bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interferon‐alpha negatively regulates Th2 development
Authors: Huber Jonathan , Farrar J. David 
Published: June 2021

Viral infections trigger the production of type I interferon (IFNα/β) as well as Th1 cytokines like IL‐12 and IFNγ. In contrast, IFNα is not associated with Th2 responses, which are controlled by IL‐4. Hence, the effect of IFNα on Th2 development has not been very well characterized despite its importance for understanding how CD4+ T cells respond to virus infections in Th2‐biased conditions like asthma. To address this issue, we studied the effects of IFNα on IL‐4‐dependent Th2 development in human CD4+ T cells. In these studies, we found that IFNα dominantly inhibits the ability of IL‐4 to promote Th2 differentiation. Further, this effect is specific to IFNα, as neither IL‐12 nor IFNγ inhibit IL‐4‐regulated Th2 development. IFNα inhibits Th2 development by blocking the induction of GATA‐3 independently of STAT6 activation. Thus, we have found a novel function of IFNα in the inhibition of Th2 responses that may be useful as a therapeutic approach to the treatment of asthma.This study is supported by a grant from the NIH/NIAID (AI56222) and by a training grant from the NIH/NIAID (5T32AI005284).
Influence on the Pulmonary Ventilation of the Patients with allergic rhinitis by Inhaling Allergen
Authors: Xiaoming Chen MIng 
Published: June 2021

Objective: To analysis the relationship between the allergic rhinitis and bronchial asthma, the pulmonary ventilation of the patients with non‐asthma allergic rhinitis were measured after inhaled allergen.Method: After the patients inhaling the allergen, the clinical score of the rhinitis manifestations and FEV1/FEC1 %£ The first 1 second the rate of exhaled volume£© were recorded. Otherwise£firstly inhaled the hydrocortiscoid for five days, measured again as above.Result: Obviously increase the score and decrease FEV1/FEC1 % after inhaled allergen immediately. But it was not apparent if inhaling the hydrocortisone firstly.Conclusion: The allergic rhinitis and bronchial asthma occur in a similar inflammatory mechanism in a common respiratory duct.
Regulatory role of B cells in a Murine Model of Allergic Airway Disease
Authors: Singh Anurag , Guernsey Linda A. , Mcnamara Jeffrey T. , Secor Eric R. , Schramm Craig M. , Thrall Roger S. 
Published: June 2021

Mice sensitized to ovalbumin (OVA) develop a biphasic response to OVA aerosols, such that acute exposure results in allergic airway disease (AAD) while chronic exposure results in local inhalational tolerance (LIT), with resolution of local pulmonary responses but persistence of the systemic allergic response. We have previously reported that B cell lymphocytosis persists in hilar lymph nodes (HLN) during LIT and that CD4+CD25+Foxp3+ Treg cells are significantly increased in the HLN of LIT mice. This raised the consideration that B cells were involved in modulating the LIT response.Methods and Results: CD19+ B cells isolated from HLN of LIT mice were transferred to sensitized mice before inhaled antigen challenge. Compared to vehicle or AAD CD19+ transferred mice, LIT CD19+ transferred mice developed less BAL leukocytosis and eosinophilia (p < 0.05). In vivo, mice with attenuated AAD following LIT HLN B cell transfer showed a significant increase in the percentages of CD4+ Foxp3+ Treg cells in BAL and HLN, but not systemically (p < 0.03). This protection was antigen specific as LIT HLN B cells did not limit inflammation when transferred to bovine serum albumin (BSA) sensitized mice that were subsequently aerosolized with BSA. In vitro, LIT HLN B cells induced conversion of CD4+CD25‐ Teff cells to CD4+CD25+Foxp3+ T regulatory cells (Treg). The ability to induce suppressive Treg cells was regional, since B cells from AAD or systemic sites during LIT failed to do so. CFSE labeling of LIT HLN B cells demonstrated that these B cells home in and are retained at active sites of inflammation.Conclusions: These observations support a novel mechanism of regional immune regulation, possibly related to the development of a subset of regulatory B cells within the LIT HLN B cell population.This work was funded by NIH/AI R01 HL‐43573
Characerization of a novel pore‐forming protein in macrophages
Authors: de Armas Lesley R , Ramos Jahir , Lyapichev Kirill , Shiratsuchi Motoaki , Deyev Vadim , Podack Eckhard 
Published: June 2021

