bluuebunny/crossref_metadata_2025 huggingface dataset:
Asteroids and Ophiuroids Associated With Sponge Aggregations as a Key to Marine Habitats. A Comparative Analysis Between Avilés Canyons System and El Cachucho, Marine Protected Area
Authors: Manjón-Cabeza Maria Eugenia , Ríos Pilar , García-Guillén Laura María , Macías-Ramírez Aurora , Sánchez Francisco , Rodríguez-Básalo Augusto , Ibarrola Teodoro P. , Cristobo Javier
Published: January 2021

This study analyzes the fauna composition of the community of brittle and sea stars associated with sponge aggregations located in Avilés Canyons System and El Cachucho, Marine Protected Area (MPA). Diverse sampling methods were used depending on bottom morphology, such as rock dredges and specific samplers for sedimentary bottoms, mainly beam trawl models. These banks are made up of sponge and coral species that build a very appropriate substrate for the proliferation of benthic species, which together create Vulnerable Marine Ecosystems that are highly relevant for management and conservation. Among these benthic species, echinoderms are of great interest due to their value as indicators of good habitat. In total, 1261 specimens were collected (934 brittle stars and 327 starfishes), belonging to 42 species (28 ophiuroids and 14 asteroids) from INDEMARES AVILÉS, ECOMARG, and SponGES project surveys. Specimens were distributed among four sponge aggregations (F: fields) that were considered according to the sponge records obtained in the same stations (36). These fields were defined and named based on the five most common sponge species:Aphrocallistes beatrixandRegadrella phoenix(F1: Avilés Canyon);Pheronema carpenteri(F2: Intraslope basin of Le Danois Bank);Asconema setubalense(F3: Le Danois Bank); andNeoschrammeniellaaff.bowerbankii(F4: Corbiro Canyon). Faunistic results show thatOphiactis abyssicola(55.55% occurrence),Brisinga endecacnemos, Ophiolycus purpureus, andPeltaster placenta(33.33%) were the most frequently found species in F1;Psilaster andromeda(80%),Pseudarchaster parelii(60%), andNymphaster arenatus(46.67%) in F2;Ophiura carnea(71.43%) andOphiacantha smitti(42.86%) in F3; andOphiacantha densa, andHenricia caudani(100%) in F4. The asteroid and ophiuroid species collected seem to be composed of four different communities that fit to areas with particular morphological and biological features, related to the presence of species specialized in the use of the resources they can find there. In general, the abiotic factor controlling this structure is depth. This assemblage structure, which favors the dissimilarity between the canyons and the bank, is not so clear, since the deepest stations are located on the intraslope basin of El Cachucho, Marine Protected Area (MPA), therefore, using ita prioricould lead to misunderstandings. Once the structure of the echinoderm community was known, we compared the expected and obtained results to analyze evidence which should prove the existence of any association between echinoderms and sponges, which enabled us to refute the incongruous hypothesis.
Variation in Species Composition, Size and Fitness of Two Multi-Species Sea Turtle Assemblages Using Different Neritic Habitats
Authors: Lamont Margaret M. , Johnson Darren
Published: January 2021

The neritic environment is rich in resources and as such plays a crucial role as foraging habitat for multi-species marine assemblages, including sea turtles. However, this habitat also experiences a wide array of anthropogenic threats. To prioritize conservation funds, targeting areas that support multi-species assemblages is ideal. This is particularly important in the Gulf of Mexico where restoration actions are currently ongoing following the Deepwater Horizon oil spill. To better understand these areas in the Gulf of Mexico, we characterized two multi-species aggregations of sea turtles captured in different neritic habitats. We described species composition and size classes of turtles, and calculated body condition index for 642 individuals of three species captured from 2011 to 2019: 13.6% loggerheads (Caretta caretta), 44.9% Kemp’s ridleys (Lepidochelys kempii) and 41.4% green turtles (Chelonia mydas). Species composition differed between the two sites with more loggerheads captured in seagrass and a greater proportion of green turtles captured in sand bottom. Turtles in sand bottom were smaller and weighed less than those captured in seagrass. Although small and large turtles were captured at both sites, the proportions differed between sites. Body condition index of green turtles was lower in sand habitat than seagrass habitat; there was no difference for Kemp’s ridleys or loggerheads. In general, smaller green turtles had a higher body condition index than larger green turtles. We have identified another habitat type used by juvenile sea turtle species in the northern Gulf of Mexico. In addition, we highlight the importance of habitat selection by immature turtles recruiting from the oceanic to the neritic environment, particularly for green turtles.
Protection of Photosynthesis by Halotolerant Staphylococcus sciuri ET101 in Tomato (Lycoperiscon esculentum) and Rice (Oryza sativa) Plants During Salinity Stress: Possible Interplay Between Carboxylation and Oxygenation in Stress Mitigation
Authors: Taj Zarin , Challabathula Dinakar
Published: January 2021

