Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). In the murine experimental autoimmune encephalomyelitis (EAE) model of MS, T regulatory (Treg) cell therapy has ...proved to be beneficial, but generation of stable CNS-targeting Tregs needs further development. Here, we propose gene engineering to achieve CNS-targeting Tregs from naïve CD4 cells and demonstrate their efficacy in the EAE model.
CD4+ T cells were modified utilizing a lentiviral vector system to express a chimeric antigen receptor (CAR) targeting myelin oligodendrocyte glycoprotein (MOG) in trans with the murine FoxP3 gene that drives Treg differentiation. The cells were evaluated in vitro for suppressive capacity and in C57BL/6 mice to treat EAE. Cells were administered by intranasal (i.n.) cell delivery.
The engineered Tregs demonstrated suppressive capacity in vitro and could efficiently access various regions in the brain via i.n cell delivery. Clinical score 3 EAE mice were treated and the engineered Tregs suppressed ongoing encephalomyelitis as demonstrated by reduced disease symptoms as well as decreased IL-12 and IFNgamma mRNAs in brain tissue. Immunohistochemical markers for myelination (MBP) and reactive astrogliosis (GFAP) confirmed recovery in mice treated with engineered Tregs compared to controls. Symptom-free mice were rechallenged with a second EAE-inducing inoculum but remained healthy, demonstrating the sustained effect of engineered Tregs.
CNS-targeting Tregs delivered i.n. localized to the CNS and efficiently suppressed ongoing inflammation leading to diminished disease symptoms.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Panchromatic observations of the best candidate hyperluminous infrared galaxies from the widest Herschel extragalactic imaging survey have led to the discovery of at least four intrinsically luminous ...z = 2.41 galaxies across an approximately 100 kpc region-a cluster of starbursting protoellipticals. Via subarcsecond interferometric imaging we have measured accurate gas and star formation surface densities. The two brightest galaxies span ~3 kpc FWHM in submillimeter/radio continuum and CO J = 4-3, and double that in CO J = 1-0. The broad CO line is due partly to the multitude of constituent galaxies and partly to large rotational velocities in two counter-rotating gas disks-a scenario predicted to lead to the most intense starbursts, which will therefore come in pairs. The disks have M sub(dyn) of several x 10 super(11) M sub(middot in circle) and gas fractions of ~40%. Velocity dispersions are modest so the disks are unstable, potentially on scales commensurate with their radii: these galaxies are undergoing extreme bursts of star formation, not confined to their nuclei, at close to the Eddington limit. Their specific star formation rates place them gap 5x above the main sequence, which supposedly comprises large gas disks like these. Their high star formation efficiencies are difficult to reconcile with a simple volumetric star formation law. N-body and dark matter simulations suggest that this system is the progenitor of a B(inary)-type gap 10 super(14.6)-M sub(mid dot in circle) cluster.
Macrophage infiltration of the kidney is a prominent feature associated with the severity of renal injury and progressive renal failure. To determine the influence of macrophages in renal disease ...models in the absence of endogenous T and B cells, we performed adoptive transfer of macrophages into severe combined immunodeficient (SCID) mice. In this study, macrophages were isolated from the spleens of BALB/c mice and stimulated with lipopolysaccharide to induce classically activated M1 macrophages or with interleukin-4 (IL-4) and IL-13 to induce alternatively activated M2 macrophages. These macrophages were then infused into SCID mice with adriamycin nephropathy; an in vivo model of chronic inflammatory renal disease analogous to human focal segmental glomerulosclerosis. Mice infused with M1 macrophages had a more severe histological and functional injury, whereas M2 macrophage-induced transfused mice had reduced histological and functional injury. Both M1 and M2 macrophages localized preferentially to the area of injury and maintained their phenotypes even after 4 weeks. The protective effect of M2 macrophages was associated with reduced accumulation and possibly downregulated chemokine and inflammatory cytokine expression of the host infiltrating macrophages. Our findings demonstrate that macrophages not only act as effectors of immune injury but can be induced to provide protection against immune injury.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Studies have consistently shown that subthreshold depression is associated with an increased risk of developing major depression. However, no study has yet calculated a pooled estimate that ...quantifies the magnitude of this risk across multiple studies.
