A key feature of the immune system is its ability to discriminate self from nonself. Breakdown in any of the mechanisms that maintain unresponsiveness to self (a state known as self-tolerance) contributes to the development of autoimmune conditions. Recent studies in mice show that CD8+ T cells specific for the unconventional MHC class I molecule Qa-1 bound to peptides derived from the signal sequence of Hsp60 (Hsp60sp) contribute to self/nonself discrimination. However, it is unclear whether they exist in humans and play a role in human autoimmune diseases. Here we have shown that CD8+ T cells specific for Hsp60sp bound to HLA-E (the human homolog of Qa-1) exist and play an important role in maintaining peripheral self-tolerance by discriminating self from nonself in humans. Furthermore, in the majority of type 1 diabetes (T1D) patients tested, there was a specific defect in CD8+ T cell recognition of HLA-E/Hsp60sp, which was associated with failure of self/nonself discrimination. However, the defect in the CD8+ T cells from most of the T1D patients tested could be corrected in vitro by exposure to autologous immature DCs loaded with the Hsp60sp peptide. These data suggest that HLA-E–restricted CD8+ T cells may play an important role in keeping self-reactive T cells in check. Thus, correction of this defect could be a potentially effective and safe approach in the therapy of T1D.
Parkinson disease (PD), a devastating neurodegenerative disorder, affects motor abilities and cognition as well. It is not clear whether the proapoptotic protein, Bid, is involved in tumor necrosis factor death receptor I (TNFRI)–mediated destructive signal transduction pathways such as cell dysfunction or neurodegeneration in the temporal cortex of patients with PD.
Molecular and biochemical approaches were used to dissect mitochondrial related components of the destructive signaling pathway in the temporal cortex from rapidly autopsied brains (postmortem interval mean 2.6 hours). Brains from patients with PD (n = 15) had an average age of 81.4 years, compared to the average age of 84.36 years in age-matched control patient brains (n = 15).
TNFRI and its adaptor protein, TRADD, were not only present in the cytoplasm of the temporal cortex, but were significantly elevated (42.3% and 136.1%, respectively) in PD brains compared to age-matched control brains. Bid in the PD temporal cortex could be further cleaved into tBid in the cytosol, which is translocated into the mitochondria, where cytochrome c is then released and caspase-3 is subsequently activated.
Patients with PD have an activated Bid-mediated destructive signal pathway via TNFRI in the temporal cortex. Such deficits are pervasive, suggesting that they might contribute to cortex degeneration as PD manifests.
The Sir2 family of enzymes or sirtuins are known as nicotinamide adenine dinucleotide (NAD)-dependent deacetylases1 and have been implicated in the regulation of transcription, genome stability, metabolism, and lifespan2, 3. However, four of the seven mammalian sirtuins have very weak deacetylase activity in vitro. Here we show that human Sirt6 efficiently removes long chain fatty acyl groups, such as myristoyl, from lysine residues. The crystal structure of Sirt6 reveals a large hydrophobic pocket that can accommodate long chain fatty acyl groups. We demonstrate further that Sirt6 promotes the secretion of tumor necrosis factor α (TNFα) by removing the fatty acyl modification on K19 and K20 of TNFα. Protein lysine fatty acylation has been known to occur in mammalian cells, but the function and regulatory mechanisms of this modification were unknown. Our data suggest that protein lysine fatty acylation is a novel mechanism that regulates protein secretion. The discovery of Sirt6 as an enzyme that controls protein lysine fatty acylation provides new opportunities to investigate the physiological function of the previously ignored protein posttranslational modification.
Histone3-lysine79 (H3K79) methyltransferase DOT1L has been found to be a drug target for acute leukemia with MLL (mixed lineage leukemia) gene translocations. A total of 55 adenosine-containing compounds were designed and synthesized, among which several potent DOT1L inhibitors were identified with Ki values as low as 0.5 nM. These compounds also show high selectivity (>4,500-fold) over three other histone methyltransferases. Structure activity relationships (SAR) of these compounds for their inhibitory activities against DOT1L are discussed. Potent DOT1L inhibitors exhibit selective activity against the proliferation of MLL-translocated leukemia cell lines MV4;11 and THP1 with EC50 values of 4–11 μM. Isothermal titration calorimetry studies showed two representative inhibitors bind with a high affinity to the DOT1L:nucleosome complex, and only compete with the enzyme cofactor SAM (S-adenosyl-L-methionine), but not the substrate nucleosome.