Tomato (Lycoperiscon esculentum) and rice (Oryza sativa) are the two most important agricultural crops whose productivity is severely impacted by salinity stress. Soil salinity causes an irreversible damage to the photosynthetic apparatus in plants at all developmental stages leading to significant reduction in agricultural productivity. Reduction in photosynthesis is the primary response that is observed in all glycophytic plants during salt stress. Employment of salt-tolerant plant growth-promoting bacteria (PGPB) is an economical and viable approach for the remediation of saline soils and improvement of plant growth. The current study is aimed towards investigating the growth patterns and photosynthetic responses of rice and tomato plants upon inoculation with halotolerant PGPB Staphylococcus sciuri ET101 under salt stress conditions. Tomato and rice plants inoculated with PGPB showed increased growth rate and stimulated root growth, along with higher transpiration rates (E), stomatal conductance (gs), and intracellular CO2 accumulation (Ci). Additionally, correlation of relative water content (RWC) to electrolyte leakage (EL) in tomato and rice plants showed decreased EL in inoculated plants during salt stress conditions, along with higher proline and glycine betaine content. Energy dissipation by non-photochemical quenching (NPQ) and increased photorespiration of 179.47% in tomato and 264.14% in rice plants were observed in uninoculated plants subjected to salinity stress. Furthermore, reduced photorespiration with improved salinity tolerance is observed in inoculated plants. The higher rates of photosynthesis in inoculated plants during salt stress were accompanied by increased quantum efficiency (ΦPSII) and maximum quantum yield (Fv/Fm) of photosystem II. Furthermore, inoculated plants showed increased carboxylation efficiency of RuBisCO, along with higher photosynthetic electron transport rate (ETR) (J) during salinity stress. Although the total cellular ATP levels are drastically affected by salt stress in tomato and rice plants along with increased reactive oxygen species (ROS) accumulation, the restoration of cellular ATP levels in leaves of inoculated plants along with decreased ROS accumulation suggests the protective role of PGPB. Our results reveal the beneficial role of S. sciuri ET101 in protection of photosynthesis and amelioration of salinity stress responses in rice and tomato plants.
Predicted Structural Variability of Mycobacterium tuberculosis PPE18 Protein With Immunological Implications Among Clinical Strains
Authors: Hakim Jill M. C. , Yang Zhenhua
Published: January 2021

Recent advancements in vaccinology have led to the development of the M72/AS01E subunit vaccine, of which the major component is the Mycobacterium tuberculosis (MTB) PPE18 protein. Previous studies have demonstrated the genetic variability of the gene encoding PPE18 protein and the resulting peptide changes in diverse clinical strains of MTB; however, none have modeled the structural changes resulting from these peptide changes and their immunological implications. In this study, we investigated the structural predictions of 29 variant PPE18 proteins previously reported. We found evidence that PPE18 is at least a two-domain protein, with a highly conserved first domain and a largely variable second domain that has different coevolutionary clusters. Further, we investigated putative epitope sites in the clinical variants of PPE18 using prediction software. We found a negative relationship between T-cell epitope number and residue variability, while B-cell epitope likelihood was positively correlated with residue variability. Moreover, we found far more residues in the second domain predicted to be B-cell epitopes compared with the first domain. These results suggest an important functional role of the first domain and a role in immune evasion for the second, which extends our knowledge base of the basic biology of the PPE18 protein and indicates the need for further study into non-traditional immunological responses to TB.
Extracellular Vesicles Derived From Talaromyces marneffei Yeasts Mediate Inflammatory Response in Macrophage Cells by Bioactive Protein Components
Authors: Yang Biao , Wang Jingyu , Jiang Hongye , Lin Huixian , Ou Zihao , Ullah Amir , Hua Yuneng , Chen Juanjiang , Lin Xiaomin , Hu Xiumei , Zheng Lei , Wang Qian
Published: January 2021

Extracellular vesicles (EVs) loaded with proteins, nucleic acids, membrane lipids, and other virulence factors could participate in pathogenic processes in some fungi such as Cryptococcus neoformans and Candida albicans. However, the specific characteristics of EVs derived from Talaromyces marneffei (TM) still have not been figured out yet. In the present study, it has been observed that TM-derived EVs were a heterogeneous group of nanosized membrane vesicles (30–300 nm) under nanoparticle tracking analysis and transmission electron microscopy. The DiI-labeled EVs could be taken up by RAW 264.7 macrophage cells. Incubation of EVs with macrophages would result in increased expression levels of reactive oxygen species, nitric oxide, and some inflammatory factors including interleukin-1β, interleukin-6, interleukin-10, and tumor necrosis factor. Furthermore, the expression of co-stimulatory molecules (CD80, CD86, and MHC-II) was also increased in macrophages stimulated with EVs. The level of inflammatory factors secreted by macrophages showed a significant decrease when EVs were hydrolyzed by protease, while that of DNA and RNA hydrolase treatment remained unchanged. Subsequently, some virulence factors in EVs including heat shock protein, mannoprotein 1, and peroxidase were determined by liquid chromatography–tandem mass spectrometry. Taken together, our results indicated that the TM-derived EVs could mediate inflammatory response and its protein would play a key role in regulating the function of RAW 264.7 macrophage cells.
Genomic Insights of “Candidatus Nitrosocaldaceae” Based on Nine New Metagenome-Assembled Genomes, Including “Candidatus Nitrosothermus” Gen Nov. and Two New Species of “Candidatus Nitrosocaldus”
Authors: Luo Zhen-Hao , Narsing Rao Manik Prabhu , Chen Hao , Hua Zheng-Shuang , Li Qi , Hedlund Brian P. , Dong Zhou-Yan , Liu Bing-Bing , Guo Shu-Xian , Shu Wen-Sheng , Li Wen-Jun
Published: January 2021

