Cdk1 and SUMO Regulate Swe1 Stability

The Swe1/Wee1 kinase phosphorylates and inhibits Cdk1-Clb2 and is a major mitotic switch. Swe1 levels are controlled by ubiquitin mediated degradation, which is regulated by interactions with various mitotic kinases. We have recently reported that Swe1 levels are capable of sensing the progress of the cell cycle by measuring the levels of Cdk1-Clb2, Cdc5 and Hsl1. We report here a novel mechanism that regulates the levels of Swe1. We show that S.cerevisiae Swe1 is modified by Smt3/SUMO on residue K594 in a Cdk1 dependant manner. A degradation of the swe1K594R mutant that cannot be modified by Smt3 is considerably delayed in comparison to wild type Swe1. Swe1K594R cells express elevated levels of Swe1 protein and demonstrate higher levels of Swe1 activity as manifested by Cdk1-Y19 phosphorylation. Interestingly this mutant is not targeted, like wild type Swe1, to the bud neck where Swe1 degradation takes place. We show that Swe1 is SUMOylated by the Siz1 SUMO ligase, and consequently siz1Δ cells express elevated levels of Swe1 protein and activity. Finally we show that swe1K594R cells are sensitive to osmotic stress, which is in line with their compromised regulation of Swe1 degradation

Visual field defects of optic neuritis in neuromyelitis optica compared with multiple sclerosis

<p>Abstract</p> <p>Background</p> <p>Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that predominantly affects the optic nerves and the spinal cord, and is possibly mediated by an immune mechanism distinct from that of multiple sclerosis (MS). Central scotoma is recognized as a characteristic visual field defect pattern of optic neuritis (ON), however, the differing pathogenic mechanisms of NMO and MS may result in different patterns of visual field defects for ON.</p> <p>Methods</p> <p>Medical records of 15 patients with NMO and 20 patients with MS having ON were retrospectively analyzed. A thorough systemic and neurological examination was performed for evaluating ON. The total number of relapses of ON and visual fields was investigated. Visual fields were obtained by Goldmann perimeter with each ON relapse.</p> <p>Results</p> <p>All MS patients experienced central scotoma, with 90% of them showing central scotoma with every ON relapse. However, 53% of NMO patients showed central scotoma with every ON relapse (p = 0.022), and the remaining 47% of patients experienced non-central scotoma (altitudinal, quadrant, three quadrant, hemianopia, and bitemporal hemianopia). Thirteen percent of NMO patients did not experience central scotoma during their disease course. Altitudinal hemianopia was the most frequent non-central scotoma pattern in NMO.</p> <p>Conclusions</p> <p>NMO patients showed higher incidence of non-central scotoma than MS, and altitudinal hemianopia may be characteristic of ON occurring in NMO. As altitudinal hemianopia is highly characteristic of ischemic optic neuropathy, we suggest that an ischemic mechanism mediated by anti-aquaporin-4 antibody may play a role in ON in NMO patients.</p

Patient with neuromyelitis optica and inflammatory demyelinating lesions comprising whole spinal cord from C2 level till conus: case report

BACKGROUND: Neuromyelitis optica (NMO) is an idiopathic, severe, inflammatory demyelinating disease of the central nervous system, that causes severe optic neuritis and myelitis attacks. Early discrimination between multiple sclerosis (MS) and NMO is important, as optimum treatment for both diseases may differ considerably. ----- CASE PRESENTATION: We report a case of a patient who initially presented as longitudinally extensive transverse myelitis (LETM), having spastic upper extremities diparesis and spastic paraplegia, C2/C3 sensory level and urinary incontinence, as well as extensive inflammatory spinal cord lesions from C2 level to conus. After 5 months the patient had another attack of transverse myelitis, had electrophysiological findings consistent with optic neuritis, was seropositive for NMO-IgG (aquaporin-4 IgG) and thus fulfilled NMO diagnostic criteria. Following treatment of disease attacks with pulse corticosteroid therapy and intravenous immunoglobulins, we included oral azathioprine in a combination with oral prednisone in the therapy. Since there was no significant clinical improvement, we decided to use cyclophosphamide therapy, which resulted in good clinical improvement and gradual decrease of cord swelling. ----- CONCLUSION: In this NMO case report we wanted to emphasize the extensiveness of inflammatory spinal cord changes in our patient, from C2 level to conus. In the conclusion it is important to say that accurate, early diagnosis and distinction from MS is critical to facilitate initiation of immunosuppressive therapy for attack prevention

Cytotoxic T lymphocytes that recognize decameric peptide sequences of retinoblastoma binding protein 1 (RBP-1) associated with human breast cancer

Retinoblastoma binding protein 1 (RBP-1) is a 143-kDa nuclear phosphoprotein that promotes cell growth by inhibiting the product of retinoblastoma tumour suppressor gene (pRB). We recently found that RBP-1 contains KASIFLK, a heptameric peptide (250–256) recognized by human antibodies and overexpressed by breast cancer cells. In the present study, we demonstrate that human T-cells stimulated with RBP-1 decameric peptides containing KASIFLK can kill human breast cancer cells. These decamers, GLQKASIFLK (247–256) and KASIFLKTRV (250–259), have anchor motifs for both HLA-A2 and HLA-A3. Peripheral blood lymphocytes from 41 normal donors were stimulated by these peptides in culture media containing 15 IU ml−1 interleukin-2, 25 IU ml−1 interleukin-7 and 500 IU ml−1 granulocyte–macrophage colony-stimulating factor. Cytotoxic activity of the T-cells was assessed against autologous B lymphoblastoid cells pulsed with each peptide. Stimulation by GLQKASIFLK generated specific cytotoxic T lymphocyte (CTL) lines from HLA-A2, A3 donors, HLA-A2 donors and HLA-A3 donors. Stimulation with KASIFLKTRV generated specific CTL lines from HLA-A2 donors. No HLA-A2−, A3− CTL line showed specific cytotoxicity against these target cells. These CTL lines were also cytotoxic against HLA-A2 and HLA-A3 breast cancer cells but not against normal fibroblastoid cell lines, normal epidermal cell lines, or a melanoma cell line. RBP-1 peptide antigens may be of clinical significance as a potential peptide vaccine against human breast cancer. © 1999 Cancer Research Campaig

Pesticides and Parkinson’s Disease—Is There a Link?

