bluuebunny/crossref_metadata_2025 huggingface dataset:
First detection of the malaria vector Anopheles arabiensis in Côte d’Ivoire: urbanization in question
Authors: Fournet Florence , Adja Akre M. , Adou Kouassi A. , Dahoui Milossé M. C. , Coulibaly Baba , Assouho Konan F. , Zoh Dounin D. , Koné Moussa , Koné Aboubacar , Niamien Koffi L. , Cornelie Sylvie , Tia Emmanuel , Moiroux Nicolas
Published: September 2022

Background

Previous studies have revealed high malaria transmission in Bouaké, Côte d’Ivoire. The sociopolitical crisis in the country and the resulting environmental changes have raised the need to update existing knowledge on mosquito vector species and malaria transmission.

Methods

Adult mosquitoes were caught using the human landing catch (HLC) sampling method in Bouaké. They were collected in six districts representative of the diversity in urban landscapes. Sampling points were selected along the water network crossing the city and monitored from 2020 to 2021 to detect the presence of anopheline larvae. PCR techniques were used to ascertain the species of the Anopheles gambiae complex, Plasmodium falciparum sporozoite infection in a subset of Anopheles vectors, and insecticide resistance mechanisms in Anopheles arabiensis only.

Results

A total of 4599 Anopheles mosquitoes were collected and then identified. Anopheles gambiae sensu lato (s.l.) made up the majority of the whole collection (99%) while Anopheles funestus (0.7%), Anopheles ziemanni (0.2%), Anopheles pharoensis (0.2%) represented the remaining proportion of collection. Among the Anopheles gambiae complex, three species were identified namely An. gambiae sensu stricto (45.9%), Anopheles coluzzii (52.2%), and Anopheles arabiensis (1.9%). The first two species had already been collected in Bouaké, however this is the first time that An. arabiensis is reported in Côte d’Ivoire. Anopheles arabiensis was also collected during the larval surveys in a similar proportion (1.1%) in the same areas as the adults.

Conclusions

This study detected the presence of An. arabiensis for the first time in Côte d’Ivoire. This species was found quite far from its usual geographic area and its expansion could be linked to the urbanization process. Although no An. arabiensis was found to be infected by Plasmodium sp., its role in malaria transmission in Bouaké has to be explored, particularly since its exophagic behaviour raises the issue of control measures and the use of insecticide-impregnated nets. The spread of this species in Côte d'Ivoire should be assessed through further research in additional towns in the country.
The reversion of DNA methylation-induced miRNA silence via biomimetic nanoparticles-mediated gene delivery for efficient lung adenocarcinoma therapy
Authors: Liang Lu , Cen Huiyu , Huang Jionghua , Qin Aiping , Xu Wenyan , Wang Siran , Chen Zhijun , Tan Lin , Zhang Qiqi , Yu Xiyong , Yang Xin , Zhang Lingmin
Published: September 2022

Background

Lung cancer is one of the fatal cancers worldwide, and over 60% of patients are lung adenocarcinoma (LUAD). Our clinical data demonstrated that DNA methylation of the promoter region of miR-126-3p was upregulated, which led to the decreased expression of miR-126-3p in 67 cases of lung cancer tissues, implying that miR-126-3p acted as a tumor suppressor. Transduction of miR-126-3p is a potential therapeutic strategy for treating LUAD, yet the physiological environment and properties of miRNA challenge current transduction approaches.

Methods

We evaluated the expression of miR-126-3p in 67 pairs of lung cancer tissues and the corresponding adjacent non-tumorous tissues by Reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The relationship between the overall survival of lung cancer patients and miR-126-3p was analyzed by the Cancer Genome Atlas cohort database (Oncolnc, http://www.oncolnc.org). We analyzed DNA methylation Methylation-specific PCR (MSP) analysis. To determine whether ADAM9 is the direct target of miR-126-3p, we performed the 3′-UTR luciferase reporter assay. The protein levels in the cells or tissues were evaluated with western blotting (WB) analysis. The biodistribution of nanoparticles were monitored by in vivo tracking system.

Results

We describe the development of novel stealth and matrix metalloproteinase 2 (MMP2)-activated biomimetic nanoparticles, which are constructed using MMP2-responsive peptides to bind the miR-126-3p (known as MAIN), and further camouflaged with red blood cell (RBC) membranes (hence named REMAIN). REMAIN was able to effectively transduce miRNA into lung cancer cells and release them via MMP2 responsiveness. Additionally, REMAIN possessed the advantages of the natural RBC membrane, including extended circulation time, lower toxicity, better biocompatibility, and immune escape. Moreover, in vitro and in vivo results demonstrated that REMAIN effectively induced apoptosis of lung cancer cells and inhibited LUAD development and progression by targeting ADAM9.

Conclusion

The novel style of stealth and MMP2-activated biomimetic nanoparticles show great potential in miRNA delivery.
Surgical and oncological outcomes of robotic- versus laparoscopic-assisted distal gastrectomy with D2 lymphadenectomy for advanced gastric cancer: a propensity score‑matched analysis of 1164 patients
Authors: Gao Gengmei , Liao Hualin , Jiang Qunguang , Liu Dongning , Li Taiyuan
Published: September 2022

Background

Studies on surgical outcomes after robotic surgery are increasing; however, long-term oncological results of studies comparing robotic-assisted distal gastrectomy (RADG) versus laparoscopic-assisted distal gastrectomy (LADG) for advanced gastric cancer (AGC) are still limited. This study aimed to assess the surgical and oncological outcomes of RADG and LADG for the treatment of AGC.

Methods

A total of 1164 consecutive AGC patients undergoing RADG or LADG were enrolled between January 2015 and October 2021. Propensity score-matched (PSM) analysis was performed to minimize selection bias. The perioperative and oncological outcomes between the two groups were compared.

