bluuebunny/crossref_metadata_2025 huggingface dataset:
Rain Forest Fragmentation and Environmental Dynamics on Nosy Be Island (NW Madagascar) at 1300 cal BP Is Attributable to Intensified Human Impact
Authors: Reinhardt Antonia L. , Kasper Thomas , Lochner Maximilian , Bliedtner Marcel , Krahn Kim J. , Haberzettl Torsten , Shumilovskikh Lyudmila , Rahobisoa Jean-Jacques , Zech Roland , Favier Charly , Behling Hermann , Bremond Laurent , Daut Gerhard , Montade Vincent
Published: February 2022

Madagascar houses one of the Earth’s biologically richest, but also one of most endangered, terrestrial ecoregions. Although it is obvious that humans substantially altered the natural ecosystems during the past decades, the timing of arrival of early inhabitants on Madagascar as well as their environmental impact is still intensively debated. This research aims to study the beginning of early human impact on Malagasy natural ecosystems, specifically on Nosy Be island (NW Madagascar) by targeting the sedimentary archive of Lake Amparihibe, an ancient volcanic crater. Based on pollen, fungal spore, other non-pollen palynomorph, charcoal particle and diatom analyses combined with high-resolution sediment-physical and (in)organic geochemical data, paleoenvironmental dynamics during the past three millennia were reconstructed. Results indicate a major environmental change at ca. 1300 cal BP characterized by an abrupt development of grass (C4) dominated and fire disturbed landscape showing the alteration of natural rain forest. Further, increased soil erodibility is suggested by distinct increase in sediment accumulation rates, a strong pulse of nutrient input, higher water turbidity and contemporaneous increase in spores of mycorrhizal fungi. These parameters are interpreted to show a strong early anthropogenic transformation of the landscape from rain forest to open grassland. After ca. 1000 cal BP, fires remain frequent and vegetation is dominated by forest/grassland mosaic. While natural vegetation should be dominated by rain forest on Nosy Be, these last results indicate that human continuously impacted the landscapes surrounding the lake. At a local scale, our data support the “subsistence shift hypothesis” which proposed that population expansion with development of herding/farming altered the natural ecosystems. However, a precise regional synthesis is challenging, since high-resolution multi-proxy records from continuous sedimentary archives as well as records located further north and in the hinterland are still scarce in Madagascar. The lack of such regional synthesis also prevents precise comparison between different regions in Madagascar to detect potential (dis)similarities in climate dynamics, ecosystem responses and anthropogenic influences at the island’s scale during the (late) Holocene.
Potentials of Non-Invasive 18F-FDG PET/CT in Immunotherapy Prediction for Non–Small Cell Lung Cancer
Authors: Liao Xuhe , Liu Meng , Wang Rongfu , Zhang Jianhua
Published: February 2022

The immune checkpoint inhibitors (ICIs), by targeting cytotoxic-T-lymphocyte-associated protein 4, programmed cell death 1 (PD-1), or PD-ligand 1, have dramatically changed the natural history of several cancers, including non–small cell lung cancer (NSCLC). There are unusual response manifestations (such as pseudo-progression, hyper-progression, and immune-related adverse events) observed in patients with ICIs because of the unique mechanisms of these agents. These specific situations challenge response and prognostic assessment to ICIs challenging. This review demonstrates how 18F-FDG PET/CT can help identify these unusual response patterns in a non-invasive and effective way. Then, a series of semi-quantitative parameters derived from 18F-FDG PET/CT are introduced. These indexes have been recognized as the non-invasive biomarkers to predicting the efficacy of ICIs and survival of NSCLC patients according to the latest clinical studies. Moreover, the current situation regarding the functional criteria based on 18F-FDG PET/CT for immunotherapeutic response assessment is presented and analyzed. Although the criteria based on 18F-FDG PET/CT proposed some resolutions to overcome limitations of morphologic criteria in the assessment of tumor response to ICIs, further researches should be performed to validate and improve these assessing systems. Then, the last part in this review displays the present status and a perspective of novel specific PET probes targeting key molecules relevant to immunotherapy in prediction and response assessment.
Integration of Transcriptomics and Metabolomics for Understanding the Different Vegetative Growth in Morchella Sextelata
Authors: Deng Kejun , Lan Xiuhua , Chen Ying , Wang Ting , Li Mengke , Xu Yingyin , Cao Xuelian , Xie Guangbo , Xie Liyuan
Published: February 2022

Morchella sextelatais an edible and medicinal fungus with high nutritional, medicinal, and economic value. Recently,M.sextelatahas been produced through artificial cultivation in China, but its stable production remains problematic because the details of its growth and development process are limitedly understood. Herein, to investigate the dynamic process ofM.sextelatadevelopment, we integrated the transcriptomics and metabolomics data ofM. sextelatafrom three developmental stages: the young mushroom period (YMP), marketable mature period (MMP), and physiological maturity period (PMP). The results showed that the transcriptome changed dynamically at different stages and demonstrated the significant enrichment of pathways that regulate plant growth and development, such as N-glycan biosynthesis and carbon and purine metabolism. Similarly, small-molecule metabolites, such as D-fructose-1,6-biphosphate, which was upregulated during the YMP, dihydromyricetin, which was upregulated during the MMP, and L-citrulline, which was upregulated during the PMP, also showed phase-dependent characteristics. Then, combined analysis of the transcriptome data and metabolome traits revealed that the transcriptome may affect metabolic molecules during different growth stages ofM. sextelata viaspecific enzymes, such as α-glucosidase and glucanase, which were included in two opposite transcriptome modules. In summary, this integration of transcriptomics and metabolomics data for understanding the vegetative growth ofM. sextelataduring different developmental stages implicated several key genes, metabolites, and pathways involved in the vegetative growth. We believe that these findings will provide comprehensive insights into the dynamic process of growth and development inM. sextelataand new clues for optimizing the methods for its cultivation application.
Mendelian Randomization: A Review of Methods for the Prevention, Assessment, and Discussion of Pleiotropy in Studies Using the Fat Mass and Obesity-Associated Gene as an Instrument for Adiposity
Authors: Mbutiwi Fiston Ikwa Ndol , Dessy Tatiana , Sylvestre Marie-Pierre
Published: February 2022