“Candidatus Nitrosocaldaceae” are globally distributed in neutral or slightly alkaline hot springs and geothermally heated soils. Despite their essential role in the nitrogen cycle in high-temperature ecosystems, they remain poorly understood because they have never been isolated in pure culture, and very few genomes are available. In the present study, a metagenomics approach was employed to obtain “Ca. Nitrosocaldaceae” metagenomic-assembled genomes (MAGs) from hot spring samples collected from India and China. Phylogenomic analysis placed these MAGs within “Ca. Nitrosocaldaceae.” Average nucleotide identity and average amino acid identity analysis suggested the new MAGs represent two novel species of “Candidatus Nitrosocaldus” and a novel genus, herein proposed as “Candidatus Nitrosothermus.” Key genes responsible for chemolithotrophic ammonia oxidation and a thaumarchaeal 3HP/4HB cycle were detected in all MAGs. Furthermore, genes coding for urea degradation were only present in “Ca. Nitrosocaldus,” while biosynthesis of the vitamins, biotin, cobalamin, and riboflavin were detected in almost all MAGs. Comparison of “Ca. Nitrosocaldales/Nitrosocaldaceae” with other AOA revealed 526 specific orthogroups. This included genes related to thermal adaptation (cyclic 2,3-diphosphoglycerate, and S-adenosylmethionine decarboxylase), indicating their importance for life at high temperature. In addition, these MAGs acquired genes from members from archaea (Crenarchaeota) and bacteria (Firmicutes), mainly involved in metabolism and stress responses, which might play a role to allow this group to adapt to thermal habitats.
Impact of Bacillus on Phthalides Accumulation in Angelica sinensis (Oliv.) by Stoichiometry and Microbial Diversity Analysis
Authors: Feng Wei-Meng , Liu Pei , Yan Hui , Zhang Sen , Shang Er-Xin , Yu Guang , Jiang Shu , Qian Da-Wei , Ma Jun-Wei , Duan Jin-Ao
Published: January 2021

Plant-microorganism interaction in the rhizosphere is thought to play an important role in the formation of soil fertility, transformation and absorption of nutrients, growth and development of medicinal plants, and accumulation of medicinal ingredients. Yet, the role that they play in the phthalides accumulation of Angelica sinensis (Oliv.) Diels remains unclear. In the present study, we report a correlative analysis between rhizosphere microorganisms and phthalides accumulation in A. sinensis from Gansu, China where was the major production areas. Meanwhile, Bacillus was explored the potential functions in the plant growth and phthalide accumulation. Results revealed that the common bacterial species detected in six samples comprised 1150 OTUs which were involved in 368 genera, and predominant taxa include Actinobacteria, Acidobacteria, and Proteobacteria. The average contents of the six phthalides were 4.0329 mg/g. The correlation analysis indicated that 20 high abundance strains showed positive or negative correlations with phthalides accumulation. Flavobacterium, Nitrospira, Gaiella, Bradyrhizobium, Mycobacterium, Bacillus, RB41, Blastococcus, Nocardioides, and Solirubrobacter may be the key strains that affect phthalides accumulation on the genus level. By the plant-bacterial co-culture and fermentation, Bacillus which were isolated from rhizosphere soils can promote the plant growth, biomass accumulation and increased the contents of the butylidenephthalide (36∼415%) while the ligustilide (12∼67%) was decreased. Altogether, there is an interaction between rhizosphere microorganisms and phthalides accumulation in A. sinensis, Bacillus could promote butylidenephthalide accumulation while inhibiting ligustilide accumulation.
Sprawling Quadruped Robot Driven by Decentralized Control With Cross-Coupled Sensory Feedback Between Legs and Trunk
Authors: Suzuki Shura , Kano Takeshi , Ijspeert Auke J. , Ishiguro Akio
Published: January 2021

Quadruped animals achieve agile and highly adaptive locomotion owing to the coordination between their legs and other body parts, such as the trunk, head, and tail, that is, body–limb coordination. This study aims to understand the sensorimotor control underlying body–limb coordination. To this end, we adopted sprawling locomotion in vertebrate animals as a model behavior. This is a quadruped walking gait with lateral body bending used by many amphibians and lizards. Our previous simulation study demonstrated that cross-coupled sensory feedback between the legs and trunk helps to rapidly establish body–limb coordination and improve locomotion performance. This paper presented an experimental validation of the cross-coupled sensory feedback control using a newly developed quadruped robot. The results show similar tendencies to the simulation study. Sensory feedback provides rapid convergence to stable gait, robustness against leg failure, and morphological changes. Our study suggests that sensory feedback potentially plays an essential role in body–limb coordination and provides a robust, sensory-driven control principle for quadruped robots.
Critical and Ictal Phases in Simulated EEG Signals on a Small-World Network
Authors: Nemzer Louis R. , Cravens Gary D. , Worth Robert M. , Motta Francis , Placzek Andon , Castro Victor , Lou Jennie Q.
Published: January 2021

Healthy brain function is marked by neuronal network dynamics at or near the critical phase, which separates regimes of instability and stasis. A failure to remain at this critical point can lead to neurological disorders such as epilepsy, which is associated with pathological synchronization of neuronal oscillations. Using full Hodgkin-Huxley (HH) simulations on a Small-World Network, we are able to generate synthetic electroencephalogram (EEG) signals with intervals corresponding to seizure (ictal) or non-seizure (interictal) states that can occur based on the hyperexcitability of the artificial neurons and the strength and topology of the synaptic connections between them. These interictal simulations can be further classified into scale-free critical phases and disjoint subcritical exponential phases. By changing the HH parameters, we can model seizures due to a variety of causes, including traumatic brain injury (TBI), congenital channelopathies, and idiopathic etiologies, as well as the effects of anticonvulsant drugs. The results of this work may be used to help identify parameters from actual patient EEG or electrocorticographic (ECoG) data associated with ictogenesis, as well as generating simulated data for training machine-learning seizure prediction algorithms.
Auditory Event-Related “Global Effect” Predicts Recovery of Overt Consciousness
Authors: Perez Pauline , Valente Mélanie , Hermann Bertrand , Sitt Jacobo , Faugeras Frédéric , Demeret Sophie , Rohaut Benjamin , Naccache Lionel
Published: January 2021

Objective: To explore whether the presence of an event-related potential (ERP) “global effect” (GE+)—that corresponds to a correlate of conscious processing in the local–global auditory task—predicts behaviorally overt consciousness recovery in a large cohort of patients suffering from disorders of consciousness (DOC).