Results

Patient’s characteristics were comparable between the two groups after PSM. RADG group represented a longer operative time (205.2 ± 43.1 vs 185.3 ± 42.8 min, P < 0.001), less operative blood loss (139.3 ± 97.8 vs 167.3 ± 134.2 ml, P < 0.001), greater retrieved lymph nodes (LNs) number (31.4 ± 12.1 vs 29.4 ± 12.3, P = 0.015), more retrieved LNs in the supra-pancreatic areas (13.4 ± 5.0 vs 11.4 ± 5.1, P < 0.001), and higher medical costs (13,608 ± 4326 vs 10,925 ± US $3925, P < 0.001) than LADG group. The overall complication rate was 13.7% in the RADG group and 16.6% in the LADG group, respectively; the difference was not significantly different (P = 0.242). In the subgroup analysis, the benefits of RADG were more evident in high BMI patients. Moreover, the 3-year overall survival (75.5% vs 73.1%, P = 0.471) and 3-year disease-free survival (72.9% vs 71.4%, P = 0.763) were similar between the two groups.

Conclusion

RADG appears to be a safe and feasible procedure and could serve as an alternative treatment for AGC in experienced centers.
A Gated Recurrent Unit based architecture for recognizing ontology concepts from biological literature
Authors: Devkota Pratik , Mohanty Somya D. , Manda Prashanti
Published: September 2022

Background

Annotating scientific literature with ontology concepts is a critical task in biology and several other domains for knowledge discovery. Ontology based annotations can power large-scale comparative analyses in a wide range of applications ranging from evolutionary phenotypes to rare human diseases to the study of protein functions. Computational methods that can tag scientific text with ontology terms have included lexical/syntactic methods, traditional machine learning, and most recently, deep learning.

Results

Here, we present state of the art deep learning architectures based on Gated Recurrent Units for annotating text with ontology concepts. We use the Colorado Richly Annotated Full Text Corpus (CRAFT) as a gold standard for training and testing. We explore a number of additional information sources including NCBI’s BioThesauraus and Unified Medical Language System (UMLS) to augment information from CRAFT for increasing prediction accuracy. Our best model results in a 0.84 F1 and semantic similarity.

Conclusion

The results shown here underscore the impact for using deep learning architectures for automatically recognizing ontology concepts from literature. The augmentation of the models with biological information beyond that present in the gold standard corpus shows a distinct improvement in prediction accuracy.
Effects of two exercise programs on health-related fitness, quality of life and exercise enjoyment in adults with visual impairment: a randomized crossover trial
Authors: da Silva Rafael B. P. , Caputo Eduardo L , Feter Natan , Reichert Felipe F
Published: September 2022

Background

So far there is no study comparing two distinct exercise interventions in people with visual impairment. This study aimed to evaluate the effects of two exercise programs on health-related fitness, quality of life, and exercise enjoyment in people with visual impairment.

Methods

Two exercise interventions were conducted: sports (i.e., Goalball, Football 5-a-side and Martial Arts) and functional training (i.e., Bodyweight exercises). Physical fitness was assessed by handgrip strength, flexibility, abdominal endurance, and cardiorespiratory fitness. The Physical Activity Enjoyment Scale (PACES) measured the pleasure in the practice of physical exercises, and the quality of life was measured by the WHOQOL-Bref.

Results

A significant time x group interaction terms were observed for flexibility (P < 0.001; Cohen d = 0.08), abdominal muscular endurance (P < 0.001; Cohen d = 0.15), and distance covered in the 6-min walk/run test (P = 0.018; Cohen d = 0.02). An improvement of 13.3% and 5.1% on the distance covered on the 6-min walk/run test after sports and functional training was also observed.

Conclusion

The functional training program was reported as more pleasant for participants. Sports-related exercises and functional training improved health-related fitness and quality of life for people with visual impairment.
Magnetic resonance imaging correlation with molecular and epigenetic markers in assessment of breast cancer
Authors: El-Rawy Aya S. , Abdallah Hoda Y. , Suliman Marwa A. , Habba Mohamed R. , Gad Azza A.
Published: September 2022

Background

Breast cancer is a heterogeneous disease with a wide range of clinical behavior, histologic subtypes, therapeutic options, and outcomes. The different biology and histology of breast cancer display different tumor morphology at breast magnetic resonance imaging (MRI). However, few studies have examined the relationship between the MRI morphological, kinetic features and molecular and epigenetic markers in breast cancer assessment. The study aimed to evaluate the correlation between MRI morphological and kinetic features, molecular and an epigenetic marker (linc-ITGB1) in breast cancer cases. A total of 115 women (80 cases and 35 controls) with BIRAD 4 category breast lesions were included. The association between the MRI morphological & kinetic features, apparent diffusion coefficient (ADC) values, and molecular and the epigenetic marker (linc-ITGB1) was evaluated using Mann–Whitney and Chi-square tests.

Results

The shape (p = 0.009), size of the lesion (p = 0.003), and pattern of enhancement (p ≤ 0.001) were significantly correlated with the molecular markers. Luminal subtypes are more likely to be presented with irregular shaped and non-circumscribed margin masses (97% for luminal A and 94.1% for luminal B). Triple-negative cancers are frequently presented with regular masses, circumscribed margins, and peripheral rim enhancement (50% of TN tumors). HER2-positive cancers are more likely to be multifocal/multicentric and are more associated with non-mass pattern of enhancement as compared to HER2-negative cancers. Perilesional edema was also significantly correlated with HER2-positive lesions (p = 0.009). Although the epigenetic marker linc-ITGB1 was overexpressed by 4.85-folds in breast cancer cases compared to benign controls, we could not find any significant correlation between its expression level and the MRI features or molecular subtypes (p = 0.948).