Perforin 2 (P2) is the predicted protein of Macrophage specific gene 1 (Mpg‐1) expressed in differentiated macrophages. The function of Perforin 2 is not known. When P2 is overexpressed in 293 cells it forms polymeric pore complexes similar to poly C9 and poly Perforin1 in membranes that are observed by negative staining and electron microscopy. The pore structure of poly P2 suggests cytolytic function similar to Perforin1 and C9. P2 has a predicted transmembrane domain followed by a short cytoplasmic domain containing a cluster of lysine residues followed by a conserved tyrosine and serine residue, suggesting functional roles in P2 polymerization and expression of cytolytic activity. In this study, we isolated enriched subcellular fractions containing P2 from 293 cells transfected with eGFP tagged P2. The fractions were digested with TPCK‐treated trypsin for various amounts of time to determine P2 susceptibility to proteolytic cleavage. We found that with increasing exposure to trypsin, P2 was cleaved into 2 pieces whose molecular weights by SDS‐PAGE corresponded to cleavage at the cluster of lysines in the cytoplasmic domain of P2. The electronmicroscopic pore structure of poly P2 however remained intact indicating protease resistance of the pore complex. The proteolytic cleavage of P2 is likely important for P2 function in macrophages.Supported by NIH CA039201
Neutrophils from burn patients suppress the beta‐defensin production by human epidermal keratinocytes
Authors: Kawasaki Takashi , Jeschke Marc G , Shigematsu Kenji , Kobayashi Makiko , Herndon David N , Suzuki Fujio 
Published: June 2021

Recently, we have isolated immunosuppressive neutrophils (PMN‐II) from patients with severe thermal injuries. PMN‐II play a role on the increased susceptibility of burn hosts to various infections. Since antimicrobial peptides have been described as important effector molecules on host antimicrobial innate immunities, in the present study, the influence of PMN‐II on the beta‐defensins (BD) production by human keratinocytes has been studied.Normal human epidermal keratinocytes (NHEK: 5×105 cells, Lonza) were cultured with neutrophils (1×105 cells, upper chamber), isolated from burn patients or normal volunteers, in dual‐chamber transwells. Culture fluids harvested 24 hrs after cultivation were assayed for BD by ELISA. Also, these culture fluids were analyzed for their antimicrobial activities by a standard colony counting method using Pseudomonas aeruginosa. PMN from burn patients were confirmed as PMN‐II by their cytokine/chemokine producing profiles.The production of BD2 and BD3 by NHEK was suppressed by PMN from burn patients. The culture fluids of NHEK transwell‐cultured with burn patient PMN showed decreased antimicrobial activities, as compared with controls (culture fluids of NHEK transwell‐cultured with healthy PMN). PMN isolated from peripheral blood of burn patients were confirmed as PMN‐II, because these cells produced IL‐10 and CCL2, but not IL‐12 and CCL3.These results indicate that PMN‐II appeared in association with burn injury contribute to the decreased production of BD in thermally injured patients. (Supported by SHC NA #8840.)
Immunoregulatory role of Toll‐like receptor 9 in septic peritonitis
Authors: Ishii Makoto , Hogaboam Cory M , Standiford Theodore J , Kunkel Steven L 
Published: June 2021

