bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-Wide Association and Mendelian Randomization Analysis Reveal the Causal Relationship Between White Blood Cell Subtypes and Asthma in Africans
Authors: Soremekun Opeyemi , Soremekun Chisom , Machipisa Tafadzwa , Soliman Mahmoud , Nashiru Oyekanmi , Chikowore Tinashe , Fatumo Segun
Published: December 2021

Background: White blood cell (WBC) traits and their subtypes such as basophil count (Bas), eosinophil count (Eos), lymphocyte count (Lym), monocyte count (Mon), and neutrophil counts (Neu) are known to be associated with diseases such as stroke, peripheral arterial disease, and coronary heart disease.

Methods: We meta-analyze summary statistics from genome-wide association studies in 17,802 participants from the African Partnership for Chronic Disease Research (APCDR) and African ancestry individuals from the Blood Cell Consortium (BCX2) using GWAMA. We further carried out a Bayesian fine mapping to identify causal variants driving the association with WBC subtypes. To access the causal relationship between WBC subtypes and asthma, we conducted a two-sample Mendelian randomization (MR) analysis using summary statistics of the Consortium on Asthma among African Ancestry Populations (CAAPA: ncases = 7,009, ncontrol = 7,645) as our outcome phenotype.

Results: Our metanalysis identified 269 loci at a genome-wide significant value of (p = 5 × 10−9) in a composite of the WBC subtypes while the Bayesian fine-mapping analysis identified genetic variants that are more causal than the sentinel single-nucleotide polymorphism (SNP). We found for the first time five novel genes (LOC126987/MTCO3P14, LINC01525, GAPDHP32/HSD3BP3, FLG-AS1/HMGN3P1, and TRK-CTT13-1/MGST3) not previously reported to be associated with any WBC subtype. Our MR analysis showed that Mon (IVW estimate = 0.38, CI: 0.221, 0.539, p < 0.001), Neu (IVW estimate = 0.189, CI: 0.133, 0.245, p < 0.001), and WBCc (IVW estimate = 0.185, CI: 0.108, 0.262, p < 0.001) are associated with increased risk of asthma. However, there was no evidence of causal relationship between Lym and asthma risk.

Conclusion: This study provides insight into the relationship between some WBC subtypes and asthma and potential route in the treatment of asthma and may further inform a new therapeutic approach.
Single-Cell Analysis of Antigen-Specific CD8+ T-Cell Transcripts Reveals Profiles Specific to mRNA or Adjuvanted Protein Vaccines
Authors: Meldgaard Trine Sundebo , Blengio Fabiola , Maffione Denise , Sammicheli Chiara , Tavarini Simona , Nuti Sandra , Kratzer Roland , Medini Duccio , Siena Emilio , Bertholet Sylvie
Published: December 2021

CD8+ T cells play a key role in mediating protective immunity after immune challenges such as infection or vaccination. Several subsets of differentiated CD8+ T cells have been identified, however, a deeper understanding of the molecular mechanism that underlies T-cell differentiation is lacking. Conventional approaches to the study of immune responses are typically limited to the analysis of bulk groups of cells that mask the cells’ heterogeneity (RNA-seq, microarray) and to the assessment of a relatively limited number of biomarkers that can be evaluated simultaneously at the population level (flow and mass cytometry). Single-cell analysis, on the other hand, represents a possible alternative that enables a deeper characterization of the underlying cellular heterogeneity. In this study, a murine model was used to characterize immunodominant hemagglutinin (HA533-541)-specific CD8+ T-cell responses to nucleic- and protein-based influenza vaccine candidates, using single-cell sorting followed by transcriptomic analysis. Investigation of single-cell gene expression profiles enabled the discovery of unique subsets of CD8+ T cells that co-expressed cytotoxic genes after vaccination. Moreover, this method enabled the characterization of antigen specific CD8+ T cells that were previously undetected. Single-cell transcriptome profiling has the potential to allow for qualitative discrimination of cells, which could lead to novel insights on biological pathways involved in cellular responses. This approach could be further validated and allow for more informed decision making in preclinical and clinical settings.
FcER1: A Novel Molecule Implicated in the Progression of Human Diabetic Kidney Disease
Authors: Sur Swastika , Nguyen Mark , Boada Patrick , Sigdel Tara K. , Sollinger Hans , Sarwal Minnie M.
Published: December 2021

Diabetic kidney disease (DKD) is a key microvascular complication of diabetes, with few therapies for targeting renal disease pathogenesis and progression. We performed transcriptional and protein studies on 103 unique blood and kidney tissue samples from patients with and without diabetes to understand the pathophysiology of DKD injury and its progression. The study was based on the use of 3 unique patient cohorts: peripheral blood mononuclear cell (PBMC) transcriptional studies were conducted on 30 patients with DKD with advancing kidney injury; Gene Expression Omnibus (GEO) data was downloaded, containing transcriptional measures from 51 microdissected glomerulous from patients with DKD. Additionally, 12 independent kidney tissue sections from patients with or without DKD were used for validation of target genes in diabetic kidney injury by kidney tissue immunohistochemistry and immunofluorescence. PBMC DKD transcriptional analysis, identified 853 genes (p < 0.05) with increasing expression with progression of albuminuria and kidney injury in patients with diabetes. GEO data was downloaded, normalized, and analyzed for significantly changed genes. Of the 325 significantly up regulated genes in DKD glomerulous (p < 0.05), 28 overlapped in PBMC and diabetic kidney, with perturbed FcER1 signaling as a significantly enriched canonical pathway. FcER1 was validated to be significantly increased in advanced DKD, where it was also seen to be specifically co-expressed in the kidney biopsy with tissue mast cells. In conclusion, we demonstrate how leveraging public and private human transcriptional datasets can discover and validate innate immunity and inflammation as key mechanistic pathways in DKD progression, and uncover FcER1 as a putative new DKD target for rational drug design.
Crossed Pathways for Radiation-Induced and Immunotherapy-Related Lung Injury
Authors: Zhang Zengfu , Zhou Jialin , Verma Vivek , Liu Xu , Wu Meng , Yu Jinming , Chen Dawei
Published: December 2021