Conclusions

MRI features can be a reliable predictor of breast cancer molecular subtypes. The epigenetic marker linc-ITGB1 has a potential role in breast cancer pathogenesis but with no significant correlation with either the MRI features or molecular subtypes of the lesions.
CXC chemokines in angiogenesis
Authors: Belperio John A , Keane Michael P , Arenberg Douglas A , Addison Christina L , Ehlert Jan E , Burdick Marie D , Strieter Robert M
Published: September 2022

A variety of factors have been identified that regulate angiogenesis, including the CXC chemokine family. The CXC chemokines are a unique family of cytokines for their ability to behave in a disparate manner in the regulation of angiogenesis. CXC chemokines have four highly conserved cysteine amino acid residues, with the first two cysteine amino acid residues separated by one non-conserved amino acid residue (i.e., CXC). A second structural domain within this family determines their angiogenic potential. The NH2 terminus of the majority of the CXC chemokines contains three amino acid residues (Glu-Leu-Arg: the ELR motif), which precedes the first cysteine amino acid residue of the primary structure of these cytokines. Members that contain the ELR motif (ELR+) are potent promoters of angiogenesis. In contrast, members that are inducible by interferons and lack the ELR motif (ELR−) are potent inhibitors of angiogenesis. This difference in angiogenic activity may impact on the pathogenesis of a variety of disorders.
The loss of Mcl-1 expression in human polymorphonuclear leukocytes promotes apoptosis
Authors: Leuenroth Stephanie J , Grutkoski Patricia S , Ayala Alfred , Simms H Hank
Published: September 2022

The regulation of polymorphonuclear leukoctye (PMN) apoptosis can influence the duration of the inflammatory response. We have previously shown that PMN apoptosis is delayed by matrix adhesion and hypoxia; however, the mechanisms responsible for this delay are not well understood. Mcl-1, an antiapoptotic Bcl-2 family member, is present in neutrophils; therefore, we sought to characterize its localization and function as it relates to PMN apoptosis. We found that Mcl-1 localized to the nucleus and cytoplasm and that expression levels decreased as PMN were aged in culture. Reducing available Mcl-1 through the use of antisense oligonucleotides demonstrated that Mcl-1 is necessary to delay apoptosis during normal PMN aging and hypoxia but is not required for suppression of apoptosis by laminin adhesion. Our results demonstrate a distinct expression pattern of Mcl-1 and that Mcl-1 is crucial for the delay of apoptosis initiated by certain antiapoptotic factors.
Trafficking of neutrophils across airway epithelium is dependent upon both thioredoxin- and pertussis toxin-sensitive signaling mechanisms
Authors: Miller Lisa A , Usachenko Jodie , McDonald Ruth J , Hyde Dallas M
Published: September 2022

Leukocyte recruitment from the circulation into the airways is a multi-step process, involving both chemotactic and adhesive mechanisms. Using an in vitro model of leukocyte transepithelial trafficking, we show that movement of human peripheral blood neutrophils (PMN) across airway epithelium in the optimal basolateral-to-apical surface direction is partially blocked by pertussis toxin, an inhibitor of Gαi-protein-linked receptors. A neutralizing monoclonal antibody against interleukin-8 (IL-8; constitutively expressed by airway epithelium) did not inhibit PMN transepithelial migration, suggesting that alternative pertussis toxin-sensitive signaling mechanisms are involved in this process. However, a neutralizing antibody against thioredoxin, a redox enzyme with pertussis toxin-insensitive chemoattractant activity, did reduce PMN migration across airway epithelium. We conclude that trafficking of PMN across airway epithelium is mediated by both thioredoxin- and pertussis toxin-sensitive signaling mechanisms that are independent of IL-8.
Nonlymphoid reservoirs of HIV replication in children with chronic-progressive disease
Authors: Brodie Scott J
Published: September 2022

Autopsy tissues from 2 cohorts of age-matched HIV-infected children with similar plasma viral load (>105 HIV RNA copies/ml), but with distinct AIDS-associated disease manifestations, were examined for sites of persistent HIV replication. One group consisted of 3 children with severe lymphoid atrophy and peripheral blood CD4+ T cell counts of <10/mm3. Another group was composed of 6 children with extensive hyperplasia of mucosal-associated lymphoid tissues and blood CD4+ T cell counts >500/mm3. Hyperplastic bronchiole- and gut-associated lymphoid tissues were characterized by extensive networks of germinal center follicular dendritic cells (FDC) containing large amounts of immune-complexed virion RNA. Conversely, pulmonary and gastrointestinal tissues from children with severe CD4+ T cell depletion were devoid of any secondary lymphoid structures, yet these tissues also harbored high concentrations of HIV RNA. Dual in situ procedures showed that only macrophage (Mφ) within these sites contained tat fusion transcripts, a product of post-transcriptional splicing and a correlate of productive infection. When examining explant cultures of Mφ and FDC, only Mφ harbored HIV tat mRNA and only Mφ demonstrated budding retroviral particles. Hence, germinal center FDC in secondary lymphoid tissues are key reservoirs of immune-complexed HIV RNA and are likely to contribute to AIDS-associated lymphoproliferations; however, these cells do not support HIV replication, and failure to do so results from a post-transcriptional block in the virus life cycle. Moreover, gut and pulmonary Mφ represent a lineage of cells that are permissive to HIV replication and contribute significantly to the high viral load in children with severe CD4+ T cell depletion. It will be important to identify the molecular mechanisms that allow for these highly productive infections of Mφ.
Regulation of chemokine/cytokine network during in vitro differentiation and HIV-1 infection of human monocytes: possible importance in the pathogenesis of AIDS
Authors: Fantuzzi Laura , Conti Lucia , Gauzzi Maria Cristina , Eid Pierre , Del Cornò Manuela , Varano Barbara , Canini Irene , Belardelli Filippo , Gessani Sandra
Published: September 2022