Objective: Toll‐like receptor 9 (TLR9) is recognized as a key receptor in the innate immune response. But little is known about the role of TLR9 in sepsis. In this study, experiments were performed to determine the role of TLR9 during septic peritonitis.Methods: Female wild‐type (WT) and TLR9‐deficient (TLR9−/−) BALB/c mice were subjected to cecal ligation and puncture (CLP) surgery. After 24 hours of CLP surgery, the peritoneal lavage and the serum were collected (n=10). The cytokine expression in peritoneal lavage was measured by sandwich ELISA. The serum chemistry analysis was performed by the Animal Diagnostic Laboratory at the University of Michigan. In a survival study, mice were monitored for 7days after CLP surgery (n=17).Results: The total number of peritoneal leukocytes was significantly higher in TLR9−/− CLP‐treated mice as compared with WT CLP‐treated mice, which was due to an increase in peritoneal neutrophils. The level of TNF‐α, CCL2, and CCL3 in peritoneal lavage was significantly lower in TLR9−/− mice compared with levels in WT mice. In addition, the serum level of BUN, Creatinine, and LDH were lower in TLR9−/− mice. Finally, we observed that TLR9−/− mice were highly resistant to CLP‐induced peritoneal sepsis.Conclusion: The absence of TLR9 promotes a protective innate immunity during experimental septic peritonitis.(Funded by NIH HL31237, NIH HL74024, NIH HL31963)
Functional Analysis of Recombinant Human Mannan‐binding Lectin and its Structural Variants expressed in Insect Cells
Authors: Rawal Nenoo , Salvi Veena P. , Rajagopalan Rema 
Published: June 2021

Mannan‐binding lectin alleles (MBL/B, C, and D) arise due to point mutations in the structural gene and are associated with increased susceptibility to recurrent infections in children and adults. Our data show that mutations in the collagen region have no effect on the ability of the recombinant forms of the structural variants (rMBL/B, C, and D) to form higher order oligomers. Purification of structural variants on mannose‐ and mannan‐Sepharose columns indicated that the structural variants bind to sugars. When binding to mannan was determined by ELISA using monoclonal antibody (mAb 131‐01), the structural variants bound poorly compared to wild type MBL purified from plasma (pMBL/A) or rMBL/A. The weak binding is attributed to the 16 to 60‐fold weaker avidity of the mAb for the variants than for pMBL/A or rMBL/A. Preliminary studies using surface plasmon resonance (Biacore) that does not require antibody, show pMBL/A and rMBL/A as well as rMBL/D bind to mannan with high affinity (KD range = 0.47 to 1.2 nM). The variants, rMBL/B and rMBL/C also bind to mannan but with a 35 to 54‐fold weaker affinity than pMBL/A. The effect of point mutations in MBL on complement activation was studied by hemolytic assay using MBL depleted serum and mannan coated sheep erythrocytes. The results show that rMBL/C was ineffective and rMBL/B activated complement weakly where as rMBL/D was fully functional like pMBL/A and rMBL/A.Research supported by NIH grant HL073804
Surfactant Protein D enhances phagocytosis of Cryptococcus neoformans hypocapsular strain cap59Δ by murine macrophages
Authors: Geunes‐Boyer Scarlett Gabriel , Oliver Timothy N , Heitman Joseph , Perfect John R , Wright Jo Rae 
Published: June 2021

Cryptococcus neoformans is an opportunistic pathogen and the leading cause of fungal meningitis in humans. Infection occurs following inhalation of C. neoformans cells, which, in the absence of a cellular immune response, results in pulmonary infection. C. neoformans cells produce a polysaccharide capsule composed predominantly of glucuronoxylomannan (GXM), which makes up approximately 90% of the capsular material. In the lungs, surfactant proteins SP‐A and SP‐D contribute to innate defense by facilitating the aggregation, uptake and killing of microorganisms by phagocytic cells. We hypothesized that SP‐D plays a role in C. neoformans pathogenesis by facilitating its clearance. We examined the ability of SP‐D to modulate the innate immune response to C. neoformans serotype A using wild type encapsulated strain H99 and mutant hypocapsular strain cap59Δ. We assessed the ability of SP‐D to bind to and facilitate phagocytosis of both C. neoformans strains. We found that SP‐D binds to cap59Δ approximately six‐fold better than to H99, and enhances phagocytosis of cap59Δ about four‐fold in vitro. To investigate SP‐D binding in vivo, SP‐D−−/− mice were intranasally instilled with AF488‐labeled cap59Δ. We observed a greater number of phagocytosed C. neoformans cells in wild type compared to SP‐D−/− mice, consistent with our in vitro data, using confocal microscopy. These studies suggest that SP‐D plays a role in host defense against C. neoformans by binding to and enhancing its phagocytosis.This work was supported by NIH grant HL‐30923
TLR9 activation is a key event for the maintenance of a mycobacterial antigen‐elicited pulmonary granuloma
Authors: Ito Toshihiro , Schaller Matthew , Hogaboam Cory M. , Stolberg Valerie , Chensue Stephen W. , Kunkel Steven L. 
Published: June 2021