Radiation-induced lung injury (RILI) is a form of radiation damage to normal lung tissue caused by radiotherapy (RT) for thoracic cancers, which is most commonly comprised of radiation pneumonitis (RP) and radiation pulmonary fibrosis (RPF). Moreover, with the widespread utilization of immunotherapies such as immune checkpoint inhibitors as first- and second-line treatments for various cancers, the incidence of immunotherapy-related lung injury (IRLI), a severe immune-related adverse event (irAE), has rapidly increased. To date, we know relatively little about the underlying mechanisms and signaling pathways of these complications. A better understanding of the signaling pathways may facilitate the prevention of lung injury and exploration of potential therapeutic targets. Therefore, this review provides an overview of the signaling pathways of RILI and IRLI and focuses on their crosstalk in diverse signaling pathways as well as on possible mechanisms of adverse events resulting from combined radiotherapy and immunotherapy. Furthermore, this review proposes potential therapeutic targets and avenues of further research based on signaling pathways. Many new studies on pyroptosis have renewed appreciation for the value and importance of pyroptosis in lung injury. Therefore, the authors posit that pyroptosis may be the common downstream pathway of RILI and IRLI; discussion is also conducted regarding further perspectives on pyroptosis as a crucial signaling pathway in lung injury treatment.
Macrophage-Osteoclast Associations: Origin, Polarization, and Subgroups
Authors: Sun Yang , Li Jiangbi , Xie Xiaoping , Gu Feng , Sui Zhenjiang , Zhang Ke , Yu Tiecheng
Published: December 2021

Cellular associations in the bone microenvironment are involved in modulating the balance between bone remodeling and resorption, which is necessary for maintaining a normal bone morphology. Macrophages and osteoclasts are both vital components of the bone marrow. Macrophages can interact with osteoclasts and regulate bone metabolism by secreting a variety of cytokines, which make a significant contribution to the associations. Although, recent studies have fully explored either macrophages or osteoclasts, indicating the significance of these two types of cells. However, it is of high importance to report the latest discoveries on the relationships between these two myeloid-derived cells in the field of osteoimmunology. Therefore, this paper reviews this topic from three novel aspects of the origin, polarization, and subgroups based on the previous work, to provide a reference for future research and treatment of bone-related diseases.
Antiviral Responses in Cancer: Boosting Antitumor Immunity Through Activation of Interferon Pathway in the Tumor Microenvironment
Authors: Vitiello Glauco Akelinghton Freire , Ferreira Wallax Augusto Silva , Cordeiro de Lima Vladmir Cláudio , Medina Tiago da Silva
Published: December 2021

In recent years, it became apparent that cancers either associated with viral infections or aberrantly expressing endogenous retroviral elements (EREs) are more immunogenic, exhibiting an intense intra-tumor immune cell infiltration characterized by a robust cytolytic apparatus. On the other hand, epigenetic regulation of EREs is crucial to maintain steady-state conditions and cell homeostasis. In line with this, epigenetic disruptions within steady-state cells can lead to cancer development and trigger the release of EREs into the cytoplasmic compartment. As such, detection of viral molecules by intracellular innate immune sensors leads to the production of type I and type III interferons that act to induce an antiviral state, thus restraining viral replication. This knowledge has recently gained momentum due to the possibility of triggering intratumoral activation of interferon responses, which could be used as an adjuvant to elicit strong anti-tumor immune responses that ultimately lead to a cascade of cytokine production. Accordingly, several therapeutic approaches are currently being tested using this rationale to improve responses to cancer immunotherapies. In this review, we discuss the immune mechanisms operating in viral infections, show evidence that exogenous viruses and endogenous retroviruses in cancer may enhance tumor immunogenicity, dissect the epigenetic control of EREs, and point to interferon pathway activation in the tumor milieu as a promising molecular predictive marker and immunotherapy target. Finally, we briefly discuss current strategies to modulate these responses within tumor tissues, including the clinical use of innate immune receptor agonists and DNA demethylating agents.
CCR5 and Biological Complexity: The Need for Data Integration and Educational Materials to Address Genetic/Biological Reductionism at the Interface of Ethical, Legal, and Social Implications
Authors: Bauss Jacob , Morris Michele , Shankar Rama , Olivero Rosemary , Buck Leah N. , Stenger Cynthia L. , Hinds David , Mills Joshua , Eby Alexandra , Zagorski Joseph W. , Smith Caitlin , Cline Sara , Hartog Nicholas L. , Chen Bin , Huss John , Carcillo Joseph A. , Rajasekaran Surender , Bupp Caleb P. , Prokop Jeremy W.
Published: December 2021

