bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temperature Trajectory Sub-phenotypes and the Immuno-Inflammatory Response in Pediatric Sepsis
Authors: Yehya Nadir , Fitzgerald Julie C. , Hayes Katie , Zhang Donglan , Bush Jenny , Koterba Natalka , Chen Fang , Tuluc Florin , Teachey David T. , Balamuth Fran , Lacey Simon F. , Melenhorst Jan Joseph , Weiss Scott L. 
Published: January 2022

ABSTRACT

Objective:
Heterogeneity has hampered sepsis trials, and sub-phenotyping may assist with enrichment strategies. However, biomarker-based strategies are difficult to operationalize. Four sub-phenotypes defined by distinct temperature trajectories in the first 72 h have been reported in adult sepsis. Given the distinct epidemiology of pediatric sepsis, the existence and relevance of temperature trajectory-defined sub-phenotypes in children is unknown. We aimed to classify septic children into de novo sub-phenotypes derived from temperature trajectories in the first 72 h, and compare cytokine, immune function, and immunometabolic markers across subgroups.

Methods:
This was a secondary analysis of a prospective cohort of 191 critically ill septic children recruited from a single academic pediatric intensive care unit. We performed group-based trajectory modeling using temperatures over the first 72 h of sepsis to identify latent profiles. We then used mixed effects regression to determine if temperature trajectory-defined sub-phenotypes were associated with cytokine levels, immune function, and mitochondrial respiration.

Results:
We identified four temperature trajectory-defined sub-phenotypes: hypothermic, normothermic, hyperthermic fast-resolvers, and hyperthermic slow-resolvers. Hypothermic patients were less often previously healthy and exhibited lower levels of pro- and anti-inflammatory cytokines and chemokines. Hospital mortality did not differ between hypothermic children (17%) and other sub-phenotypes (3–11%; P = 0.26).

Conclusions:
Critically ill septic children can be categorized into temperature trajectory-defined sub-phenotypes that parallel adult sepsis. Hypothermic children exhibit a blunted cytokine and chemokine profile. Group-based trajectory modeling has utility for identifying subtypes of clinical syndromes by incorporating readily available longitudinal data, rather than relying on inputs from a single timepoint.
Systemic Review of Animal Models Used in the Study of Crush Syndrome
Authors: Liu Yahua , Yu Mengyang , Chen Li , Liu Jing , Li Xin , Zhang Chengying , Xiang Xueyuan , Li Xiaoxue , Lv Qi 
Published: January 2022

ABSTRACT
Crush syndrome (CS), also known as traumatic rhabdomyolysis, is the leading cause of death following extrication from structural collapse due to earthquakes. Due to the unfeasibility of human studies, animal models are used to study crush syndrome pathophysiology, including biochemistry and treatment regimes. The aim of this systematic literature review was to identify the differences and benefits of various animal models used in the study of CS and provide valuable information for design of future research. A systematic search was conducted in two methods: with the filters “(crush syndrome) AND (crush muscle injury)” and with the keywords “(crush syndrome) AND (animal model)” covering all articles in the PubMed databases. The search generated 378 articles. After screening abstracts, 91 articles were retrieved and read, then 11 repeated articles were removed and 2 reference papers were included. We finally reviewed 82 original articles. There appear to be two primary methods employed for inducing crush syndrome in animal models, which are chemically induced injury and physically induced injury. Chemical method mainly includes intramuscular (IM) injection of tissue extract solution and IM injection of 50% glycerine. Physical method can be classified into invasive and non-invasive physical compression by elasticated material, inflatable band and heavy load. Various species of animals have been used to study CS, including mice (13.4%), rats (68.3%), rabbits (11.0%), canines (4.9%), goats (1.2%), and pigs (1.2%). Small animals are suitable for researches exploring the mechanism of disease or drug efficacy while large animals can work better with clinical application-related researches. In regard to the choice of modeling method, compressing the certain muscle of animals by heavy things is superior to others to cause systemic trauma-related rhabdomyolysis signs. In addition, due to the significant burden of crush injuries on animals, further attention shall be paid to the selection of the most suitable anesthetics and appropriate analgesics.
CIGARETTE SMOKING IS ASSOCIATED WITH DECREASED MORTALITY IN CRITICALLY ILL TRAUMA PATIENTS
Authors: Grigorian Areg , Kuza Catherine M. , Delaplain Patrick T. , Singh Mandeep , Dominguez Oscar Hernandez , Vu Trung , Kim Michael P. , Nahmias Jeffry 
Published: January 2022