The monocyte/macrophage lineage represents heterogeneous cell populations characterized by major differences in the phenotype and functional activities. These cells are a major source of soluble factors, such as cytokines and chemokines, which can both affect HIV replication and AIDS pathogenesis. Although monocytes/macrophages are unanimously considered important targets of HIV-1 infection, the HIV-induced alterations in their physiological functions at different stages of differentiation are still matter of debate. In this article, we review our data on the regulation of chemokine/cytokine network with regard to macrophage differentiation and HIV-1 infection, in comparison with studies from other groups. The ensemble of the results emphasizes that: 1) macrophages markedly differ with respect to monocytes for a variety of responses potentially important in the pathogenesis of HIV infection; and 2) the experimental conditions can influence the HIV-monocyte/macrophage interactions, reflecting the possible in vivo existence of a spectrum of responses among macrophage populations.
Activation-dependent expression of the blood group-related Lewis Y antigen on peripheral blood granulocytes
Authors: Dettke M , Pálfi G , Loibner H
Published: September 2022

The expression of the difucosyl-lactosamine type 2 oligosaccharide Lewis Y (LeY) on peripheral blood cells was investigated. As assessed by the reactivity with the mouse anti-LeY monoclonal antibody (mAb) ABL 364 among circulating blood cells, the expression of the LeY oligosaccharide was uniquely restricted to granulocytes. Although the density of LeY expressed on resting granulocytes was weak, in vitro activation of granulocytes with fMLP induced a rapid and pronounced increase in granulocyte LeY expression. Analysis of CEA-related glycoproteins immunoprecipitated with anti-CD66 mAbs followed by immunoblotting with mAb ABL 364 showed that granulocyte LeY is attached to members of the CD66 cluster, in particular to the 160/90 kD glycoprotein recognized by anti-CD66 mAb CBL/gran 10. The activation-associated increase in LeY attached to CD66 adhesion molecules implicates a role of the LeY determinant in the cytoadhesive properties of granulocytes.
A novel tumor necrosis factor (TNF) mimetic peptide prevents recrudescence ofMycobacterium bovisbacillus Calmette-Guerin (BCG) infection in CD4+ T cell-depleted mice
Authors: Briscoe Helen , Roach Daniel R , Meadows Natalie , Rathjen Deborah , Britton Warwick J
Published: September 2022

Tumor necrosis factor (TNF) is required to control mycobacterial infections, but its therapeutic value is limited by its in vivo instability and toxicity. The efficacy of a nontoxic TNF-mimetic peptide (TNF70–80) was tested in mice infected with Mycobacterium bovis bacillus Calmette-Guerin (BCG).In vitro TNF70–80 and recombinant human TNF (hTNF) acted with interferon gamma (IFN-γ) to reduce bacterial replication and to induce synthesis of bactericidal nitric oxide (NO) in BCG-infected, bone marrow-derived murine macrophages. The dose-dependent inhibitory effect on bacterial replication was blocked by neutralizing anti-IFN-γ and anti-hTNF mAbs. Further,n-monomethyl-l-arginine (n-MMA) and a soluble TNF-receptor I (TNFRI-IgG) blocked bacterial growth and NO synthesis. Therefore, the peptide acted with IFN-γ via induction of NO synthase and signaled through TNFRI receptors. Concomitantin vivo treatment with TNF70–80 or hTNF prevented reactivation of chronic BCG infection in mice depleted of CD4+ T cells by injecting anti-CD4 antibodies. Granuloma number and bacterial load were comparable in treated, T cell-depleted mice and in chronically infected, intact animals. Thus, TNF70–80 and hTNF can modulate recrudescent BCG infection in CD4+ T cell-deficient mice.
Transcription factor Sp3 activates the liver/bone/kidney-type alkaline phosphatase promoter in hematopoietic cells
Authors: Yusa Nozomi , Watanabe Kunihito , Yoshida Satoru , Shirafuji Naoki , Shimomura Satoshi , Tani Kenzaburo , Asano Shigetaka , Sato Noriharu
Published: September 2022

The promoter region of the liver/bone/kidney-type alkaline phosphatase gene was examined to define the cis-acting regulatory sequences and transcription factors responsible for its expression in hematopoietic cells. Transient transfection experiments revealed that regions deleted up to -154 base pairs upstream from the transcription initiation site had significant activities to induce bacterial chloramphenicol acetyltransferase gene. The shortest DNA fragment was found to contain three GC boxes in addition to a TATA box. Electrophoretic mobility shift assay and Southwestern analysis showed that Sp3 could bind to the fragment. Western blot analysis also detected Sp3 protein in eluate from the DNA probe mixed with the nuclear extracts. Through the use of Drosophila Schneider cells that lack the Sp1 family of transcription factors, Sp3 was shown to activate the basal promoter in a dose-dependent manner. When the amount of Sp3 was limited, the most proximal GC box was found to be critical for the basal promoter activity.
Leukocyte antimicrobial peptides: multifunctional effector molecules of innate immunity
Authors: Risso Angela
Published: September 2022