In the age of genomics, public understanding of complex scientific knowledge is critical. To combat reductionistic views, it is necessary to generate and organize educational material and data that keep pace with advances in genomics. The view that CCR5 is solely the receptor for HIV gave rise to demand to remove the gene in patients to create host HIV resistance, underestimating the broader roles and complex genetic inheritance of CCR5. A program aimed at providing research projects to undergraduates, known as CODE, has been expanded to build educational material for genes such asCCR5in a rapid approach, exposing students and trainees to large bioinformatics databases and previous experiments for broader data to challenge commitment to biological reductionism. Our students organize expression databases, query environmental responses, assess genetic factors, generate protein models/dynamics, and profile evolutionary insights into a protein such as CCR5. The knowledgebase generated in the initiative opens the door for public educational information and tools (molecular videos, 3D printed models, and handouts), classroom materials, and strategy for future genetic ideas that can be distributed in formal, semiformal, and informal educational environments. This work highlights that many factors are missing from the reductionist view of CCR5, including the role of missense variants or expression of CCR5 with neurological phenotypes and the role of CCR5 and the delta32 variant in complex critical care patients with sepsis. When connected to genomic stories in the news, these tools offer critically needed Ethical, Legal, and Social Implication (ELSI) education to combat biological reductionism.
Immunosenescence and Autoimmunity: Exploiting the T-Cell Receptor Repertoire to Investigate the Impact of Aging on Multiple Sclerosis
Authors: Amoriello Roberta , Mariottini Alice , Ballerini Clara
Published: December 2021

T-cell receptor (TCR) repertoire diversity is a determining factor for the immune system capability in fighting infections and preventing autoimmunity. During life, the TCR repertoire diversity progressively declines as a physiological aging progress. The investigation of TCR repertoire dynamics over life represents a powerful tool unraveling the impact of immunosenescence in health and disease. Multiple Sclerosis (MS) is a demyelinating, inflammatory, T-cell mediated autoimmune disease of the Central Nervous System in which age is crucial: it is the most widespread neurological disease among young adults and, furthermore, patients age may impact on MS progression and treatments outcome. Crossing knowledge on the TCR repertoire dynamics over MS patients’ life is fundamental to investigate disease mechanisms, and the advent of high- throughput sequencing (HTS) has significantly increased our knowledge on the topic. Here we report an overview of current literature about the impact of immunosenescence and age-related TCR dynamics variation in autoimmunity, including MS.
Regulation of the Immune System in Health and Disease by Members of the Bone Morphogenetic Protein Family
Authors: Sconocchia Tommaso , Sconocchia Giuseppe
Published: December 2021

Bone morphogenetic proteins (BMPs) are potent signaling molecules initially described as osteopromoting proteins. BMPs represent one of the members of the larger TGFβ family and today are recognized for their important role in numerous processes. Among the wide array of functions recently attributed to them, BMPs were also described to be involved in the regulation of components of the innate and adaptive immune response. This review focuses on the signaling pathway of BMPs and highlights the effects of BMP signaling on the differentiation, activation, and function of the main cell types of the immune system.
Leishmania infantum Infection Modulates the Jak-STAT Pathway in Lutzomyia longipalpis LL5 Embryonic Cells and Adult Females, and Affects Parasite Growth in the Sand Fly
Authors: Telleria Erich Loza , Azevedo-Brito Daisy Aline , Kykalová Barbora , Tinoco-Nunes Bruno , Pitaluga André Nóbrega , Volf Petr , Traub-Csekö Yara Maria
Published: December 2021

Phlebotomine sand flies (Diptera, Psychodidae) belonging to the Lutzomyia genus transmit zoonoses in the New World. Lutzomyia longipalpis is the main vector of Leishmania infantum, which is the causative agent of visceral leishmaniasis in Brazil. To identify key molecular aspects involved in the interaction between vector and pathogens and contribute to developing disease transmission controls, we investigated the sand fly innate immunity mediated by the Janus kinase/signal transducer and activator of transcription (Jak-STAT) pathway in response to L. infantum infection. We used two study models: L. longipalpis LL5 embryonic cells co-cultured with L. infantum and sand fly females artificially infected with the parasite. We used qPCR to follow the L. longipalpis gene expression of molecules involved in the Jak-STAT pathway. Also, we modulated the Jak-STAT mediated immune response to understand its role in Leishmania parasite infection. For that, we used RNAi to silence the pathway regulators, protein inhibitor of activated STATs (PIAS) in LL5 cells, and STAT in adult females. In addition, the pathway suppression effect on parasite development within the vector was assessed by light microscopy in late-phase infection. The silencing of the repressor PIAS in LL5 cells led to a moderate increase in a protein tyrosine phosphatase 61F (PTP61F) expression. It suggests a compensatory regulation between these two repressors. L. infantum co-culture with LL5 cells upregulated repressors PIAS, suppressor of cytokine signaling (SOCS), and PTP61F. It also downmodulated virus-induced RNA-1 (VIR-1), a pathway effector, indicating that the parasite could repress the Jak-STAT pathway in LL5 cells. In Leishmania-infected L. longipalpis females, STAT and the antimicrobial peptide attacin were downregulated on the third day post-infection, suggesting a correlation that favors the parasite survival at the end of blood digestion in the sand fly. The antibiotic treatment of infected females showed that the reduction of gut bacteria had little effect on the Jak-STAT pathway regulation. STAT gene silencing mediated by RNAi reduced the expression of inducible nitric oxide synthase (iNOS) and favored Leishmania growth in sand flies on the first day post-infection. These results indicate that STAT participated in the iNOS regulation with subsequent effect on parasite survival.
Propaedeutic Study of Biocomposites Obtained With Natural Fibers for Oceanographic Observing Platforms
Authors: Aracri Simona , Contardi Marco , Bayer Ilker S. , Zahid Muhammad , Giorgio-Serchi Francesco , Stokes Adam A.
Published: December 2021