Methods: We conducted a prospective study on all DOC patients evaluated during the 2009–2018 period. Behavioral examination included Coma Recovery Scale-Revised (CRS-R) scores and bedside high-density EEG recordings. Consciousness recovery was evaluated at 6 months by a structured phone interview. The predictive value of a GE+ was calculated both on survivors and on all patients.

Results: A total of 236 patients with a documented outcome and technically valid EEG recordings could be included. Among them, 66 patients had a GE+ status (28%). Presence of GE+ predicted behaviorally overt consciousness recovery in survivors with high specificity (Sp = 84%) and high positive predictive value (PPV = 80%) but with low sensitivity (Se = 35%) and low negative predictive value (NPV = 42%). Positive likelihood ratio (LR+) of GE+ was superior to LR+ of initial clinical status and of ERP effect indexing unconscious auditory processing [local effect (LE)].

Interpretation: Our results demonstrate that the presence of a bedside ERP GE+ is highly predictive of behaviorally overt consciousness recovery in DOC patients, regardless of the delay, of behavioral status, and of the etiology of brain dysfunction. However, the absence of this effect is not a reliable predictor of negative outcome. This study provides Class III evidence that the presence of an ERP “global effect” predicts consciousness recovery in DOC patients.
Revisiting the Neuropathology of Sudden Infant Death Syndrome (SIDS)
Authors: Blackburn Jessica , Chapur Valeria F. , Stephens Julie A. , Zhao Jing , Shepler Anne , Pierson Christopher R. , Otero José Javier
Published: January 2021

Background: Sudden infant death syndrome (SIDS) is one of the leading causes of infant mortality in the United States (US). The extent to which SIDS manifests with an underlying neuropathological mechanism is highly controversial. SIDS correlates with markers of poor prenatal and postnatal care, generally rooted in the lack of access and quality of healthcare endemic to select racial and ethnic groups, and thus can be viewed in the context of health disparities. However, some evidence suggests that at least a subset of SIDS cases may result from a neuropathological mechanism. To explain these issues, a triple-risk hypothesis has been proposed, whereby an underlying biological abnormality in an infant facing an extrinsic risk during a critical developmental period SIDS is hypothesized to occur. Each SIDS decedent is thus thought to have a unique combination of these risk factors leading to their death. This article reviews the neuropathological literature of SIDS and uses machine learning tools to identify distinct subtypes of SIDS decedents based on epidemiological data.

Methods: We analyzed US Period Linked Birth/Infant Mortality Files from 1990 to 2017 (excluding 1992–1994). Using t-SNE, an unsupervised machine learning dimensionality reduction algorithm, we identified clusters of SIDS decedents. Following identification of these groups, we identified changes in the rates of SIDS at the state level and across three countries.

Results: Through t-SNE and distance based statistical analysis, we identified three groups of SIDS decedents, each with a unique peak age of death. Within the US, SIDS is geographically heterogeneous. Following this, we found low birth weight and normal birth weight SIDS rates have not been equally impacted by implementation of clinical guidelines. We show that across countries with different levels of cultural heterogeneity, reduction in SIDS rates has also been distinct between decedents with low vs. normal birth weight.

Conclusions: Different epidemiological and extrinsic risk factors exist based on the three unique SIDS groups we identified with t-SNE and distance based statistical measurements. Clinical guidelines have not equally impacted the groups, and normal birth weight infants comprise more of the cases of SIDS even though low birth weight infants have a higher SIDS rate.
Molecular Pathological Markers Correlated With the Recurrence Patterns of Glioma
Authors: Ge Shunnan , Shi Yingwu , Zhu Gang , Li Songlun , Cai Yaning , Ji Peigang , Liu Jinghui , Guo Wei , Gong Li , Lou Miao , Feng Fuqiang , Wang Yuan , Zhai Yulong , Qu Yan , Wang Liang
Published: January 2021

Purpose

Glioma is one of the most common tumors of the central nervous system, and many patients suffer from recurrence even after standard comprehensive treatment. However, little is known about the molecular markers that predict the recurrence patterns of glioma. This study aimed to demonstrate the correlations between molecular markers and glioma recurrence patterns, which included local/nonlocal recurrence and paraventricular/nonparaventricular recurrence.

Methods

Immunohistochemical techniques were used to assess the molecular markers of 88 glioma tissues following surgical resection. The recurrence patterns were divided into local recurrence, marginal recurrence, distant recurrence, multirecurrence, and subarachniod recurrence, with the last four recurrence patterns being collectively called nonlocal recurrence. According to whether the recurrence invaded ventricles, the nonlocal recurrence patterns were divided into paraventricular and nonparaventricular recurrence. Then, we compared the different recurrence patterns and their clinical characteristics, focusing on the expression of molecular markers.