Quercetin is the most abundant flavonoid in fruit and vegetables and is believed to attenuate cardiovascular disease. We hypothesized that quercetin inhibits cardiac hypertrophy by blocking AP-1 (c-fos, c-jun) and activating PPAR-γ signaling pathways.
The aim of this study was to identify the mechanism underlying quercetin-mediated attenuation of cardiac hypertrophy. Quercetin therapy reduced blood pressure and markedly reduced the ratio of left ventricular to body weight (LVW/BW) (P<0.05, vs. spontaneously hypertensive rats (SHRs)). In vitro, quercetin also significantly attenuated Ang II-induced H9C2 cells hypertrophy, as indicated by its concentration dependent inhibitory effects on [3H]leucine incorporation into H9C2 cells (64% reduction) and by the reduced hypertrophic surface area in H9C2 cells compared with the Ang II group (P<0.01, vs. Ang II group). Concurrently, we found that PPAR-γ activity was significantly increased in the quercetin-treated group both in vivo and in vitro when analyzed using immunofluorescent or immunohistochemical assays (P<0.05, vs. SHRs or P<0.01, vs. the Ang II group). Conversely, in vivo, AP-1 (c-fos, s-jun) activation was suppressed in the quercetin-treated group, as was the downstream hypertrophy gene, including mRNA levels of ANP and BNP (P<0.05, vs. SHRs). Additionally, both western blotting and real time-PCR demonstrated that PPAR-γ protein and mRNA were increased in the myocardium and AP-1 protein and mRNA were significantly decreased in the quercetin-treated group (P<0.05, vs. SHRs). Furthermore, western blotting and real time-PCR analyses also showed that transfection with PPAR-γ siRNA significantly increased AP-1 signaling and reversed the effects of quercetin inhibition on mRNA expression levels of genes such as ANP and BNP in hypertrophic H9C2 cells.
Our data indicate that quercetin may inhibit cardiac hypertrophy by enhancing PPAR-γ expression and by suppressing the AP-1 signaling pathway.
The fate of a hole injected in an antiferromagnet is an outstanding issue of strongly correlated physics. It provides important insights into doped Mott insulators closely related to high-temperature superconductivity. Here, we report a systematic numerical study of t-J ladder systems based on the density matrix renormalization group. It reveals a surprising result for the single hole's motion in an otherwise well-understood undoped system. Specifically, we find that the common belief of quasiparticle picture is invalidated by the self-localization of the doped hole. In contrast to Anderson localization caused by disorders, the charge localization discovered here is an entirely new phenomenon purely of strong correlation origin. It results from destructive quantum interference of novel signs picked up by the hole, and since the same effect is of a generic feature of doped Mott physics, our findings unveil a new paradigm which may go beyond the single hole doped system.
A possible mechanism of susceptibility to superinfection with simian-human immunodeficiency virus (SHIV)-1157ipd3N4 was explored in twelve SHIVSF162P3-infected Chinese rhesus macaques. Based on the kinetics of viral replication for the second infecting virus following SHIV-1157ipd3N4 inoculation, the monkeys were divided into two groups: those relatively resistant to superinfection (SIR) and those relatively sensitive to superinfection (SIS). We found that superinfection-resistant macaques had high primary viremia, whereas superinfection-sensitive macaques had low primary viremia, suggesting that primary SHIVSF162P3 infection with a high viral-replication level would repress superinfection with a heterologous SHIV-1157ipd3N4. Although no correlation of protection against superinfection with virus-specific CD4+ T cell or CD8+ T cell immune responses from gut was observed prior to superinfection, superinfection susceptibility was strongly correlated with CD4+ Tcm cells from gut both prior to the second infecting virus inoculation and on day 7 after superinfection, but not with CD4+ Tem cells from gut or with CD4+ Tcm cells from peripheral blood and lymph node. These results point to the important roles of gut-derived CD4+ Tcm cells for the study of the mechanisms of protection against superinfection and the evaluation of the safety and efficacy of vaccines and therapies against acquired immune deficiency syndrome (AIDS).
