.67–3.19]), fibrinogen levels (RR = 1.45 [1.17–1.82] per g/L increase), prothrombin fragments 1+2 higher than 290 pM (RR = 2.39 [1.20–3.30]), and thrombin peak (RR = 1.28 [1.03–1.59] per 50 nM increase) were associated with an increased risk of clinical worsening. A fibrinogen level threshold of 5.5 g/L, a thrombin peak measurement threshold of 99 pM, and O2 requirement associated with clinical outcome in more than 80% of our cohort. In conclusion, we identified fibrinogen and thrombin peak at admission as coagulation biomarkers associated with an increased risk of ICU admission or death. This finding allows initiating steroids and triage for worsening patients. Our results should therefore be considered as exploratory and deserve confirmation.
SARS-CoV-2 Gastrointestinal Infection Prolongs the Time to Recover From COVID-19
Authors: Xu Zhijie , Tang Meiwen , Chen Ping , Cai Hongyu , Xiao Fei
Published: June 2021

Objectives: We previously reported that SARS-CoV-2 infects the gastrointestinal (GI) epithelium. In this study, we aimed to explore the impact of SARS-CoV-2 GI infection on clinical outcomes of COVID-19.

Materials and Methods: For this retrospective cohort study, 104 patients with COVID-19 were classified into a SARS-CoV-2 GI infection group and a non-infection group. The primary endpoint was the time of negative conversion of SARS-CoV-2 RNA in respiratory tract samples. The secondary outcome was the time of hospitalization for COVID-19.

Results: Patients with SARS-CoV-2 GI infection had a longer duration of positive SARS-CoV-2 RNA in respiratory tract samples (median 12.0 days [95% CI: 10.0–13.2] vs. 9.0 days [95% CI: 7.5–10.5]; HR 0.575 [95% CI: 0.386–0.857]; P = 0.003) and hospitalization (median 28.0 days [95% CI: 23.2–32.8] vs. 15.0 days [95% CI: 13.6–16.4]; HR 0.149 [95% CI: 0.087–0.252]; P < 0.001) than patients without SARS-CoV-2 GI infection. Subgroup analyses for sex, age, epidemiological history, clinical classification and antiviral treatment showed consistent results.

Conclusion: Our study indicates that SARS-CoV-2 GI infection prolongs the duration of SARS-CoV-2 shedding and hospitalization in the patients with COVID-19. More attention should be paid to SARS-CoV-2 GI infection of COVID-19 and fecal SARS-CoV-2 RNA test should be completed in time.
Analysis of Two SusE-Like Enzymes From Bacteroides thetaiotaomicron Reveals a Potential Degradative Capacity for This Protein Family
Authors: Stevenson James , Ngo Maria , Brandt Alicia , Weadge Joel T. , Suits Michael D. L.
Published: June 2021

