Aslam Khan - Academia.edu (original) (raw)

Papers by Aslam Khan

ISTFA 2021: Conference Proceedings from the 47th International Symposium for Testing and Failure Analysis, 2021

Semiconductor manufacturing has been outsourced to un-trusted regions due to globalization. The c... more Semiconductor manufacturing has been outsourced to un-trusted regions due to globalization. The complex multistep fabrication of micro-scale integrated circuits (ICs) and the tedious assembly of macro-scale Printed Circuit Boards (PCBs) are vulnerable to malicious attacks from design to final delivery. PCBs provide the functional connections of Integrated Circuits (ICs), sensors, power supplies, etc. of many critical electronic systems for consumers, corporations, and governments. The feature sizes of PCB signal traces in 2D and vias in 3D are an order of magnitude larger than IC devices, and are thereby more vulnerable to non-destructive attacks such as X-ray or probing. Active and passive countermeasures have been successfully developed for IC devices, however PCBs devices are difficult to wholly secure from all attacks. Passive countermeasures for X-ray attacks using high-z materials to block and scatter X-rays are effective, but there is a lack of active and passive countermeasu...

Journal of Molecular Liquids, 2019

, et al., Synthesis and characterization of egg-albumen-formaldehyde based magnetic polymeric res... more , et al., Synthesis and characterization of egg-albumen-formaldehyde based magnetic polymeric resin (MPR): Highly efficient adsorbent for Cd(II) ion removal from aqueous medium, Journal of Molecular Liquids,

The Journal of biological chemistry, Oct 6, 2017

Salivary gland inflammation is a hallmark of Sjögren's syndrome (SS), a common autoimmune dis... more Salivary gland inflammation is a hallmark of Sjögren's syndrome (SS), a common autoimmune disease characterized by lymphocytic infiltration of the salivary gland and loss of saliva secretion, predominantly in women. The P2X7 receptor (P2X7R) is an ATP-gated nonselective cation channel that induces inflammatory responses in cells and tissues, including salivary gland epithelium. In immune cells, P2X7R activation induces the production of proinflammatory cytokines, including IL-1β and IL-18, by inducing the oligomerization of the multiprotein complex NLRP3-type inflammasome. Here, our results show that in primary mouse submandibular gland (SMG) epithelial cells, P2X7R activation also induces the assembly of the NLRP3 inflammasome and the maturation and release of IL-1β, a response that is absent in SMG cells isolated from mice deficient in P2X7Rs (P2X7R(-/-)). P2X7R-mediated IL-1β release in SMG epithelial cells is dependent on transmembrane Na(+) and/or K(+) flux and the activati...

Pantnagar Journal of Research, 2011

Soil Biology, 2015

Lepidopterans are major pests of economically important crops with extensive host ranges. Entomop... more Lepidopterans are major pests of economically important crops with extensive host ranges. Entomopathogenic fungi can provide an alternative and more environment friendly approach for the control of Spodoptera spp. These fungi have wide host range and have been isolated from a variety of insect orders. In the following compilation, data on natural occurrence and distribution, general biology, mode of action, host range, isolation, multiplication, and bioassay of entomopathogenic fungi against lepidopteran pests are summarized. Use of entomopathogenic fungi as insect biological control agent, their current status as mycoinsecticides, and compatibility of fungi with other crop protection techniques along with control measures of Spodopteran spp. are also mentioned.

Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2011

Spinal motion measurement during dynamic conditions may help identify differences between individ... more Spinal motion measurement during dynamic conditions may help identify differences between individuals with and without low back pain (LBP). The purpose of this paper is to demonstrate the feasibility of an inertial sensing based, portable spinal motion measurement system for investigating the differences of the spinal motions between an LBP group and a healthy control group. During a fast flexion/extension test, we measured 3D angular motions of the pelvis, lumbar spine and thoracic spine of the two groups using the inertial sensing based system. Range of motions (ROM) and peak angular velocities were investigated to determine which variables have significant differences between the two groups (p < 0.05). Also, a logistic regression analysis was carried out to see the classifying ability of the LBP patients from controls using the proposed system. The result shows that LBP was particularly associated with significant decreases in peak velocities of the lumbar spinal extension mot...