In response to the pervasive anthropogenic pollution of the ocean, this manuscript suggests the use of biodegradable elastomers in marine applications. The present study characterizes 25 samples of highly biodegradable polymers, obtained blending a base elastomer with natural fibers. Mechanical analysis and Scanning Electron Microscope imaging, reveal how base polymers behave differently depending on the plant fiber chosen, on the external forcing—exposure to water—and on the doses that constitute the final biocomposite. Results suggest that EcoflexTM 00-30 and EcoflexTM 00-50, mixed with potato starch, perform best mechanically, maintaining up to 70% of their maximum tensile strain. Moreover, early signs of degradation are visible on polysiloxane rubber blended with 50% vegetable fibers after 19 hours in distilled water. Analyses demonstrate that highly biodegradable elastomers are good candidates to satisfy the requirements of aquatic devices. Furthermore, the discussed materials can improve the dexterity and biodegradability of marine technology.
Hawksbill Nesting in Hawai‘i: 30-Year Dataset Reveals Recent Positive Trend for a Small, Yet Vital Population
Authors: Gaos Alexander R. , Kurpita Lauren , Bernard Hannah , Sundquist Luke , King Cheryl S. , Browning Joy H. , Naboa Eldridge , Kelly Irene K. , Downs Kelleigh , Eguchi Tomo , Balazs George , Van Houtan Kyle , Johnson Devin , Jones T. Todd , Martin Summer L.
Published: December 2021

Evaluating wildlife population trends is necessary for the development of effective management strategies, which are particularly relevant for highly threatened species. Hawksbill marine turtles (Eretmochelys imbricata) are considered endangered globally and are rare in Hawai‘i. Remnant hawksbill nesting beaches were identified in Hawai‘i in the late 1980s and the primary sites have been monitored since that time. In this study we summarize all available hawksbill nesting activity around the Hawaiian Islands between 1988 and 2018, highlighting relevant demographic and geographic data for the species. Because monitoring effort varied substantially across space and time, we implemented a predictive modeling approach that accounted for varying effort to explore potential trends in annual number of nesting females and nests over time. Field monitoring efforts documented an annual average of 14 ± 4.3 (range: 5–26) nesting females and 48 ± 19.0 (range: 12–93) nests, with a cumulative total of 178 individual nesting females and 1,280 nests recorded across all years. Nesting has been documented on four Hawaiian Islands, with the overwhelming majority of nesting females (78.4%) and nests (86.5%) recorded at four beaches along the southern coast of Hawai‘i Island. Recent monitoring (2018) at a beach on Moloka‘i Island revealed numbers similar to the most important beaches on Hawai‘i Island. Despite difficulty discerning obvious trends when looking solely at the raw tabulated numbers from field monitoring, our analysis suggests both the number of nesting females and nests have been positively trending since 2006, and this is supported by a higher percentage (57.1% of annual cohorts) of neophyte (vs. remigrant) nesters over the second half of the monitoring timeframe. The masking of obvious trends in the tabulated numbers is likely due to decreased overall monitoring effort as a result of reduced funding in recent years, coupled with a shift in focal monitoring effort from the historical primary nesting site of Kamehame, to the more recently established nesting site of Pōhue. Although the positive trend is encouraging, our findings highlight the precarious state of hawksbills in Hawai‘i and the need to enhance monitoring across all sites to support more robust population assessments and management decision making.
Retinal Microvasculature and Conjunctival Vessel Alterations in Patients With Systemic Lupus Erythematosus—An Optical Coherence Tomography Angiography Study
Authors: Shi Wen-Qing , Han Ting , Liu Ren , Xia Qiang , Xu Tian , Wang Yan , Cai Shuang , Luo Shui-Lin , Shao Yi , Wu Rui
Published: December 2021

Purpose: To evaluate the conjunctival and fundus retinal vessel density in patients with systemic lupus erythematosus (SLE) with optical coherence tomography angiography (OCTA), and to investigate the relationship between vessel density and clinical indicators.

Methods: Twelve patients with SLE (24 eyes) and 12 healthy controls (24 eyes) were recruited. OCTA was used to examine the superficial retina layer (SRL) and deep retina layer (DRL) in the macular retina and conjunctival capillary plexus of each eye. We calculated the density of the temporal conjunctival vessels, fundus microvascular (MIR), macrovascular (MAR) and total MIR(TMI) and compared the results in both groups. We used annular partitioning (C1–C6), hemispheric quadrants, and Early Treatment Diabetic Retinopathy Study partitioning (ETDRS) to analyze changes in the retinal vascular density. Correlation analysis was used to investigate the association between blood capillary density and clinical indicators.

Results: OCTA results showed significant differences in the conjunctival microvascular density (p < 0.001). There was no significant difference in MIR, TMI, and MAR in the superficial layers between the SLE and healthy group (p > 0.05). The DRL and DTMI (Deeper TMI) densities were decreased in the macular regions of SLE patients (p < 0.05). In the hemispheric segmentation analysis, the superficial MIR was significantly decreased in the IL (inferior left) region of the SLE patients (p < 0.05), and the deep MIR in the IR (inferior right) region was significantly reduced (p < 0.05). In the ETDRS partitioning analysis, the superficial MIR in the inferior, right, and left subdivisions was significantly decreased in the SLE patients (p < 0.05). In the circular segmentation analysis, the deep MIR in the C1 and C3 regions was significantly reduced in SLE patients (p < 0.05), while the superficial MIR density was decreased only in the C3 region (p < 0.05). The conjunctival vascular density was negatively correlated with the STMI (Superficial TMI) (r = −0.5107; p = 0.0108) and DTMI (r = −0.9418, p < 0.0001). There was no significant correlation between vascular density and SLEDAI-2k (Systemic Lupus Erythematosus Disease Activity Index−2000) (P > 0.05).