We conducted a systematic review to identify longitudinal cohort studies containing data on the association between subthreshold depression and future major depression. A baseline meta-analysis was conducted using the inverse variance heterogeneity method to calculate the incidence rate ratio (IRR) of major depression among people with subthreshold depression relative to non-depressed controls. Subgroup analyses were conducted to investigate whether IRR estimates differed between studies categorised by age group or sample type. Sensitivity analyses were also conducted to test the robustness of baseline results to several sources of study heterogeneity, such as the case definition for subthreshold depression.
Data from 16 studies (n = 67 318) revealed that people with subthreshold depression had an increased risk of developing major depression (IRR = 1.95, 95% confidence interval 1.28-2.97). Subgroup analyses estimated similar IRRs for different age groups (youth, adults and the elderly) and sample types (community-based and primary care). Sensitivity analyses demonstrated that baseline results were robust to different sources of study heterogeneity.
The results of this study support the scaling up of effective indicated prevention interventions for people with subthreshold depression, regardless of age group or setting.
The emergence of SARS-CoV-2 virus has resulted in a worldwide pandemic, but effective antiviral therapies are not widely available. To improve treatment options, we conducted a high-throughput screen ...to uncover compounds that block SARS-CoV-2 infection. A minimally pathogenic human betacoronavirus (OC43) was used to infect physiologically-relevant human pulmonary fibroblasts (MRC5) to facilitate rapid antiviral discovery in a preclinical model. Comprehensive profiling was conducted on more than 600 compounds, with each compound arrayed across 10 dose points. Our screening revealed several FDA-approved agents that can attenuate both OC43 and SARS-CoV-2 viral replication, including lapatinib, doramapimod, and 17-AAG. Importantly, lapatinib inhibited SARS-CoV-2 RNA replication by over 50,000-fold. Further, both lapatinib and doramapimod could be combined with remdesivir to improve antiviral activity in cells. These findings reveal novel therapeutic avenues that could limit SARS-CoV-2 infection.
•Compounds were screened across a 10-point dose-response curve for their ability to inhibit betacoronavirus-induced cell death.•Lapatinib was identified as a potent inhibitor of OC43 replication in MRC5 cells.•Transduction of MRC5 cells with ACE2 permits SARS-CoV-2 replication.•Lapatinib inhibits SARS-CoV-2 infection in MRC5-ACE2 cells.•Lapatinib increases remdesivir’s anti-viral activity against SARS-CoV-2.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Isocitrate dehydrogenase-1 (Idh1) is an important metabolic enzyme that produces NADPH by converting isocitrate to α-ketoglutarate. Idh1 is known to reduce reactive oxygen species (ROS) induced in ...cells by treatment with lipopolysaccharide (LPS) in vitro. Here, we used Idh1-deficient knockout (Idh1 KO) mice to investigate the role of Idh1 in antioxidant defense in vivo. Idh1 KO mice showed heightened susceptibility to death induced by LPS and exhibited increased serum levels of inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. The serum of LPS-injected Idh1 KO mice also contained elevated levels of AST, a marker of inflammatory liver damage. Furthermore, after LPS injection, livers of Idh1 KO mice showed histological evidence of elevated oxidative DNA damage compared with livers of wild-type (WT) mice. Idh1 KO livers showed a faster and more pronounced oxidative stress than WT livers. In line with that, Idh1 KO hepatocytes showed higher ROS levels and an increase in the NADP(+)/NADPH ratio when compared with hepatocytes isolated from WT mice. These results suggest that Idh1 has a physiological function in protecting cells from oxidative stress by regulating the intracellular NADP(+)/NADPH ratio. Our findings suggest that stimulation of Idh1 activity may be an effective therapeutic strategy for reducing oxidative stress during inflammatory responses, including the early stages of septic shock.
Full text
Available for:
DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
PDF