Antimicrobial peptides are effector molecules of innate immunity that provide a first line of defense against pathogens. In mammals, they are stored in granules of leukocytes and are present in those sites that are exposed to microbial invasion, such as mucosal surfaces and skin. In the last decade, biochemical investigations and recombinant DNA technology have allowed the identification and characterization of several antimicrobial peptides from various animal and vegetal species. Most of the mammalian peptides have been grouped in two broad families: defensins and cathelicidin-derived peptides. Functional studies have shown that the toxicity mechanisms for many peptides consist of a rapid permeabilization of the target cell membrane. In addition to their microbicidal activity, some members of both families are multifunctional molecules, playing a modulating role in the inflammation and the antigen-driven immune response.
Characterization of thyroid fibrosis in a murine model of granulomatous experimental autoimmune thyroiditis
Authors: Chen Kemin , Wei Yongzhong , Sharp Gordon C , Braley-Mullen Helen
Published: September 2022

This study was initiated to identify and characterize thyroid fibrosis in a murine model of granulomatous experimental autoimmune thyroiditis (G-EAT) and determine if TGF-β1 might be involved in fibrosis. G-EAT was induced by transfer of mouse thyroglobulin-sensitized spleen cells activated in vitro with thyroglobulin, anti-IL-2R, and IL-12. There was almost complete destruction of thyroid follicles, leading to fibrosis of the gland and reduced serum T4 levels. Fibrosis was confirmed by staining for collagen and α smooth-muscle actin, a marker of myofibroblasts. Kinetic studies characterized the onset and development of thyroid fibrosis. TGF-β1 was increased at mRNA and protein levels, and expression of TGF-β1 protein paralleled G-EAT severity. Comparison of staining patterns showed that TGF-β1 was expressed in areas of myofibroblast and collagen accumulation, implying that TGF-β1 may play a role in fibrosis in G-EAT. Further studies demonstrated that myofibroblasts, macrophages, and thyrocytes contributed to TGF-β1 production. This provides an excellent model to study the mechanisms of fibrosis associated with autoimmune damage.
TAK1 regulates multiple protein kinase cascades activated by bacterial lipopolysaccharide
Authors: Lee Jongdae , Mira-Arbibe Laurence , Ulevitch Richard J
Published: September 2022

During inflammation the balance between cell activation and cell death is determined by the tight regulation of multiple intracellular enzyme cascades. Key regulatory steps often involve protein kinases. We show that the prototypical pro-inflammatory molecule, bacterial lipopolysaccharide, activates multiple protein kinases such as p38, JNK, IKK-β, and PKB/Akt via transforming growth factor β-activated kinase-1 (TAK1). We also show that TAK1 plays an important role in similar activation pathways triggered by interleukin-1. Thus TAK1 must be considered as an important component of intracellular signaling pathways in cells involved in host responses to physiological and/or environmental stress signals during inflammation.
Activated human platelets express Fas-L and induce apoptosis in Fas-positive tumor cells
Authors: Ahmad Rasheed , Menezes José , Knafo Laurent , Ahmad Ali
Published: September 2022

In addition to their role in hemostasis and thrombosis, platelets are important modulators of immune and inflammatory responses. We provide evidence here that human platelets contain abundant quantities of Fas-L, and upon activation, they express it on their surface as well as release it into medium. This surface-expressed Fas-L is biologically active and can induce apoptosis in Fas-positive human tumor cells. Therefore, activated platelets may represent an important player in Fas/Fas-L-mediated apoptosis.
Tumor cell-derived TGF-β and IL-10 dysregulate paclitaxel-induced macrophage activation
Authors: Mullins David W , Martins Ryan S , Burger Carol J , Elgert Klaus D
Published: September 2022

Paclitaxel (TAXOL™) activates in vitro macrophage (Mø) expression of proinflammatory and cytotoxic mediators, including IL-12, tumor necrosis factor α (TNF-α), and nitric oxide (NO). However, tumors dysregulate Mø through soluble suppressor molecules, and it is possible that tumors evade paclitaxel-mediated immune effector function through the production of immunomodulatory molecules and inhibition of Mø function in situ. Because Mø activation in the tumor microenvironment is a desirable goal of anti-tumor immunotherapy, we evaluated whether tumor-derived immunomodulatory factors dysregulate paclitaxel-mediated Mø activation. Tumor cell-derived supernatant suppressed paclitaxel's capacity to induce IL-12, TNF-α, and NO production by RAW264.7 Mø. Tumor factors also dysregulated paclitaxel-induced expression of a HIV-LTR, promoter-driven luciferase construct in RAW264.7 Mø, suggesting that tumors may inhibit a broad range of Mø functionality. Depletion studies revealed that IL-10 and transforming growth factor-β1 (TGF-β1), but not prostaglandin E2 (PGE2), impaired paclitaxel-mediated activation, suggesting that abrogation of these factors in situ might restore paclitaxel's activating capacity and enhance anti-tumor efficacy.
Impaired IL-15 production associated with susceptibility of murine AIDS to mycobacterial infection
Authors: Umemura Masayuki , Hirose Kenji , Wajjwalku Worawidh , Nishimura Hitoshi , Matsuguchi Tetsuya , Gotoh Yoshitaka , Takahashi Masahide , Makino Masahiko , Yoshikai Yasunobu
Published: September 2022

LP-BM5 murine leukemia virus (MuLV) injection causes murine AIDS (MAIDS), a disease characterized by many functional abnormalities of immunocompetent cells. We show that MAIDS mice are susceptible to Mycobacterium bovis Bacille Calmette-Guérin (BCG) infection as assessed by survival rate and bacterial counts. The peritoneal exudate macrophages from MAIDS mice produced a significant level of interleukin (IL)-12 soon after inoculation with BCG, whereas IL-15 and tumor necrosis factor (TNF) production were severely impaired in BCG-infected MAIDS mice. The appearance of natural killer (NK) and CD4+ T helper type 1 (Th1) cells specific for mycobacterial antigen were depressed in MAIDS mice after BCG infection. Thus, it appeared that impaired production of IL-15, besides other inflammatory cytokines, in MAIDS mice may be involved in the poor responses of the NK and Th1 cells, resulting in an increased susceptibility to BCG.
Autocrine action of IL-10 suppresses proinflammatory mediators and inflammation in the HSV-1-infected cornea
Authors: Yan Xiao-Tian , Zhuang Minsheng , Oakes John E , Lausch Robert N
Published: September 2022