Conclusion: Clinically, patients with SLE and patients suspected of SLE should receive OCTA examination in a comprehensive eye examination to detect changes in ocular microcirculation at an early stage.
PPV May Be a Starting Point to Achieve Circulatory Protective Mechanical Ventilation
Authors: Su Longxiang , Pan Pan , He Huaiwu , Liu Dawei , Long Yun
Published: December 2021

Pulse pressure variation (PPV) is a mandatory index for hemodynamic monitoring during mechanical ventilation. The changes in pleural pressure (Ppl) and transpulmonary pressure (PL) caused by mechanical ventilation are the basis for PPV and lead to the effect of blood flow. If the state of hypovolemia exists, the effect of the increased Ppl during mechanical ventilation on the right ventricular preload will mainly affect the cardiac output, resulting in a positive PPV. However, PL is more influenced by the change in alveolar pressure, which produces an increase in right heart overload, resulting in high PPV. In particular, if spontaneous breathing is strong, the transvascular pressure will be extremely high, which may lead to the promotion of alveolar flooding and increased RV flow. Asynchronous breathing and mediastinal swing may damage the pulmonary circulation and right heart function. Therefore, according to the principle of PPV, a high PPV can be incorporated into the whole respiratory treatment process to monitor the mechanical ventilation cycle damage/protection regardless of the controlled ventilation or spontaneous breathing. Through the monitoring of PPV, the circulation-protective ventilation can be guided at bedside in real time by PPV.
Electrical Impedance Tomography Predicts Weaning Success in Adult Patients With Delayed Upper Abdominal Surgery: A Single-Center Retrospective Study
Authors: Li Jiajia , Zeng Fan , Yang Fuxun , Luo Xiaoxiu , Liu Rongan , Ren Yinjie , Lan Yunping , Lei Yu , Zhao Gaoping , Huang Xiaobo
Published: December 2021

Objective: To evaluate the predictive value of electrical impedance tomography (EIT) in patients with delayed ventilator withdrawal after upper abdominal surgery.

Methods: We retrospectively analyzed data of patients who were ventilated >24 h after upper abdominal surgery between January 2018 and August 2019. The patients were divided into successful (group S) and failed (group F) weaning groups. EIT recordings were obtained at 0, 5, 15, and 30 min of spontaneous breathing trials (SBTs) with SBT at 0 min set as baseline. We assessed the change in delta end-expiratory lung impedance and tidal volume ratio (ΔEELI/VT) from baseline, the change in compliance change percentage variation (|Δ(CW-CL)|) from baseline, the standard deviation of regional ventilation delay index (RVDSD), and global inhomogeneity (GI) using generalized estimation equation analyses. Receiver operating characteristic curve analyses were performed to evaluate the predictive value of parameters indicating weaning success.

Results: Among the 32 included patients, ventilation weaning was successful in 23 patients but failed in nine. Generalized estimation equation analysis showed that compared with group F, the ΔEELI/VT was lower, and the GI, RVDSD, and (|Δ(CW-CL)|) were higher in group S. For predicting withdrawal failure, the areas under the curve of the ΔEELI/VT, (|Δ(CW-CL)|), and the RVDSD were 0.819, 0.918, and 0.918, and 0.816, 0.884, and 0.918 at 15 and 30 min during the SBTs, respectively.

Conclusion: The electrical impedance tomography may predict the success rate of ventilator weaning in patients with delayed ventilator withdrawal after upper abdominal surgery.
Nomogram Models to Predict Postoperative Hyperlactatemia in Patients Undergoing Elective Cardiac Surgery
Authors: Wang Dashuai , Wang Su , Wu Jia , Le Sheng , Xie Fei , Li Ximei , Wang Hongfei , Huang Xiaofan , Du Xinling , Zhang Anchen
Published: December 2021

Objectives: Postoperative hyperlactatemia (POHL) is common in patients undergoing cardiac surgery and is associated with poor outcomes. The purpose of this study was to develop and validate two predictive models for POHL in patients undergoing elective cardiac surgery (ECS).

Methods: We conducted a multicenter retrospective study enrolling 13,454 adult patients who underwent ECS. All patients involved in the analysis were randomly assigned to a training set and a validation set. Univariate and multivariate analyses were performed to identify risk factors for POHL in the training cohort. Based on these independent predictors, the nomograms were constructed to predict the probability of POHL and were validated in the validation cohort.

Results: A total of 1,430 patients (10.6%) developed POHL after ECS. Age, preoperative left ventricular ejection fraction, renal insufficiency, cardiac surgery history, intraoperative red blood cell transfusion, and cardiopulmonary bypass time were independent predictors and were used to construct a full nomogram. The second nomogram was constructed comprising only the preoperative factors. Both models showed good predictive ability, calibration, and clinical utility. According to the predicted probabilities, four risk groups were defined as very low risk (<0.05), low risk (0.05–0.1), medium risk (0.1–0.3), and high risk groups (>0.3), corresponding to scores of ≤ 180 points, 181–202 points, 203–239 points, and >239 points on the full nomogram, respectively.