ABSTRACT

Background: Smoking may offer pathophysiologic adaptations that increase survivability in certain patients with cardiovascular disease. We sought to identify if smoking increases survivability in trauma patients, hypothesizing that critically ill trauma patients who smoke have a decreased risk of mortality compared with non-smokers. Methods: The Trauma Quality Improvement Program (2010-2016) database was queried for trauma patients with intensive care unit admissions. A multivariable logistic regression model was performed. Results: From the 630,278 critically ill trauma patients identified, 116,068 (18.4%) were current cigarette smokers. Critically ill trauma smokers, compared with non-smokers, had a higher rate of pneumonia (7.8% vs. 6.9%, P< 0.001) and lower mortality rate (4.0% vs. 8.0%, P< 0.001). After controlling for covariates, smokers had a decreased associated risk of mortality compared with non-smokers (OR = 0.55, CI = 0.51-0.60, P< 0.001), and no difference in the risk of major complications (OR = 0.98, CI = 0.931.03, P = 0.44). The same analysis was performed using age as a continuous variable with associated decreased risk of mortality (OR 0.57 (CI 0.53–0.62), P< 0.001). Conclusion: Critically ill trauma smokers had a decreased associated mortality risk compared with non-smokers possibly due to biologic adaptations such as increased oxygen delivery developed from smoking. Future basic science and translational studies are needed to pursue potential novel therapeutic benefits without the deleterious long-term side effects of smoking.
Functional Transcriptomic Studies of Immune Responses and Endotoxin Tolerance in Early Human Sepsis
Authors: Leligdowicz Aleksandra , Kamm Jack , Kalantar Katrina , Jauregui Alejandra , Vessel Kathryn , Caldera Saharai , Serpa Paula Hayakawa , Abbott Jason , Fang Xiaohui , Tian Xiaoli , Prakash Arun , Kangelaris Kirsten Neudoerffer , Liu Kathleen D. , Calfee Carolyn S. , Langelier Charles , Matthay Michael A. 
Published: January 2022

ABSTRACT

Background:
Limited studies have functionally evaluated the heterogeneity in early ex vivo immune responses during sepsis. Our aim was to characterize early sepsis ex vivo functional immune response heterogeneity by studying whole blood endotoxin responses and derive a transcriptional metric of ex vivo endotoxin response.

Methods:
Blood collected within 24 h of hospital presentation from 40 septic patients was divided into two fractions and incubated with media (unstimulated) or endotoxin. Supernatants and cells were isolated, and responses measured using: supernatant cytokines, lung endothelial permeability after supernatant exposure, and RNA expression. A transcriptomic signature was derived in unstimulated cells to predict the ex vivo endotoxin response. The signature was tested in a separate cohort of 191 septic patients to evaluate for association with clinical outcome. Plasma biomarkers were quantified to measure in vivo host inflammation.

Results:

Ex vivo response to endotoxin varied and was unrelated to immunosuppression, white blood cell count, or the causative pathogen. Thirty-five percent of patients demonstrated a minimal response to endotoxin, suggesting early immunosuppression. High ex vivo cytokine production by stimulated blood cells correlated with increased in vitro pulmonary endothelial cell permeability and was associated with attenuated in vivo host inflammation. A four-gene signature of endotoxin response detectable without the need for a functional assay was identified. When tested in a separate cohort of septic patients, its expression was inversely associated with hospital mortality.

Conclusions:
An attenuated ex vivo endotoxin response in early sepsis is associated with greater host in vivo inflammation and a worse clinical outcome.
Conserved Structural Motifs in the Hammerhead Ribozyme of a Chloroplast Viroid Mimic tRNA Anticodon Structure to Hijack tRNA Ligase for Viroid Circularization
Authors: Ortolá Beltrán , Daròs José-Antonio 
Published: January 2022