Bacteroides thetaiotaomicron is a major constituent of the human gut microbiome and recognized as a prolific degrader of diverse and complex carbohydrates. This capacity is due to the large number of glycan-depolymerization and acquisition systems that are encoded by gene clusters known as polysaccharide utilization loci (PUL), with the starch utilization system (Sus) serving as the established model. Sharing features with the Sus are Sus-like systems, that require the presence of a specific membrane transporter and surface lipoprotein to be classified as Sus-like. Sus-like import loci are extremely varied with respect to any additional protein components encoded, that would effectively modify the functionality of the degradative and import action of each locus. Herein we have identified eight Sus-like systems in B. thetaiotaomicron that share the feature of a homologous SusE-like factor encoded immediately downstream from the transporter/lipoprotein duo susC/D. Two SusE-like proteins from these systems, BT2857 and BT3158, were characterized by X-ray crystallography and BT2857 was further analyzed by small-angle X-ray scattering. The SusE-like proteins were found to be composed of a conserved three domain architecture: a partially disordered N-terminal domain that is predicted to be proximal to the membrane and structurally homologous to an FN3-like bundle, a middle β-sandwich domain, and a C-terminal domain homologous to family 32 carbohydrate-binding modules, that bind to galactose. Structural comparisons of SusE with SusE-like proteins suggested only a small structural divergence has occurred. However, functional analyses with BT2857 and BT3158 revealed that the SusE-like proteins exhibited galactosidase activity with para-nitrophenyl-β-D-galactopyranoside and α-(1,4)-lactose substrates, that has not been demonstrated for SusE proteins. Using a series of domain truncations of BT2857, the predominant β-D-galactosidase activity is suggested to be localized to the C-terminal DUF5126 domain that would be most distal from the outer membrane. The expanded functionality we have observed with these SusE-like proteins provides a plausible explanation of how Sus-like systems are adapted to target more diverse groups of carbohydrates, when compared to their Sus counterparts.
Incidence and Effects of Acquisition of the Phage-Encoded ssa Superantigen Gene in Invasive Group A Streptococcus
Authors: Chiang-Ni Chuan , Liu Yen-Shan , Lin Chieh-Yu , Hsu Chih-Yun , Shi Yong-An , Chen Yi-Ywan M. , Lai Chih-Ho , Chiu Cheng-Hsun
Published: June 2021

The acquisition of the phage-encoded superantigen ssa by scarlet fever-associated group A Streptococcus (Streptococcus pyogenes, GAS) is found in North Asia. Nonetheless, the impact of acquiring ssa by GAS in invasive infections is unclear. This study initially analyzed the prevalence of ssa+ GAS among isolates from sterile tissues and blood. Among 220 isolates in northern Taiwan, the prevalence of ssa+ isolates increased from 1.5% in 2008–2010 to 40% in 2017–2019. Spontaneous mutations in covR/covS, which result in the functional loss of capacity to phosphorylate CovR, are frequently recovered from GAS invasive infection cases. Consistent with this, Phostag western blot results indicated that among the invasive infection isolates studied, 10% of the ssa+ isolates lacked detectable phosphorylated CovR. Transcription of ssa is upregulated in the covS mutant. Furthermore, in emm1 and emm12 covS mutants, ssa deletion significantly reduced their capacity to grow in human whole blood. Finally, this study showed that the ssa gene could be transferred from emm12-type isolates to the emm1-type wild-type strain and covS mutants through phage infection and lysogenic conversion. As the prevalence of ssa+ isolates increased significantly, the role of streptococcal superantigen in GAS pathogenesis, particularly in invasive covR/covS mutants, should be further analyzed.
Fungal Interactions and Host Tree Preferences in the Spruce Bark Beetle Ips typographus
Authors: Tanin Sifat Munim , Kandasamy Dineshkumar , Krokene Paal
Published: June 2021

The spruce bark beetleIps typographusis the most damaging pest in European spruce forests and has caused great ecological and economic disturbances in recent years. Although native to Eurasia,I. typographushas been intercepted more than 200 times in North America and could establish there as an exotic pest if it can find suitable host trees. Usingin vitrobioassays, we compared the preference ofI. typographusfor its coevolved historical host Norway spruce (Picea abies) and two non-coevolved (naïve) North American hosts: black spruce (Picea mariana) and white spruce (Picea glauca). Additionally, we tested howI. typographusresponded to its own fungal associates (conspecific fungi) and to fungi vectored by the North American spruce beetleDendroctonus rufipennis(allospecific fungi). All tested fungi were grown on both historical and naïve host bark media. In a four-choice Petri dish bioassay,I. typographusreadily tunneled into bark medium from each of the three spruce species and showed no preference for the historical host over the naïve hosts. Additionally, the beetles showed a clear preference for bark media colonized by fungi and made longer tunnels in fungus-colonized media compared to fungus-free media. The preference for fungus-colonized media did not depend on whether the medium was colonized by conspecific or allospecific fungi. Furthermore, olfactometer bioassays demonstrated that beetles were strongly attracted toward volatiles emitted by both con- and allospecific fungi. Collectively, these results suggest thatI. typographuscould thrive in evolutionary naïve spruce hosts if it becomes established in North America. Also,I. typographuscould probably form and maintain new associations with local allospecific fungi that might increase beetle fitness in naïve host trees.
Indications for Inpatient Magnetoencephalography in Children – An Institution’s Experience
Authors: Watkins Michael W. , Shah Ekta G. , Funke Michael E. , Garcia-Tarodo Stephanie , Shah Manish N. , Tandon Nitin , Maestu Fernando , Laohathai Christopher , Sandberg David I. , Lankford Jeremy , Thompson Stephen , Mosher John , Von Allmen Gretchen
Published: June 2021