Mesenchymal stromal cells (MSCs) show promise for treatment of a variety of neurological and other disorders. Cat has a high degree of linkage with the human genome and has been used as a model for analysis of neurological disorders such as stroke, Alzheimer’s disease and motor disorders. The present study was designed to characterize bone marrow-derived MSCs from cats and to investigate the capacity to generate functional peptidergic neurons. MSCs were expanded with cells from the femurs of cats and then characterized by phenotype and function. Phenotypically, feline and human MSCs shared surface markers, and lacked hematopoietic markers, with similar morphology. As compared to a subset of human MSCs, feline MSCs showed no evidence of the major histocompatibility class II. Since the literature suggested Stro-1 as an indicator of pluripotency, we compared early and late passages feline MSCs and found its expression in >90% of the cells. However, the early passage cells showed two distinct populations of Stro-1-expressing cells. At passage 5, the MSCs were more homogeneous with regards to Stro-1 expression. The passage 5 MSCs differentiated to osteogenic and adipogenic cells, and generated neurons with electrophysiological properties. This correlated with the expression of mature neuronal markers with concomitant decrease in stem cell-associated genes. At day 12 induction, the cells were positive for MAP2, Neuronal Nuclei, tubulin βIII, Tau and synaptophysin. This correlated with electrophysiological maturity as presented by excitatory postsynaptic potentials (EPSPs). The findings indicate that the cat may constitute a promising biomedical model for evaluation of novel therapies such as stem cell therapy in such neurological disorders as Alzheimer’s disease and stroke.
cat; mesenchymal stem cells; neuronal differentiation; immunohistochemistry; feline; bone marrow
We present 2 cases of fulminant malignant hyperthermia (MH), complicated with massive rhabdomyolysis. The patients were successfully treated in the intensive care unit of our university teaching hospital, despite the lack of availability of dantrolene in our country, by early application of continuous veno-venous hemofiltration (CVVH). Both male patients developed fulminant malignant hyperthermia during anesthesia for oromaxillofacial surgery. CVVH was employed when the values of creatine phosphokinase (CPK), myoglobin (Mb), and lactate dehydrogenase (LDH) increased significantly. After emergency treatment and CVVH therapy, the values of CPK, Mb, and LDH in the blood plasma of the patients decreased significantly. The complications, including acute renal failure, disseminated intravascular coagulation, and acute respiratory distress syndrome were also treated without any obvious organ damage. Early detection and management are the keys to treat MH successfully. CVVH is a valuable therapeutic application in the initial/critical management of severe rhabdomyolysis. If these complications occur even with initial treatment with dantrolene, our experiences may be useful adjunctive treatments to consider.
Malignant hyperthermia; Continuous veno-venous hemofiltration.
The aim of this study was to assess the feasibility of evaluating the therapeutic effects of intravenous diltiazem in a newly established rat model of coronary thrombotic micro-embolism (CME). CME was induced by injecting 0.199 ml saline containing 5 mg of automicrothrombotic particulates (∼10 μm) into the aorta of Sprague Dawley rats. The injection was carried out over 10 sec using a tuberculin syringe with a 28-gauge needle. The CME model rats were randomly divided into untreated (CME, n=38) and diltiazem-treated (CME+DIL, n=38) groups. Diltiazem (1 mg/ml, 50 μg/min/kg) was intravenously injected using an infusion pump through the tail vein for 175 min, 5 min following the injection of the automicrothrombotic particulates. Hemodynamic measurements, echocardiography and pathohistological examinations were performed at various time-points (3 h, 24 h and 7 and 28 days) postoperatively. Arteriolar thrombosis, multifocal myocardial necrosis, inflammatory cell infiltration with markedly increased myocardial tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) expression, reduced left ventricular (LV) systolic function and increased plasma von Willebrand factor (vWF), endothelin-1 (ET-1) and serum c-troponin I (c-TnI) levels (indicating vascular endothelial injury and myocardial necrosis) were observed in the CME model rats. These pathological responses in CME rats were partly attenuated by intravenous diltiazem treatment. The present CME model is suitable for evaluating the therapeutic effects of intravenous diltiazem; intravenous diltiazem treatment significantly improved cardiac function through alleviating inflammatory responses and microvascular thrombotic injury in this rat model of CME.