Conclusions: We developed and validated two nomogram models to predict POHL in patients undergoing ECS. The nomograms may have clinical utility in risk estimation, risk stratification, and targeted interventions.
Association Between Base Excess and Mortality Among Patients in ICU With Acute Kidney Injury
Authors: Cheng Yi , Zhang You , Tu Boxiang , Qin Yingyi , Cheng Xin , Qi Ran , Guo Wei , Li Dongdong , Wu Shengyong , Zhu Ronghui , Zhao Yanfang , Tang Yuanjun , Wu Cheng
Published: December 2021

Objective: This study aimed to explore the association between base excess (BE) and the risk of 30-day mortality among patients with acute kidney injury (AKI) in the intensive care unit (ICU).

Methods: This retrospective study included patients with AKI from the Medical Information Mart for Intensive Care (MIMIC)-IV database. We used a multivariate Cox proportional-hazards model to obtain the hazard ratio (HR) for the risk of 30-day mortality among patients with AKI. Furthermore, we utilized a Cox proportional-hazard model with restricted cubic splines (RCS) to explore the potential non-linear associations.

Results: Among the 14,238 ICU patients with AKI, BE showed a U-shaped relationship with risk of 30-day mortality for patients with AKI, and higher or lower BE values could increase the risk. Compared with normal base excess (−3~3 mEq/L), patients in different groups (BE ≤ −9 mEq/L, −9 mEq/L < BE ≤ −3 mEq/L, 3 mEq/L < BE ≤ 9 mEq/L, and BE > 9 mEq/L) had different HRs for mortality: 1.57 (1.40, 1.76), 1.26 (1.14, 1.39), 0.97 (0.83, 1.12), 1.53 (1.17, 2.02), respectively. The RCS analyses also showed a U-shaped curve between BE and the 30-day mortality risk.

Conclusion: Our results suggest that higher and lower BE in patients with AKI would increase the risk of 30-day mortality. BE measured at administration could be a critical prognostic indicator for ICU patients with AKI and provide guidance for clinicians.
Epigenetic Modifiers Revamp Secondary Metabolite Production in Endophytic Nigrospora sphaerica
Authors: Ramesha Kolathuru Puttamadaiah , Chandra Mohana Nagabhushana , Chandra Nayaka Siddaiah , Satish Sreedharamurthy
Published: December 2021

During plant interaction, endophytes provide benefits to the host plant. Endophytes also contribute a variety of structural attributes with biological potential. Nigrospora sphaerica, which produces phomalactone from Adiantum philippense L., was subjected to epigenetic modification. High-performance liquid chromatography (HPLC) and Gas chromatography-mass spectrometry (GCMS) analysis were used to determine secondary metabolite profiling. Epigenetic modifiers like DNA Methyltransferase (DNMT) and Histone deacetylase (HDAC) inhibitors increased the expression of biosynthetic pathways. The activation of new metabolites was observed as a result of the activation of cryptic biosynthetic gene clusters, as well as the silencing of phomalactone in some treatments. When compared to DNMT treatments, HDAC treatments showed a significant increase in cryptic metabolite induction. The induction of cryptic metabolites with biological significance by HDAC treatment is supported by our findings.
A Novel Approach to Characterize the Lipidome of Marine Archaeon Nitrosopumilus maritimus by Ion Mobility Mass Spectrometry
Authors: Law Kai P. , He Wei , Tao Jianchang , Zhang Chuanlun
Published: December 2021

Archaea are differentiated from the other two domains of life by their biomolecular characteristics. One such characteristic is the unique structure and composition of their lipids. Characterization of the whole set of lipids in a biological system (the lipidome) remains technologically challenging. This is because the lipidome is innately complex, and not all lipid species are extractable, separable, or ionizable by a single analytical method. Furthermore, lipids are structurally and chemically diverse. Many lipids are isobaric or isomeric and often indistinguishable by the measurement of mass or even their fragmentation spectra. Here we developed a novel analytical protocol based on liquid chromatography ion mobility mass spectrometry to enhance the coverage of the lipidome and characterize the conformations of archaeal lipids by their collision cross-sections (CCSs). The measurements of ion mobility revealed the gas-phase ion chemistry of representative archaeal lipids and provided further insights into their attributions to the adaptability of archaea to environmental stresses. A comprehensive characterization of the lipidome of mesophilic marine thaumarchaeon, Nitrosopumilus maritimus (strain SCM1) revealed potentially an unreported phosphate- and sulfate-containing lipid candidate by negative ionization analysis. It was the first time that experimentally derived CCS values of archaeal lipids were reported. Discrimination of crenarchaeol and its proposed stereoisomer was, however, not achieved with the resolving power of the SYNAPT G2 ion mobility system, and a high-resolution ion mobility system may be required for future work. Structural and spectral libraries of archaeal lipids were constructed in non-vendor-specific formats and are being made available to the community to promote research of Archaea by lipidomics.
The LORF5 Gene Is Non-essential for Replication but Important for Duck Plague Virus Cell-to-Cell Spread Efficiently in Host Cells
Authors: Shen Bingjie , Li Yunjiao , Cheng Anchun , Wang Mingshu , Wu Ying , Yang Qiao , Jia Renyong , Tian Bin , Ou Xumin , Mao Sai , Sun Di , Zhang Shaqiu , Zhu Dekang , Chen Shun , Liu Mafeng , Zhao Xin-Xin , Huang Juan , Gao Qun , Liu Yunya , Yu Yanling , Zhang Ling , Pan Leichang
Published: December 2021