Proceedings of the National Academy of Sciences, 2012

Cranial irradiation is widely used in cancer therapy, but it often causes cognitive defects in ca... more Cranial irradiation is widely used in cancer therapy, but it often causes cognitive defects in cancer survivors. Oxidative stress is considered a major cause of tissue injury from irradiation. However, in an earlier study mice deficient in the antioxidant enzyme extracellular superoxide dismutase (EC-SOD KO) showed reduced sensitivity to radiation-induced defects in hippocampal functions. To further dissect the role of EC-SOD in neurogenesis and in response to irradiation, we generated a bigenic EC-SOD mouse model (OE mice) that expressed high levels of EC-SOD in mature neurons in an otherwise EC-SOD–deficient environment. EC-SOD deficiency was associated with reduced progenitor cell proliferation in the subgranular zone of dentate gyrus in KO and OE mice. However, high levels of EC-SOD in the granule cell layer supported normal maturation of newborn neurons in OE mice. Following irradiation, wild-type mice showed reduced hippocampal neurogenesis, reduced dendritic spine densities, ...

PLoS ONE, 2009

Background: Demyelinating polyneuropathy is a debilitating, poorly understood disease that can ex... more Background: Demyelinating polyneuropathy is a debilitating, poorly understood disease that can exist in acute (Guillain-Barré syndrome) or chronic forms. Interleukin-10 (IL-10), although traditionally considered an anti-inflammatory cytokine, has also been implicated in promoting abnormal angiogenesis in the eye and in the pathobiology of autoimmune diseases such as lupus and encephalomyelitis.

PLoS ONE, 2009

Background: Toxic Shock Syndrome (TSS) is characterized by fever, rash, hypotension, constitution... more Background: Toxic Shock Syndrome (TSS) is characterized by fever, rash, hypotension, constitutional symptoms, and multiorgan involvement and is caused by Staphylococcus aureus enterotoxins such as Staphylococcal Enterotoxin B (SEB). SEB binds to the MHC-IIa chain and is recognized by the TCRb chain of the Vb8 TCR + T cells. The binding of SEB to Vb chain results in rapid activation of T cells and production of inflammatory cytokines, such as Interleukin-2 (IL-2), Interferon-c and Tumor Necrosis Factor-a which mediate TSS. Although IL2 was originally identified as the T cell growth factor and was proposed to contribute to T cell differentiation, its role in TSS remains unexplored. Methodology/Principal Findings: Mice were injected with D-Gal (25 mg/mouse). One hour after D-Galactosamine (D-Gal) injection each mouse was injected with SEB (20 mg/mouse. Mice were then observed for 72 hrs and death was recorded at different times. We tested Interleukin-12, IFNc, and IL-2 deficient mice (IL-2 2/2), but only the IL-2 deficient mice were resistant to SEB induced toxic shock syndrome. More importantly reconstitution of IL-2 in IL-2 deficient mice restored the shock. Interestingly, SEB induced IL-2 production from T cells was dependent on p38MAPK activation in macrophages as inhibition of it in macrophages significantly inhibited IL-2 production from T cells. Conclusion: This study shows the importance of IL-2 in TSS which has not been previously explored and it also shows that regulating macrophages function can regulate T cells and TSS.

PLoS ONE, 2008

Aberrant angiogenesis in the eye is the most common cause of blindness. The current study examine... more Aberrant angiogenesis in the eye is the most common cause of blindness. The current study examined the role of interleukin-10 (IL-10) in ischemia-induced pathological angiogenesis called neovascularization during postnatal development. IL-10 deficiency resulted in significantly reduced pathological retinal angiogenesis. In contrast to the choroicapillaris where IL-10 interferes with macrophage influx, IL-10 did not prevent anti-angiogenic macrophages from migrating to the retina in response to hypoxia. Instead, IL-10 promoted retinal angiogenesis by altering macrophage angiogenic function, as macrophages from wild-type mice demonstrated increased vascular endothelial growth factor (VEGF) and nitric oxide (NO) compared to IL-10 deficient macrophages. IL-10 appears to directly affect macrophage responsiveness to hypoxia, as macrophages responded to hypoxia with increased levels of IL-10 and STAT3 phosphorylation as opposed to IL-10 deficient macrophages. Also, IL-10 deficient macrophages inhibited the proliferation of vascular endothelial cells in response to hypoxia while wild-type macrophages failed to do so. These findings suggest that hypoxia guides macrophage behavior to a pro-angiogenic phenotype via IL-10 activated pathways.