We previously described a model of polarized Th1 cell‐mediated anamnestic pulmonary granulomatous inflammation in sensitized mice induced by pulmonary embolization of agarose beads coated with covalently bound antigens of Mycobacteria bovis purified protein derivative (PPD). We have also demonstrated TLR9 plays an important role in maintaining the appropriate phenotype in a Th1 granulomatous response. We demonstrate in this study that TLR9−/− mice showed greatly increased granuloma formation as assessed by impaired myeloid dendritic cells and increased regulatory T cells, and Th‐2 skewed cytokine profile compared with wild‐type. Moreover, the expression of Th17 cytokine family members (IL‐17 and IL‐21) was abrogated in TLR9−/− mice. These data also support the concept that dendritic cells, but not macrophages, from bone marrow can promote the differentiation of Th‐17 cells, while both macrophages and dendritic cells promote Th‐1 cell differentiation after BCG stimulation. These findings support the concept that the impaired recruitment of granuloma dendritic cells alters the Th17 cytokine profile in TLR9‐deficient mice.This work was supported by NIH grants HL031963, HL074024, and HL031237.
The effects of two glycosphingolipid inhibitors on Pneumocystis‐induced lung inflammation
Authors: Vuk‐Pavlovic Zvezdana , Standing Joseph E , Limper Andrew H 
Published: June 2021

Pneumocystis, an opportunistic fungus, causes pneumonia in immunocompromized hosts. Inflammation is induced, at least partly, by β‐eta‐glucan, the major component of Pneumocystis cell wall. Airspace‐lining epithelial cells recognize glucan by membrane glycosphingolipid (GSL) lactosyl ceramide (LacCer). We treated Pneumocystis‐infected mice with two GSL inhibitors: PDMP and NB‐DNJ (Miglustat‐Actelion Pharmaceuticals). Starting at 8 weeks post infection, animals received either 150 mg PDMP or 1200 mg Miglustat/kg of body weight ‐ dissolved in saline, or equal volume of saline alone (daily i.p. injections for 10 days). Results show that PDMP‐treated mice had fewer leukocytes in bronchoalveolar lavage fluid (BALF) than saline‐treated controls, with the most marked difference in the number of neutrophils. Interestingly, BALF concentrations of MIP‐2 and TNF‐alpha (determined by ELISA) did not differ between these two groups. The analysis of Pneumocystis burden in the lung, as determined by Q‐PCR, showed decrease in PDMP‐treated animals. The anti‐inflammatory effects of Miglustat were less pronounced than PDMP effects. Neither inhibitor induced lung injury as measured by albumin leak into airspaces. Results suggest that GSL inhibitors might have an impact on inflammatory response to Pneumocystis, leading to new options in treatment of Pneumocystis pneumonia.Supported by NIH‐RO1‐HL62150 and Mayo Clinic
Korean‐American merchants’ perceptions, main barriers, and motivators related to implementing a nutrition program in Baltimore City
Authors: Song Hee‐Jung , Gittelsohn Joel , Kim Miyong , Anliker Jean , Suratkar Sonali , Sharma Sangita 
Published: June 2021