We investigated whether IL-10 produced endogenously would influence the development of HSV-1-induced acute corneal disease. Murine corneal epithelial cells and fibroblasts cultured in vitro expressed IL-10 mRNA and protein constitutively and also IL-10 receptors. Inclusion of IL-10 neutralizing antibody in the culture medium significantly (p<0.05) enhanced TNF-α-induced IL-6 and MIP-2 production by both corneal cell types. Endogenous IL-10 synthesis, which also occurred in vivo, was not modulated by Herpes virus infection or by depletion of neutrophils or natural killer cells. Antibody to IL-10 given locally at the time of HSV-1 intracorneal infection was associated with significantly (p<0.05) enhanced production of IL-6, MIP-2, and MIP-1α, increased neutrophil infiltration, and more extensive corneal disease. Similarly, mice with a disrupted IL-10 gene developed more severe corneal disease than wild-type controls. Collectively, these observations suggest that locally produced IL-10 can act in an autocrine/paracrine fashion to down-regulate the production of proinflammatory mediators and thus limit corneal inflammation.
Differences in the induction of CD8+ T cell responses by subpopulations of dendritic cells from afferent lymph are related to IL-1α secretion
Authors: Hope Jayne C , Sopp Paul , Collins Robert A , Howard Chris J
Published: September 2022

The major subset of dendritic cells (DC) from bovine afferent lymph expresses the SIRPα MyD-1 antigen, but not CD11a or the antigen recognized by mAb CC81, and potently stimulates CD4+ and CD8+ T lymphocyte proliferation. The minor subpopulation, that is CD11a+CC81+MyD-1−, effectively stimulates CD4+ but not CD8+ T lymphocyte proliferation. CD11a+CC81+MyD-1− DC did not induce anergy or death or secrete an inhibitory factor. However, supernatant from cultures of CD8+ T cells with CD11a−CC81−MyD-1+ DC significantly enhanced proliferation of CD8+ T cells in response to CD11a+CC81+MyD-1− DC, an effect that was blocked by interleukin (IL)-1α, but not IL-1β, specific mAb. The proliferation of CD8+ T cells with CD11a+CC81+MyD-1− DC was also enhanced by adding IL-1α. IL-1β slightly enhanced proliferation, whereas IL-2, IL-6, IL-12, and IL-15 had no effect. We conclude that the failure to stimulate CD8+ T cell proliferation results from the lack of IL-1α synthesis by this population, which may have important consequences in vivo.
Phagocytosis and killing ofMycobacterium aviumcomplex by human neutrophils
Authors: Hartmann Pia , Becker Ralph , Franzen Caspar , Schell-Frederick Elisabeth , Römer Jens , Jacobs Michaela , Fätkenheuer Gerd , Plum Georg
Published: September 2022

Organisms belonging to the Mycobacterium avium complex (MAC) cause life-threatening bacteremia in immunocompromised patients. Monocytes and macrophages are thought to be responsible for ingestion and killing of MAC. However, it has been suggested that neutrophils may play a role in the early immune response to MAC infection. Here, neutrophils in autologous plasma were incubated (at 0 and 37°C) withM. avium labeled with Auramine O, a potent fluorochrome. Neutrophil phagocytosis was measured by flow cytometry. Neutrophils incubated at 37°C showed an increase in fluorescence over time with a maximum at 15 min, whereas neutrophils on ice showed no time-dependent increase in FL1. At 15 min Fl 1 at 37°C was twice as high as FL1 at 0°C. Examination under the fluorescent microscope showed multiple intracellular fluorescent mycobacteria. Results in nine independent experiments showed time-dependent decrease of colony-forming units in neutrophil-associated live M. avium. Significant killing was observed within 30 min and was complete by 120 min. Observation by electron microscopy clearly confirmed the presence of intraphagosomal MAC, both intact and with evidence of degradation. These data demonstrate that MAC is rapidly phagocytized and killed by human neutrophils. The newly established flow cytometry method should be useful in further studies of neutrophil function and of the role of G-CSF and other cytokines in MAC disease.
CD86 expression correlates with amounts of HIV produced by macrophagesin vitro
Authors: Wang Xiaoping , Lewis Dorothy E
Published: September 2022

Primary macrophages from different donors produce variable levels of HIV; however, the mechanisms are unclear. We tested whether variations in cell-surface or cell-cycle characteristics influenced HIV production. We found that greater basal proliferation of the macrophages prior to infection resulted in more arrested in G2M 3 days post-infection (r2=0.7,P<0.04). Likewise, the number of G2M-arrested macrophages correlated with p24 production (r2=0.78,P<0.02) and apoptosis (r2=0.67,P<0.05) later in the infection. Serum-starvation or reduction, which limit HIV spread, reduced G2M arrest and HIV amounts. Surprisingly, the amount of HIV produced correlated with expression levels of the costimulating ligand, CD86, but not with other important molecules, including class II, CD40, or CD54 (r2=0.96, P<0.0005). These data establish donor characteristics related to variable HIV production in vitro and suggest that altered expression of costimulatory ligands may influence HIV production in vivo.
Leptin: a potential regulator of polymorphonuclear neutrophil bactericidal action?
Authors: Caldefie-Chezet F , Poulin A , Tridon A , Sion B , Vasson M-P
Published: September 2022