Journal of Musculoskeletal Pain, 2011

Objectives: Mean axes of rotation [MAR] of cervical joints are an effective measure of spine path... more Objectives: Mean axes of rotation [MAR] of cervical joints are an effective measure of spine pathology. Khan Kinetic Treatment [KKT] is known to relieve symptoms, but its biomechanical effects have not been quantified. This study assesses KKT efficacy using MAR correction and its associated effects. Methods: The intervention applies vibrations via stylus to a bony landmark of the spine. Using saggital plane cervical Xrays, pre-post intervention MARs were computed for 44 patients with chronic neck pain. The study was randomized, single blinded, and sham controlled for outcome measure comparisons. Mechanical input was assessed using a load cell and vertebral acceleration and the outcome measures were: 1. cervical MARs, 2. self-reported neck pain, 3. neck disability index scores, and 4. psycho-social assessments. Results: 1. Average peak force on vertebrae during treatment was 10.3 N and the average peak acceleration was 2.19G, 2. KKT improved pain and neck disability scores significantly over shams, 3. KKT corrected 62 percent of abnormal MARs with significantly larger MAR vector magnitude differences [pre-post] at the C5-6 level than shams, 4. in patients without changes in MAR locations, KKT significantly improved neck disability scores above shams, 5. MAR correction was significantly related to improving both pain and neck disability across all subjects. Conclusions: We present biomechanical evidence of spinal "re-alignment" and its ability to improve both pain and neck disability. Capacity to improve neck disability despite no change in MAR locations indicates that MAR correction, while effective, is not the sole mechanism behind the interventions success.

Journal of Leukocyte Biology, 2008

APCs express MHC-II molecules. Binding of enterotoxins to MHC-II generates a signal resulting in ... more APCs express MHC-II molecules. Binding of enterotoxins to MHC-II generates a signal resulting in the production of TNF-␣ that mediates toxic shock syndrome. However, the signaling events that lead to TNF-␣ production in macrophages are not well understood. We, for the first time, demonstrate that binding of staphylococcal enterotoxin B to MHC-II results in activation of TNF-␣-converting enzyme, epidermal growth factor receptor, p38MAPK, and NF-B inducing biphasic TNF-␣ production. Paraformaldehydefixed, peptide-specific T cells also activate MHC-II signaling and TNF-␣ induction in peptide-pulsed macrophages. Our results reveal a novel MHC-II signaling and bidirectional macrophage-T cell interaction regulating macrophage functions. This knowledge may help to develop novel, macrophage-directed, therapeutic strategies.

Journal of Experimental Medicine, 2003

Leishmania, a protozoan parasite, lives and multiplies as amastigote within macrophages. It is pr... more Leishmania, a protozoan parasite, lives and multiplies as amastigote within macrophages. It is proposed that the macrophage expressed CD40 interacts with CD40 ligand on T cells to induce IFN-γ, a Th1-type cytokine that restricts the amastigote growth. Here, we demonstrate that CD40 cross-linking early after infection resulted in inducible nitric oxide synthetase type-2 (iNOS2) induction and iNOS2-dependent amastigote elimination. Although CD40 expression remained unaltered on L. major–infected macrophages, delay in the treatment of macrophages or of mice with anti-CD40 antibody resulted in significant reduction in iNOS2 expression and leishmanicidal function suggesting impaired CD40 signaling in Leishmania infection. The inhibition of CD40-induced iNOS2 expression by SB203580, a p38-mitogen activated protein kinase (p38MAPK)-specific inhibitor, and the reversal of the inhibition by anisomycin, a p38MAPK activator, suggested a crucial role of p38MAPK in CD40 signaling. Indeed, the CD...

Journal of Clinical Investigation, 2007

Abnormal angiogenesis plays a key role in diseases of aging such as heart disease, certain cancer... more Abnormal angiogenesis plays a key role in diseases of aging such as heart disease, certain cancers, and eye diseases including age-related macular degeneration. Macrophages have been shown previously to be both anti-and proangiogenic, and their role in regulating angiogenesis at sites of tissue injury is critical and complex. In this study, we analyzed cytokine gene expression patterns of mouse macrophages by realtime quantitative PCR and tested the functional effects of senescence on gene expression and macrophage polarization. Following laser injury to the retina, IL-10 was upregulated and Fas ligand (FasL), IL-12, and TNF-α were downregulated in ocular macrophages of old mice (>18 months of age). Downregulation of FasL on macrophages led to a loss of the antiangiogenic phenotype, as evidenced by the inability of these macrophages to inhibit vascular endothelial cells. Our results demonstrate that senescence, FasL, and IL-10 are key determinants of macrophage function that alter the growth of abnormal postdevelopmental blood vessels in disease processes including blinding eye disease. Nonstandard abbreviations used: AMD, age-related macular degeneration; CNV, choroidal neovascularization; Ct, threshold cycle; FasL, Fas ligand; HMVEC, human dermal microvascular endothelial cell.