coronary thrombosis; microembolism; no flow phenomenon; diltiazem
In this work, sawdust, a biomass waste, is converted into a magnetic porous carbonaceous (MPC) solid acid catalyst by an integrated fast pyrolysis–sulfonation process. The resultant magnetic solid acid has a porous structure with high surface area of 296.4 m2 g−1, which can be attributed to the catalytic effect of Fe. The catalytic activity and recyclability of the solid acid catalyst are evaluated during three typical acid-catalyzed reactions: esterification, dehydration, and hydrolysis. The favorable catalytic performance in all three reactions is attributed to the acid's high strength with 2.57 mmol g−1 of total acid sites. Moreover, the solid acid can be reused five times without a noticeable decrease in catalytic activity, indicating the stability of the porous carbon (PC)–sulfonic acid group structure. The findings in the present work offer effective alternatives for environmentally friendly utilization of abundant biomass waste.
We used a unique combination of four state-of-the-art technologies to achieve a high performance spectral domain optical coherence tomography system suitable for imaging the entire ocular surface. An ultra-high resolution, extended depth range, full-phase interferometry, and high-speed complementary metal-oxide semiconductor transistor camera detection provided unprecedented performance for the precise quantification of a wide range of the ocular surface. We demonstrated the feasibility of this approach by obtaining high-speed and high-resolution images of a model eye beyond the corneal–scleral junction. Surfaces determined from the images with a segmentation algorithm demonstrated excellent accuracy and precision.
ocular surface; complex; full range; optical coherence tomography
This prospective study aimed to describe the nature and time course of HPA axis dysregulation and psychopathology among terror-bereaved spouses.
Twenty-three spouses bereaved from September 11, 2001 terror attacks and 22 nonbereaved spouses were compared using a psychiatric diagnostic interview (SCID), three days of salivary cortisol collection, and a dexamethasone suppression test. Most subjects had repeated assessments at six month intervals during the two year study.
After September 11, 2001, bereaved compared to nonbereaved had significantly higher rates of posttraumatic stress disorder (PTSD) (68.1% versus 0%) and major depressive disorder (MDD) (45.5% versus 9.5%). Bereaved had significantly higher morning basal cortisol and less afternoon postdexamethasone cortisol suppression than nonbereaved. Among bereaved, those with PTSD without comorbid MDD had significantly greater afternoon postdexamethasone cortisol suppression than those without psychiatric disorders.
Terror-related spouse death is a severe stressor associated with persistent HPA axis activation, PTSD, and MDD. However, bereaved spouses who developed PTSD and were not depressed had enhanced postdexamethasone cortisol suppression, evidence of heightened glucocorticoid receptor sensitivity.
Bereavement; Cortisol; PTSD; MDD; September 11
Published evidence suggests that the rs2233678 (−842 G>C) polymorphism in the PIN1 (peptidyl-prolyl cis/trans somerase NIMA-interacting 1) promoter region may be associated with cancer risk; however, the conclusion is still inconclusive.
We conducted a meta-analysis to determine whether −842 G>C polymorphism was associated with cancer risk. Odds ratio (OR) and 95% confidence intervals (95% CI) were used to assess the strength of association. Genotype distribution data and adjusted ORs were collected to calculate the pooled ORs. Meta-regression was conducted to detect the source of heterogeneity. Publication bias was evaluated by Egger’s test and Begg’s test.
A total of 11 eligible studies, including 9280 participants, were identified and analyzed. Overall, we found that carriers of the −842 C allele were associated with significantly decreased cancer risk (C vs. G, OR = 0.750, 95% CI: 0.639–0.880, Pheterogeneity = 0.014, estimated by genotype distribution data; CC+GC vs. GG, OR = 0.668, 95% CI: 0.594–0.751, Pheterogeneity = 0.638, estimated by adjusted ORs). No evidence of publication bias was observed. Meta-regression revealed that ethnicities (p = 0.021) and sample size (p = 0.02) but not sources of control (p = 0.069) were the source of heterogeneity.
These results suggest that the PIN1 rs2233678 (−842 G>C) polymorphism significantly reduces cancer risk.