Results

More patients in the nonlocal recurrence group received combined radiotherapy and chemotherapy than patients in the local recurrence group (p=0.019). Sex, age, extent of surgery, time to recurrence, tumor location, size, and WHO grade were not different in the defined groups (P>0.05). Recurrent tumor volume and WHO grade were significantly different between the paraventricular and nonparaventricular recurrence groups (p=0.046 and 0.033). The expression of Ki-67, P53, and PCNA in the nonlocal recurrence group was significantly higher than that in the local recurrence group (p=0.015, 0.009, and 0.037), while the expression of S-100 in the nonlocal recurrence group was significantly lower than that in the local recurrence group (p=0.015). Cox regression indicated hazard ratio (HR) for high expression level of PCNA associated with non-local recurrence was 3.43 (95% CI, 1.15, 10.24), and HR for high expression level of MGMT associated with paraventricular recurrence was 2.64 (95% CI, 1.15,6.08).

Conclusions

Ki-67, P53, PCNA, and MGMT might be important clinical markers for nonlocal recurrence and paraventricular recurrence.
Target Inhibition of CBP Induced Cell Senescence in BCR-ABL- T315I Mutant Chronic Myeloid Leukemia
Authors: Yang Ke , Wang Fang , Zhang Hong , Wang Xiaokun , Chen Likun , Su Xiaodong , Wu Xingping , Han Qianqian , Chen Zhen , Chen Zhe-Sheng , Fu Liwu
Published: January 2021

The treatment of chronic myeloid leukemia (CML) with BCR-ABL tyrosine kinase inhibitors (TKIs), such as imatinib, has yielded clinical success. However, the direct targeting of BCR-ABL does not eradicate CML cells expressing mutant BCR-ABL, especially the T315I mutation in BCR-ABL. Moreover, increasing mutations were identified in BCR-ABL domain, resulting in TKIs resistance recently. It is necessary to find BCR-ABL-independent target for treating CML patients with various mutations, including T315I mutation in BCR-ABL. The dichotomous behavior of CREB binding protein (CBP) and E1A protein (p300), recruited by β-catenin associated with self-renewal and differentiation, have been identified in hematopoietic stem cells, respectively. In this study, CBP was aberrantly expressed in CML cells on the basis of Oncomine dataset. The β-catenin bound with much more CBP than p300 in CML cells. Down-regulation of CBP inhibited cell proliferation capacity and increased the binding of β-catenin to p300, thus promoting cell differentiation and p53-dependent cell senescence in CML cells with either wild type or T315I mutant BCR-ABL in vitro and in vivo models. These demonstrate CBP blockage can be developed for the treatment of CML independent of BCR-ABL mutation status including T315I.
The Distribution of Pelvic Nodal Metastases in Prostate Cancer Reveals Potential to Advance and Personalize Pelvic Radiotherapy
Authors: Filimonova Irina , Schmidt Daniela , Mansoorian Sina , Weissmann Thomas , Siavooshhaghighi Hadi , Cavallaro Alexander , Kuwert Torsten , Bert Christoph , Frey Benjamin , Distel Luitpold Valentin , Lettmaier Sebastian , Fietkau Rainer , Putz Florian
Published: January 2021

Background

Traditional clinical target volume (CTV) definition for pelvic radiotherapy in prostate cancer consists of large volumes being treated with homogeneous doses without fully utilizing information on the probability of microscopic involvement to guide target volume design and prescription dose distribution.

Methods

We analyzed patterns of nodal involvement in 75 patients that received RT for pelvic and paraaortic lymph node metastases (LNs) from prostate cancer in regard to the new NRG-CTV recommendation. Non-rigid registration-based LN mapping and weighted three-dimensional kernel density estimation were used to visualize the average probability distribution for nodal metastases. As independent approach, the mean relative proportion of LNs observed for each level was determined manually and NRG and non-NRG levels were evaluated for frequency of involvement. Computer-automated distance measurements were used to compare LN distances in individual patients to the spatial proximity of nodal metastases at a cohort level.

Results

34.7% of patients had pelvic LNs outside NRG-consensus, of which perirectal was most common (25.3% of all patients) followed by left common iliac nodes near the left psoas major (6.7%). A substantial portion of patients (13.3%) had nodes at the posterior edge of the NRG obturator level. Observer-independent mapping consistently visualized high-probability hotspots outside NRG-consensus in the perirectal and left common iliac regions. Affected nodes in individual patients occurred in highly significantly closer proximity than at cohort-level (mean distance, 6.6 cm vs. 8.7 cm, p < 0.001).

Conclusions

Based on this analysis, the common iliac level should extend to the left psoas major and obturator levels should extend posteriorly 5 mm beyond the obturator internus. Incomplete coverage by the NRG-consensus was mostly because of perirectal involvement. We introduce three-dimensional kernel density estimation after non-rigid registration-based mapping for the analysis of recurrence data in radiotherapy. This technique provides an estimate of the underlying probability distribution of nodal involvement and may help in addressing institution- or subgroup-specific differences. Nodal metastases in individual patients occurred in highly significantly closer proximity than at a cohort-level, which supports that personalized target volumes could be reduced in size compared to a “one-size-fits-all” approach and is an important basis for further investigation into individualized field designs.
The Strange Case of Jekyll and Hyde: Parallels Between Neural Stem Cells and Glioblastoma-Initiating Cells
Authors: Bakhshinyan David , Savage Neil , Salim Sabra Khalid , Venugopal Chitra , Singh Sheila K.
Published: January 2021