Pleiotropy assessment is critical for the validity of Mendelian randomization (MR) analyses, and its management remains a challenging task for researchers. This review examines how the authors of MR studies address bias due to pleiotropy in practice. We reviewed Pubmed, Medline, Embase and Web of Science for MR studies published before 21 May 2020 that used at least one single-nucleotide polymorphism (SNP) in the fat mass and obesity-associated (FTO) gene as instrumental variable (IV) for body mass index, irrespective of the outcome. We reviewed: 1) the approaches used to prevent pleiotropy, 2) the methods cited to detect or control the independence or the exclusion restriction assumption highlighting whether pleiotropy assessment was explicitly stated to justify the use of these methods, and 3) the discussion of findings related to pleiotropy. We included 128 studies, of which thirty-three reported one approach to prevent pleiotropy, such as the use of multiple (independent) SNPs combined in a genetic risk score as IVs. One hundred and twenty studies cited at least one method to detect or account for pleiotropy, including robust and other IV estimation methods (n = 70), methods for detection of heterogeneity between estimated causal effects across IVs (n = 72), methods to detect or account associations between IV and outcome outside thought the exposure (n = 85), and other methods (n = 5). Twenty-one studies suspected IV invalidity, of which 16 explicitly referred to pleiotropy, and six incriminating FTO SNPs. Most reviewed MR studies have cited methods to prevent or to detect or control bias due to pleiotropy. These methods are heterogeneous, their triangulation should increase the reliability of causal inference.
Estimates of Variance Components and Heritability Using Random Regression Models for Semen Traits in Boars
Authors: Hong Yifeng , Yan Limin , He Xiaoyan , Wu Dan , Ye Jian , Cai Gengyuan , Liu Dewu , Wu Zhenfang , Tan Cheng
Published: February 2022

It has been proven that the random regression model has a great advantage over the repeatability model in longitudinal data analysis. At present, the random regression model has been used as a standard analysis method in longitudinal data analysis. The aim of this study was to estimate the variance components and heritability of semen traits over the reproductive lifetime of boars. The study data, including 124,941 records from 3,366 boars, were collected from seven boar AI centers in South China between 2010 and 2019. To evaluate alternative models, we compared different polynomial orders of fixed, additive, and permanent environment effects in total 216 models using Bayesian Information Criterions. The result indicated that the best model always has higher-order polynomials of permanent environment effect and lower-order polynomials of fixed effect and additive effect regression. In Landrace boars, the heritabilities ranged from 0.18 to 0.28, 0.06 to 0.43, 0.03 to 0.14, and 0.05 to 0.24 for semen volume, sperm motility, sperm concentration, and abnormal sperm percentage, respectively. In Large White boars, the heritabilities ranged from 0.20 to 0.26, 0.07 to 0.15, 0.10 to 0.23, and 0.06 to 0.34 for semen volume, sperm motility, sperm concentration, and abnormal sperm percentage, respectively.
Screening of Salt-Tolerant Thinopyrum ponticum Under Two Coastal Region Salinity Stress Levels
Authors: Tong Chunyan , Yang Guotang , AoenBolige  , Terigen  , Li Hongwei , Li Bin , Li Zhensheng , Zheng Qi
Published: February 2022

To accelerate the exploitation and use of marginal soils and develop salt-tolerant forage germplasm suitable for the coastal regions of China, seven lines of decaploid tall wheatgrass [Thinopyrum ponticum (Podp.) Barkworth and D. R. Dewey, 2n = 10x = 70] were transplanted under low (.3%) and high (.5%) salt conditions for a comprehensive analysis at the adult-plant stage. Differences were observed among these materials, especially in terms of grass yield, agronomic characteristics, and physiological and biochemical indices. Line C2 grew best with the highest shoot total fresh and dry weights under all conditions except for the milk-ripe stage in Dongying in 2019. The total membership value of C2 also reflected its excellent performance after transplanting. As superior germplasm, its relatively high antioxidant enzyme activities and chlorophyll a/b ratio suggested C2 may maintain normal metabolic and physiological functions under saline conditions. Furthermore, decaploid tall wheatgrass as a forage grass species has a high nutritive value beneficial for animal husbandry. Accordingly, line C2 may be used as excellent germplasm to develop salt-tolerant cultivars in the Circum-Bohai sea.
Pro-Inflammatory Signature in Decidua of Recurrent Pregnancy Loss Regardless of Embryonic Chromosomal Abnormalities
Authors: Wu Zaigui , Wang Miaomiao , Liang Guanmian , Jin Pengzhen , Wang Peng , Xu Yuqing , Qian Yeqing , Jiang Xiuxiu , Qian Junbin , Dong Minyue
Published: February 2022