Magnetoencephalography (MEG) is recognized as a valuable non-invasive clinical method for localization of the epileptogenic zone and critical functional areas, as part of a pre-surgical evaluation for patients with pharmaco-resistant epilepsy. MEG is also useful in localizing functional areas as part of pre-surgical planning for tumor resection. MEG is usually performed in an outpatient setting, as one part of an evaluation that can include a variety of other testing modalities including 3-Tesla MRI and inpatient video-electroencephalography monitoring. In some clinical circumstances, however, completion of the MEG as an inpatient can provide crucial ictal or interictal localization data during an ongoing inpatient evaluation, in order to expedite medical or surgical planning. Despite well-established clinical indications for performing MEG in general, there are no current reports that discuss indications or considerations for completion of MEG on an inpatient basis. We conducted a retrospective institutional review of all pediatric MEGs performed between January 2012 and December 2020, and identified 34 cases where MEG was completed as an inpatient. We then reviewed all relevant medical records to determine clinical history, all associated diagnostic procedures, and subsequent treatment plans including epilepsy surgery and post-surgical outcomes. In doing so, we were able to identify five indications for completing the MEG on an inpatient basis: (1) super-refractory status epilepticus (SRSE), (2) intractable epilepsy with frequent electroclinical seizures, and/or frequent or repeated episodes of status epilepticus, (3) intractable epilepsy with infrequent epileptiform discharges on EEG or outpatient MEG, or other special circumstances necessitating inpatient monitoring for successful and safe MEG data acquisition, (4) MEG mapping of eloquent cortex or interictal spike localization in the setting of tumor resection or other urgent neurosurgical intervention, and (5) international or long-distance patients, where outpatient MEG is not possible or practical. MEG contributed to surgical decision-making in the majority of our cases (32 of 34). Our clinical experience suggests that MEG should be considered on an inpatient basis in certain clinical circumstances, where MEG data can provide essential information regarding the localization of epileptogenic activity or eloquent cortex, and be used to develop a treatment plan for surgical management of children with complicated or intractable epilepsy.
Reciprocal Relationship Between Calcium Signaling and Circadian Clocks: Implications for Calcium Homeostasis, Clock Function, and Therapeutics
Authors: Cavieres-Lepe Javier , Ewer John
Published: June 2021

Graphical Abstract

Reciprocal relationship between Ca2+ signaling and the circadian clock. In Drosophila and mice, circadian clocks impose a daily rhythmicity to Ca2+ signaling; and, conversely, Ca2+ rhythms and signaling contribute to transmitting daily external signals to the clock TTFL. This bidirectional regulation is critical to the daily rhythmicity of many physiological and behavioral processes.
Selenium in Human Health and Gut Microflora: Bioavailability of Selenocompounds and Relationship With Diseases
Authors: Ferreira Rannapaula Lawrynhuk Urbano , Sena-Evangelista Karine Cavalcanti Maurício , de Azevedo Eduardo Pereira , Pinheiro Francisco Irochima , Cobucci Ricardo Ney , Pedrosa Lucia Fatima Campos
Published: June 2021