The canonical transient receptor potential (TRPC) channels are Ca2+-permeable cationic channels controlling the Ca2+ influx evoked by G protein-coupled receptor activation and/or by Ca2+ store depletion. Here we investigate the involvement of TRPCs in the cell differentiation of lung cancer. The expression of TRPCs and the correlation to cancer differentiation grade in non-small cell lung cancer (NSCLC) were analyzed by real-time PCR and immunostaining using tissue microarrays from 28 patient lung cancer samples. The association of TRPCs with cell differentiation was also investigated in the lung cancer cell line A549 by PCR and Western blotting. The channel activity was monitored by Ca2+ imaging and patch recording after treatment with all-trans-retinoic acid (ATRA). The expression of TRPC1, 3, 4 and 6 was correlated to the differentiation grade of NSCLC in patients, but there was no correlation to age, sex, smoking history and lung cancer cell type. ATRA upregulated TRPC3, TRPC4 and TRPC6 expression and enhanced Ca2+ influx in A549 cells, however, ATRA showed no direct effect on TRPC channels. Inhibition of TRPC channels by pore-blocking antibodies decreased the cell mitosis, which was counteracted by chronic treatment with ATRA. Blockade of TRPC channels inhibited A549 cell proliferation, while overexpression of TRPCs increased the proliferation. We conclude that TRPC expression correlates to lung cancer differentiation. TRPCs mediate the pharmacological effect of ATRA and play important roles in regulating lung cancer cell differentiation and proliferation, which gives a new understanding of lung cancer biology and potential anti-cancer therapy.
Lumican is a dermatan sulfate proteoglycan highly expressed in connective tissue and has the ability to regulate collagen fibril assembly. Previous studies have shown that lumican is involved in wound healing, but the precise effects of lumican on reepithelialization and wound contraction, the two pivotal aspects of skin wound healing, have not been investigated. Here we explored the roles of lumican in fibroblast contractility, a main aspect of skin wound healing, by adopting mice skin wound healing model and the corresponding in vitro cellular experiments. Our results showed that lumican can promote skin wound healing by facilitating wound fibroblast activation and contraction but not by promoting keratinocyte proliferation and migration. Silencing of integrin α2 completely abolished the pro-contractility of lumican, indicating lumican enhances fibroblast contractility via integrin α2. Our study for the first time demonstrated that lumican can affect fibroblast’s mechanical property, which is pivotal for many important pathological processes, such as wound healing, fibrosis, and tumor development, suggesting that lumican might have a potential to be used to modulate these processes.
The present data on the evaluation of platelet (PLT) parameters in Chinese Han population and Tibetans are still limited. The objective of this study was to determine the differences in common PLT indices between Han population and Tibetans in China, through a large-scale investigation of healthy people.
2131 Han people from Chengdu Plain, 1099 Tibetans from Qinghai-Tibet Plateau and 956 Plateau Han migrants were included in this study. All the subjects were healthy people through the health screening. PLT indices were measured with Sysmex XE-2100 and XT-1800i blood cell automatic analyzer.
Compared with Han people in Chendu Plain, Tibetans had higher PLT count (P<0.01) but lower mean platelet volume (MPV), platelet distribution width (PDW) and platelet-large cell ratio (P-LCR) (P<0.01); while Plateau Han migrants had lower PLT count, MPV and P-LCR (P<0.05). When compared with Tibetans, Plateau Han migrants had lower levels of mean PLT count but higher PDW and P-LCR (P<0.05).
There are ethnic differences in PLT indices between Chinese Han population and Tibetans. Based on this finding, it would be reasonable to conduct formal prospective studies to determine the clinical significance of these differences and to explore the effects of genetic background on these indices.