Duck plague virus (DPV) can cause high morbidity and mortality in many waterfowl species within the order Anseriformes. The DPV genome contains 78 open reading frames (ORFs), among which the LORF2, LORF3, LORF4, LORF5, and SORF3 genes are unique genes of avian herpesvirus. In this study, to investigate the role of this unique LORF5 gene in DPV proliferation, we generated a recombinant virus that lacks the LORF5 gene by a two-step red recombination system, which cloned the DPV Chinese virulent strain (DPV CHv) genome into a bacterial artificial chromosome (DPV CHv-BAC); the proliferation law of LORF5-deleted mutant virus on DEF cells and the effect of LORF5 gene on the life cycle stages of DPV compared with the parent strain were tested. Our data revealed that the LORF5 gene contributes to the cell-to-cell transmission of DPV but is not relevant to virus invasion, replication, assembly, and release formation. Taken together, this study sheds light on the role of the avian herpesvirus-specific gene LORF5 in the DPV proliferation life cycle. These findings lay the foundation for in-depth functional studies of the LORF5 gene in DPV or other avian herpesviruses.
Lacticaseibacillus casei Strain T21 Attenuates Clostridioides difficile Infection in a Murine Model Through Reduction of Inflammation and Gut Dysbiosis With Decreased Toxin Lethality and Enhanced Mucin Production
Authors: Panpetch Wimonrat , Phuengmaung Pornpimol , Cheibchalard Thanya , Somboonna Naraporn , Leelahavanichkul Asada , Tumwasorn Somying
Published: December 2021

Clostridioides difficileis a major cause of diarrhea in patients with antibiotic administration.Lacticaseibacillus caseiT21, isolated from a human gastric biopsy, was tested in a murineC. difficileinfection (CDI) model and colonic epithelial cells (Caco-2 and HT-29). Daily administration ofL. caseiT21 [1 × 108colony forming units (CFU)/dose] for 4 days starting at 1 day beforeC. difficilechallenge attenuated CDI as demonstrated by a reduction in mortality rate, weight loss, diarrhea, gut leakage, gut dysbiosis, intestinal pathology changes, and levels of pro-inflammatory cytokines [interleukin (IL)-1β, tumor necrosis factor (TNF)-α, macrophage inflammatory protein 2 (MIP-2), and keratinocyte chemoattractant (KC)] in the intestinal tissue and serum. Conditioned media fromL. caseiT21 exerted biological activities that fight againstC. difficileas demonstrated in colonic epithelial cells by the following: (i) suppression of gene expression and production of IL-8, an important chemokine involved inC. difficilepathogenesis, (ii) reduction in the expression ofSLC11A1(solute carrier family 11 member 1) andHuR(human antigen R), important genes for the lethality ofC. difficiletoxin B, (iii) augmentation of intestinal integrity, and (iv) up-regulation ofMUC2, a mucosal protective gene. These results supported the therapeutic potential ofL. caseiT21 for CDI and the need for further study on the intervention capabilities of CDI.
Microbial Technologies Employed for Biodegradation of Neonicotinoids in the Agroecosystem
Authors: Ahmad Sajjad , Cui Dongming , Zhong Guohua , Liu Jie
Published: December 2021

Neonicotinoids are synthetic pesticides widely used for the control of various pests in agriculture throughout the world. They mainly attack the nicotinic acetylcholine receptors, generate nervous stimulation, receptor clot, paralysis and finally cause death. They are low volatile, highly soluble and have a long half-life in soil and water. Due to their extensive use, the environmental residues have immensely increased in the last two decades and caused many hazardous effects on non-target organisms, including humans. Hence, for the protection of the environment and diversity of living organism’s the degradation of neonicotinoids has received widespread attention. Compared to the other methods, biological methods are considered cost-effective, eco-friendly and most efficient. In particular, the use of microbial species makes the degradation of xenobiotics more accessible fast and active due to their smaller size. Since this degradation also converts xenobiotics into less toxic substances, the various metabolic pathways for the microbial degradation of neonicotinoids have been systematically discussed. Additionally, different enzymes, genes, plasmids and proteins are also investigated here. At last, this review highlights the implementation of innovative tools, databases, multi-omics strategies and immobilization techniques of microbial cells to detect and degrade neonicotinoids in the environment.
Identifying Components of a Halobacterium salinarum N-Glycosylation Pathway
Authors: Vershinin Zlata , Zaretsky Marianna , Guan Ziqiang , Eichler Jerry
Published: December 2021

Whereas N-glycosylation is a seemingly universal process in Archaea, pathways of N-glycosylation have only been experimentally verified in a mere handful of species. Toward expanding the number of delineated archaeal N-glycosylation pathways, the involvement of the putative Halobacterium salinarum glycosyltransferases VNG1067G, VNG1066C, and VNG1062G in the assembly of an N-linked tetrasaccharide decorating glycoproteins in this species was addressed. Following deletion of each encoding gene, the impact on N-glycosylation of the S-layer glycoprotein and archaellins, major glycoproteins in this organism, was assessed by mass spectrometry. Likewise, the pool of dolichol phosphate, the lipid upon which this glycan is assembled, was also considered in each deletion strain. Finally, the impacts of such deletions were characterized in a series of biochemical, structural and physiological assays. The results revealed that VNG1067G, VNG1066C, and VNG1062G, renamed Agl25, Agl26, and Agl27 according to the nomenclature used for archaeal N-glycosylation pathway components, are responsible for adding the second, third and fourth sugars of the N-linked tetrasaccharide decorating Hbt. salinarum glycoproteins. Moreover, this study demonstrated how compromised N-glycosylation affects various facets of Hbt. salinarum cell behavior, including the transcription of archaellin-encoding genes.
Survival Comes at a Cost: A Coevolution of Phage and Its Host Leads to Phage Resistance and Antibiotic Sensitivity of Pseudomonas aeruginosa Multidrug Resistant Strains
Authors: Koderi Valappil Sarshad , Shetty Prateek , Deim Zoltán , Terhes Gabriella , Urbán Edit , Váczi Sándor , Patai Roland , Polgár Tamás , Pertics Botond Zsombor , Schneider György , Kovács Tamás , Rákhely Gábor
Published: December 2021