Immunobiology, 2008

We have developed an assay that quantifies the potential of macrophages to regulate proliferation... more We have developed an assay that quantifies the potential of macrophages to regulate proliferation of endothelial cells. We show that young mice macrophages can be distinguished from old mice macrophages by their ability to inhibit vascular endothelial cell proliferation. While young mice macrophages robustly inhibit proliferation, old mice macrophages fail to do so and actually promote the proliferation of endothelial cells. In this report, we outline a technique that directly assesses the effect of macrophages on modulation of endothelial cell proliferation. This assay will help us in understanding the mechanisms of macrophage function in several disease states characterized by abnormal angiogenesis including cancers, angiogenic eye disease and atherosclerotic heart disease.

Gait & Posture, 2011

This article appeared in a journal published by Elsevier. The attached copy is furnished to the a... more This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright

Free Radical Biology and Medicine, 2010

Mn superoxide dismutase (MnSOD) is an important mitochondrial antioxidant enzyme, and elevated Mn... more Mn superoxide dismutase (MnSOD) is an important mitochondrial antioxidant enzyme, and elevated MnSOD levels have been shown to reduce tumor growth in part by suppressing cell proliferation. Studies with fibroblasts have shown that increased MnSOD expression prolongs cell cycle transition time in G1/S and favors entrance into the quiescent state. To determine if the same effect occurs during tissue regeneration in vivo, we used a transgenic mouse system with liver-specific MnSOD expression and a partial hepatectomy paradigm to induce synchronized in vivo cell proliferation during liver regeneration. We show in this experimental system that a 2.6 fold increase in MnSOD activities leads to delayed entry into S phase, as measured by reduction in bromodeoxyuridine (BrdU) incorporation, and decreased expression of proliferative cell nuclear antigen (PCNA). Thus, compared to control mice with baseline MnSOD levels, transgenic mice with increased MnSOD expression in the liver have 23% fewer BrdU positive cells and a marked attenuation of PCNA expression. The increase in MnSOD activity also leads to an increase of the mitochondrial form of thioredoxin (thioredoxin 2), but not of several other peroxidases examined, suggesting the importance of thioredoxin 2 in maintaining redox balance in mitochondria with elevated levels of MnSOD.

Chinese Journal of Chemistry, 2009

The binding interaction of captopril (CPL) with biologically active metal ions Mg 2＋ , Ca 2＋ , Mn... more The binding interaction of captopril (CPL) with biologically active metal ions Mg 2＋ , Ca 2＋ , Mn 2＋ , Co 2＋ , Ni 2＋ , Cu 2＋ and Zn 2＋ was investigated in an aqueous acidic medium by fluorescence spectroscopy. The experimental results showed that the metal ions quenched the intrinsic fluorescence of CPL by forming CPL-metal complexes. It was found that static quenching was the main reason for the fluorescence quenching. The quenching constant in the case of Cu 2＋ was highest among all quenchers, perhaps due to its high nuclear charge and small size. Quenching of CPL by metal ions follows the order Cu 2＋ ＞Ni 2＋ ＞Co 2＋ ＞Ca 2＋ ＞Zn 2＋ ＞Mn 2＋ ＞Mg 2＋. The quenching constant K sv , bimolecular quenching constant K q , binding constant K and the binding sites "n" were determined together with their thermodynamic parameters at 27 and 37 ℃. The positive entropy change indicated the gain in configurational entropy as a result of chelation. The process of interaction was spontaneous and mainly ∆S-driven.

Cell Metabolism, 2013

Pathologic angiogenesis mediated by abnormally polarized macrophages plays a central role in comm... more Pathologic angiogenesis mediated by abnormally polarized macrophages plays a central role in common age-associated diseases such as atherosclerosis, cancer, and macular degeneration. Here we demonstrate that abnormal polarization in older macrophages is caused by programmatic changes that lead to reduced expression of ATP binding cassette transporter ABCA1. Downregulation of ABCA1 by microRNA-33 impairs the ability of macrophages to effectively efflux intracellular cholesterol, which in turn leads to higher levels of free cholesterol within senescent macrophages. Elevated intracellular lipid polarizes older macrophages to an abnormal, alternatively activated phenotype that promotes pathologic vascular proliferation. Mice deficient for Abca1, but not Abcg1, demonstrate an accelerated aging phenotype, whereas restoration of cholesterol efflux using LXR agonists or miR-33 inhibitors reverses it. Monocytes from older humans with age-related macular degeneration showed similar changes. These findings provide an avenue for therapeutic modulation of macrophage function in common age-related diseases. (F) Measurement of proliferation of HMVECs after incubation with DIO or control macrophages. (G and H) Representative illustration (G) and quantification of CNV (white circle) volume (H) demonstrated an inability of DIO macrophages to inhibit CNV as compared to controls. Values are expressed as mean + SE. Statistically significant difference, **p < 0.01, ***p < 0.001.