Recurrent pregnancy loss (RPL), especially the unexplained RPL, is associated with the disruption of maternal immune tolerance. However, little is known about the immune status at the decidua of RPL with embryonic chromosomal aberrations. Herein, mass cytometry (CyTOF) was used to interrogate the immune atlas at the decidua which was obtained from 15 RPL women—six with normal chromosome and nine with chromosomal aberrations—and five controls. The total frequency of CCR2−CD11chigh macrophages increased, while CD39high NK cells and CCR2−CD11clow macrophages decrease significantly in RPL when RPLs were stratified, compared with controls. Pro-inflammatory subsets of CD11chigh macrophages increased, while less pro-inflammatory or suppressive subsets decreased statistically in RPL decidua whenever RPLs were stratified or not. However, CD11chigh NK and CD161highCD8+ T cells increased only in RPL with normal chromosome, while the inactivated and naive CD8+/CD4+ T cells were enriched only in RPL with chromosomal aberrations. A pro-inflammatory signature is observed in RPL decidua; however, differences exist between RPL with and without chromosomal abnormalities.
The HVEM-BTLA Immune Checkpoint Restrains Murine Chronic Cholestatic Liver Injury by Regulating the Gut Microbiota
Authors: Kou Yanbo , Zheng Xingping , Meng Liyuan , Liu Mengnan , Xu Shihong , Jing Qiyue , Zhang Shenghan , Wang Hanying , Han Jinzhi , Liu Zhuanzhuan , Wei Yanxia , Wang Yugang
Published: February 2022

The herpes virus entry mediator (HVEM) is an immune checkpoint molecule regulating immune response, but its role in tissue repair remains unclear. Here, we reported that HVEM deficiency aggravated hepatobiliary damage and compromised liver repair after 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced injury. A similar phenotype was observed in B and T lymphocyte attenuator (BTLA)-deficient mice. These were correlated with impairment of neutrophil accumulation in the liver after injury. The hepatic neutrophil accumulation was regulated by microbial-derived secondary bile acids. HVEM-deficient mice had reduced ability to deconjugate bile acids during DDC-feeding, suggesting a gut microbiota defect. Consistently, both HVEM and BTLA deficiency had dysregulated intestinal IgA responses targeting the gut microbes. These results suggest that the HVEM-BTLA signaling may restrain liver injury by regulating the gut microbiota.
Emerging Role of Platelet-Endothelium Interactions in the Pathogenesis of Severe SARS-CoV-2 Infection-Associated Myocardial Injury
Authors: Rossouw Theresa M. , Anderson Ronald , Manga Pravin , Feldman Charles
Published: February 2022

Cardiovascular dysfunction and disease are common and frequently fatal complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Indeed, from early on during the SARS-CoV-2 virus pandemic it was recognized that cardiac complications may occur, even in patients with no underlying cardiac disorders, as part of the acute infection, and that these were associated with more severe disease and increased morbidity and mortality. The most common cardiac complication is acute cardiac injury, defined by significant elevation of cardiac troponins. The potential mechanisms of cardiovascular complications include direct viral myocardial injury, systemic inflammation induced by the virus, sepsis, arrhythmia, myocardial oxygen supply-demand mismatch, electrolyte abnormalities, and hypercoagulability. This review is focused on the prevalence, risk factors and clinical course of COVID-19-related myocardial injury, as well as on current data with regard to disease pathogenesis, specifically the interaction of platelets with the vascular endothelium. The latter section includes consideration of the role of SARS-CoV-2 proteins in triggering development of a generalized endotheliitis that, in turn, drives intense activation of platelets. Most prominently, SARS-CoV-2–induced endotheliitis involves interaction of the viral spike protein with endothelial angiotensin-converting enzyme 2 (ACE2) together with alternative mechanisms that involve the nucleocapsid and viroporin. In addition, the mechanisms by which activated platelets intensify endothelial activation and dysfunction, seemingly driven by release of the platelet-derived calcium-binding proteins, SA100A8 and SA100A9, are described. These events create a SARS-CoV-2–driven cycle of intravascular inflammation and coagulation, which contributes significantly to a poor clinical outcome in patients with severe disease.
Elevated Detection of Dual Antibody B Cells Identifies Lupus Patients With B Cell-Reactive VH4-34 Autoantibodies
Authors: Peterson Jacob N. , Boackle Susan A. , Taitano Sophina H. , Sang Allison , Lang Julie , Kelly Margot , Rahkola Jeremy T. , Miranda Anjelica M. , Sheridan Ryan M. , Thurman Joshua M. , Rao V. Koneti , Torres Raul M. , Pelanda Roberta
Published: February 2022