During embryonic development, radial glial precursor cells give rise to neural lineages, and a small proportion persist in the adult mammalian brain to contribute to long-term neuroplasticity. Neural stem cells (NSCs) reside in two neurogenic niches of the adult brain, the hippocampus and the subventricular zone (SVZ). NSCs in the SVZ are endowed with the defining stem cell properties of self-renewal and multipotent differentiation, which are maintained by intrinsic cellular programs, and extrinsic cellular and niche-specific interactions. In glioblastoma, the most aggressive primary malignant brain cancer, a subpopulation of cells termed glioblastoma stem cells (GSCs) exhibit similar stem-like properties. While there is an extensive overlap between NSCs and GSCs in function, distinct genetic profiles, transcriptional programs, and external environmental cues influence their divergent behavior. This review highlights the similarities and differences between GSCs and SVZ NSCs in terms of their gene expression, regulatory molecular pathways, niche organization, metabolic programs, and current therapies designed to exploit these differences.
Carriage Dynamics of Pneumococcal Serotypes in Naturally Colonized Infants in a Rural African Setting During the First Year of Life
Authors: Chaguza Chrispin , Senghore Madikay , Bojang Ebrima , Lo Stephanie W. , Ebruke Chinelo , Gladstone Rebecca A. , Tientcheu Peggy-Estelle , Bancroft Rowan E. , Worwui Archibald , Foster-Nyarko Ebenezer , Ceesay Fatima , Okoi Catherine , McGee Lesley , Klugman Keith P. , Breiman Robert F. , Barer Michael R. , Adegbola Richard A. , Antonio Martin , Bentley Stephen D. , Kwambana-Adams Brenda A.
Published: January 2021

Streptococcus pneumoniae (the pneumococcus) carriage precedes invasive disease and influences population-wide strain dynamics, but limited data exist on temporal carriage patterns of serotypes due to the prohibitive costs of longitudinal studies. Here, we report carriage prevalence, clearance and acquisition rates of pneumococcal serotypes sampled from newborn infants bi-weekly from weeks 1 to 27, and then bi-monthly from weeks 35 to 52 in the Gambia. We used sweep latex agglutination and whole genome sequencing to serotype the isolates. We show rapid pneumococcal acquisition with nearly 31% of the infants colonized by the end of first week after birth and quickly exceeding 95% after 2 months. Co-colonization with multiple serotypes was consistently observed in over 40% of the infants at each sampling point during the first year of life. Overall, the mean acquisition time and carriage duration regardless of serotype was 38 and 24 days, respectively, but varied considerably between serotypes comparable to observations from other regions. Our data will inform disease prevention and control measures including providing baseline data for parameterising infectious disease mathematical models including those assessing the impact of clinical interventions such as pneumococcal conjugate vaccines.
Drug Allergy Profile From a National Drug Allergy Registry
Authors: Al-Ahmad Mona , Edin Jusufovic , Musa Fardous , Rodriguez-Bouza Tito
Published: January 2021

Background: Drug hypersensitivity reactions (DHRs) are among the most frequent reasons for consultation in allergy departments and are becoming more common due to increasing prevalence and case complexity.

Objective: To describe the most common drugs associated with clinical reactions, diagnostic methods used, and outcomes of allergic evaluations of a national drug allergy registry over a 12-year period were used.

Methods: An observational, prospective, patient’s data registry-based study was conducted to analyze all referrals to the drug allergy outpatient clinics at Al-Rashed Allergy Center, Kuwait, between 2007 and 2019. Demographics, description of DHRs, and results of allergy tests to potential causative medications were reviewed. Diagnostic methods were focused mainly on skin tests (STs) and drug provocation test (DPT), when indicated.

Results: We evaluated 1,553 patients with reported DHRs. The mean age of the population was 41.52 ± 16.93 years, and the study population consisted of 63.7% female patients. Hypersensitivity was finally confirmed in 645 (41.5%) of patients, probable in 199 (12.8%), and not confirmed/nonallergic in 709 (45.6%) patients. Anti-inflammatory drugs and analgesics contributed to 39.22% of all confirmed drug allergies, followed by antibiotics 38.1% (β-lactam antibiotics (BLs) constituted 73.98% of all antibiotics and 28.21% of all drugs), anesthetics 1.8%, and radio-contrast media 0.31%. The majority of reactions were non-immediate 51.44%. The most commonly presenting symptoms among confirmed patients were urticaria 57.80%, angioedema 42.50%, respiratory symptoms 47.60%, and erythema 33.60%. Symptoms of anaphylaxis/anaphylactic shock were reported by 284 patients (44.00%) among confirmed cases. The most common method of diagnosis was a positive clinical history (54.4% in BLs and 90.45% in nonsteroidal anti-inflammatory drugs (NSAIDs). Among confirmed allergy to BLs, a positive ST was obtained in 31.9% of patients and positive DPT in 13.7%.

Conclusion: NSAIDs and antibiotics, mainly BLs, are the most commonly implicated in confirmed allergy. In both confirmed and not confirmed/nonallergic cases, BLs are the most frequently involved DHRs which are mainly immediate, and the most commonly presenting symptoms were urticaria, angioedema, and respiratory symptoms. Diagnosis was confirmed mainly by a positive clinical history and when indicated, by positive STs or a DPT.
Alda-1 Attenuates Hyperoxia-Induced Acute Lung Injury in Mice
Authors: Sidramagowda Patil Sahebgowda , Hernández-Cuervo Helena , Fukumoto Jutaro , Krishnamurthy Sudarshan , Lin Muling , Alleyn Matthew , Breitzig Mason , Narala Venkata Ramireddy , Soundararajan Ramani , Lockey Richard F. , Kolliputi Narasaiah , Galam Lakshmi
Published: January 2021