This review covers current knowledge of selenium in the dietary intake, its bioavailability, metabolism, functions, biomarkers, supplementation and toxicity, as well as its relationship with diseases and gut microbiota specifically on the symbiotic relationship between gut microflora and selenium status. Selenium is essential for the maintenance of the immune system, conversion of thyroid hormones, protection against the harmful action of heavy metals and xenobiotics as well as for the reduction of the risk of chronic diseases. Selenium is able to balance the microbial flora avoiding health damage associated with dysbiosis. Experimental studies have shown that inorganic and organic selenocompounds are metabolized to selenomethionine and incorporated by bacteria from the gut microflora, therefore highlighting their role in improving the bioavailability of selenocompounds. Dietary selenium can affect the gut microbial colonization, which in turn influences the host's selenium status and expression of selenoproteoma. Selenium deficiency may result in a phenotype of gut microbiota that is more susceptible to cancer, thyroid dysfunctions, inflammatory bowel disease, and cardiovascular disorders. Although the host and gut microbiota benefit each other from their symbiotic relationship, they may become competitors if the supply of micronutrients is limited. Intestinal bacteria can remove selenium from the host resulting in two to three times lower levels of host's selenoproteins under selenium-limiting conditions. There are still gaps in whether these consequences are unfavorable to humans and animals or whether the daily intake of selenium is also adapted to meet the needs of the bacteria.
Transarterial Chemoembolization in Treatment-Naïve and Recurrent Hepatocellular Carcinoma: A Propensity-Matched Outcome and Risk Signature Analysis
Authors: Liu Yiming , Ren Yanqiao , Ge Sangluobu , Xiong Bin , Zhou Guofeng , Feng Gansheng , Song Songlin , Zheng Chuansheng
Published: June 2021

Objectives

The purpose of this study was to evaluate the efficacy and safety of transarterial chemoembolization (TACE) in the treatment of patients with treatment-naïve hepatocellular carcinoma (TN-HCC) and recurrent HCC (R-HCC). In addition, risk signature analysis was performed to accurately assess patients’ recurrence and survival.

Methods

This retrospective study assessed the consecutive medical records of TN-HCC and R-HCC patients from January 2014 to December 2018. In order to reduce the patient selection bias, propensity score matching (PSM) analysis was applied. Conditional inference tree was used to establish a risk signature.

Results

A total of 401 eligible patients were included in our study, including 346 patients in the TN-HCC group and 55 patients in the R-HCC group. Forty-seven pairs of patients were chosen after the PSM analysis. Before the PSM analysis, the objective tumor regression (ORR) and disease control rate (DCR) of R-HCC patients were better than that of TN-HCC patients; however, after the PSM analysis, there was no significant difference in the ORR and DCR between the two groups (P>0.05). Before the PSM analysis, the median overall survival (OS) and progression-free survival (PFS) in the R-HCC group were significantly greater than those of the TN-HCC group (OS: 24 months vs. 18 months, P =0.004; PFS: 9 months vs. 6 months, P =0.012). However, after the PSM analysis, the median OS and PFS in the R-HCC group were inferior to those in the TN-HCC group (OS: 24 months vs. 33 months, P= 0.0035; PFS: 10 months vs. 12 months, P = 0.01). The conditional inference tree divided patients into different subgroups according to tumor size, BCLC stage, and TACE sessions and shared different hazards ratio to recurrence or survival.

Conclusion

Patients with R-HCC treated with TACE achieved satisfactory results, although survival after the PSM analysis was not as good as in the TN-HCC group. In addition, risk signature based on conditional inference tree analysis can more accurately predict the recurrence and survival in both groups of patients.
Blood-Based Biomarkers for Glioma in the Context of Gliomagenesis: A Systematic Review
Authors: Ali Hamza , Harting Romée , de Vries Ralph , Ali Meedie , Wurdinger Thomas , Best Myron G.
Published: June 2021

Background

Gliomas are the most common and aggressive tumors of the central nervous system. A robust and widely used blood-based biomarker for glioma has not yet been identified. In recent years, a plethora of new research on blood-based biomarkers for glial tumors has been published. In this review, we question which molecules, including proteins, nucleic acids, circulating cells, and metabolomics, are most promising blood-based biomarkers for glioma diagnosis, prognosis, monitoring and other purposes, and align them to the seminal processes of cancer.

