bluuebunny/crossref_metadata_2025 huggingface dataset:
Rise in Percutaneous Vascular Procedures and Extracorporeal Membrane Oxygenation Is Associated With Increase in Emergent Vascular Operations
Authors: Silverberg Daniel , Hater Haitam , Halak Moshe
Published: September 2022

Background: The workload of vascular surgeons is widely affected by the procedural activity of other departments within the same medical center. The purpose of this study was to evaluate the trend in emergent vascular surgery procedures over a 5 year period in a tertiary referral hospital and categorize these procedures based on the nature of the operative procedure required. Methods: A single center, retrospective review of all emergent surgical operations performed at our tertiary referral hospital between the years 2017-2021. Data collected included types of emergent vascular surgery performed, in addition to procedures performed by the departments of interventional cardiology (IC), interventional radiology (IR), neurointerventional radiology (NIR) and extracorporeal membrane oxygenation (ECMO) at our institution. Results: During the study period were performed a total of 1783 operative procedures (mean 356 ± 26/year). Of those, 485 (27%) were emergent cases. We observed a gradual increase in emergent operative procedures performed from 2017 to 2021 (22% to 34% of all cases, increase of 56%, P<.01). A striking increase was seen with vascular repairs performed for iatrogenic vascular injuries secondary to arterial access complications (47% to 65% of all iatrogenic vascular injuries, increase of 38%). The increase correlated with an increase in activity seen in the departments of IC, IR/NIR and ECMO (15%, 31% and 300%, respectively). Conclusions: An increasing number of emergent surgical procedures performed by our vascular surgery department correlates with the increasing number of endovascular procedures performed by non- vascular services. As these procedures are expected to increase, together with the number of stroke units and ECMO units being created, medical centers must be aware that these may result in a significant increase in the workload of the vascular surgery department in order to deal with complications associated with these procedures.
Equivalent characteristic model of a rough contact interface based on virtual material method
Authors: Shi Kun , Zhang Guangpeng , Shi Junping , Gao Qiang
Published: September 2022

The characteristic of rough contact interface has a major influence on overall performance of machines. To facilitate the setting of contact interface characteristics during the performance analysis of the whole machine, an equivalent characteristic model of a rough contact interface based on virtual material method is established. The normal and tangential properties of the rough contact interface per unit area are first experimentally conducted. Furthermore, according to the Greenwood-Williamson (GW) model and stress wave propagation conditions of discrete elements, the relationship between normal and tangential contact characteristics is explored by assuming the rough contact interface per unit area as a thin virtual layer. Based on virtual material method, the equivalent characteristic model of a rough contact interface is established, including equivalent virtual elastic modulus, Poisson’s ratio, thickness, and density. Finally, taking two step-shaped steel plates connected by four bolts for example, a numerical simulation of structural characteristics under different preloads is carried out. Numerical analysis results are then compared with tested results to verify the validity of the equivalent virtual material model of rough contact interface, and a good agreement between them is obtained.
Proximity and Police Departments: Spatial Dynamics of the Misdemeanor Arrest Decline
Authors: Beck Brenden , Holder Eaven
Published: September 2022

What makes police departments change their practices? Do they transform in isolation, or do they mimic their neighbors? Combining insights from organizational theory and urban sociology, the authors argue that organizational change diffuses, in part, through physically proximate institutions. They apply this theory to an underexamined trend: the decline of misdemeanor arrests in the United States between 1990 and 2018. The study first explores the spatial dynamics of low-level law enforcement by graphing and mapping trends across a range of metropolitan types, finding that suburbs made the fewest low-level arrests and central cities reduced their arrests the most during these years. A spatial autoregressive panel data model reveals that police departments decreased their misdemeanor arrests more when nearby departments did so, net of crime rates and other controls, evincing spatial mimicry. Police reform efforts need not target only state and federal governments but can diffuse outward from city-level changes.
Conceptualising comorbidity and multimorbidity in dementia: A scoping review and syndemic framework
Authors: Dunn Rosie , Clayton Eleanor , Wolverson Emma , Hilton Andrea
Published: September 2022

Background

Older people and people with dementia experience a high prevalence of multiple health conditions. The terms ‘comorbidity’ and ‘multimorbidity’ are often used interchangeably to describe this, however there are key conceptual differences between these terms and their definitions. This has led to issues in the validity and comparability of research findings, potentially inappropriate intervention development and differences in quality of health care.

Objective

To review how the terms ‘comorbidity’ and ‘multimorbidity’ are defined within peer-reviewed dementia research and propose an operational framework.

Design

A scoping review of definitions within dementia research was carried out. Searches took place across five databases: Academic Search Premier, CINAHL Complete, MEDLINE, PsycARTICLES and PsycINFO. PRISMA-ScR guidelines were followed.

Results

Content analysis revealed five key themes, showing significant overlap and inconsistencies from both within, and between, the comorbidity and multimorbidity definitions; 1. Number of conditions; 2. Type of health conditions; 3. The co-occurrence of conditions; 4. The inclusion of an index disease (or not); 5. Use of medical language. The analysis also revealed gaps in how the underlying concepts of the definitions relate to people with dementia living with multiple health conditions.

