NLRC3, a member of the NLR family, has been reported as a negative regulator of inflammatory signaling pathways in innate immune cells. However, the direct role of NLRC3 in modulation of CD4+ T-cell ...responses in infectious diseases has not been studied. In the present study, we showed that NLRC3 plays an intrinsic role by suppressing the CD4+ T cell phenotype in lung and spleen, including differentiation, activation, and proliferation. NLRC3 deficiency in CD4+ T cells enhanced the protective immune response against Mycobacterium tuberculosis infection. Finally, we demonstrated that NLRC3 deficiency promoted the activation, proliferation, and cytokine production of CD4+ T cells via negatively regulating the NF-κB and MEK-ERK signaling pathways. This study reveals a critical role of NLRC3 as a direct regulator of the adaptive immune response and its protective effects on immunity during M. tuberculosis infection. Our findings also suggested that NLRC3 serves as a potential target for therapeutic intervention against tuberculosis.
Tuberculosis, caused by
(Mtb), remains a global health crisis with substantial morbidity and mortality rates. Type II alveolar epithelial cells (AEC-II) play a critical role in the pulmonary immune ...response against Mtb infection by secreting effector molecules such as antimicrobial peptides (AMPs). Here, human β-defensin 1 (hBD1), an important AMP produced by AEC-II, has been demonstrated to exert potent anti-tuberculosis activity. HBD1 overexpression effectively inhibited Mtb proliferation in AEC-II, while mice lacking hBD1 exhibited susceptibility to Mtb and increased lung tissue inflammation. Mechanistically, in A549 cells infected with Mtb, STAT1 negatively regulated hBD1 transcription, while CEBPB was the primary transcription factor upregulating hBD1 expression. Furthermore, we revealed that the ERK1/2 signaling pathway activated by Mtb infection led to CEBPB phosphorylation and nuclear translocation, which subsequently promoted hBD1 expression. Our findings suggest that the ERK1/2-CEBPB-hBD1 regulatory axis can be a potential therapeutic target for anti-tuberculosis therapy aimed at enhancing the immune response of AEC-II cells.
The mechanisms by which vitamins regulate immunity and their effect as an adjuvant treatment for tuberculosis have gradually become very important research topics. Studies have found that vitamin B5 ...(VB5) can promote epithelial cells to express inflammatory cytokines. We aimed to examine the proinflammatory and antibacterial effect of VB5 in macrophages infected with
(MTB) strain H37Rv and the therapeutic potential of VB5
with tuberculosis. We investigated the activation of inflammatory signal molecules (NF-κB, AKT, JNK, ERK, and p38), the expression of two primary inflammatory cytokines (tumor necrosis factor and interleukin-6) and the bacterial burdens in H37Rv-infected macrophages stimulated with VB5 to explore the effect of VB5 on the inflammatory and antibacterial responses of macrophages. We further treated the H37Rv-infected mice with VB5 to explore VB5's promotion of the clearance of H37Rv in the lungs and the effect of VB5 on regulating the percentage of inflammatory cells. Our data showed that VB5 enhanced the phagocytosis and inflammatory response in macrophages infected with H37Rv. Oral administration of VB5 decreased the number of colony-forming units of H37Rv in lungs of mice at 1, 2, and 4 weeks after infection. In addition, VB5 regulated the percentage of macrophages and promoted CD4
T cells to express interferon-γ and interleukin-17; however, it had no effect on the percentage of polymorphonuclear neutrophils, CD4
and CD8
T cells. In conclusion, VB5 significantly inhibits the growth of MTB by regulating innate immunity and adaptive immunity.
Text tokenization is a fundamental pre-processing step for almost all the information processing applications. This task is nontrivial for the scarce resourced languages such as Urdu, as there is ...inconsistent use of space between words. In this paper a morpheme matching based approach has been proposed for Urdu text tokenization, along with some other algorithms to solve the additional issues of boundary detection of compound words, affixation, reduplication, names and abbreviations. This study resulted into 97.28% precision, 93.71% recall, and 95.46% F1-measure; while tokenizing a corpus of 57000 words by using a morpheme list with 6400 entries.