ABSTRACTViroids belonging to the family Avsunviroidae contain hammerhead ribozymes that process to unit length the oligomeric RNAs of both polarities generated during the rolling-circle replication that occurs in chloroplasts of host plants. Linear products, with 5’-hydroxyl and 2’,3’-phosphodiester termini, are then recognized and circularized by the host chloroplastic isoform of the tRNA ligase. Here we analyze the circularization process of eggplant latent viroid (ELVd), an asymptomatic viroid that infects eggplants (Solanum melongena L.), using an Escherichia coli co-expression system in which longer-than-unit linear ELVd (+) precursors are expressed along with the eggplant chloroplastic tRNA ligase. The RNA precursor contains two copies of the hammerhead ribozyme and yields the appropriate termini for the tRNA ligase-mediated ligation in bacteria. We have determined that the ligation efficiency is highly dependent on the presence of ribozyme sequences in the ligatable termini, since the circularization of a series of viroid variants in which the ligation position was rearranged increased substantially in the presence of these sequences. Further in silico analysis showed sequence and structure similarity between the hammerhead ribozyme catalytic pocket and the anticodon loop of tRNAs, both of which harbor a characteristic U-turn of the phosphodiester backbone. Directed mutagenesis in the ribozyme domain supports the role of this U-turn loop in the ligation process. We propose that, in addition to its self-cleavage function, the viroid ribozymes have evolved to mimic the structure of the tRNA anticodon loop to recruit host tRNA ligase for the circularization of the monomeric linear replication intermediates.IMPORTANCEViroids are a very particular class of infectious agents because they only consist of a small RNA that, to our current knowledge, does not encode for proteins. Consequently, viroids parasite host factors and structures to mediate all processes in the infectious cycle. How these small infectious RNAs are able to hijack host resources is currently a mystery. In this work, we shed some light on the functionality of hammerhead ribozymes during replication of viroids that belong to the family Avsunviroidae, which replicate in the chloroplasts. Our findings suggest that, in addition to mediate self-cleavage of replication intermediates, hammerhead ribozymes also recruit tRNA ligase for monomer circularization, likely mimicking a common host tRNA structural motif.
Iron Deficiency Induces Heart Failure with Ectopic Cardiac Calcification in Mice with Metabolic Syndrome
Authors: Naito Yoshiro , Sawada Hisashi , Yasumura Seiki , Horimatsu Tetsuo , Okuno Keisuke , Tahara Saki , Nishimura Koichi , Asakura Masanori , Tsujino Takeshi , Masuyama Tohru , Ishihara Masaharu 
Published: January 2022

AbstractIron deficiency is linked to worse clinical status and outcomes in heart failure. Although metabolic syndrome contributes to the development of heart failure, the impact of iron deficiency in heart failure complicated with metabolic syndrome remains obscure. KKAy mice were used as a model of metabolic syndrome. Four-week-old male C57BL/6J and KKAy mice were fed either a normal diet or iron-restricted (IR) diet for 12 weeks. During the experiment, 40% of mice died due to pulmonary congestion in KKAy mice with IR diet (KKAy-IR), while no mice died in other groups. Necropsy showed the presence of multiple white lesions on the cardiac surface in those KKAy-IR mice. Echocardiography and histological analyses revealed that KKAy-IR mice exhibited cardiac hypertrophy and cardiac dysfunction with cardiac calcification. Cardiac mRNA of ectonucleotide pyrophosphatase/phosphodiesterase-1 (Enpp1), a key enzyme for bone mineralization, was highly abundant in KKAy-IR mice. Of note, iron restriction-induced cardiac calcification and dysfunction were attenuated by etidronate, an inhibitor of bone mineralization, with decreased cardiac Enpp1 mRNA abundance in KKAy-IR mice. In conclusion, iron deficiency leads to ectopic cardiac calcification and dysfunction with the increase of Enpp1 in metabolic syndrome model mice.
Predicting evolution in experimental range expansions of an aquatic model system
Authors: Zilio Giacomo , Krenek Sascha , Gougat-Barbera Claire , Fronhofer Emanuel A. , Kaltz Oliver 
Published: January 2022