About 5% of B cells in healthy mice and humans are allelically or isotypically included and hence co-express two different antibodies. In mice, dual antibody B cells (B2R) expand with systemic autoimmunity, co-express autoreactive and non-autoreactive antibodies, and participate in immune responses, but this phenomenon is strain dependent. This study was developed with two goals: 1) to establish the contribution of TLR and IFN receptor signaling to the development of germinal center B cells that express two antibodies in MRL/lprmice; and 2) to determine whether B2RB cells are increased and particularly activated in a subset of adult patients diagnosed with systemic lupus erythematosus (SLE). Results from the MRL/lprstudies indicate that the enhanced differentiation of dual-κ B cells into germinal center B cells is due to a heightened response to TLR7 and TLR9 signaling, further fueled by an increased response to type II IFN. To understand the clinical and translational implications of our observations in mouse B2RB cells, cohorts of SLE patients and healthy controls were recruited and evaluated for expression of dual BCRs. Results from flow cytometry and microscopy revealed supraphysiological frequencies of κ+λ+B2Rcells in one fourth of the SLE patients. Abnormal numbers of κ+λ+B cells correlated with higher frequencies of activated naïve B cells and age-associated B cells, and a lower proportion of “B cells that are naïve IgD+” (BND). However, results from single cell V(D)J sequencing demonstrated that these high κ+λ+SLE patients harbored normal frequencies of κ+λ+and other B2RB cells. and we further show that their B cells were instead decorated by κ and λ VH4-34 autoantibodies. Thus, our findings indicate that elevated flow cytometric detection of isotypically-included B cells can identify patients with high titers of B cell-reactive VH4-34 autoantibodies and abnormal distribution of B cell subsets relevant to autoimmunity.
C-Reactive Protein Levels Predict Responses to PD-1 Inhibitors in Hepatocellular Carcinoma Patients
Authors: Zhang Yiyang , Lu Lianghe , He Zhangping , Xu Zhishen , Xiang Zhicheng , Nie Run-Cong , Lin Wenping , Chen Wenxu , Zhou Jie , Yin Yixin , Xie Juanjuan , Zhang Youcheng , Zheng Xueyi , Zhu Tianchen , Cai Xiaoxia , Li Peng , Chao Xue , Cai Mu-Yan
Published: February 2022

Background

Serum C-reactive protein (CRP) is a biomarker of an acute inflammatory response and has been successfully used as a prognostic predictor for several malignancies. However, the clinicopathological significance of CRP levels in hepatocellular carcinoma (HCC) patients being treated with PD-1 inhibitors remains unclear.

Methods

Serum CRP levels were measured for a total of 101 HCC patients that had been treated with PD-1 inhibitors from July 2018 to November 2019. The clinicopathological data was retrospectively analyzed to identify any clinical implications between CRP levels and responses to PD-1 inhibitors and patients’ progression-free survival (PFS).

Results

The median PFS was 8.87 months in the CRP-low subgroup and 3.67 months in the CRP-high subgroup (P = 0.009). Univariate and multivariate Cox regression analysis demonstrated that both serum CRP and AFP levels were independent risk factors for the PFS of HCC patients treated with PD-1 inhibitors (P < 0.05). Moreover, Cox regression analysis after Propensity Score Matching showed the similar results. A prognostic model combining CRP and AFP levels could significantly stratify HCC patients receiving PD-1 inhibitors into low-, intermediate-, and high-risk subgroups (P < 0.001). Patients in the risk subgroups reported similar overall response rates (P = 0.625) and significantly different disease control rates (low- vs. intermediate- vs. high-risk groups: 81.6% vs. 65.1% vs. 35%, respectively, P = 0.002).

Conclusions

The results of this study support the association between high serum CRP levels with the response and PFS for HCC patients receiving PD-1 inhibitors. Furthermore, the levels of both CRP and AFP in an HCC patient before treatment initiation show great potential for determining the efficacy of PD-1 inhibitors.
Angiogenic Role of Mesothelium-Derived Chemokine CXCL1 During Unfavorable Peritoneal Tissue Remodeling in Patients Receiving Peritoneal Dialysis as Renal Replacement Therapy
Authors: Catar Rusan Ali , Bartosova Maria , Kawka Edyta , Chen Lei , Marinovic Iva , Zhang Conghui , Zhao Hongfan , Wu Dashan , Zickler Daniel , Stadnik Honorata , Karczewski Marek , Kamhieh-Milz Julian , Jörres Achim , Moll Guido , Schmitt Claus Peter , Witowski Janusz
Published: February 2022

Peritoneal dialysis (PD) is a valuable ‘home treatment’ option, even more so during the ongoing Coronavirus pandemic. However, the long-term use of PD is limited by unfavourable tissue remodelling in the peritoneal membrane, which is associated with inflammation-induced angiogenesis. This appears to be driven primarily through vascular endothelial growth factor (VEGF), while the involvement of other angiogenic signaling pathways is still poorly understood. Here, we have identified the crucial contribution of mesothelial cell-derived angiogenic CXC chemokine ligand 1 (CXCL1) to peritoneal angiogenesis in PD. CXCL1 expression and peritoneal microvessel density were analysed in biopsies obtained by the International Peritoneal Biobank (NCT01893710 atwww.clinicaltrials.gov), comparing 13 children with end-stage kidney disease before initiating PD to 43 children on chronic PD. The angiogenic potential of mesothelial cell-derived CXCL1 was assessedin vitroby measuring endothelial tube formation of human microvascular endothelial cells (HMECs) treated with conditioned medium from human peritoneal mesothelial cells (HPMCs) stimulated to release CXCL1 by treatment with either recombinant IL-17 or PD effluent. We found that the capillary density in the human peritoneum correlated with local CXCL1 expression. Both CXCL1 expression and microvessel density were higher in PD patients than in the age-matched patients prior to initiation of PD. Exposure of HMECs to recombinant CXCL1 or conditioned medium from IL-17-stimulated HPMCs resulted in increased endothelial tube formation, while selective inhibition of mesothelial CXCL1 production by specific antibodies or through silencing of relevant transcription factors abolished the proangiogenic effect of HPMC-conditioned medium. In conclusion, peritoneal mesothelium-derived CXCL1 promotes endothelial tube formationin vitroand associates with peritoneal microvessel density in uremic patients undergoing PD, thus providing novel targets for therapeutic intervention to prolong PD therapy.
A Variety of Nucleic Acid Species Are Sensed by cGAS, Implications for Its Diverse Functions
Authors: Wang Dawei , Zhao Heng , Shen Yangkun , Chen Qi
Published: February 2022