A numerical investigation into the effects of flapping modes on the aerodynamic performance of insect hovering flight is carried out through the solution of the two-dimensional unsteady Navier-Stokes ...equations. Four types of idealized flapping modes with the identical quasi-steady lift force are compared, and the influences of the Reynolds number (
Re
), the translational duration and the rotational duration on the aerodynamic characteristics of the hovering are systematically analyzed flight. It is found that the instantaneous aerodynamic forces of the wing differ significantly in each flapping mode. The mode with harmonic translation and harmonic rotation leading the highest lifting efficiency is suitable for long-time flight while the mode with harmonic translation and trapezoid rotation giving the largest instantaneous forces is suitable for maneuvering flight. When
Re
increases from 100 to 1000, the lift force and lifting efficiency of the wing are increased significantly with the increasing
Re
first, and then slow down with the further increase in
Re
. In addition, the fast-translational mode with short translational duration will reduce the time-averaged lift force and the efficiency, whereas the fastrotational mode with short rotational duration can enhance the time-averaged lift force with the sustained efficiency.
A conceptual model is proposed for the characteristic sub-ranges in the velocity and temperature spectra in the boundary layer of tropical cyclones (hurricanes or typhoons). The model is based on ...observations and computation of radial and vertical profiles of the mean flow and turbulence, and on the interpretation of eddy mechanisms determined by shear (namely roll and streak structures near the surface), convection, rotation, blocking and sheltering effects at the ground/sea surface and in internal shear layers. The significant sub-ranges, as the frequency increases, are associated with larger energy containing eddies, shear and blocking, inertial transfer between large and small scales, and intense small-scale eddies generated near the surface caused by waves, coastal roughness change, and the buoyancy force associated with the evaporation of spray droplets. These sub-ranges vary with the locations at which the spectra are measured, i.e. the level
z
in relation to the height
z
m
a
x
of the peak mean velocity and the depth
h
of the boundary layer, and the radius
r
in relation to the eyewall radius
R
e
w
and the outer-vortex radius
R
o
v
. For two tropical cyclones (Nuri and Hagupit), experimental data were analyzed. Spectra were measured where
r
is near to
R
e
w
and
R
o
v
using four 1-h long datasets at coastal towers, at 10- and 60-m heights for tropical cyclone Nuri, and at 60-m height for tropical cyclone Hagupit at the south China coast. The field measurements of spectra within the boundary layer show significant sub-ranges of self-similar energy spectra (lying between the length scale 1,000 m and the smallest scales less than 40 m) that are consistent with the above conceptual model of the surface layer. However, with very high wind speeds near the eyewall, the energy of the independently generated intense surface eddy motions, associated with surface waves and water droplets in the airflow, greatly exceeds the energies of the small scales in the inertial sub-range of the boundary layer, over scales less than about 3–40 m depending on the height
z
and the radius
r
. This rise in the small-scale frequency weighted spectra (
n
S
u
(
n
)
, where
n
is natural frequency, and
S
u
(
n
)
is the energy spectrum of the longitudinal wind component) is consistent with the hypothesis that these processes are only weakly correlated with the main boundary-layer turbulence.
Mesenchymal stem cells (MSCs) play a crucial role in tissue repair by secretion of tissue nutrient factors such as hepatocyte growth factor (HGF). However, studies examining the effects of HGF on the ...proliferation and differentiation of MSCs used different concentrations of HGF and reported conflicting conclusions. This study aimed to determine the mechanisms by which different concentrations of HGF regulate MSC proliferation and osteogenic differentiation, and validate the mechanism in an animal model of early stage avascular necrosis of femoral head (ANFH). Our results demonstrate that a low concentration of HGF (20 ng/ml) preferentially promotes MSC osteogenic differentiation through increased c‐Met expression and phosphorylation, Akt pathway activation, and increased expression of p27, Runx2 and Osterix. In contrast, a high concentration of HGF (100 ng/ml) strongly induced proliferation by inducing strong activation of the ERK1/2 signalling pathway. As validated by animal experiments, high localized expression of HGF achieved by transplantation of HGF transgenic MSCs into ANFH rabbits increased the number of MSCs. Subsequently, 2 weeks after transplantation, HGF levels decreased and MSCs differentiated into osteoblasts and resulted in efficient tissue repair. Our results demonstrate that sequential concentration changes in HGF control the proliferation and osteogenic differentiation of MSCs in vivo. This phenomenon can be exploited therapeutically to induce bone regeneration and, in turn, improve the efficacy of pharmacological intervention for ANFH treatment.