ISTFA 2021: Conference Proceedings from the 47th International Symposium for Testing and Failure Analysis, 2021

Semiconductor manufacturing has been outsourced to un-trusted regions due to globalization. The c... more Semiconductor manufacturing has been outsourced to un-trusted regions due to globalization. The complex multistep fabrication of micro-scale integrated circuits (ICs) and the tedious assembly of macro-scale Printed Circuit Boards (PCBs) are vulnerable to malicious attacks from design to final delivery. PCBs provide the functional connections of Integrated Circuits (ICs), sensors, power supplies, etc. of many critical electronic systems for consumers, corporations, and governments. The feature sizes of PCB signal traces in 2D and vias in 3D are an order of magnitude larger than IC devices, and are thereby more vulnerable to non-destructive attacks such as X-ray or probing. Active and passive countermeasures have been successfully developed for IC devices, however PCBs devices are difficult to wholly secure from all attacks. Passive countermeasures for X-ray attacks using high-z materials to block and scatter X-rays are effective, but there is a lack of active and passive countermeasu...

Journal of Molecular Liquids, 2019

, et al., Synthesis and characterization of egg-albumen-formaldehyde based magnetic polymeric res... more , et al., Synthesis and characterization of egg-albumen-formaldehyde based magnetic polymeric resin (MPR): Highly efficient adsorbent for Cd(II) ion removal from aqueous medium, Journal of Molecular Liquids,

The Journal of biological chemistry, Oct 6, 2017

Salivary gland inflammation is a hallmark of Sjögren's syndrome (SS), a common autoimmune dis... more Salivary gland inflammation is a hallmark of Sjögren's syndrome (SS), a common autoimmune disease characterized by lymphocytic infiltration of the salivary gland and loss of saliva secretion, predominantly in women. The P2X7 receptor (P2X7R) is an ATP-gated nonselective cation channel that induces inflammatory responses in cells and tissues, including salivary gland epithelium. In immune cells, P2X7R activation induces the production of proinflammatory cytokines, including IL-1β and IL-18, by inducing the oligomerization of the multiprotein complex NLRP3-type inflammasome. Here, our results show that in primary mouse submandibular gland (SMG) epithelial cells, P2X7R activation also induces the assembly of the NLRP3 inflammasome and the maturation and release of IL-1β, a response that is absent in SMG cells isolated from mice deficient in P2X7Rs (P2X7R(-/-)). P2X7R-mediated IL-1β release in SMG epithelial cells is dependent on transmembrane Na(+) and/or K(+) flux and the activati...

Pantnagar Journal of Research, 2011

Soil Biology, 2015

Lepidopterans are major pests of economically important crops with extensive host ranges. Entomop... more Lepidopterans are major pests of economically important crops with extensive host ranges. Entomopathogenic fungi can provide an alternative and more environment friendly approach for the control of Spodoptera spp. These fungi have wide host range and have been isolated from a variety of insect orders. In the following compilation, data on natural occurrence and distribution, general biology, mode of action, host range, isolation, multiplication, and bioassay of entomopathogenic fungi against lepidopteran pests are summarized. Use of entomopathogenic fungi as insect biological control agent, their current status as mycoinsecticides, and compatibility of fungi with other crop protection techniques along with control measures of Spodopteran spp. are also mentioned.

Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2011

Spinal motion measurement during dynamic conditions may help identify differences between individ... more Spinal motion measurement during dynamic conditions may help identify differences between individuals with and without low back pain (LBP). The purpose of this paper is to demonstrate the feasibility of an inertial sensing based, portable spinal motion measurement system for investigating the differences of the spinal motions between an LBP group and a healthy control group. During a fast flexion/extension test, we measured 3D angular motions of the pelvis, lumbar spine and thoracic spine of the two groups using the inertial sensing based system. Range of motions (ROM) and peak angular velocities were investigated to determine which variables have significant differences between the two groups (p < 0.05). Also, a logistic regression analysis was carried out to see the classifying ability of the LBP patients from controls using the proposed system. The result shows that LBP was particularly associated with significant decreases in peak velocities of the lumbar spinal extension mot...