Conclusion

This scoping review found that current definitions of comorbidity and multimorbidity are heterogeneous, reductionist and disease-focussed. Recommendations are made on the design of research studies including transparency and consistency of any terms and definitions used. A syndemic framework could be a useful tool for researchers, clinicians and policy makers to consider a more holistic picture of a person with dementia’s health and wellbeing.
Burden of influenza hospitalization among high-risk groups in the United States
Authors: Near Aimee M. , Tse Jenny , Young-Xu Yinong , Hong David K. , Reyes Carolina M.
Published: September 2022

Background

Seasonal influenza poses a substantial clinical and economic burden in the United States and vulnerable populations, including the elderly and those with comorbidities, are at elevated risk for influenza-related medical complications.

Methods

We conducted a retrospective cohort study using the IQVIA PharMetrics® Plus claims database in two stages. In Stage 1, we identified patients with evidence of medically-attended influenza during influenza seasons from October 1, 2014 to May 31, 2018 (latest available data for Stage 1) and used a multivariable logistic regression model to identify patient characteristics that predicted 30-day influenza-related hospitalization. The findings from Stage 1 informed high-risk subgroups of interest for Stage 2, where we selected cohorts of influenza patients during influenza seasons from October 1, 2014 to March 1, 2019 and used 1:1 propensity score matching to patients without influenza with similar high-risk characteristics to compare influenza-attributable rates of all-cause hospital and emergency department (ED) visits during follow-up (30-day and in the index influenza season).

Results

In Stage 1, more than 1.6 million influenza cases were identified, of which 18,509 (1.2%) had a hospitalization. Elderly age was associated with 9 times the odds of hospitalization (≥65 years vs. 5–17 years; OR = 9.4, 95% CI 8.8–10.1) and select comorbidities were associated with 2–3 times the odds of hospitalization. In Stage 2, elderly influenza patients with comorbidities had 3 to 7 times higher 30-day hospitalization rates compared to matched patients without influenza, including patients with congestive heart failure (41.0% vs.7.9%), chronic obstructive pulmonary disease (34.6% vs. 6.1%), coronary artery disease (22.8% vs. 3.8%), and late-stage chronic kidney disease (44.1% vs. 13.1%; all p < 0.05).

Conclusions

The risk of influenza-related complications is elevated in the elderly, especially those with certain underlying comorbidities, leading to excess healthcare resource utilization. Continued efforts, beyond currently available vaccines, are needed to reduce influenza burden in high-risk populations.
The impact of accountability on local officials’ behavior in the pandemic prevention and control in China based on utility maximization
Authors: Zeng Shian , Yi Chengdong
Published: September 2022

Background

The COVID-19 pandemic is a public health crisis and an inspection of national governance systems and crisis response capabilities of countries globally. China has adopted a tough accountability system for officials and has succeeded in containing the spread of the pandemic. This study aimed to assess the impact of accountability on local officials’ behavior in the pandemic prevention and control based on the official promotion tournament theory and utility maximization analysis framework.

Methods

The panel data of 237 Chinese cities were extracted with local officials’ characteristics, confirmed cases, Baidu migration index, Baidu search index according to city names, and data were excluded with local officials’ relocation or sub-provincial cities between January 1, 2020 and May 5, 2020. Promotion gain and accountability cost were constructed by adopting promotion speed indicator, and the research hypotheses were assumed based on the utility maximization. It was the first time to apply the interaction model to empirically investigate the relationship between the promotion speed of local officials and the COVID-19 confirmed cases.

Results

Our study showed that the promotion speed of provincial governors and mayors significantly affected the number of confirmed cases (β = − 11.615, P < 0.01). There was a significant interaction between the promotion speeds of provincial governors and mayors (β = − 2594.1, P < 0.01), indicating that they had a coordinated effect on the pandemic control. Additionally, mayors with different promotion speeds made a significant difference in controlling the imported cases and those who promoted faster better controlled the imported cases (β = − 0.841, P < 0.01). Mayors with full-time postgraduate education, titles, and majors in science and engineering had a better effect on controlling the number of confirmed cases.

Conclusions

Our study provides evidence that the official accountability system has played an important role in containing the pandemic, which suggests that local officials motivated by the accountability system would respond to the pandemic actively for higher utility. Furthermore, provincial governors and mayors have played a coordinated effect in pandemic control. The above evidences reveal that implementing the official accountability system could improve the government’s emergency management capability and the efficiency of pandemic control. Therefore, adopting a strict accountability system could be effective in pandemic containment globally, especially in centralized countries.
Retraction Note: Phycoremediation of automobile exhaust gases using green microalgae: a twofold advantage for pollutant removal and concurrent biomass/lipid yields
Authors: Kandimalla Pooja , Vatte Priyanka , Bandaru Chandra Sekhar Rao
Published: September 2022

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s42834-020-0046-z
Mediastinal aberrant goiter characterized by high radiodensity on non-enhanced computed tomography: a case report
Authors: Suzuki Mikito , Horio Hirotoshi , Nakamura Azusa , Shimizu Reiko , Shima Toshiyuki , Harada Masahiko , Hishima Tsunekazu
Published: September 2022

Background

A mediastinal aberrant goiter is extremely rare, characterized by independence from the thyroid gland. This tumor most commonly develops in the anterior mediastinum and should be differentiated from a thymoma. Moreover, as mediastinal aberrant goiters frequently have a blood supply arising from the thoracic great vessels, preoperative diagnosis and evaluation of the feeding vessel are vital for safe surgery. Herein, we report a rare case of mediastinal aberrant goiter characterized by high radiodensity on non-enhanced computed tomography (CT).