There are over 25,000 Korean American food stores in the U.S, most in low‐income urban communities, making them a potential venue for nutrition interventions. However, such programs should be perceived to be feasible by storeowners. As part of the data collection for a store‐based intervention (Baltimore Healthy Stores), we examined motivators and barriers to the program participation and implementation, and perceived effectiveness of the intervention. In‐depth interviews with seven corner storeowners were conducted during the intervention. Detailed field notes by interventionists during the 10 month trial were also used to explore how the program was implemented at each store. A follow‐up survey with store owners was conducted to evaluate sustainability of the program. Stores were differentiated by ‘active involvement into activities’, ‘compliance with intervention protocol’ and ‘overall supportive atmosphere’. Stores which showed strong supports for the program by providing high traffic locations for interventionists, encouraging customers to participate in activities, and having good relationships with interventionists were more likely to perceive the program to be feasible leading to more sustainable promoted food stocks compared to the stores which showed weak support for the program. These findings could be used to develop successful corner store based nutrition interventions in urban communities.Funded by USDA/FANRP and the Center for a Livable Future.
Consumption of three supplements with identical micronutrient content in Mexican children
Authors: Neufeld Lynnette M , Dominguez Clara P , Cabrera Amira Hernandez , Guerra Armando Garcia 
Published: June 2021

The objective of this analysis was to compare consumption of three nutritional supplements with identical micronutrient content for children. Communities (18 per supplement) were randomly assigned to receive a fortified food (FF, 44 g of milk‐based powder dissolved in water to form a pap), syrup (SY, 5 ml) or Sprinkles (SK, 1 g dissolved in food). Children 6 to 12 mo of age, beneficiaries of the Oportunidades program were recruited. Supplements were delivered daily (6 mo) then weekly from recruitment to 24 mo of age. Compliance and consumed amount (0, ¼, ½, ¾, 1 doses) were recorded for the dose (SY) or the portion served (FF and SK). 927 children were assigned to treatment (FF n=265; SY n=323; SK n=339). There were no observed differences between groups at baseline. There was no difference (p>0.10) between groups in the mean proportion of days offered that the supplements were consumed (FF 85.8±13.4; SY 87.6±13.6; SK 88.9±10.5%). The proportion of days that the entire dose was consumed was significantly (p<0.05) higher in the SK (80.9±17.1%) than the FF (56.5±29.3%) and SY (67.8±24.6%) groups. Over the first 12 mo of the study, children in the SK group consumed significantly (p<0.01) more doses (225.6±54.2) than the FF (187.8±64.3) or SY (184.3±53.4) groups. Despite the controlled nature of this study, consumption of the entire dose varied considerably by group. Further analyses are needed to determine how this might relate to consumption of each in the context of a large scale program such as Oportunidades.The Oportunidades program financed this study and holds the rites to the data presented.
A FEW HYPERTENSIVE HUMANS RESPOND TO MAGNESIUM SUPPLEMENTS WITH A RISE IN BLOOD PRESSURE, suggesting a genetic subgroup in response to nutritional Mg
Authors: Rosanoff A. 
Published: June 2021