The increasing ineffectiveness of traditional antibiotics and the rise of multidrug resistant (MDR) bacteria have necessitated the revival of bacteriophage (phage) therapy. However, bacteria might also evolve resistance against phages. Phages and their bacterial hosts coexist in nature, resulting in a continuous coevolutionary competition for survival. We have isolated several clinical strains of Pseudomonas aeruginosa and phages that infect them. Among these, the PIAS (Phage Induced Antibiotic Sensitivity) phage belonging to the Myoviridae family can induce multistep genomic deletion in drug-resistant clinical strains of P. aeruginosa, producing a compromised drug efflux system in the bacterial host. We identified two types of mutant lines in the process: green mutants with SNPs (single nucleotide polymorphisms) and smaller deletions and brown mutants with large (∼250 kbp) genomic deletion. We demonstrated that PIAS used the MexXY-OprM system to initiate the infection. P. aeruginosa clogged PIAS phage infection by either modifying or deleting these receptors. The green mutant gaining phage resistance by SNPs could be overcome by evolved PIASs (E-PIASs) with a mutation in its tail-fiber protein. Characterization of the mutant phages will provide a deeper understanding of phage-host interaction. The coevolutionary process continued with large deletions in the same regions of the bacterial genomes to block the (E-)PIAS infection. These mutants gained phage resistance via either complete loss or substantial modifications of the phage receptor, MexXY-OprM, negating its essential role in antibiotic resistance. In vitro and in vivo studies indicated that combined use of PIAS and antibiotics could effectively inhibit P. aeruginosa growth. The phage can either eradicate bacteria or induce antibiotic sensitivity in MDR-resistant clinical strains. We have explored the potential use of combination therapy as an alternative approach against MDR P. aeruginosa infection.
On the Verge of a Catastrophic Collapse? The Need for a Multi-Ecosystem Approach to Microbiome Studies
Authors: Larsen Olaf F. A. , van de Burgwal Linda H. M.
Published: December 2021

While the COVID-19 pandemic has led to increased focus on pathogenic microbes that cross the animal-human species barrier, calls to include non-pathogenic interactions in our perspective on public health are gaining traction in the academic community. Over generations, the diversity of the human gut microbiota is being challenged by external perturbations and reduced acquisition of symbiotic species throughout life. When such reduced diversity concerns not only the microbial species, but also the higher taxonomic levels and even the guild level, adequate compensation for possible losses may be lacking. Shifts from a high-abundance to a low-abundance state, known as a tipping point, may result in simultaneous shifts in covarying taxa and ultimately to a catastrophic collapse in which the ecosystem abruptly and possibly irreversibly shifts to an alternative state. Here, we propose that co-occurrence patterns within and between microbial communities across human, animal, soil, water, and other environmental domains should be studied in light of such critical transitions. Improved mechanistic understanding of factors that shape structure and function is needed to understand whether interventions can sustainably remodel disease-prone microbiota compositions to robust and resilient healthy microbiota. Prerequisites for a rational approach are a better understanding of the microbial interaction network, both within and inter-domain, as well as the identification of early warning signs for a catastrophic collapse, warranting a timely response for intervention. We should not forget that mutualism and pathogenicity are two sides of the same coin. Building upon the planetary health concept, we argue that microbiome research should include system level approaches to conserve ecosystem resilience.

HIGHLIGHTS

1. Non-pathogenic interactions between ecosystems play a key role in maintaining health.

2. The human gut microbiome may be on the verge of a catastrophic collapse.

3. Research should identify keystone taxa and guilds that interconnect different domains.

4. We should not forget that mutualism and pathogenicity are two sides of the same coin.
Genomic Analysis of Global Staphylococcus argenteus Strains Reveals Distinct Lineages With Differing Virulence and Antibiotic Resistance Gene Content
Authors: Goswami Cosmika , Fox Stephen , Holden Matthew , Leanord Alistair , Evans Thomas J.
Published: December 2021

Infections due to Staphylococcus argenteus have been increasingly reported worldwide and the microbe cannot be distinguished from Staphylococcus aureus by standard methods. Its complement of virulence determinants and antibiotic resistance genes remain unclear, and how far these are distinct from those produced by S. aureus remains undetermined. In order to address these uncertainties, we have collected 132 publicly available sequences from fourteen different countries, including the United Kingdom, between 2005 and 2018 to study the global genetic structure of the population. We have compared the genomes for antibiotic resistance genes, virulence determinants and mobile genetic elements such as phages, pathogenicity islands and presence of plasmid groups between different clades. 20% (n = 26) isolates were methicillin resistant harboring a mecA gene and 88% were penicillin resistant, harboring the blaZ gene. ST2250 was identified as the most frequent strain, but ST1223, which was the second largest group, contained a marginally larger number of virulence genes compared to the other STs. Novel S. argenteus pathogenicity islands were identified in our isolates harboring tsst-1, seb, sec3, ear, selk, selq toxin genes, as well as chromosomal clusters of enterotoxin and superantigen-like genes. Strain-specific type I modification systems were widespread which would limit interstrain transfer of genetic material. In addition, ST2250 possessed a CRISPR/Cas system, lacking in most other STs. S. argenteus possesses important genetic differences from S. aureus, as well as between different STs, with the potential to produce distinct clinical manifestations.