Case presentation

A 77-year-old woman underwent non-enhanced CT, which showed a 2.2-cm, well-circumscribed, homogeneous anterior mediastinal nodule with high radiodensity. The CT attenuation value of the nodule was as high as 91.9 Hounsfield units. A thymoma or mediastinal goiter was suspected owing to the tumor location and the lack of a cystic component. We performed anterior mediastinal tumor resection using video-assisted thoracoscopic surgery. Pathologically, variably sized follicles, indicative of thyroid tissue, were observed with hemorrhage and hemosiderin deposition. Moreover, papillary projections of small follicles (Sanderson’s polsters) were scattered without atypia of the follicular epithelium, indicative of an adenomatous goiter. The diagnosis of a mediastinal aberrant goiter was supported by the absence of an anatomical connection with the thyroid gland. The postoperative course was uneventful, and the patient was discharged on postoperative day 5.

Conclusion

The thyroid gland has a high radiodensity on non-enhanced CT, which correlates with iodine concentration. This radiological feature may be useful for the preoperative differentiation of mediastinal aberrant goiters containing thyroid tissue.
Targeting apoptosis pathways in infections
Authors: Naderer Thomas , Fulcher Maria Cecilia
Published: September 2022

The programmed cell death pathway of apoptosis is essential for mammalian development and immunity as it eliminates unwanted and dangerous cells. As part of the cellular immune response, apoptosis removes the replicative niche of intracellular pathogens and enables the resolution of infections. To subvert apoptosis, pathogens have evolved a diverse range of mechanisms. In some circumstances, however, pathogens express effector molecules that induce apoptotic cell death. In this review, we focus on selected host-pathogen interactions that affect apoptotic pathways. We discuss how pathogens control the fate of host cells and how this determines the outcome of infections. Finally, small molecule inhibitors that activate apoptosis in cancer cells can also induce apoptotic cell death of infected cells. This suggests that targeting host death factors to kill infected cells is a potential therapeutic option to treat infectious diseases.
Ligand activation of nerve growth factor receptor TrkA protects monocytes from apoptosis
Authors: la Sala Andrea , Corinti Silvia , Federici Monica , Saragovi H Uri , Girolomoni Giampiero
Published: September 2022

Nerve growth factor (NGF) receptors are expressed in different cell types outside the nervous system, and increasing evidence indicates that NGF can act as a regulatory molecule during inflammatory and immune responses. In this study, we show that triggering of the high-affinity NGF receptor TrkA with agonists protects monocytes from apoptosis induced by gliotoxin or UVB radiation. TrkA stimulation up-regulates the expression of the anti-apoptotic Bcl-2 family members, Bcl-2, Bcl-XL, and Bfl-1. On the other hand, TrkA stimulation does not change the expression of MHC, CD80, CD86, CD40, and CD54 molecules, nor the antigen-presenting function of monocytes. In addition, during in vitro monocyte to dendritic cell differentiation TrkA expression is progressively lost, suggesting that NGF selectively affects monocyte but not dendritic cell survival.
IL-4 production by human polymorphonuclear neutrophils
Authors: Brandt Eric , Woerly Gaëtane , Younes Amena Ben , Loiseau Sylvie , Capron Monique
Published: September 2022

Polymorphonuclear neutrophils (PMN) are phagocytic cells, able to secrete a large range of cytokines, including inflammatory cytokines, chemokines, as well as the Th1 cytokines interferon-γ (IFN-γ) and interleukin (IL)-12. Although PMN do not seem to express IL-10 and IL-13, no information exists on the ability of PMN to produce IL-4. Therefore intracellular flow cytometry was performed in the presence or absence of Brefeldin A. Similarly to eosinophils, freshly isolated neutrophils from normal donors contained low amounts of IL-4, which significantly increased upon culture with Brefeldin A (P < 0001). Immunostaining performed on cytospin preparations of normal granulocytes confirmed the presence of intracellular IL-4. Using a highly sensitive ELISA, the levels of IL-4 secreted by cultured PMN and peripheral blood mononuclear cells (PBMC) were compared. PBMC secrete up to 60 times more IL-4 as PMN but, in the presence of calcium ionophore, only PMN showed a slight but significant increase in IL-4 secretion (P < 0.05). In conclusion, we report here the presence within human PMN of intracellular IL-4, which can at least partly be released under calcium ionophore stimulation. The relevance of this production of IL-4 by human PMN is discussed.
Gene profiling approach in the analysis of lymphotoxin and TNF deficiencies
Authors: Shakhov Alexander N , Lyakhov Ilya G , Tumanov Alexei V , Rubtsov Anatoly V , Drutskaya Ludmila N , Marino Michael W , Nedospasov Sergei A
Published: September 2022

Mice with combined lymphotoxin-α (LTα) and tumor necrosis factor (TNF) deficiencies show defects in the structure of peripheral lymphoid organs such as spleen, lymph nodes, and gut-associated lymphoid tissues. To identify genes associated with this defective phenotype in spleen, we applied a gene profiling approach, including subtractive cloning and gene array hybridizations, to mice with combined TNF/LT deficiency. The differentially expressed genes identified by these techniques was then evaluated by Northern blot analysis for splenic expression in knockout mice with single LTα or single TNF deficiency. Most of the genes detected in this analysis are directly or indirectly associated with disrupted LT and not TNF signaling.
Expression on human eosinophils of CD148: a membrane tyrosine phosphatase. Implications in the effector function of eosinophils
Authors: del Pozo Victoria , Pirotto Fiorella , Cárdaba Blanca , Cortegano Isabel , Gallardo Soledad , Rojo Marta , Arrieta Ignacio , Aceituno Esther , Palomino Pilar , Gaya Antoni , Lahoz Carlos
Published: September 2022