Cyclic GMP-AMP synthase (cGAS) recognizes double-stranded DNA (dsDNA) derived from invading pathogens and induces an interferon responseviaactivation of the key downstream adaptor protein stimulator of interferon genes (STING). This is the most classic biological function of the cGAS-STING signaling pathway and is critical for preventing pathogenic microorganism invasion. In addition, cGAS can interact with various types of nucleic acids, including cDNA, DNA : RNA hybrids, and circular RNA, to contribute to a diverse set of biological functions. An increasing number of studies have revealed an important relationship between the cGAS-STING signaling pathway and autophagy, cellular senescence, antitumor immunity, inflammation, and autoimmune diseases. This review details the mechanism of action of cGAS as it interacts with different types of nucleic acids, its rich biological functions, and the potential for targeting this pathway to treat various diseases.
Primary Immune Deficiency: Patients’ Preferences for Replacement Immunoglobulin Therapy
Authors: Gonzalez Juan Marcos , Ballow Mark , Fairchild Angelyn , Runken Michael Chris
Published: February 2022

Purpose

Immunoglobulin (Ig) replacement therapy is an important life-saving treatment modality for patients with primary antibody immune deficiency disorders (PAD). IVIG and SCIg are suitable alternatives to treat patients with PAD but vary in key ways. Existing evidence on patient preferences for Ig treatments given the complexities associated with IVIG and SCIg treatment is limited and fails to account for variations in preferences across patients. For this reason, we sought to evaluate PAD patient preferences for features of IVIG and SCIg across different patient characteristics.

Materials and Methods

119 PAD patients completed a discrete-choice experiment (DCE) survey. The DCE asked respondents to make choices between carefully constructed treatment alternatives described in terms of generic treatment features. Choices from the DCE were analyzed to determine the relative influence of attribute changes on treatment preferences. We used subgroup analysis to evaluate systematic variations in preferences by patients’ age, gender, time since diagnosis, and treatment experience.

Results

Patients were primarily concerned about the duration of treatment side effects, but preferences were heterogeneous. This was particularly true around administration features. Time since diagnosis was associated with an increase in patients’ concerns with the number of needles required per infusion. Also, patients appear to prefer the kind of therapy they are currently using which could be the result of properly aligned patient preferences or evidence of patient adaptive behavior.

Conclusions

Heterogeneity in preferences for Ig replacement treatments suggests that a formal shared decision making process could have an important role in improving patient care.
Itaconate, Arginine, and Gamma-Aminobutyric Acid: A Host Metabolite Triad Protective Against Mycobacterial Infection
Authors: Kim Jin Kyung , Park Eun-Jin , Jo Eun-Kyeong
Published: February 2022

Immune metabolic regulation shapes the host-pathogen interaction during infection with Mycobacterium tuberculosis (Mtb), the pathogen of human tuberculosis (TB). Several immunometabolites generated by metabolic remodeling in macrophages are implicated in innate immune protection against Mtb infection by fine-tuning defensive pathways. Itaconate, produced by the mitochondrial enzyme immunoresponsive gene 1 (IRG1), has antimicrobial and anti-inflammatory effects, restricting intracellular mycobacterial growth. L-arginine, a component of the urea cycle, is critical for the synthesis of nitric oxide (NO) and is implicated in M1-mediated antimycobacterial responses in myeloid cells. L-citrulline, a by-product of NO production, contributes to host defense and generates L-arginine in myeloid cells. In arginase 1-expressing cells, L-arginine can be converted into ornithine, a polyamine precursor that enhances autophagy and antimicrobial protection against Mtb in Kupffer cells. Gamma-aminobutyric acid (GABA), a metabolite and neurotransmitter, activate autophagy to induce antimycobacterial host defenses. This review discusses the recent updates of the functions of the three metabolites in host protection against mycobacterial infection. Understanding the mechanisms by which these metabolites promote host defense will facilitate the development of novel host-directed therapeutics against Mtb and drug-resistant bacteria.
Design and Analysis of Prosthetic Heart Valves and Assessing the Effects of Leaflet Design on the Mechanical Attributes of the Valves
Authors: Ghanbari Jaafar , Dehparvar Amirhossein , Zakeri Amirhossein
Published: February 2022

Prosthetic heart valves are commonly used as a treatment for aortic valve deficiencies. The performance of these prosthetic valves should be in accordance with the natural heart valve with respect to opening and closing, blood flow, and vortex formation. These performance parameters depend on the design of leaflets and overall geometrical parameters of the valve. To better understand the effects of leaflet design on the performance of the valve, we have carried out fully coupled fluid–structure interaction analyses of opening and closing of prosthetic heart valves with various leaflet designs. Maximum stress, valve opening, and flow stream pattern are obtained for different valve designs and used to assess the performance of the valves. The results show that the stress and the valve opening depend on the curvature and the inclination of the leaflets. A 3D model is designed based on the obtained results, and a full FSI analysis is performed to assess its performance. The results show that the presented design gives better values for valve opening area and leaflet stresses than that in the published data.
Evaluation of the Whole Proteome of Achromobacter xylosoxidans to Identify Vaccine Targets for mRNA and Peptides-Based Vaccine Designing Against the Emerging Respiratory and Lung Cancer-Causing Bacteria
Authors: Khan Taimoor , Abdullah Muhammad , Toor Tayyba Fatima , Almajhdi Fahad N. , Suleman Muhammad , Iqbal Arshad , Ali Liaqat , Khan Abbas , Waheed Yasir , Wei Dong-Qing
Published: February 2022