Far back as 1942, Winkler showed that i.v. Mg infusion lowered blood pressure (BP) in humans; that study also showed one subject's systolic blood pressure rose upon i.v. Mg infusion. Analysis of 41 clinical studies of Mg supplements on blood pressure show that 20 mmol (486 mg)/day Mg will significantly decrease high blood pressure in humans, with half that dose being effective for subjects on anti‐hypertnesive medications.Few of these 41 studies report individual blood pressure results, but in the 8 that do, all but one show “outliers” for whom magnesium supplements resulted in INCREASED blood pressure during the study. For this almost completely consistent finding (7 of 8 studies), 15 – 52% of 7 studies’ subjects had at least a slight rise in diastolic, systolic or mean blood pressure upon Mg supplementation, while 1 – 17% of studies’ individuals were significant outliers, showing large rises in these blood pressure parameters, [i.e. > 5 mm Hg rise for DBP, > 20 mm Hg rise for SBP or > 10 Hg mm rise for MBP]. Only one of the 8 studies reporting individual subjects’ results showed all subjects with a drop in blood pressure.Combined, these 8 studies show 207 individual results of Mg therapy for blood pressure, of which 6.3 – 7.3% showed a substantial rise in the measured BP parameter, opposite the majority and group statistical results, suggesting variant genetic allele(s) or polymorphism(s) in the human genome for the handling of Mg supplements and how they effect a blood pressure response. Mg supplementation for blood pressure, while therapeutic for the majority of hypertensives, may be contra‐indicated for a small minority beyond the gastro‐intestinal considerations.
Dietary selenium (Se) and copper (Cu) interact to affect homocysteine metabolism in rats
Authors: Uthus Eric O , Ross Sharon A 
Published: June 2021

Previously we reported that both Se deficiency (SeD) and Cu deficiency (CuD) decreased plasma homocysteine (pHcys) and increased plasma glutathione (pGSH) in rats. We also showed that the catalytic subunit of glutamate‐cysteine ligase (Gclc), which catalyzes the rate limiting step in glutathione biosynthesis, was upregulated in SeD as well as in CuD. We suggested that in both deficiencies, that Hcys was being shunted through the transsulfuration pathway as a result of this upregulation. Because both SeD and CuD have similar effects, we hypothesized that a combined deficiency would exacerbate the decrease in pHcys and the increase in pGSH by further upregulating Gclc. In a 2 × 2 experiment, male weanling Sprague‐Dawley rats (N=8–10/group) were fed an amino acid‐based diet containing either 0 or 0.2 μg Se (as selenite)/g and <1 or 6 μg Cu (as Cu carbonate)/g for 5 wk. Values in the table are means±SD. Both SeD and CuD resulted in decreased pHcys; however, CuD in rats fed 0.2 μg Se/g resulted in a greater decrease in pHcys than did CuD in the SeD rats. SeD and CuD resulted in increased pGSH and the combined deficiencies further exacerbated the increase. Plasma cysteine (pCys) was decreased by SeD and increased by CuD.The findings show that a combined deficiency of both Se and Cu results in lower pHcys and significantly elevated pGSH most likely as a result of increased GSH biosynthesis subsequent to upregulation of Gclc.
Zinc deficiency‐induced hypertension is not caused by augmentation of renin‐angiotensin system
Authors: Konomi Aki , Yokoi Katsuhiko 
Published: June 2021

Some scientists reported that zinc (Zn) deficiency induces hypertension, although the mechanism is not established. To investigate the physiological role of Zn in blood pressure control, thirty 3‐week‐old male Sprague‐Dawley rats were assigned into 3 dietary treatment groups of 10 for the 4‐week study: control group (AIN‐93G; Cont), Zn‐deficient group (4.5 mg Zn/kg; ZD) and pair‐fed group (AIN‐93G; PF). At day 24–25, blood pressures (SBP, DBP and MBP) were measured by tail cuff method. At day 27–28, body water distribution was measured. Statistical analysis was performed by PLSD. Blood pressures of ZD were highest and those of PF were lowest among all treatment groups. Blood pressures of ZD were significantly higher than PF. Hematocrit of ZD and PF were significantly higher than Cont, and that of ZD was similar to PF. Peripheral and bone marrow blood of ZD were very sticky and hard to spread on the slide glass. Blood cells were more concentrated in the blood smears of ZD. ACE activity and relative heart weight of ZD were significantly higher than PF and Cont. Ang II and ICW/ECW of ZD were marginally lower than PF. These results suggest that “zinc deficiency hypertension” is not caused by augmentation of renin‐angiotensin system and hemoconcetration. Subsets of essential hypertension in humans might include “zinc deficiency hypertension”.This research was financially supported by Japan Science Society (The Sasakawa Scientific Research Grant No. 18–144)