The role of protein tyrosine phosphatases (PTP) is crucial in regulating the phosphorylation status of cells. CD148 is a recently described membrane-type PTP. In this study, we have demonstrated that this molecule is expressed on human eosinophils and eosinophilic cell line EoL-3. Interestingly, our data also showed that this molecule acts as a transduction molecule on these cells. Thus, the crosslinking of CD148 was able to induce the degranulation and the induction of superoxide anion generation. By using specific inhibitor and by western blotting, we have shown that tyrosine kinase activation is involved in this transduction pathway. In addition, we have shown the presence of a serine/threonin kinase activity associated with CD148. In conclusion, the activation capacity of CD148 on eosinophils suggests a potential role of this molecule on inflammatory diseases, such as allergic and parasitic diseases, associated with eosinophilia.
Preferential sites for stationary adhesion of neutrophils to cytokine-stimulated HUVEC under flow conditions
Authors: Gopalan Priya K , Burns Alan R , Simon Scott I , Sparks Scott , McIntire Larry V , Smith C Wayne
Published: September 2022

Neutrophils form CD18-dependent adhesions to endothelial cells at sites of inflammation. This phenomenon was investigated under conditions of flow in vitro using isolated human neutrophils and monolayers of HUVEC. The efficiency of conversion of neutrophil rolling to stable adhesion in this model was >95%. Neither anti-CD11a nor anti-CD11b antibodies significantly altered the extent of this conversion, but a combination of both antibodies inhibited the arrest of rolling neutrophils by >95%. The efficiency of transendothelial migration of arrested neutrophils was >90%, and the site of transmigration was typically <6 μm from the site of stationary adhesion. Approximately 70% of transmigrating neutrophils migrated at tricellular corners between three adjacent endothelial cells. A model of neutrophils randomly distributed on endothelium predicted a significantly greater migration distance to these preferred sites of transmigration, but a model of neutrophils adhering to endothelial borders is consistent with observed distances. It appears that stable adhesions form very near tricellular corners.
T cell lysis of murine renal cancer: multiple signaling pathways for cell death via Fas
Authors: Sayers Thomas J , Brooks Alan D , Seki Naoko , Smyth Mark J , Yagita Hideo , Blazar Bruce R , Malyguine Anatoli M
Published: September 2022

Activated T cells lyse the murine renal cancer Renca. We have examined the mechanism of tumor cell lysis with the use of T cells derived from C57BL/6, BALB/c, B6.gld, and B6.Pfp-/- mice. C57BL/6 and BALB/c T cells can lyse Renca cells through the use of both granule- and Fas ligand (FasL)-mediated pathways. However, B6.gld T cells predominantly use granule-mediated killing, whereas B6.Pfp-/- T cells use FasL. The lysis of Renca by Pfp-/- T cells is only partially inhibited by the caspase inhibitor ZVAD-FMK, suggesting that caspase-independent signaling is also important for Renca cell lysis. When the reactive oxygen scavenger butylated hydroxyanisole was used alone or in combination with ZVAD-FMK a substantial reduction of Renca lysis was observed. Therefore, the caspase-independent generation of reactive oxygen intermediates in Renca after Fas triggering contributes to the lysis of these cells.
Oxidative stress as a necessary factor in room temperature-induced apoptosis of HL-60 cells
Authors: Shimura Mari , Osawa Yutaka , Yuo Akira , Hatake Kiyohiko , Takaku Fumimaro , Ishizaka Yukihito
Published: September 2022

HL-60 cells undergo apoptosis when placed at room temperature (RT) [Shimura et al. (1997) FEBS Lett. 417, 379–384]. We report that superoxide anion radical, one of the reactive oxygen species (ROS), was produced after RT treatment. Affinity blot analysis with a biotinylated YVAD-CHO detected the generation of processed peptides with molecular masses of 15–25 kDa. Activation of such an ICE-like protease was completely abolished by N-acetylcysteine and exogenously expressed Bcl-2, known as antioxidants. We concluded that oxidative stress was a critical factor in the signal cascade of the apoptosis. Western blot analysis and experiments using tetrapeptide inhibitors suggested that caspases-1, -3, -4, -6, and -9 did not have an essential role in the apoptotic cascade. It is interesting that cyclosporin A (CsA) blocked RT-induced apoptosis with an inhibition of cytochrome c release from mitochondria. CsA, however, generated a significant amount of ROS with considerable reduction of mitochondrial membrane potential, implying that oxidative stress was one necessary factor for RT-induced apoptosis. It is also likely that mitochondrial membrane potential and the release of apoptotic factors from cytoplasm are differently regulated. Taken together with the reports that some Burkitt lymphoma cells showed apoptosis when exposed at low temperature followed by rewarming, and that hepatocytes or liver endothelial cells are susceptible to cold-induced apoptosis through the ROS function, we propose that studying the mechanism of RT-induced apoptosis of HL-60 cells may provide a therapeutic strategy for pathological conditions involving ROS, such as neurodegenerative diseases and ischemia.
Chemokine signaling and HIV-1 fusion mediated by macrophage CXCR4: implications for target cell tropism
Authors: Collman Ronald G , Yi Yanjie , Liu Qing-Hua , Freedman Bruce D
Published: September 2022