Achromobacter xylosoxidans is a rod-shaped Gram-negative bacterium linked with causing several infections which mostly includes hematological malignancies. It has been recently reported to be associated with the development and progression of lung cancer and is an emerging respiratory disease-causing bacterium. The treatment of individuals infected with A. xylosoxidans bacteremia is difficult due to the fact that this pathogen has both intrinsic and acquired resistance mechanisms, typically resulting in a phenotype of multidrug resistance (MDR). Efforts are needed to design effective therapeutic strategies to curtail the emergence of this bacterium. Computational vaccine designing has proven its effectiveness, specificity, safety, and stability compared to conventional approaches of vaccine development. Therefore, the whole proteome of A. xylosoxidans was screened for the characterization of potential vaccine targets through subtractive proteomics pipeline for therapeutics design. Annotation of the whole proteome confirmed the three immunogenic vaccine targets, such as (E3HHR6), (E3HH04), and (E3HWA2), which were used to map the putative immune epitopes. The shortlisted epitopes, specific against Cytotoxic T Lymphocytes, Helper T-cell Lymphocytes, and linear B-Cell, were used to design the mRNA and multi-epitopes vaccine (MEVC). Initial validations confirmed the antigenic and non-allergenic properties of these constructs, followed by docking with the immune receptor, TLR-5, which resulted in robust interactions. The interaction pattern that followed in the docking complex included formation of 5 hydrogen bonds, 2 salt bridges, and 165 non-bonded contacts. This stronger binding affinity was also assessed through using the mmGBSA approach, showing a total of free binding energy of −34.64 kcal/mol. Further validations based on in silico cloning revealed a CAI score of 0.98 and an optimal percentage of GC contents (54.4%) indicated a putatively higher expression of the vaccine construct in Escherichia coli. Moreover, immune simulation revealed strong antibodies production upon the injection of the designed MEVC that resulted in the highest peaks of IgM+ IgG production (>3,500) between 10 and 15 days. In conclusion the current study provide basis for vaccine designing against the emerging A. xylosoxidans, which demands further experimental studies for in vitro and in vivo validations.
Case Report: Acute Kidney Injury Due to Chronic Milk-Alkali Syndrome in a Patient With Colon Cancer
Authors: Lee Hyo Jin , Yoon Seokho , Choi Bong-Hoi , Lee Seunghye , Jung Sehyun , Jang Ha Nee , Chang Se-Ho , Kim Hyun-Jung
Published: February 2022

Background

Common causes of hypercalcemia include primary hyperparathyroidism and paraneoplastic syndrome of malignancy. Because of this, physicians can easily miss extrinsic causes of hypercalcemia such as milk-alkali syndrome in patients with cancer. We successfully treated a case of acute kidney injury due to severe hypercalcemia caused by milk-alkali syndrome due to long-term milk drinking in a patient with colon cancer.

Case Description

A 62-year-old man was referred to nephrology for hypercalcemia and azotemia that was found during preoperative evaluation for colon cancer surgery. The patient had experienced several months of dizziness and anorexia. We started hemodialysis because hypercalcemia and azotemia were not improved despite large amounts of hydration and diuretics. We suspected paraneoplastic syndrome because of concomitant colon cancer and low intact parathyroid hormone (PTH). Renal microcalcifications were observed on ultrasonography. Metastatic calcifications of the lung and stomach were present, but no malignant metastasis appeared on bone scans. There was no evidence of metastatic malignant lesions on chest or abdominal enhanced computed tomography. PTH-related peptide was not detected. Thus, other causes of hypercalcemia beyond malignancy were considered. On history-taking, the patient reported consuming 1,000 to 1,200 mL of milk daily for the prior 3 months. Hypercalcemia was due to chronic milk-alkali syndrome. We advised withdrawal of milk and nutritional pills. Hemodialysis was stopped after 2 weeks since azotemia and hypercalcemia were resolving. Acute kidney injury was improved, and mild hypercalcemia remained when he underwent hemicolectomy after 1 month. Thereafter, serum calcium and creatinine remained normal at discharge and follow-up for 1 year in the outpatient clinic. However, lung calcifications still remained on bone scan after 1 year.