Acute lung injury (ALI), a milder form of acute respiratory distress syndrome (ARDS), is a leading cause of mortality in older adults with an increasing prevalence. Oxygen therapy, is a common treatment for ALI, involving exposure to a high concentration of oxygen. Unfortunately, hyperoxia induces the formation of reactive oxygen species which can cause an increase in 4-HNE (4-hydroxy 2 nonenal), a toxic byproduct of lipid peroxidation. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) serves as an endogenous shield against oxidative stress-mediated damage by clearing 4-HNE. Alda-1 [(N-(1, 3 benzodioxol-5-ylmethyl)-2, 6- dichloro-benzamide)], a small molecular activator of ALDH2, protects against reactive oxygen species-mediated oxidative stress by promoting ALDH2 activity. As a result, Alda-1 shields against ischemic reperfusion injury, heart failure, stroke, and myocardial infarction. However, the mechanisms of Alda-1 in hyperoxia-induced ALI remains unclear. C57BL/6 mice implanted with Alzet pumps received Alda-1 in a sustained fashion while being exposed to hyperoxia for 48 h. The mice displayed suppressed immune cell infiltration, decreased protein leakage and alveolar permeability compared to controls. Mechanistic analysis shows that mice pretreated with Alda-1 also experience decreased oxidative stress and enhanced levels of p-Akt and mTOR pathway associated proteins. These results show that continuous delivery of Alda-1 protects against hyperoxia-induced lung injury in mice.
Antibody-Based Targeting of Interferon-Beta-1a Mutein in HER2-Positive Cancer Enhances Antitumor Effects Through Immune Responses and Direct Cell Killing
Authors: Lee Chan Gyu , Kim TaeEun , Hong Sungyoul , Chu Jongwan , Kang Ju Eun , Park Hee Geon , Choi Jun Young , Song Kyoung , Rha Sun Young , Lee Soohyeon , Choi Joon-Seok , Kim Sun Min , Jeong Hae Min , Shin Young Kee
Published: January 2021

Type I interferon (IFN) has been approved as an anticancer agent to treat some malignancies. However, IFNs have a shortin vivohalf-life, systemic toxicity, and poor biophysical properties, which prevent it from being widely used for cancer therapy. This study aimed to construct recombinant IFN-β-1a mutein immunocytokines that comprise a human epidermal growth factor receptor 2 (HER2)-targeting antibody and IFN-β muteins with an additional glycosylation, which can overcome the limitation of the cytokine itself. Hence, the molecular design aims to 1) enhance productivity and biophysical properties by adding secondary glycosylation in IFN-β, 2) increase the therapeutic index of IFN-β therapy by preferential retention at the tumor by possessing high affinity for HER2-expressing cancer cells, and 3) improve the pharmacokinetics and, thus, the convenience of IFN-β administration. The yield of trastuzumab-IFN-β mutein was higher than that of trastuzumab-wild-type IFN-β in the mammalian cell culture system. Trastuzumab-IFN-β mutein showed similar IFN activity and HER2-targeting ability equivalent to that of IFN-β mutein and trastuzumab, respectively. Trastuzumab-IFN-β mutein directly inhibited the growth of HER2-positive gastric cancer cell lines and was more effective than trastuzumab or IFN-β mutein alone. Trastuzumab-IFN-β mutein and IFN-β mutein displayed enhanced immune cell-mediated cytotoxicity. Collectively, trastuzumab-IFN-β mutein may have indirect immune cell-mediated antitumor effects and direct cell growth inhibitory effects. Tumor-targeting effect of trastuzumab-IFN-β mutein was analyzed usingin vivofluorescence imaging. The accumulation of trastuzumab-IFN-β mutein was observed in HER2-positive tumors rather than other tissues except the liver. To evaluate the both direct tumor growth inhibition effect and indirect immune cell-mediated antitumor effect, we tested the effect of trastuzumab-IFN-β mutein in HER2-positive cancer xenograft models using nude mice or humanized mice. Trastuzumab-IFN-β mutein could significantly enhance tumor regression when compared with trastuzumab or IFN-β mutein. In addition, an increase in tumor-infiltrating lymphocytes was observed in the trastuzumab-IFN-β mutein-treated group, implying that the tumor-targeting IFN-β may have an enhanced antitumor effect through increased immune response. Therefore, targeting IFN-β with an anti-HER2 monoclonal antibody makes the immunocytokine more potent than either agent alone. These novel findings suggest that trastuzumab-IFN-β mutein merits clinical evaluation as a new candidate of anticancer therapeutics.
Hirsutella Sinensis Fungus Regulates CD8+ T Cell Exhaustion Through Involvement of T-Bet/Eomes in the Tumor Microenvironment
Authors: Jin Lu , Jin Lushuai , Wu Renjie , Liu Xia , Zhu Xinhai , Shou Qiyang , Fu Huiying
Published: January 2021

Background: Targeting exhausted T (Tex) cells is a promising strategy for anti-tumour treatment. Previously, we demonstrated that Hirsutella sinensis fungus (HSF) could significantly increase T cell infiltration and the effector T cell ratio in the tumor microenvironment, activating systemic immune responses. However, we do not know how HSF regulates Tex cells in the tumor microenvironment. Here, we explored the mechanism underlying HSF inhibition of Tex cells and tumor growth and metastasis in breast cancer.

Methods: We examined the effects of HSF on various tumor mouse models using in vivo imaging technology. Lung metastasis was detected by H&E staining and the T cell subsets in the tumor microenvironment were assayed with flow cytometry. The in vitro proliferation, function and apoptosis of CD8+ T cells were measured, as well as the T-bet and PD-1 mRNA expressions.