Proceedings of the National Academy of Sciences, 2012

Cranial irradiation is widely used in cancer therapy, but it often causes cognitive defects in ca... more Cranial irradiation is widely used in cancer therapy, but it often causes cognitive defects in cancer survivors. Oxidative stress is considered a major cause of tissue injury from irradiation. However, in an earlier study mice deficient in the antioxidant enzyme extracellular superoxide dismutase (EC-SOD KO) showed reduced sensitivity to radiation-induced defects in hippocampal functions. To further dissect the role of EC-SOD in neurogenesis and in response to irradiation, we generated a bigenic EC-SOD mouse model (OE mice) that expressed high levels of EC-SOD in mature neurons in an otherwise EC-SOD–deficient environment. EC-SOD deficiency was associated with reduced progenitor cell proliferation in the subgranular zone of dentate gyrus in KO and OE mice. However, high levels of EC-SOD in the granule cell layer supported normal maturation of newborn neurons in OE mice. Following irradiation, wild-type mice showed reduced hippocampal neurogenesis, reduced dendritic spine densities, ...

PLoS ONE, 2009

Background: Demyelinating polyneuropathy is a debilitating, poorly understood disease that can ex... more Background: Demyelinating polyneuropathy is a debilitating, poorly understood disease that can exist in acute (Guillain-Barré syndrome) or chronic forms. Interleukin-10 (IL-10), although traditionally considered an anti-inflammatory cytokine, has also been implicated in promoting abnormal angiogenesis in the eye and in the pathobiology of autoimmune diseases such as lupus and encephalomyelitis.

PLoS ONE, 2009

Background: Toxic Shock Syndrome (TSS) is characterized by fever, rash, hypotension, constitution... more Background: Toxic Shock Syndrome (TSS) is characterized by fever, rash, hypotension, constitutional symptoms, and multiorgan involvement and is caused by Staphylococcus aureus enterotoxins such as Staphylococcal Enterotoxin B (SEB). SEB binds to the MHC-IIa chain and is recognized by the TCRb chain of the Vb8 TCR + T cells. The binding of SEB to Vb chain results in rapid activation of T cells and production of inflammatory cytokines, such as Interleukin-2 (IL-2), Interferon-c and Tumor Necrosis Factor-a which mediate TSS. Although IL2 was originally identified as the T cell growth factor and was proposed to contribute to T cell differentiation, its role in TSS remains unexplored. Methodology/Principal Findings: Mice were injected with D-Gal (25 mg/mouse). One hour after D-Galactosamine (D-Gal) injection each mouse was injected with SEB (20 mg/mouse. Mice were then observed for 72 hrs and death was recorded at different times. We tested Interleukin-12, IFNc, and IL-2 deficient mice (IL-2 2/2), but only the IL-2 deficient mice were resistant to SEB induced toxic shock syndrome. More importantly reconstitution of IL-2 in IL-2 deficient mice restored the shock. Interestingly, SEB induced IL-2 production from T cells was dependent on p38MAPK activation in macrophages as inhibition of it in macrophages significantly inhibited IL-2 production from T cells. Conclusion: This study shows the importance of IL-2 in TSS which has not been previously explored and it also shows that regulating macrophages function can regulate T cells and TSS.

PLoS ONE, 2008

Aberrant angiogenesis in the eye is the most common cause of blindness. The current study examine... more Aberrant angiogenesis in the eye is the most common cause of blindness. The current study examined the role of interleukin-10 (IL-10) in ischemia-induced pathological angiogenesis called neovascularization during postnatal development. IL-10 deficiency resulted in significantly reduced pathological retinal angiogenesis. In contrast to the choroicapillaris where IL-10 interferes with macrophage influx, IL-10 did not prevent anti-angiogenic macrophages from migrating to the retina in response to hypoxia. Instead, IL-10 promoted retinal angiogenesis by altering macrophage angiogenic function, as macrophages from wild-type mice demonstrated increased vascular endothelial growth factor (VEGF) and nitric oxide (NO) compared to IL-10 deficient macrophages. IL-10 appears to directly affect macrophage responsiveness to hypoxia, as macrophages responded to hypoxia with increased levels of IL-10 and STAT3 phosphorylation as opposed to IL-10 deficient macrophages. Also, IL-10 deficient macrophages inhibited the proliferation of vascular endothelial cells in response to hypoxia while wild-type macrophages failed to do so. These findings suggest that hypoxia guides macrophage behavior to a pro-angiogenic phenotype via IL-10 activated pathways.