AbstractPredicting range expansion dynamics is a challenge for both fundamental and applied research in conservation and global change biology. However, if ecological and evolutionary processes occur on the same time scale, predictions are challenging to make. Combining experimental evolution and mathematical modelling, we assessed the predictability of independent realisations of range expansions in a laboratory model system, the freshwater protozoan Paramecium caudatum. We followed ecological dynamics and evolutionary change in range core and front populations in the experiment. These settings were recreated in a predictive mathematical model, parametrized with dispersal and growth data of the of the 20 founder strains in the experiment. We find that short-term evolution was driven by selection for increased dispersal at the front and general selection for higher growth rates in all treatments. There was a good quantitative match of predicted and observed trait changes. Phenotypic divergence was mirrored by a complete genotypic divergence, indicating the highly repeatable fixation of strains that also were the most likely winners in our model. Long-term evolution in the experimental range front lines resulted in the emergence of a dispersal syndrome, namely a competition - colonisation trade-off. Altogether, both model and experiment highlight the importance of dispersal evolution as a driver of range expansions. Our study suggests that evolution at range fronts may follow predictable trajectories, at least for simple scenarios, and that predicting these dynamics may be possible from knowledge of few key parameters.
Proteomic deconvolution reveals distinct immune cell fractions in different body sites in SARS-Cov-2 positive individuals
Authors: Okendo Javan , Okanda David , Mwangi Peter , Nyaga Martin 
Published: January 2022

AbstractBackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be a significant public health challenge globally. SARS-CoV-2 is a novel virus, and what constitutes immunological responses in different human body sites in infected individuals is yet to be presented. We set to determine the various immune cell fractions in gargle solution, bronchoalveolar lavage fluid, nasopharyngeal, and urine samples post-SARS-CoV-2 infection in humans.Materials and methodsWe downloaded proteomics data from (https://www.ebi.ac.uk/pride/) with the following identifiers: PXD019423, n=3 (gargle solution), PXD018970, n=15 (urine), PXD022085, n=5 (Bronchoalveolar lavage fluid), PXD022889, n=18 (nasopharyngeal). MaxQuant was used for the peptide spectral matching using humans, and SARS-CoV-2 was downloaded from the UniProt database (Access date 9th January 2022). The protein count matrix was extracted from the proteins group file and used as an input for the cibersort for the immune cells fraction determination.ResultsThe body of individuals infected with the SARS-CoV-2 virus is characterized by different fractions of immune cells in Bronchoalveolar lavage fluid (BALF), nasopharyngeal, urine, and gargle solution. BALF has more abundant memory B cells, CD8, activated mast cells, and resting macrophages than urine, nasopharyngeal, and gargle solution. Our analysis also demonstrates that each body site comprises different immune cell fractions post-SARS-CoV-2 infection in humans.ConclusionDifferent body sites are characterized by different immune cells fractions in SARS-CoV-2 infected individuals. The findings in this study can inform public health policies and health professionals on treatment strategies and drive SARS-CoV-2 diagnosis procedures.
Impact of persistent COVID-19 symptoms on social life of female long haulers: A qualitative study
Authors: Aghaei Atefeh , Zhang Ran , Taylor Slone , Tam Cheuk-Chi , Yang Chih-Hsiang , Li Xiaoming , Qiao Shan 
Published: January 2022

AbstractIntroductionPersistent COVID-19 symptoms (long COVID) may bring numerous challenges to long haulers’ social lives. Women may have to endure more profound impacts given their social roles and existing structural inequality. This study aims to explore the impacts of long COVID on various aspects of social life among female long haulers.MethodsWe conducted 15 semi-structured interviews with female long haulers in the United States purposely recruited from Facebook groups, Slack groups, and organization websites. The interviews were audio recorded after appropriate consent and transcribed verbatim. Inductive approach was applied in thematic analysis, which consists of six stages: becoming familiar with data, developing initial codes, extracting themes, refining themes, labeling themes, and reporting. The MAXQDA software was used in data analysis.ResultsPersistent COVID-19 symptoms negatively affected female long haulers’ social lives in many aspects including physical function, financial security, social relationship, conflict of social roles, and social stigma. Physical limitations changed their body image. Social isolation and work-family conflicts caused huge stress. They experienced internalization of stigma and job insecurities. Shifting to new methods of communication, especially social media may buffer the negative effects of social isolation because of long COVID.ConclusionExisting policies and intervention programs need to be adapted to address the challenges and barriers that long haulers face in returning to normal social life, especially for females. Tailored social life-related recommendations and social support are needed for female long haulers.
Piperlongumine (PL) conjugates induce targeted protein degradation
Authors: Pei Jing , Xiao Yufeng , Liu Xingui , Hu Wanyi , Sobh Amin , Yuan Yaxia , Zhou Shuo , Hua Nan , Mackintosh Samuel G , Zhang Xuan , Basso Kari B. , Kamat Manasi , Yang Qingping , Licht Jonathan D. , Zheng Guangrong , Zhou Daohong , Lv Dongwen 
Published: January 2022

SUMMARYPROteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that degrade target proteins through recruiting E3 ligases. However, their application is limited in part because few E3 ligases can be recruited by known E3 ligase ligands. In this study, we identified piperlongumine (PL), a natural product, as a covalent E3 ligase recruiter, which induces CDK9 degradation when it is conjugated with SNS-032, a CDK9 inhibitor. The lead conjugate955can potently degrade CDK9 in a ubiquitin-proteasome-dependent manner and is much more potent than SNS-032 against various tumor cellsin vitro. Mechanistically, we identified KEAP1 as the E3 ligase recruited by955to degrade CDK9 through a TurboID-based proteomics study, which was further confirmed by KEAP1 knockout and the nanoBRET ternary complex formation assay. In addition, PL-Ceritinib conjugate can degrade EML4-ALK fusion oncoprotein, suggesting that PL may have a broader application as a covalent E3 ligase ligand in targeted protein degradation.
The architecture of the actin network can balance the pushing forces produced by growing microtubules
Authors: Yamamoto Shohei , Gaillard Jérémie , Vianay Benoit , Guerin Christophe , Orhant-Prioux Magali , Blanchoin Laurent , Théry Manuel 
Published: January 2022

AbstractThe position of centrosome, the main microtubule-organizing center (MTOC), is instrumental in the definition of cell polarity. It is defined by the balance of tension and pressure forces in the network of microtubules (MTs). As MTs polymerize against the cell periphery, pressure increases and produces pushing forces on the MTOC. How the mechanical interplay between MTs and the actin network is involved in the regulation of these forces remains poorly understood, in particular because its investigation is technically limited by the structural and biochemical complexity of the cell cytoplasm. Here, in a cell-free assay, we used purified proteins to reconstitute the interaction of an aster of dynamic MTs with actin networks of various compositions and architectures in cell-sized microwells. In the absence of actin filaments, the positioning of the MTOC was highly sensitive to variations in MT length. The presence of a bulk actin filament network limited MTs deformation and displacement, and MTOCs were hold in place. In contrast, the assembly of a dense and branched actin network along the edges of the wells centered the MTOCs by preventing MT slippage and thus maintaining an isotropic balance of pushing forces. In agreement with this, an asymmetric peripheral actin network caused the MTOC to decenter by creating an asymmetry in the pushing forces. Numerical simulations demonstrated that steric hindrance by actin networks, at the tip or along the entire length of MTs, can modulate MTOC positioning, as observed in the experiments. Overall, our results show that actin networks can limit the sensitivity of MTOC positioning to MT length and enforce robust MTOC centering or decentering depending on its architecture.
Mast cell-mediated inflammation relies on insulin-regulated aminopeptidase controlling cytokine export from the Golgi
Authors: Weimershaus Mirjana , Carvalho Caroline , Rignault Rachel , Waeckel-Enee Emmanuelle , Dussiot Michael , van Endert Peter , Maciel Thiago Trovati , Hermine Olivier 
Published: January 2022

AbstractUpon activation, mast cells rapidly release preformed inflammatory mediators from large cytoplasmic granules via regulated exocytosis. This acute degranulation is followed by a late activation phase involving synthesis and secretion of cytokines, growth factors and other inflammatory molecules via the constitutive pathway that remains ill-defined. Here we describe a role for an insulin-responsive vesicle-like endosomal compartment, marked by insulin-regulated aminopeptidase (IRAP), in the secretion of TNF-α- and IL-6 in mast cells and macrophages. IRAP-deficient mice are protected from TNF-α-dependent kidney injury and inflammatory arthritis. In the absence of IRAP, TNF-α fails to be efficiently exported from the Golgi. Subsequently, reduced co-localization of VAMP3+ endosomes with Stx4 was observed, while VAMP8-dependent exocytosis of secretory granules was facilitated. Chemical targeting of IRAP+ endosomes reduced pro-inflammatory cytokine secretion thereby highlighting this compartment as a promising target for the therapeutic control of inflammation.