Ultraviolet-B (UV-B) exposure in the course of litter decomposition may have a direct effect on decomposition rates via changing states of photodegradation or decomposer constitution in litter while UV-B exposure during growth periods may alter chemical compositions and physical properties of plants. Consequently, these changes will indirectly affect subsequent litter decomposition processes in soil. Although studies are available on both the positive and negative effects (including no observable effects) of UV-B exposure on litter decomposition, a comprehensive analysis leading to an adequate understanding remains unresolved. Using data from 93 studies across six biomes, this introductory meta-analysis found that elevated UV-B directly increased litter decomposition rates by 7% and indirectly by 12% while attenuated UV-B directly decreased litter decomposition rates by 23% and indirectly increased litter decomposition rates by 7%. However, neither positive nor negative effects were statistically significant. Woody plant litter decomposition seemed more sensitive to UV-B than herbaceous plant litter except under conditions of indirect effects of elevated UV-B. Furthermore, levels of UV-B intensity significantly affected litter decomposition response to UV-B (P<0.05). UV-B effects on litter decomposition were to a large degree compounded by climatic factors (e.g., MAP and MAT) (P<0.05) and litter chemistry (e.g., lignin content) (P<0.01). Results suggest these factors likely have a bearing on masking the important role of UV-B on litter decomposition. No significant differences in UV-B effects on litter decomposition were found between study types (field experiment vs. laboratory incubation), litter forms (leaf vs. needle), and decay duration. Indirect effects of elevated UV-B on litter decomposition significantly increased with decay duration (P<0.001). Additionally, relatively small changes in UV-B exposure intensity (30%) had significant direct effects on litter decomposition (P<0.05). The intent of this meta-analysis was to improve our understanding of the overall effects of UV-B on litter decomposition.
Isothermal titration calorimetry (ITC) was used to investigate the binding of six inhibitors to 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), a target for developing novel anti-infectives. The binding of hydroxamate inhibitors to E. coli DXR is Mg2+-dependent, highly endothermic (ΔH: 22.7–24.3 kJ/mol) and entropy-driven, while that of non-hydroxamate compounds is metal ion independent and exothermic (ΔH: −19.4– −13.8 kJ/mol), showing hydration/dehydration of the enzyme metal ion binding pocket account for the drastic ΔH change. However, for DXRs from Plasmodium falciparum and Mycobacterium tuberculosis, the binding of all inhibitors is exothermic (ΔH: −24.9 – −9.2 kJ/mol), suggesting the metal ion binding sites of these two enzymes are considerably less hydrated. The dissociation constants measured by ITC are well correlated with those obtained by enzyme inhibition assays (R2 = 0.75). Given the rapid rise of antibiotic resistance, this work is of interest since it provides novel structural implications for rational development of potent DXR inhibitors.
Previous studies have shown that cysteine-rich secretory protein containing LCCL domain 2 (CRISPLD2) is a novel lipopolysaccharide (LPS)-binding protein, and the upregulation of CRISPLD2 expression protects mice against LPS-induced lethality. The aim of this study was to examine the expression of CRISPLD2 in patients with sepsis and characterize the association of this protein with procalcitonin.
The expression of CRISPLD2 was determined in100 healthy volunteers and 119 septic patients. According to the definition of sepsis, patients were divided into three groups sepsis, severe sepsis, and septic shock. The relationship between CRISPLD2 levels and procalcitonin was also examined and statistically analyzed.
The CRISPLD2 levels in healthy individuals were 219.3±69.1 µg/ml. Patients with sepsis exhibited higher CRISPLD2 levels than observed in healthy individuals (p = 0.001), but CRISPLD2 expression was not upregulated in patients with septic shock. No significant differences were observed between the levels of CRISPLD2 in surviving and non-surviving spesis patients. CRISPLD2 levels were negatively correlated with procalcitonin levels(r = −0.334, p<0.001).
The present study is the first to demonstrate the decreased expression of CRISPLD2 in septic shock and its association with PCT in sepsis. Further studies are needed to clarify the potential association between CRISPLD2 expression and clinical outcomes to determine if it could be used as a novel sepsis biomarker.
We demonstrated the feasibility of a CMOS-based spectral domain OCT (SD-OCT) for versatile ophthalmic applications of imaging the corneal epithelium, limbus, ocular surface, contact lens, crystalline lens, retina, and full eye in vivo. The system was based on a single spectrometer and an alternating reference arm with four mirrors. A galvanometer scanner was used to switch the reference beam among the four mirrors, depending on the imaging application. An axial resolution of 7.7 μm in air, a scan depth of up to 37.7 mm in air, and a scan speed of up to 70,000 A-lines per second were achieved. The approach has the capability to provide high-resolution imaging of the corneal epithelium, contact lens, ocular surface, and tear meniscus. Using two reference mirrors, the zero delay lines were alternatively placed on the front cornea or on the back lens. The entire ocular anterior segment was imaged by registering and overlapping the two images. The full eye through the pupil was measured when the reference arm was switched among the four reference mirrors. After mounting a 60 D lens in the sample arm, this SD-OCT was used to image the retina, including the macula and optical nerve head. This system demonstrates versatility and simplicity for multi-purpose ophthalmic applications.