To better understand CXCR4 function on macrophages and the relationship between coreceptor use and macrophage tropism among diverse HIV-1 isolates, we analyzed macrophage pathways involved in Env-mediated fusion, productive HIV-1 infection, and chemokine-elicited signaling. We found that both CXCR4 and CCR5 transduced intracellular signals in monocyte-derived macrophages, activating K+ and Cl− ion channels and elevating intracellular calcium in response to their chemokine ligands stromal cell-derived factor-1α and macrophage inflammatory protein-1β, respectively. The prototype T-tropic X4 strain IIIB infected macrophages poorly, and this was associated with failure of the IIIB Env to fuse efficiently with target macrophages despite functional CXCR4. In contrast, several primary X4 isolates mediated efficient CXCR4-dependent fusion and productive macrophage infection. Several R5X4 strains could fuse with and infect macrophages through both CCR5 and CXCR4. Thus, macrophages express functional CXCR4 and CCR5 but primary and prototype X4 isolates differ in their ability to utilize macrophage CXCR4. Isolates classified as X4 based on coreceptor use may be phenotypically either T-tropic or dual-tropic and, conversely, phenotypically dual-tropic isolates may be either R5X4 or X4 based on coreceptor use.
Co-receptor usage was more predictive than NSI/SI phenotype for HIV replication in macrophages: is NSI/SI phenotyping sufficient?
Authors: Lathey Janet L , Brambilla Donald , Goodenow Maureen M , Nokta Mostafa , Rasheed Suraiya , Siwak Edward B , Bremer James W , Huang Diana D , Yi Yanjie , Reichelderfer Patricia S , Collman Ronald G
Published: September 2022

A monocyte-derived macrophage (MDM) culture assay was used to define the replication kinetics of HIV isolates. Ten-day-old MDMs were infected with HIV. Supernatants were collected and assayed for HIV p24 on days 3, 7, 10, and 14 post-infection (PI). In this assay, SF162 (macrophage tropic, NSI) produced increasing amounts of HIV p24 antigen with increasing time in culture. BRU (nonmacrophage tropic, SI) infection resulted in low levels of HIV p24 antigen with no increase in production during the culture period. A panel of 12 clinical isolates was evaluated. All isolates produced detectable levels of HIV p24 antigen in MDMs. However, the NSI viruses had significantly higher log10 HIV p24 antigen values at all times PI (P < 0.01). Co-receptor usage was determined for all 12 isolates (8 NSI and 4 SI). All SI isolates used CXCR4 for entry; two used CXCR4 only, one used CXCR4, CCR5, and CCR3, and one was a mixture of two isolates using CXCR4 and CCR5. None of the NSI viruses used CXCR4 for entry. All used CCR5 as their predominant co-receptor. Of the eight NSI isolates, three used CCR5 only, two used CCR5 and CCR2b, one used CCR5 and CCR3, and one used CCR5, CCR3, and CCR2b. Log10 HIV p24 antigen production on day 14 PI for viruses that used CCR5+CCR3 (3.79 + 1.40) was greater than for viruses that used CCR5+CCR2b (3.22 + 1.55) or CCR5 (3.32 + 1.49), and all were greater than those that used CXCR4 only (1.69 + 0.28), regardless of SI phenotype (P < 0.05). Thus, in these primary isolates, macrophage tropism and replication kinetics were closely linked to CCR5 utilization, whereas SI capacity was closely linked to CXCR4 utilization. Furthermore, viruses, which could use CCR5 and CCR3 for entry, had a replication advantage in macrophages, regardless of SI phenotype.
Monocyte:astrocyte interactions regulate MCP-1 expression in both cell types
Authors: Andjelkovic Anuska V , Kerkovich Danielle , Pachter Joel S
Published: September 2022

As astrocytes are a source of monocyte chemoattractant protein-1 (MCP-1) and lie in close apposition to brain microvessels, interactions between astrocytes and infiltrating monocytes might regulate production of this chemokine. To investigate this possibility, a monocyte:astrocyte co-culture model was utilized to assess the respective roles of these two cell types in regulating MCP-1 production. Results indicate that, while neither monocytes nor astrocytes alone produce detectable levels of MCP-1, co-culture of these two cell types results in time-dependent production of this chemokine. Such production requires de novo protein synthesis and is dependent on physical contact between monocytes and astrocytes, involving engagement of the cell-adhesion molecules ICAM-1 and VCAM-1. Additionally, interleukin 1-beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) are soluble mediators of this response. These findings imply that monocyte extravasation into the CNS may be critically regulated at the blood-brain barrier by specialized monocyte:astrocyte interactions.
Recognition of CHO cells by inhibitory and activating Ly-49 receptors
Authors: Mason Llewellyn H
Published: September 2022

Upon ligand recognition, members of the murine Ly-49 receptor family can transmit inhibitory or activating signals that regulate NK cell function. Ly-49A, G, and D have been shown to recognize the murine class I molecule H-2Dd as a potential ligand. Recent studies also have demonstrated also that Ly-49D+ NK cells can lyse CHO cells, although the ligand responsible for this recognition was not identified. Because allorecognition by NK cells may be important in bone-marrow transplantation and because of the overlapping class I recognition by these receptors, recognition of CHO cells by Ly-49G and A was investigated. Our data suggest that Ly-49G and probably A transmit inhibitory signals in response to CHO cells. Receptor inhibition was assessed by examining NK lytic function, IFN-γ secretion, and DAP12 phosphorylation in response to CHO cells by sorted subsets of Ly-49D vs. G B6 NK cells. Our results suggest that CHO cells may express a common ligand(s) that is capable of engaging Ly-49D, G, and possibly A in C576BL/6 NK cells. In addition to our findings that Ly-49 inhibitory receptors also recognize CHO cells, activating receptors other than Ly-49D are present in B6 mice that can lyse CHO cells.
Src kinase-mediated signaling in leukocytes
Authors: Korade-Mirnics Željka , Corey Seth J
Published: September 2022