Journal of Musculoskeletal Pain, 2011

Objectives: Mean axes of rotation [MAR] of cervical joints are an effective measure of spine path... more Objectives: Mean axes of rotation [MAR] of cervical joints are an effective measure of spine pathology. Khan Kinetic Treatment [KKT] is known to relieve symptoms, but its biomechanical effects have not been quantified. This study assesses KKT efficacy using MAR correction and its associated effects. Methods: The intervention applies vibrations via stylus to a bony landmark of the spine. Using saggital plane cervical Xrays, pre-post intervention MARs were computed for 44 patients with chronic neck pain. The study was randomized, single blinded, and sham controlled for outcome measure comparisons. Mechanical input was assessed using a load cell and vertebral acceleration and the outcome measures were: 1. cervical MARs, 2. self-reported neck pain, 3. neck disability index scores, and 4. psycho-social assessments. Results: 1. Average peak force on vertebrae during treatment was 10.3 N and the average peak acceleration was 2.19G, 2. KKT improved pain and neck disability scores significantly over shams, 3. KKT corrected 62 percent of abnormal MARs with significantly larger MAR vector magnitude differences [pre-post] at the C5-6 level than shams, 4. in patients without changes in MAR locations, KKT significantly improved neck disability scores above shams, 5. MAR correction was significantly related to improving both pain and neck disability across all subjects. Conclusions: We present biomechanical evidence of spinal "re-alignment" and its ability to improve both pain and neck disability. Capacity to improve neck disability despite no change in MAR locations indicates that MAR correction, while effective, is not the sole mechanism behind the interventions success.

Journal of Leukocyte Biology, 2008

APCs express MHC-II molecules. Binding of enterotoxins to MHC-II generates a signal resulting in ... more APCs express MHC-II molecules. Binding of enterotoxins to MHC-II generates a signal resulting in the production of TNF-␣ that mediates toxic shock syndrome. However, the signaling events that lead to TNF-␣ production in macrophages are not well understood. We, for the first time, demonstrate that binding of staphylococcal enterotoxin B to MHC-II results in activation of TNF-␣-converting enzyme, epidermal growth factor receptor, p38MAPK, and NF-B inducing biphasic TNF-␣ production. Paraformaldehydefixed, peptide-specific T cells also activate MHC-II signaling and TNF-␣ induction in peptide-pulsed macrophages. Our results reveal a novel MHC-II signaling and bidirectional macrophage-T cell interaction regulating macrophage functions. This knowledge may help to develop novel, macrophage-directed, therapeutic strategies.

Journal of Experimental Medicine, 2003

Leishmania, a protozoan parasite, lives and multiplies as amastigote within macrophages. It is pr... more Leishmania, a protozoan parasite, lives and multiplies as amastigote within macrophages. It is proposed that the macrophage expressed CD40 interacts with CD40 ligand on T cells to induce IFN-γ, a Th1-type cytokine that restricts the amastigote growth. Here, we demonstrate that CD40 cross-linking early after infection resulted in inducible nitric oxide synthetase type-2 (iNOS2) induction and iNOS2-dependent amastigote elimination. Although CD40 expression remained unaltered on L. major–infected macrophages, delay in the treatment of macrophages or of mice with anti-CD40 antibody resulted in significant reduction in iNOS2 expression and leishmanicidal function suggesting impaired CD40 signaling in Leishmania infection. The inhibition of CD40-induced iNOS2 expression by SB203580, a p38-mitogen activated protein kinase (p38MAPK)-specific inhibitor, and the reversal of the inhibition by anisomycin, a p38MAPK activator, suggested a crucial role of p38MAPK in CD40 signaling. Indeed, the CD...

Journal of Clinical Investigation, 2007

Abnormal angiogenesis plays a key role in diseases of aging such as heart disease, certain cancer... more Abnormal angiogenesis plays a key role in diseases of aging such as heart disease, certain cancers, and eye diseases including age-related macular degeneration. Macrophages have been shown previously to be both anti-and proangiogenic, and their role in regulating angiogenesis at sites of tissue injury is critical and complex. In this study, we analyzed cytokine gene expression patterns of mouse macrophages by realtime quantitative PCR and tested the functional effects of senescence on gene expression and macrophage polarization. Following laser injury to the retina, IL-10 was upregulated and Fas ligand (FasL), IL-12, and TNF-α were downregulated in ocular macrophages of old mice (>18 months of age). Downregulation of FasL on macrophages led to a loss of the antiangiogenic phenotype, as evidenced by the inability of these macrophages to inhibit vascular endothelial cells. Our results demonstrate that senescence, FasL, and IL-10 are key determinants of macrophage function that alter the growth of abnormal postdevelopmental blood vessels in disease processes including blinding eye disease. Nonstandard abbreviations used: AMD, age-related macular degeneration; CNV, choroidal neovascularization; Ct, threshold cycle; FasL, Fas ligand; HMVEC, human dermal microvascular endothelial cell.