Tuberculosis (TB) caused by
(Mtb) represents one of the greatest threats to human health., Interferons (IFNs) in combination with the first-line of anti-TB drugs have been used for treating TB for ...decades in the clinic, but how Mtb infection regulates interferon-stimulated genes (ISGs) in human macrophages (Mϕs) remains unknown. In this study, we investigated the expression-signature and associated innate signaling mechanisms of ISGs in Mtb-infected human monocyte-derived Mϕs (hMDMs) and THP-1-derived Mϕs (THP-1-Mϕs). Among 28 of the detected ISGs, 90% of them exerted a significant increase in Mtb-infected Mϕs. Additionally, we found that cytosolic cyclic (GMP-AMP) synthase (cGAS), toll-like receptor-2 (TLR-2) and TLR-4 signaling pathways participated in ISG induction. Their downstream elements of TANK-binding kinase 1 (TBK1), nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and Janus kinase-signal transducer and activator of transcription (JAK-STAT) were selectively involved in Mtb-mediated ISG production. Finally, the numerous types of ISG expression in hMDMs of TB patients were more susceptible to restimulation of Mtb infection or/and IFN treatment than that of healthy people. Hence, different signaling pathways define different ISG expression during Mtb infection and this helps to illustrate how ISGs are elucidated and to better understand the host immune responses to Mtb infection in Mϕs.
Tuberculosis (TB) caused by
(Mtb) infection is the deadliest infectious disease and a global health problem. Macrophages (Mφs) and neutrophils that can phagocytose Mtb represent the first line of ...immune response to infection. Glycogen synthase kinase-3α/β (GSK-3α/β) represents a regulatory switch in host immune responses. However, the efficacy and molecular mechanisms of how GSK-3α/β interacts with Mtb infection in Mφs remain undefined. Here, we demonstrated that Mtb infection downregulated GSK-3α/β activity and promoted matrix metalloproteinase-1 (MMP-1) and MMP-9 expressions in Mφs derived from acute monocytic human leukemia THP-1 cells (THP-1-Mφs). We confirmed the upregulation of MMP-9 expression in tissues of TB patients compared with patients of chronic inflammation (CI). In THP-1-Mφs and C57BL/6 mice, GSK-3α/β inhibitor SB216763 significantly increased MMP-1/9 production and facilitated Mtb load, while MMP inhibitors blocked MMP-1/9 expression and Mtb infection. Consistently, GSK-3α/β silencing significantly increased MMP-1/9 expression and Mtb infection, while overexpression of GSK-3α/β and constitutive activated GSK-3α/β mutants significantly reduced MMP-1/9 expression and Mtb infection in THP-1-Mφs. MMP-1/9 silencing reduced Mtb infection, while overexpression of MMP-1/9 promoted Mtb infection in THP-1-Mφs. We further found that GSK-3α/β inhibition increased Mtb infection and MMP-1/9 expression was blocked by ERK1/2 inhibitor. Additionally, we showed that protein kinase C-δ (PKC-δ) and mammalian target of rapamycin (mTOR) reduced GSK-3α/β activity and promoted MMP-1/9 production in Mtb-infected THP-1-Mφs. In conclusion, this study suggests that PKC-δ-mTOR axis suppresses GSK-3α/β activation with acceleration of MMP-1/9 expression through phospho-ERK1/2. These results reveal a novel immune escape mechanism of Mtb and a novel crosstalk between these critical signaling pathways in anti-TB immunity.
It is known that vitamin B1 (VB1) has a protective effect against oxidative retinal damage induced by anti-tuberculosis drugs. However, it remains unclear whether VB1 regulates immune responses ...during
(MTB) infection. We report here that VB1 promotes the protective immune response to limit the survival of MTB within macrophages and
through regulation of peroxisome proliferator-activated receptor γ (PPAR-γ). VB1 promotes macrophage polarization into classically activated phenotypes with strong microbicidal activity and enhanced tumor necrosis factor-α and interleukin-6 expression at least in part by promoting nuclear factor-κB signaling. In addition, VB1 increases mitochondrial respiration and lipid metabolism and PPAR-γ integrates the metabolic and inflammatory signals regulated by VB1. Using both PPAR-γ agonists and deficient mice, we demonstrate that VB1 enhances anti-MTB activities in macrophages and
by down-regulating PPAR-γ activity. Our data demonstrate important functions of VB1 in regulating innate immune responses against MTB and reveal novel mechanisms by which VB1 exerts its function in macrophages.
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