A concert of antigens, antibodies, cytokines, adhesion molecules, lipid factors, and their different receptors mediate leukocyte development and inflammatory responses. Regardless of the stimulus and receptor type, members of the Src family of protein tyrosine kinases (PTKs) play a critical role in initiating the numerous intracellular signaling pathways. Recruited and activated by the receptor, these Src PTKs amplify and diversify the signal. Multiple pathways arise, which affect cell migration, adhesion, phagocytosis, cell cycle, and cell survival. Essential nonredundant properties of Src PTKs have been identified through the use of gene targeting in mice or in the somatic cell line DT40. Because of their role in mediating leukocyte proliferation and activation, Src PTKs serve as excellent drug targets. Inhibitors of Src family members and dependent pathways may be useful in the treatment of human diseases similar to drugs known to inhibit other signal transduction pathways.
Structural requirements for intracellular processing and sorting of bactericidal/permeability-increasing protein (BPI): comparison with lipopolysaccharide-binding protein
Authors: Bülow Elinor , Gullberg Urban , Olsson Inge
Published: September 2022

The bactericidal/permeability-increasing protein (BPI), which is stored in the azurophil granules of neutrophils, and the circulating lipopolysaccharide-binding protein (LBP) share the same structure. Both bind lipopolysaccharide of gram-negative bacteria through their amino-terminal domains. The carboxy-terminal domain of BPI promotes bacterial attachment to phagocytes, whereas the corresponding domain of LBP delivers lipopolysaccharide to monocytes/macrophages. Our aim was to investigate the role of the amino- and carboxy-terminal domains of BPI and LBP for sorting and storage in myeloid cells after transfection of cDNA to two rodent hematopoietic cell lines. Full-length BPI and LBP were both targeted for storage in these cells. Deletion of the carboxy-terminal half of BPI resulted in storage followed by degradation while the reciprocal deletion of the amino-terminal half led to retention in the endoplasmic reticulum for proteasomal degradation. Chimeras between halves of BPI and LBP were also targeted for storage, but those containing carboxy-terminal BPI had the highest stability, again indicating a role for the carboxy-terminal domain of BPI in protection against degradation. Therefore, we propose a critical stability function for the hydrophobic carboxy-terminal domain of BPI during intracellular sorting for storage while the amino-terminal domain may confer targeting for storage.
Modulation of H2 histamine receptor-mediated cAMP generation and granulocytic differentiation by extracellular nucleotides via activation of protein kinase C
Authors: Suh Byung-Chang , Lee Hyosang , Lee Ihn-Soon , Kim Kyong-Tai
Published: September 2022

Extracellular ATP exerts a variety of biological actions through several kinds of P2 receptor in HL-60 promyelocytes. We show that stimulation of P2Y2 receptors with ATP and analogs resulted in the inhibition of a subsequently histamine-induced cAMP production and functional differentiation. Treatment of the cells with phorbol 12-myristate 13-acetate also blocked the histamine-mediated cAMP generation just as ATP did. Incubation of the cells with the protein kinase C inhibitor bisindolylmaleimide (GF109203X) abolished the inhibitory effects of extracellular nucleotides, suggesting that protein kinase C may act as an inter-regulator between two receptors. However, ATP did not affect the binding affinity or total binding of [3H]histamine to membrane receptors; it also did not heterologously desensitize H2 receptors. The ATP treatment synergistically elevated the cAMP levels induced directly by forskolin or indirectly by G protein activation after cholera toxin treatment. This indicates that the site of the protein kinase C action is not the G protein or effector enzyme. Co-stimulation of the cells with nucleotides and histamine inhibited histamine-mediated granulocytic differentiation, which was evaluated by looking at the extent of N-formyl-methionyl-leucyl-phenylalanine responses. Taken together, the results demonstrate that extracellular nucleotides are negatively involved in the modulation of histamine signaling via activation of protein kinase C, probably by inhibiting coupling between receptor and G protein.
MAP kinase activation in macrophages
Authors: Rao K Murali Krishna
Published: September 2022

Stimulation of macrophages by a variety of agents causes activation of mitogen-activated protein kinases (MAPKs). Activation of MAPKs by lipopolysaccharide involves CD14 and Toll receptors. Subsequent steps still remain to be explored. Tumor necrosis factor-α (TNF-α)-induced activation of MAPKs has been shown to involve the death domain proteins (TRADD, FADD, MADD) and TRAFs. Other molecules involved in this pathway include the protein kinases, ASK1, germinal center kinase (GCK), hematopoietic progenitor kinase 1 (HPK1), and GCK-related kinase (GCKR). Although, these pathways have been described in various cell types, their role in macrophages remains to be established. The availability of knockout mice and constitutively active and dominant-negative mutants of MAPKs should greatly enhance our understanding of this field. The activation of MAPKs seems to be different in cell lines compared with primary cells. Among the macrophages, cells from different compartments show different expression of receptors and signal transduction molecules. These differences may account for differences in MAPK activation and other phenotypic differences in macrophages from different compartments. Therefore, it is important to use primary cells for studying MAPK signal-transduction pathways, and the data from cell lines should not be extrapolated to primary cells.
Iron transport intoMycobacterium avium-containing phagosomes from anNramp1Gly169-transfected RAW264.7 macrophage cell line
Authors: Kuhn Donald E , Lafuse William P , Zwilling Bruce S
Published: September 2022