Immunobiology, 2008

We have developed an assay that quantifies the potential of macrophages to regulate proliferation... more We have developed an assay that quantifies the potential of macrophages to regulate proliferation of endothelial cells. We show that young mice macrophages can be distinguished from old mice macrophages by their ability to inhibit vascular endothelial cell proliferation. While young mice macrophages robustly inhibit proliferation, old mice macrophages fail to do so and actually promote the proliferation of endothelial cells. In this report, we outline a technique that directly assesses the effect of macrophages on modulation of endothelial cell proliferation. This assay will help us in understanding the mechanisms of macrophage function in several disease states characterized by abnormal angiogenesis including cancers, angiogenic eye disease and atherosclerotic heart disease.

Gait & Posture, 2011

This article appeared in a journal published by Elsevier. The attached copy is furnished to the a... more This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright

Free Radical Biology and Medicine, 2010

Mn superoxide dismutase (MnSOD) is an important mitochondrial antioxidant enzyme, and elevated Mn... more Mn superoxide dismutase (MnSOD) is an important mitochondrial antioxidant enzyme, and elevated MnSOD levels have been shown to reduce tumor growth in part by suppressing cell proliferation. Studies with fibroblasts have shown that increased MnSOD expression prolongs cell cycle transition time in G1/S and favors entrance into the quiescent state. To determine if the same effect occurs during tissue regeneration in vivo, we used a transgenic mouse system with liver-specific MnSOD expression and a partial hepatectomy paradigm to induce synchronized in vivo cell proliferation during liver regeneration. We show in this experimental system that a 2.6 fold increase in MnSOD activities leads to delayed entry into S phase, as measured by reduction in bromodeoxyuridine (BrdU) incorporation, and decreased expression of proliferative cell nuclear antigen (PCNA). Thus, compared to control mice with baseline MnSOD levels, transgenic mice with increased MnSOD expression in the liver have 23% fewer BrdU positive cells and a marked attenuation of PCNA expression. The increase in MnSOD activity also leads to an increase of the mitochondrial form of thioredoxin (thioredoxin 2), but not of several other peroxidases examined, suggesting the importance of thioredoxin 2 in maintaining redox balance in mitochondria with elevated levels of MnSOD.

Chinese Journal of Chemistry, 2009

The binding interaction of captopril (CPL) with biologically active metal ions Mg 2＋ , Ca 2＋ , Mn... more The binding interaction of captopril (CPL) with biologically active metal ions Mg 2＋ , Ca 2＋ , Mn 2＋ , Co 2＋ , Ni 2＋ , Cu 2＋ and Zn 2＋ was investigated in an aqueous acidic medium by fluorescence spectroscopy. The experimental results showed that the metal ions quenched the intrinsic fluorescence of CPL by forming CPL-metal complexes. It was found that static quenching was the main reason for the fluorescence quenching. The quenching constant in the case of Cu 2＋ was highest among all quenchers, perhaps due to its high nuclear charge and small size. Quenching of CPL by metal ions follows the order Cu 2＋ ＞Ni 2＋ ＞Co 2＋ ＞Ca 2＋ ＞Zn 2＋ ＞Mn 2＋ ＞Mg 2＋. The quenching constant K sv , bimolecular quenching constant K q , binding constant K and the binding sites "n" were determined together with their thermodynamic parameters at 27 and 37 ℃. The positive entropy change indicated the gain in configurational entropy as a result of chelation. The process of interaction was spontaneous and mainly ∆S-driven.

Cell Metabolism, 2013

Pathologic angiogenesis mediated by abnormally polarized macrophages plays a central role in comm... more Pathologic angiogenesis mediated by abnormally polarized macrophages plays a central role in common age-associated diseases such as atherosclerosis, cancer, and macular degeneration. Here we demonstrate that abnormal polarization in older macrophages is caused by programmatic changes that lead to reduced expression of ATP binding cassette transporter ABCA1. Downregulation of ABCA1 by microRNA-33 impairs the ability of macrophages to effectively efflux intracellular cholesterol, which in turn leads to higher levels of free cholesterol within senescent macrophages. Elevated intracellular lipid polarizes older macrophages to an abnormal, alternatively activated phenotype that promotes pathologic vascular proliferation. Mice deficient for Abca1, but not Abcg1, demonstrate an accelerated aging phenotype, whereas restoration of cholesterol efflux using LXR agonists or miR-33 inhibitors reverses it. Monocytes from older humans with age-related macular degeneration showed similar changes. These findings provide an avenue for therapeutic modulation of macrophage function in common age-related diseases. (F) Measurement of proliferation of HMVECs after incubation with DIO or control macrophages. (G and H) Representative illustration (G) and quantification of CNV (white circle) volume (H) demonstrated an inability of DIO macrophages to inhibit CNV as compared to controls. Values are expressed as mean + SE. Statistically significant difference, **p < 0.01, ***p < 0.001.