Results: HSF inhibited tumor growth and lung metastasis in the mice, and had significantly higher CD44LowCD62LHi and CD44HiCD62LLowpopulations in the tumour-infiltrating CD8+ T cells. However, HSF significantly reduced levels of inhibitory receptors, such as PD-1, TIGIT, CTLA-4, and regulatory T cells. In vitro, HSF inhibited the CD8+ T cell apoptosis rate, and promoted CD8+ T cell proliferation and secretion of interferon (IFN)-γ and granzyme B. Furthermore, HSF treatment both in vivo and in vitro significantly increased Eomes expression, while decreasing T-bet expression.

Conclusion: HSF exerted anti-tumour effects mainly through the immune system, by promoting effector/memory T cells and reducing Tex cell production in the tumor microenvironment. The specific mechanisms involved inhibiting T-bet and promoting Eomes to decrease the expression of immune inhibitor receptors and enhance the T cell function, respectively.
Homocysteine Impairs Endothelial Cell Barrier Function and Angiogenic Potential via the Progranulin/EphA2 Pathway
Authors: Tian Dan , Qin Qing , Li Mingfei , Li Xiaoyu , Xu Qing , Lv Qianzhou
Published: January 2021

Hyperhomocysteinemia is a well-recognized independent risk factor for cardiovascular disease. To date, the mechanism of pathological plasma homocysteine (Hcy) level elevation remains to be elucidated. We aimed to investigate the levels of progranulin (PGRN), Eph-receptor tyrosine kinase-type A2 (EphA2), vascular cell adhesion molecule-1 (VCAM-1), and Hcy in patients with arteriosclerosis and investigate their functions in Hcy-injured human umbilical vein endothelial cells (HUVECs). EphA2 knockdown was induced in HUVECs by shRNA lentivirus infection with EphA2-RNAi, and bulk RNA-seq assay was performed. Then we investigated the mechanism underlying the effect of recombinant human PGRN (rhPGRN) combined with shRNA interference of EphA2 on cell proliferation, migration, and angiogenesis in Hcy-injured HUVECs. Results showed that serum EphA2, VCAM-1, and Hcy levels in acute coronary syndrome patients were significantly higher than those in chronic coronary syndrome patients (p = 0.000; p = 0.000; p = 0.033, respectively). In vitro, we demonstrated that knockdown of EphA2 significantly impaired cell adhesion and inhibited HUVECs migration and angiogenesis (p < 0.001), which was associated with reduction in VCAM1 and VE-cadherin (p < 0.05). Hcy modulated the expression of PGRN and EphA2 in a time-and dose-dependent manner. However, rhPGRN ameliorated the Hcy-induced reduction in cell viability and migration (p < 0.05). Mechanistically, we found that PGRN/EphA2 and its downstream AKT/NF-κB signaling might be the primary signal transduction pathways underlying Hcy-induced injury. The present study illustrated that PGRN plays a previously unrecognized role in Hcy-induced endothelial injury, which is achieved through its interaction with EphA2 signaling, implying a promising therapeutic target for cardiovascular disease.
The Generalized-Growth Modeling of COVID-19
Authors: Wu Ye , Zhang Lin , Cao Wenjing , Liu Xiaofei , Feng Xin
Published: January 2021

The global spread of the COVID-19 pandemic is changing everything in 2020. It is of crucial importance to characterize the growth patterns during the transmission. In this paper, a generalized-growth model is established to present the evolution of the number of the total confirmed cases changing with time. Due to effective containment, the generalized growth model reveals a piecewise pattern, referred to as the sub-exponential and the sub-linear stages. Moreover, the parameters can quantify the effectiveness of the containment and the trend of resurgence in different regions all over the world. Our model provides a phenomenological approach, which is simple and transparent for better understanding of the typical patterns within the general dynamics. Our model may have implications for possible nowcasting and forecasting of the pandemic trend.
A Narrative Review of Injury Incidence, Location, and Injury Factor of Elite Athletes in Snowsport Events
Authors: Xu Yongxin , Yang Chenhao , Yang Yang , Zhang Xini , Zhang Shen , Zhang Mingwen , Liu Li , Fu Weijie
Published: January 2021

Snowsport athletes face a high injury risk both during training and in competitions. Reducing injury incidence is crucial for athletes to achieve breakthroughs. This narrative review aimed to summarize and analyze injury data of elite athletes in snowsports and provide references for injury prevention and health security for these athletes and their coaches. A total of 39 studies that investigated snowsport injury were analyzed in the present study. On the basis of injury data of elite athletes in snowsports events, this narrative review focused on four aspects, namely, injury incidence, severity, location and causes. The findings of this review were as follows. (1) The highest injury incidence was recorded in freestyle skiing, followed by alpine skiing and snowboarding, the majority of which were moderate and severe injuries. (2) The proportion of injury in competitions and during training was similar. However, more injuries occurred in official training during the Winter Olympic Games; by contrast, injury proportion was higher in competitions during World Cup/World Championships. (3) The most commonly and severely injured body parts were the knees (29.9%), head and face (12.1%), shoulders and clavicula (10.5%), and lower back (8.9%). The most common injury types were joint and ligament injury (41.5%), fracture and bone stress (24.4%), concussion (11.1%), and muscle/tendon injury (10.7%). (4) The main causes of snowsport injury were collisions, falls, and non-contact injuries. Snowsport injury was also influenced by the skill level of the athletes, gender, course setup and equipment. Future studies should further explore the influence of event characteristics and intrinsic and extrinsic risk factors on snowsport injury. An injury or trauma reconstruction may be developed to predict athletic injuries and provide effective prevention strategies.