Nramp1 is an important determinant of innate resistance of macrophages to the growth of intracellular microorganisms. We previously showed that Nramp1 functions to transport iron from the cytoplasm into phagosomes of Mycobacterium avium-infected macrophages. The purpose of this investigation was to further characterize the factors that regulate Nramp1-mediated iron transport into phagosomes. Treatment of Nramp1Gly169 macrophages with the lysomotrophic agents chloroquine or ammonium chloride reduced the import of iron significantly. We found that macrophage-activating cytokines, including TNF-α, IFN-γ, IL-1α, and GM-CSF, when added prior to M. avium, increased the transport of iron into the phagosome. This increase in iron transport was not a result of an increased amount of Nramp1 protein in the phagosome nor to new protein synthesis. Treatment of Nramp1Gly169-transfected macrophages with inhibitors of protein kinase C (PKC) diminished the import of iron into the phagosomes. Iron import was inhibited by an anti-Nramp1 antibody against the putative fourth outer-loop region of Nramp1 but not by an anti-Nramp1 antibody against the carboxy terminus. The significance of these results on the orientation of Nramp1 in the phagosome membrane and on the transport of iron is discussed.
CpG DNA increases primary malignant B cell expression of costimulatory molecules and target antigens
Authors: Jahrsdörfer Bernd , Hartmann Gunther , Racila Emil , Jackson Wallen , Mühlenhoff Lars , Meinhardt Gerold , Endres Stefan , Link Brian K , Krieg Arthur M , Weiner George J
Published: September 2022

Multiple factors, including expression of costimulatory molecules, antigen-presenting molecules, and target antigens, likely impact the efficacy of antibody therapy and other approaches to the immunotherapy of B cell malignancy. Unmethylated CpG-dinucleotides in select base contexts (“CpG motifs”) that resemble sequences found in bacterial DNA are potent immunostimulatory agents capable of inducing a complex immune response, including a strong B cell stimulus. We examined the effect of a potent human CpG oligonucleotide (CpG ODN 2006) on different types of primary human malignant B cells and reactive follicular hyperplasia. CpG oligodeoxynucleotide (CpG ODN), but not control (non-CpG ODN), increased the expression of costimulatory molecules (CD40, CD80, CD86, CD54) on malignant B cells without altering the phenotype of B cells obtained from reactive follicular hyperplasia. CpG ODN also enhanced expression of class I and class II MHC in most samples. CD20 expression was increased in response to CpG ODN, most notably in B-CLL and marginal zone lymphoma. An inverse correlation was found between baseline expression of CD20 and CD40 and their expression after exposure to CpG ODN, thus the most significant increase in expression of these molecules was found in those samples that had the lowest baseline levels. In conclusion, CpG ODN can lead to increasing expression of molecules involved in costimulation, antigen presentation, and as targets for antibody-based therapy and deserve further evaluation as potential immunotherapeutic agents for B cell malignancy.
Proteinase 3, Wegener's autoantigen: from gene to antigen
Authors: van der Geld Y M , Limburg P C , Kallenberg C G M
Published: September 2022

Proteinase 3 (PR3) is one of four serine protease homologues in the azurophilic granules of neutrophils and granules of monocytes. It is of importance that anti-neutrophil cytoplasmic antibodies (ANCA) in patients with Wegener's granulomatosis (WG) are mainly directed against PR3 only. Furthermore, PR3 is overexpressed in a variety of acute and chronic myeloid leukemia cells. Cytotoxic T lymphocytes specific for a PR3-derived peptide have been shown to specifically lyse leukemia cells that overexpress PR3. This review will focus on PR3 and the characteristics of PR3 that might implicate this particular antigen in the pathogenesis of WG and as target for immunotherapy in myeloid leukemias. We will discuss the genetic localization and gene regulation of PR3, the processing, storage, and expression of the PR3 protein, and the physiological functions of PR3, and compare this with the three other neutrophil-derived serine proteases: human leukocyte elastase, cathepsin G, and azurocidin. Three main differences are described between PR3 and the other serine proteases. This makes PR3 a very intriguing protein with a large array of physiological functions, some of which may play a role in ANCA-associated vasculitidis and myeloid leukemia.
Antibodies recognizing CD24 LAP epitope on human T cells enhance CD28 and IL-2 T cell proliferation
Authors: del C. Salamone María , Rosselot Carolina , Salamone Gabriela V , Barboza Marcos , Kado Miguel , Fainboim Leonardo
Published: September 2022

Membrane expression of the CD24 molecule on activated T lymphocytes is not elucidated fully. We previously described the intracellular and cell-surface expression of the CD24 sialic acid-dependent epitope(s) on phytohemagglutinin-activated peripheral blood mononuclear cells. However, the CD24 core protein was not detected previously on human T cells. This study reinvestigated the expression and role of CD24 in T cell subsets. We analyzed binding of anti-CD24 monoclonal antibodies (mAbs) to sialic and leucine-alanine-proline (LAP) epitopes in resting and activated, normal T lymphocytes. CD24 LAP and CD24 sialic epitopes were detected on activated CD4- and CD8-positive cells. Although expression of CD24 sialic epitopes remained stably expressed in interleukin (IL)-2-dependent cultures, T cell expression of the LAP epitope was transient. Anti-LAP antibodies strongly enhanced the response of T cells to a combination of anti-CD3/CD28 mAbs and enhanced proliferative response induced by recombinant IL-2. We found similarities in the tissue distribution and function of the human CD24LAP molecule and the murine, heat-stable antigen, which suggests that CD24 might function as a signaling molecule on human T cells.
Characteristics of the free cytosolic calcium timelag following IgE-mediated stimulation of human basophils: significance for the nonreleasing basophil phenotype
Authors: MacGlashan Donald , Lavens-Phillips Sandra
Published: September 2022