Conclusions

Chronic milk-alkali syndrome is a rare condition resulting from excessive calcium and alkali intake through various routes, like milk, nutritional supplements, and medicines for osteoporosis. Therefore, early management for hypercalcemia should include precise history taking including diet, previous diagnoses, and current medications.
Antimicrobial Resistance Dynamics in Chilean Shigella sonnei Strains Within Two Decades: Role of Shigella Resistance Locus Pathogenicity Island and Class 1 and Class 2 Integrons
Authors: Toro Cecilia S. , Salazar Juan Carlos , Montero David A. , Ugalde Juan Antonio , Díaz Janepsy , Cádiz Leandro A. , Henríquez Tania , García Camila , Díaz Patricia , Camponovo Rossanna , Hermosilla Germán , Ulloa María Teresa
Published: February 2022

Shigellosis is an enteric infectious disease in which antibiotic treatment is effective, shortening the duration of symptoms and reducing the excretion of the pathogen into the environment. Shigella spp., the etiologic agent, are considered emerging pathogens with a high public health impact due to the increase and global spread of multidrug-resistant (MDR) strains. Since Shigella resistance phenotype varies worldwide, we present an overview of the resistance phenotypes and associated genetic determinants present in 349 Chilean S. sonnei strains isolated during the periods 1995–1997, 2002–2004, 2008–2009, and 2010–2013. We detected a great variability in antibiotic susceptibility patterns, finding 300 (86%) MDR strains. Mobile genetic elements (MGE), such as plasmids, integrons, and genomic islands, have been associated with the MDR phenotypes. The Shigella resistance locus pathogenicity island (SRL PAI), which encodes for ampicillin, streptomycin, chloramphenicol, and tetracycline resistance genes, was detected by PCR in 100% of the strains isolated in 2008–2009 but was less frequent in isolates from other periods. The presence or absence of SRL PAI was also differentiated by pulsed-field gel electrophoresis. An atypical class 1 integron which harbors the blaOXA–1-aadA1-IS1 organization was detected as part of SRL PAI. The dfrA14 gene conferring trimethoprim resistance was present in 98.8% of the 2008–2009 isolates, distinguishing them from the SRL-positive strains isolated before that. Thus, it seems an SRL-dfrA14 S. sonnei clone spread during the 2008–2009 period and declined thereafter. Besides these, SRL-negative strains harboring class 2 integrons with or without resistance to nalidixic acid were detected from 2011 onward, suggesting the circulation of another clone. Whole-genome sequencing of selected strains confirmed the results obtained by PCR and phenotypic analysis. It is highlighted that 70.8% of the MDR strains harbored one or more of the MGE evaluated, while 15.2% lacked both SRL PAI and integrons. These results underscore the temporal dynamics of antimicrobial resistance in S. sonnei strains circulating in Chile, mainly determined by the spread of MGE conferring MDR phenotypes. Since shigellosis is endemic in Chile, constant surveillance of antimicrobial resistance phenotypes and their genetic basis is a priority to contribute to public health policies.
Preterm Delivery: Microbial Dysbiosis, Gut Inflammation and Hyperpermeability
Authors: Arboleya Silvia , Rios-Covian David , Maillard Flore , Langella Philippe , Gueimonde Miguel , Martín Rebeca
Published: February 2022

Preterm birth is one of the main health problems encountered in the neonatal period, especially because it is also the first cause of death in the critical 1st month of life and the second in children under 5 years of age. Not only preterm birth entails short term health risks due to low weight and underdeveloped organs, but also increases the risk of suffering from non-transmissible diseases in the long term. To date, it is known that medical conditions and lifestyle factors could increase the risk of preterm birth, but the molecular mechanisms that control this process remain unclear. Luteolysis, increased inflammation or oxidative stress have been described as possible triggers for preterm birth and, in some cases, the cause of dysbiosis in preterm neonates. Several murine models have been developed to shed light into the mechanistic of preterm birth but, for the most part, are inflammation-based labor induction models and the offspring health readouts are mainly limited to survival and weight. Using a set of SWISS-CD1 mice born prematurely we analyzed inflammation and gut permeability parameters compared with term pups at weaning age. Overall, preterm mice presented higher systemic inflammation and gastrointestinal tract permeability. In this perspective article, we discuss the recent discoveries on preterm birth and the necessity of non-inflammatory murine models to really understand these phenotypes and be able to design strategies to prevent the sequels of this traumatic event in neonates.
Acetylation at Lysine 86 of Escherichia coli HUβ Modulates the DNA-Binding Capability of the Protein
Authors: Barlow Victoria L. , Tsai Yu-Hsuan
Published: February 2022

DNA-binding protein HU is highly conserved in bacteria and has been implicated in a range of cellular processes and phenotypes. Like eukaryotic histones, HU is subjected to post-translational modifications. Specifically, acetylation of several lysine residues have been reported in both homologs of Escherichia coli HU. Here, we investigated the effect of acetylation at Lys67 and Lys86, located in the DNA binding-loop and interface of E. coli HUβ, respectively. Using the technique of genetic code expansion, homogeneous HUβ(K67ac) and HUβ(K86ac) protein units were obtained. Acetylation at Lys86 seemed to have negligible effects on protein secondary structure and thermal stability. Nevertheless, we found that this site-specific acetylation can regulate DNA binding by the HU homodimer but not the heterodimer. Intriguingly, while Lys86 acetylation reduced the interaction of the HU homodimer with short double-stranded DNA containing a 2-nucleotide gap or nick, it enhanced the interaction with longer DNA fragments and had minimal effect on a short, fully complementary DNA fragment. These results demonstrate the complexity of post-translational modifications in functional regulation, as well as indicating the role of lysine acetylation in tuning bacterial gene transcription and epigenetic regulation.
Case Report: One-Year Delay in the Effect of Conversion Surgery Therapy for Advanced Hepatocellular Carcinoma After Systemic Therapy
Authors: Xie Qing-Yu , Liu Hai-Yan , Guo Ze-Yi , Wu Yan-Ping , He Guo-Lin , Cai Lei , Pan Ming-Xin , Fu Shun-Jun
Published: February 2022