It is well known that leptin, the ob gene product, is involved in the regulation of food intake and thermogenesis. Recent studies also demonstrate that leptin may be able to modulate functions of cells involved in nonspecific immune response such as phagocytosis and secretion of cytokines by macrophages. This and the prominent implication of polymorphonuclear neutrophils (PMNs) in infectious response suggested a possible role of leptin as a modulator of PMN functions. We detected a leptin receptor on the PMN membrane by immunocytochemistry with an anti-leptin receptor. Using chemiluminescence we then demonstrated that leptin enhances oxidative species production by stimulated PMNs. These results show for the first time that a functional leptin receptor is present on PMNs and that leptin may be able to influence their oxidative capacity.
Leukocyte-specific gene 1 protein (LSP1) is involved in chemokine KC-activated cytoskeletal reorganization in murine neutrophilsin vitro
Authors: Hannigan Michael , Zhan Lijun , Ai Youxi , Huang Chi-Kuang
Published: September 2022

Leukocyte-specific gene 1 protein (LSP1) is a cytoskeletal-associated protein of leukocytes that in vitro cross-links F-actin into extensively branched bundles of mixed polarity. In this study, we examined chemotaxis and superoxide production in neutrophils prepared from wild-type (WT) and Lsp1 knockout mice. Compared to WT neutrophils, Lsp1-/- neutrophils showed impairment in both migration speed and chemotaxis direction during chemokine KC-directed chemotaxis. When examined by confocal microscopy, chemotaxing Lsp1-/- neutrophils showed abnormal morphologies. They had discontinuous primary actin-rich cortexes and large membrane protrusions. When stimulated by phorbol 12-myristate 13-acetate (PMA), Lsp1-/- peritoneal neutrophils produce more superoxide than WT. The data presented suggest that LSP1 plays important roles in the regulation of neutrophil morphology, motility, and superoxide production.
Induction of soluble antitumoral mediators by synthetic analogues of bacterial lipoprotein in bone marrow-derived macrophages from LPS-responder and -nonresponder mice
Authors: Pfannes Silke D C , Müller Bernd , Körner Stephan , Bessler Wolfgang G , Hoffmann Petra
Published: September 2022

Macrophage-dependent antitumoral activity is partly mediated by soluble factors including cytokines, reactive-oxygen intermediates (ROIs), and reactive-nitrogen intermediates (RNIs). Activation of macrophages for tumor cytotoxicity can be achieved with various bacterial compounds, such as lipopolysaccharides (LPSs), muramyl-dipeptides, and lipopeptides. We studied the production and release of oxygen radicals, nitric oxide, and tumor necrosis factor α (TNF-α) by bone marrow-derived macrophages (BMDMs) of different mouse inbred strains after they were stimulated with the lipopeptide P3CSK4, a water-soluble synthetic analogue of the lipidated N terminus of bacterial lipoprotein. The lipopeptide was able to induce a strong, long lasting release of oxygen radicals in BALB/c mouse macrophages. Furthermore, it induced nitric oxide release from BMDMs of several mouse strains (BALB/c, C57Bl/6, C57Bl/10ScSn, Sv129, NMRI, and LPS-nonresponder C57Bl/10ScCr). Stimulation with P3CSK4 also resulted in comparable production of TNF-α in LPS-responder and nonresponder BMDMs from C57Bl/10ScSn mice and C57Bl/10ScCr mice, respectively. All three antitumoral mediators reached functional levels or concentrations as shown by the strong cytostatic/cytotoxic activity of lipopeptide-activated macrophages for the cell lines Abelson 8-1, M12.5/P815, and L929, which are sensitive to ROIs, nitric oxide, and TNF-α, respectively. We found that synthetic lipopeptides can induce the secretion of effective levels of soluble tumor-cytotoxic/cytostatic mediators in BMDMs of LPS-responsive and, of particular interest, also of LPS-unresponsive mice. This result could indicate that the highly effective bacterial-macrophage activators P3CSK4 and LPS use different receptors and/or different intracellular signal transduction pathways.
Inflammatory macrophage nuclear factor-κB and proteasome activity are inhibited following exposure to inhaled isobutyl nitrite
Authors: Ponnappan Usha , Soderberg Lee S F
Published: September 2022

A history of abuse of nitrite inhalants has been correlated with HIVseropositivity and Kaposi's sarcoma. A series of 14 daily, 45-minexposures of mice to 900-ppm isobutyl nitrite in an inhalation chamberreduced the number of peritoneal exudate macrophages (PEM) by 35% andthe number of resident peritoneal macrophages (RPM) by 18%. Althoughthe tumoricidal activity of RPM was not affected by the inhalant, thecytotoxicity of PEM was reduced by 26%. The induction of nitric oxide(NO) and the inducible NO synthase (iNOS) protein in PEM were inhibitedby the inhalant to a similar extent. Inhibition of NF-κB activationin PEM from mice exposed to the inhalant corresponded to reduceddegradation of the NF-κB inhibitor, IκBα. Proteasome-associated,enzymatic activity was compromised in PEM from inhalant-exposed mice,suggesting that inhaled isobutyl nitrite compromised macrophage,tumoricidal activity by inhibiting proteasomal degradation of theNF-κB inhibitor, IκBα.
Green tea polyphenol (−)-epigallocatechin-3-gallate treatment to mouse skin prevents UVB-induced infiltration of leukocytes, depletion of antigen-presenting cells, and oxidative stress
Authors: Katiyar Santosh K , Mukhtar Hasan
Published: September 2022