Methods

The Pubmed and Embase databases were systematically searched. Biomarkers were categorized in the identified biomolecules and biosources. Biomarker characteristics were assessed using the area under the curve (AUC), accuracy, sensitivity and/or specificity values and the degree of statistical significance among the assessed clinical groups was reported.

Results

7,919 references were identified: 3,596 in PubMed and 4,323 in Embase. Following screening of titles, abstracts and availability of full-text, 262 articles were included in the final systematic review. Panels of multiple biomarkers together consistently reached AUCs >0.8 and accuracies >80% for various purposes but especially for diagnostics. The accuracy of single biomarkers, consisting of only one measurement, was far more variable, but single microRNAs and proteins are generally more promising as compared to other biomarker types.

Conclusion

Panels of microRNAs and proteins are most promising biomarkers, while single biomarkers such as GFAP, IL-10 and individual miRNAs also hold promise. It is possible that panels are more accurate once these are involved in different, complementary cancer-related molecular pathways, because not all pathways may be dysregulated in cancer patients. As biomarkers seem to be increasingly dysregulated in patients with short survival, higher tumor grades and more pathological tumor types, it can be hypothesized that more pathways are dysregulated as the degree of malignancy of the glial tumor increases. Despite, none of the biomarkers found in the literature search seem to be currently ready for clinical implementation, and most of the studies report only preliminary application of the identified biomarkers. Hence, large-scale validation of currently identified and potential novel biomarkers to show clinical utility is warranted.
Prognostic Implication of a Novel Metabolism-Related Gene Signature in Hepatocellular Carcinoma
Authors: Yuan Chaoyan , Yuan Mengqin , Chen Mingqian , Ouyang Jinhua , Tan Wei , Dai Fangfang , Yang Dongyong , Liu Shiyi , Zheng Yajing , Zhou Chenliang , Cheng Yanxiang
Published: June 2021

Background

Hepatocellular carcinoma (HCC) is one of the main causes of cancer-associated deaths globally, accounts for 90% of primary liver cancers. However, further studies are needed to confirm the metabolism-related gene signature related to the prognosis of patients with HCC.

Methods

Using the “limma” R package and univariate Cox analysis, combined with LASSO regression analysis, a metabolism-related gene signature was established. The relationship between the gene signature and overall survival (OS) of HCC patients was analyzed. RT-qPCR was used to evaluate the expression of metabolism-related genes in clinical samples. GSEA and ssGSEA algorithms were used to evaluate differences in metabolism and immune status, respectively. Simultaneously, data downloaded from ICGC were used as an external verification set.

Results

From a total of 1,382 metabolism-related genes, a novel six-gene signature (G6PD, AKR1B15, HMMR, CSPG5, ELOVL3, FABP6) was constructed based on data from TCGA. Patients were divided into two risk groups based on risk scores calculated for these six genes. Survival analysis showed a significant correlation between high-risk patients and poor prognosis. ROC analysis demonstrated that the gene signature had good predictive capability, and the mRNA expression levels of the six genes were upregulated in HCC tissues than those in adjacent normal liver tissues. Independent prognosis analysis confirmed that the risk score and tumor grade were independent risk factors for HCC. Furthermore, a nomogram of the risk score combined with tumor stage was constructed. The calibration graph results demonstrated that the OS probability predicted by the nomogram had almost no deviation from the actual OS probability, especially for 3-year OS. Both the C-index and DCA curve indicated that the nomogram provides higher reliability than the tumor stage and risk scores. Moreover, the metabolic and immune infiltration statuses of the two risk groups were significantly different. In the high-risk group, the expression levels of immune checkpoints, TGF-β, and C-ECM genes, whose functions are related to immune escape and immunotherapy failure, were also upregulated.