(170.4500) Optical coherence tomography; (170.3880) Medical and biological imaging; (170.4580) Optical diagnostics for medicine; (330.4460) Ophthalmic optics and devices
Cystitis glandularis (CG) is a proliferative disorder in the urinary bladder. The outcome of current treatments in some patients is not satisfactory. Curcumin, a herbal medicine that has been used for centuries, has shown great potential in treating various diseases. Our pilot study aimed to explore the feasibility of an intravesical treatment for CG using curcumin. 14 patients diagnosed with CG that remained symptomatic after primary treatments were enrolled, underwent a 3-month curcumin intravesical treatment (50 mg/50 mL, 1 hour, once per week for first 4 weeks and once per month for next 2 months) and were followed up for 3 months. Efficacy of the treatment was evaluated using core lower urinary tract symptom score (CLSS) questionnaire. 10 patients demonstrated persistent improvement in symptoms up to the end of the 6-month study. Their CLSS decreased significantly after the 3-month treatment (6.0 ± 0.8; P < 0.01) from the baseline (10.5 ± 1.6) and maintained decreasing till the end of the study (6.2 ± 0.7; P < 0.01). 4 patients were classified as nonresponders. Our study suggests the feasibility of further randomized controlled trials on curcumin intravesical treatment in CG patients who remain symptomatic after primary treatments.
Anti-ApoE antibody reduces amyloid deposition and enhances the microglial response to Aβ plaques in an Alzheimer’s disease mouse model.
The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD). The influence of apoE on amyloid β (Aβ) accumulation may be the major mechanism by which apoE affects AD. ApoE interacts with Aβ and facilitates Aβ fibrillogenesis in vitro. In addition, apoE is one of the protein components in plaques. We hypothesized that certain anti-apoE antibodies, similar to certain anti-Aβ antibodies, may have antiamyloidogenic effects by binding to apoE in the plaques and activating microglia-mediated amyloid clearance. To test this hypothesis, we developed several monoclonal anti-apoE antibodies. Among them, we administered HJ6.3 antibody intraperitoneally to 4-mo-old male APPswe/PS1ΔE9 mice weekly for 14 wk. HJ6.3 dramatically decreased amyloid deposition by 60–80% and significantly reduced insoluble Aβ40 and Aβ42 levels. Short-term treatment with HJ6.3 resulted in strong changes in microglial responses around Aβ plaques. Collectively, these results suggest that anti-apoE immunization may represent a novel AD therapeutic strategy and that other proteins involved in Aβ binding and aggregation might also be a target for immunotherapy. Our data also have important broader implications for other amyloidosis. Immunotherapy to proteins tightly associated with misfolded proteins might open up a new treatment option for many protein misfolding diseases.
DNA variants, such as single nucleotide polymorphisms (SNPs) and copy number variants (CNVs), are unevenly distributed across the human genome. Currently, dbSNP contains more than 6 million human SNPs, and whole-genome genotyping arrays can assay more than 4 million of them simultaneously. In our study, we first questioned whether published genome-wide association studies (GWASs) assays cover all regions well in the genome. Using dbSNP build 135 data, we identified 50 genomic regions longer than 100 Kb that do not contain any common SNPs, i.e., those with minor allele frequency (MAF)≥1%. Secondly, because conserved regions are generally of functional importance, we tested genes in those large genomic regions without common SNPs. We found 97 genes and were enriched for reproduction function. In addition, we further filtered out regions with CNVs listed in the Database of Genomic Variants (DGV), segmental duplications from Human Genome Project and common variants identified by personal genome sequencing (UCSC). No region survived after those filtering. Our analysis suggests that, while there may not be many large genomic regions free of common variants, there are still some “holes” in the current human genomic map for common SNPs. Because GWAS only focused on common SNPs, interpretation of GWAS results should take this limitation into account. Particularly, two recent GWAS of fertility may be incomplete due to the map deficit. Additional SNP discovery efforts should pay close attention to these regions.