Ultraviolet (UV) radiation-induced infiltrating leukocytes, depletionof antigen-presenting cells, and oxidative stress in the skin play animportant role in the induction of immune suppression andphotocarcinogenesis. Earlier we have shown that topical application ofpolyphenols from green tea or its major chemopreventive constituent(−)-epigallocatechin-3-gallate (EGCG) prevents UV-B-inducedimmunosuppression in mice. To define the mechanism of prevention, wefound that topical application of EGCG (3 mg/mouse/3 cm2 ofskin area) to C3H/HeN mice before a single dose of UV-B (90mJ/cm2) exposure inhibited UV-B-induced infiltration ofleukocytes, specifically the CD11b+ cell type, and myeloperoxidaseactivity, a marker of tissue infiltration of leukocytes. EGCG treatmentwas also found to prevent UV-B-induced depletion in the number ofantigen-presenting cells when immunohistochemically detected as classII MHC+ Ia+ cells. UV-B-induced infiltrating cell production of H2O2 and nitric oxide (NO) was determined as amarker of oxidative stress. We found that pretreatment of EGCGdecreased the number of UV-B-induced increases inH2O2-producing cells and inducible nitric oxidesynthase-expressing cells and the production of H2O2 and NO in both epidermis and dermis at aUV-B-irradiated site. Together, these data suggest that prevention of UV-B-induced infiltrating leukocytes, antigen-presenting cells, andoxidative stress by EGCG treatment of mouse skin may be associated withthe prevention of UV-B-induced immunosuppression andphotocarcinogenesis.
Effect of vibrational stress and spaceflight on regulation of heat shock proteins hsp70 and hsp27 in human lymphocytes (Jurkat)
Authors: Cubano Luis A , Lewis Marian L
Published: September 2022

Heat shock protein levels are increased in cells as a result of exposure to stress. To determine whether heat shock protein regulation could be used to evaluate stress in cells during spaceflight, the response of Jurkat cells to spaceflight and simulated space shuttle launch vibration was investigated by evaluating hsp70 and hsp27 gene expression. Gene expression was assessed by reverse transcription-polymerase chain reaction using mRNA extracted from vibrated, nonvibrated, space-flown, and ground control cells. Results indicate that mechanical stresses of vibration and low gravity do not up-regulate the mRNA for hsp70, although the gene encoding hsp27 is up-regulated by spaceflight but not by vibration. In ground controls, the mRNA for hsp70 and hsp27 increased with time in culture. We conclude that hsp70 gene expression is a useful indicator of stress related to culture density but is not an indicator of the stresses of launch vibration or microgravity. Up-regulation of hsp27 gene expression in microgravity is a new finding.
Interleukin-18 expression induced by Epstein-Barr virus-infected cells
Authors: Yao Lei , Setsuda Joyce , Sgadari Cecilia , Cherney Barry , Tosato Giovanna
Published: September 2022

Human Epstein-Barr virus (EBV)-negative Burkitt lymphomas cells usually grow as malignant subcutaneous tumors in athymic mice, but these tumors regress when the Burkitt cells are injected in conjunction with EBV-positive lymphoblastoid cells or when the Burkitt cells are transfected with the EBV latent membrane protein-1 (LMP-1) gene. Tumor regression is mediated, in part, by murine interferon γ (IFN-γ) and the IFN-γ-induced murine chemokine IFN-γ-inducible protein-10 (IP-10). The mechanisms by which EBV-LMP-1 promotes the expression of IFN-γ has remained unclear. Here we show that murine interleukin (IL)-18 was consistently expressed in regressing Burkitt tumors but was either expressed at low levels or absent from progressively growing Burkitt tumors. By immunohistochemical methods, IL-18 protein was visualized in regressing but not in progressively growing Burkitt tumors. In contrast, IL-12 p35 and IL-12 p40 were only rarely expressed in regressing Burkitt tumors. In splenocyte cultures, EBV-infected lymphoblastoid cells and LMP-1-transfected Burkitt cells promoted the expression of IL-18 but not the expression of IL-12 p35 and IL-12 p40. A neutralizing antibody directed at murine IL-18 reduced murine IP-10 expression induced by EBV-immortalized cells in splenocyte cultures. These results provide evidence for IL-18 expression in response to a viral latency protein and suggest that IL-18 may play an important role as an endogenous inducer of IFN-γ expression, thereby contributing to tumor regression.
Novel chemokine functions in lymphocyte migration through vascular endothelium under shear flow
Authors: Cinamon Guy , Grabovsky Valentin , Winter Eitan , Franitza Suzanna , Feigelson Sara , Shamri Revital , Dwir Oren , Alon Ronen
Published: September 2022

The recruitment of circulating leukocytes at vascular sites in target tissue has been linked to activation of Gi-protein signaling in leukocytes by endothelial chemokines. The mechanisms by which apical and subendothelial chemokines regulate leukocyte adhesion to and migration across endothelial barriers have been elusive. We recently found that endothelial chemokines not only stimulate integrin-mediated arrest on vascular endothelial ligands but also trigger earlier very late antigen (VLA)-4 integrin-mediated capture (tethering) of lymphocytes to vascular cell adhesion molecule 1 (VCAM-1)-bearing surfaces by extremely rapid modulation of integrin clustering at adhesive contact zones. This rapid modulation of integrin avidity requires chemokine immobilization in juxtaposition with the VLA-4 ligand VCAM-1. We also observed that endothelial-bound chemokines promote massive lymphocyte transendothelial migration (TEM). It is interesting that chemokine-promoted lymphocyte TEM requires continuous exposure of lymphocytes but not of the endothelial barrier to fluid shear. It is noteworthy that lymphocyte stimulation by soluble chemokines did not promote lymphocyte TEM. Our results suggest new roles for apical endothelial chemokines both in triggering lymphocyte capture to the endothelial surface and in driving post-arrest events that promote lymphocyte transmigration across endothelial barriers under shear flow.