Conclusions

In summary, we developed a novel metabolism-related gene signature to provide more powerful prognostic evaluation information with potential ability to predict the immunotherapy efficiency and guide early treatment for HCC.
PD-1 Expression Status on CD8+ Tumour Infiltrating Lymphocytes Associates With Survival in Cervical Cancer
Authors: Fan Peiwen , Li Xi , Feng Yaning , Cai Hongchao , Dong Danning , Peng Yanchun , Yao Xuan , Guo Yuping , Ma Miaomiao , Dong Tao , Wang Ruozheng
Published: June 2021

Despite the expansion of PD-1 checkpoint blockade to multiple types of cancer, whether the programmed cell death 1 (PD-1) expression status on CD8+ tumour infiltrating lymphocytes (TILs) could be a prognostic factor in cervical cancer is still unclear. In this study, we performed ex vivo phenotypic analysis of PD-1 expression on CD8+ TILs by flow cytometry from 47 treatment-naïve cervical cancer patients. With a median follow-up of 26.1 months (95% confidence interval [CI], 24-28.2 months), we then linked the quantitative cellular expression results to progression-free survival and overall survival. Based on the intensity of PD-1 expression, we further categorised the cervical cancer patients into PD-1high expressers (29.8%, 14/47) and PD-1low expressers (70.2%, 33/47). Multivariate analysis revealed that PD-1high expressers are correlated with early recurrence (HR, 5.91; 95% CI, 1.03-33.82; P= 0.046). Univariate analysis also demonstrated that PD-1high expressers are associated with poor overall survival in cervical cancer (HR, 5.365; 95% CI, 1.55-18.6; P=0.008). Moreover, our study also demonstrated that CD8+/CD4+ TIL ratio and HPV infection status are risk factors for early relapse and mortality in cervical cancer patients. In conclusion, this study confirms that PD-1 expression status is an independent prognostic factor for progression free survival in cervical cancer. These findings could be important in predicting the relapse of cervical cancer as a cellular diagnosis method and could be important knowledge for the selection of prospective PD-1 blockade candidates.
Case Report: Solitary Extramedullary Plasmacytoma in the Cervix Misdiagnosed as Cervical Cancer
Authors: Wang Ji , Jiang Lin , Ma Xuejin , Li Tingchao , Liu Heng , Chen Xiaoxi , Li Shiguang
Published: June 2021

Solitary plasmacytoma (SP) is a malignant tumor caused by the monoclonal proliferation of plasma cells, representing less than 5% of plasma cell tumors. SP can be categorized into two groups: solitary bone plasmacytoma (SBP) and solitary extramedullary plasmacytoma (SEP). SEP most commonly occurs in the head and neck and is rarely located in the reproductive system. Here, we report a case of a 77-year-old woman with SEP in the cervix who had a 7-day history of vaginal bleeding. Ultrasonography and magnetic resonance imaging (MRI) showed an oval mass in the cervix, which was initially considered as neoplastic lesions and highly suspected to be cervical cancer, but cervical leiomyoma and other benign tumors cannot be completely excluded. Subsequently, cervical biopsy showed that the tumor was SEP, and then the patient underwent surgery. The postoperative pathological diagnosis was also SEP, which confirmed the radiologist’s misjudgment. In conclusion, SEP that occurs in the cervix is remarkably rare, and only nine cases have been reported in the cervix. No case reports to date have described in detail the imaging findings of cervical SEP. This study demonstrates the MRI imaging characteristics of a patient with SEP of the cervix and reviews the imaging findings of SEP reported in the previous literature, in order to provide more extensive insights for radiologists to consider the differential diagnosis of cervical lesions.