Hepatocellular carcinoma (HCC) is the sixth most commonly diagnosed malignancy and the third leading cause of cancer-related deaths worldwide. A 58-year-old man visited his local hospital due to abdominal discomfort and was diagnosed with lung metastasis. After admission to our hospital in April 2020, he received two cycles of transcatheter arterial embolization (TAE), hepatic arterial infusion chemotherapy (HAIC-Folfox), sorafenib, and camrelizumab every 3 weeks. Due to the end of HAIC treatment, he underwent drug-eluting transcatheter arterial chemoembolization (dTACE) once, sorafenib, and camrelizumab. However, because of worsening liver function, we interrupted TACE and only gave sorafenib and camrelizumab in August 2020. Although he received systemic therapy, the tumors still rapidly progressed and we considered the possibility of tumor resistance. Subsequently, regorafenib was given. In September, the patient underwent conventional TACE (cTACE) once, regorafenib, and camrelizumab. After half a year of comprehensive treatment, the treatment effect was not satisfactory, and he returned to the local hospital to received regorafenib every day and camrelizumab once every 3 weeks. The patient found that the tumor and lung metastasis had shrunk significantly after 1 year of the initial diagnosis, then he was admitted to our hospital and received surgery treatment, and now he has survived disease-free for 6 months.
Conservation of the Direct and Indirect Pathway Dichotomy in Mouse Caudal Striatum With Uneven Distribution of Dopamine Receptor D1- and D2-Expressing Neurons
Authors: Ogata Kumiko , Kadono Fuko , Hirai Yasuharu , Inoue Ken-ichi , Takada Masahiko , Karube Fuyuki , Fujiyama Fumino
Published: February 2022

The striatum is one of the key nuclei for adequate control of voluntary behaviors and reinforcement learning. Two striatal projection neuron types, expressing either dopamine receptor D1 (D1R) or dopamine receptor D2 (D2R) constitute two independent output routes: the direct or indirect pathways, respectively. These pathways co-work in balance to achieve coordinated behavior. Two projection neuron types are equivalently intermingled in most striatal space. However, recent studies revealed two atypical zones in the caudal striatum: the zone in which D1R-neurons are the minor population (D1R-poor zone) and that in which D2R-neurons are the minority (D2R-poor zone). It remains obscure as to whether these imbalanced zones have similar properties on axonal projections and electrophysiology compared to other striatal regions. Based on morphological experiments in mice using immunofluorescence, in situ hybridization, and neural tracing, here, we revealed that the poor zones densely projected to the globus pallidus and substantia nigra pars lateralis, with a few collaterals in substantia nigra pars reticulata and compacta. Similar to that in other striatal regions, D1R-neurons were the direct pathway neurons. We also showed that the membrane properties of projection neurons in the poor zones were largely similar to those in the conventional striatum using in vitro electrophysiological recording. In addition, the poor zones existed irrespective of the age or sex of mice. We also identified the poor zones in the common marmoset as well as other rodents. These results suggest that the poor zones in the caudal striatum follow the conventional projection patterns irrespective of the imbalanced distribution of projection neurons. The poor zones could be an innate structure and common in mammals. The unique striatal zones possessing highly restricted projections could relate to functions different from those of motor-related striatum.
Lateral Fluid Percussion Injury Causes Sex-Specific Deficits in Anterograde but Not Retrograde Memory
Authors: Fitzgerald Julie , Houle Samuel , Cotter Christopher , Zimomra Zachary , Martens Kris M. , Vonder Haar Cole , Kokiko-Cochran Olga N.
Published: February 2022

Cognitive impairment is a common symptom after traumatic brain injury (TBI). Memory, in particular, is often disrupted during chronic post-injury recovery. To understand the sex-specific effects of brain injury on retrograde and anterograde memory, we examined paired associate learning (PAL), spatial learning and memory, and fear memory after lateral fluid percussion TBI. We hypothesized that male and female mice would display unique memory deficits after TBI. PAL task acquisition was initiated via touchscreen operant conditioning 22 weeks before sham injury or TBI. Post-injury PAL testing occurred 7 weeks post-injury. Barnes maze and fear conditioning were completed at 14- and 15-weeks post-injury, respectively. Contrary to our expectations, behavioral outcomes were not primarily influenced by TBI. Instead, sex-specific differences were observed in all tasks which exposed task-specific trends in male TBI mice. Male mice took longer to complete the PAL task, but this was not affected by TBI and did not compromise the ability to make a correct choice. Latency to reach the goal box decreased across testing days in Barnes maze, but male TBI mice lagged in improvement compared to all other groups. Use of two learning indices revealed that male TBI mice were deficient in transferring information from 1 day to the next. Finally, acquisition and contextual retention of fear memory were similar between all groups. Cued retention of the tone-shock pairing was influenced by both injury and sex. Male sham mice displayed the strongest cued retention of fear memory, evidenced by increased freezing behavior across the test trial. In contrast, male TBI mice displayed reduced freezing behavior with repetitive tone exposure. An inverse relationship in freezing behavior to tone exposure was detected between female sham and TBI mice, although the difference was not as striking. Together, these studies show that retrograde memory is intact after lateral TBI. However, male mice are more vulnerable to post-injury anterograde memory deficits. These behaviors were not associated with gross pathological change near the site injury or in subcortical brain regions associated with memory formation. Future studies that incorporate pre- and post-injury behavioral analysis will be integral in defining sex-specific memory impairment after TBI.