These studies examine characteristics of the quiescent period (timelag) of the free cytosolic calcium ([Ca++]i) elevation that follows stimulation of human basophils through the IgE receptor. Previous studies established that the [Ca++]i timelag was sensitive to the rate of ligand binding, but little else is known about this response characteristic. The [Ca++]i timelag could be lengthened using antigenic stimulation that is rapid but only weakly induces secretion: tenfold differences in the “strength” of the stimulus, as assessed by histamine release, are associated with threefold differences in the timelag. Inhibiting p53/56lyn kinase with low concentrations of the specific inhibitor, PP1, lengthened the [Ca++]i timelag dramatically. PP1 was also found to delay the onset of syk phosphorylation and histamine release. Staurosporine and genistein, which are known to inhibit early tyrosine kinases, had, at best, only modest effects on the [Ca++]i timelag. Specific inhibitors of protein kinase C (PKC) had no effect on the [Ca++]i timelag, and direct activation of PKC with PMA had only very modest effects on the timelag. Contrary to expectations, basophils with the so-called nonreleasing phenotype demonstrated an IgE-mediated [Ca++]i response at the single-cell level. However, the length of [Ca++]i timelag in nonreleasing basophils was threefold longer than normally found in releasing basophils. Furthermore, the [Ca++]i response was significantly more asynchronous than in releasing basophils and lacking in a sustained [Ca++]ielevation. These studies indicate that the [Ca++]i timelag following stimulation through the IgE receptor is sensitive to inhibition of lyn kinase but not other agents that have been demonstrated to inhibit early tyrosine kinases previously. However, only one characteristic of the [Ca++]i response phenotype of nonreleasing basophils—the [Ca++]i timelag but not the absence of a sus-tained [Ca++]ielevation—could be mimicked by inhibition of lyn kinase with PP1.
Stromal derived factor-1α (SDF-1α) induces CD4+ T cell apoptosis via the functional up-regulation of the Fas (CD95)/Fas ligand (CD95L) pathway
Authors: Colamussi Maria Luisa , Secchiero Paola , Gonelli Arianna , Marchisio Marco , Zauli Giorgio , Capitani Silvano
Published: September 2022

Stromal-derived factor-1α (SDF-1α), the high-affinity ligand of CXC-chemokine receptor 4 (CXCR4), induced a progressive increase of apoptosis when added to the Jurkat CD4+/CXCR4+ T cell line. The SDF-1α-mediated Jurkat cell apoptosis was observed in serum-free or serum-containing cultures, peaked at SDF-1α concentrations of 10–100 ng/ml, required 3 days to take place, and was completely blocked by the z-VAD-fmk tripeptide caspase inhibitor. Although SDF-1α did not modify the expression of TNF-α or that of TNF-RI and TNF-RII, it increased the expression of surface Fas/APO-1 (CD95) and intracellular Fas ligand (CD95L) significantly. Moreover, the ability of SDF-1α to induce apoptosis was inhibited by an anti-CD95 Fab′ neutralizing antibody. These findings suggest a role for SDF-1α in the homeostatic control of CD4+ T-cell survival/apoptosis mediated by the CD95-CD95L pathway.
Cloning, mRNA distribution, and functional expression of an avian counterpart of the chemokine receptor/HIV coreceptor CXCR4
Authors: Liang Thomas S , Hartt Jennifer K , Lu Shuyan , Martins-Green Manuela , Gao Ji-Liang , Murphy Philip M
Published: September 2022

The chemokine signaling system, which coordinates the basal and emergency trafficking of leukocytes, presumably coevolved with the hematopoietic system. To study its phylogenetic origins, we used the open reading frame (ORF) of the human chemokine receptor CXCR4 as a genomic probe, since in mammals it is the most highly conserved chemokine receptor known. CXCR4 cross-hybridized to genomic DNA from mouse and chicken, but not zebrafish, Drosophila, orCaenorhabditis elegans. Accordingly, we cloned the corresponding chicken cDNA. The ORF is 359 codons long versus 352 for human CXCR4, and encodes a protein 82% identical to human CXCR4. In a calcium flux assay of receptor function, CHO-K1 cells stably transfected with the chicken cDNA responded specifically to human SDF-1, the specific ligand for CXCR4, but not to a panel of other chemokines tested at 100 nM. SDF-1 activated the cells in a dose-dependent manner (EC50 ∼5 nM), whereas parental CHO-K1 cells did not respond. The CHO-K1 cell transfectants also bound125I-SDF-1 specifically. Leukocytes from chicken peripheral blood expressed chCXCR4 mRNA and responded to human SDF-1 in a calcium flux assay with an EC50 similar to that for chCXCR4-transfected CHO cells, suggesting that this response is mediated by native chCXCR4. Analysis of chicken genomic DNA with the chicken cDNA as probe revealed a pattern consistent with a single copy gene, and the absence of any closely related genes. mRNA was detected in brain, bursa, liver, small and large intestine, embryonal fibroblasts, and blood leukocytes, but not in stomach or pancreas. These results, which identify the first functional non-viral, non-mammalian chemokine receptor, suggest that the origins of a functional chemokine system extend at least to birds and suggest that, as in mammals, CXCR4 functions in many avian tissues.