Parkinson’s disease (PD) is an idiopathic disease of the nervous system characterized by progressive tremor, bradykinesia, rigidity, and postural instability. It has been postulated that exogenous toxicants, including pesticides, might be involved in the etiology of PD. In this article we present a comprehensive review of the published epidemiologic and toxicologic literature and critically evaluate whether a relationship exists between pesticide exposure and PD. From the epidemiologic literature, there does appear to be a relatively consistent relationship between pesticide exposure and PD. This relationship appears strongest for exposure to herbicides and insecticides, and after long durations of exposure. Toxicologic data suggest that paraquat and rotenone may have neurotoxic actions that potentially play a role in the development of PD, with limited data for other pesticides. However, both the epidemiology and toxicology studies were limited by methodologic weaknesses. Particular issues of current and future interest include multiple exposures (both pesticides and other exogenous toxicants), developmental exposures, and gene–environment interactions. At present, the weight of evidence is sufficient to conclude that a generic association between pesticide exposure and PD exists but is insufficient for concluding that this is a causal relationship or that such a relationship exists for any particular pesticide compound or combined pesticide and other exogenous toxicant exposure

Gelsolin dysfunction causes photoreceptor loss in induced pluripotent cell and animal retinitis pigmentosa models

Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause X-linked RP (XLRP), an untreatable, inherited retinal dystrophy that leads to premature blindness. RPGR localises to the photoreceptor connecting cilium where its function remains unknown. Here we show, using murine and human induced pluripotent stem cell models, that RPGR interacts with and activates the actin-severing protein gelsolin, and that gelsolin regulates actin disassembly in the connecting cilium, thus facilitating rhodopsin transport to photoreceptor outer segments. Disease-causing RPGR mutations perturb this RPGR-gelsolin interaction, compromising gelsolin activation. Both RPGR and Gelsolin knockout mice show abnormalities of actin polymerisation and mislocalisation of rhodopsin in photoreceptors. These findings reveal a clinically-significant role for RPGR in the activation of gelsolin, without which abnormalities in actin polymerisation in the photoreceptor connecting cilia cause rhodopsin mislocalisation and eventual retinal degeneration in XLRP.Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause retinal dystrophy, but how this arises at a molecular level is unclear. Here, the authors show in induced pluripotent stem cells and mouse knockouts that RPGR mediates actin dynamics in photoreceptors via the actin-severing protein, gelsolin

Prioritizing sleep for healthy work schedules

Good sleep is advantageous to the quality of life. Sleep-related benefits are particularly helpful for the working class, since poor or inadequate amounts of sleep degrade work productivity and overall health. This review paper explores the essential role of sleep in healthy work schedules and primarily focuses on the timing of sleep in relation to the work period (that is, before, during and after work). Data from laboratory, field and modeling studies indicate that consistent amounts of sleep prior to work are fundamental to improved performance and alertness in the workplace. In addition, planned naps taken during work maintain appropriate levels of waking function for both daytime and night-time work. Clearly, sufficient sleep after work is vital in promoting recovery from fatigue. Recent data also suggest that the time interval between shifts should be adjusted according to the biological timing of sleep. Although sleep is more likely to be replaced by job and other activities in the real life, research shows that it is worthwhile to revise the work schedules in order to optimize sleep before, sometime during and after the work period. Therefore, we suggest establishing work-sleep balance, similar to work-life balance, as a principle for designing and improving work schedules

Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts

Cortical microinfarcts (CMIs) observed in brains of patients with Alzheimer’s disease tend to be located close to vessels afflicted with cerebral amyloid angiopathy (CAA). CMIs in Alzheimer’s disease are preferentially distributed in the arterial borderzone, an area most vulnerable to hypoperfusion. However, the causal association between CAA and CMIs remains to be elucidated. This study consists of two parts: (1) an observational study using postmortem human brains (n = 31) to determine the association between CAA and CMIs, and (2) an experimental study to determine whether hypoperfusion worsens CAA and induces CMIs in a CAA mouse model. In postmortem human brains, the density of CMIs was 0.113/cm2 in mild, 0.584/cm2 in moderate, and 4.370/cm2 in severe CAA groups with a positive linear correlation (r = 0.6736, p < 0.0001). Multivariate analysis revealed that, among seven variables (age, disease, senile plaques, neurofibrillary tangles, CAA, atherosclerosis and white matter damage), only the severity of CAA was a significant multivariate predictor of CMIs (p = 0.0022). Consistent with the data from human brains, CAA model mice following chronic cerebral hypoperfusion due to bilateral common carotid artery stenosis induced with 0.18-mm diameter microcoils showed accelerated deposition of leptomeningeal amyloid β (Aβ) with a subset of them developing microinfarcts. In contrast, the CAA mice without hypoperfusion exhibited very few leptomeningeal Aβ depositions and no microinfarcts by 32 weeks of age. Following 12 weeks of hypoperfusion, cerebral blood flow decreased by 26% in CAA mice and by 15% in wild-type mice, suggesting impaired microvascular function due to perivascular Aβ accumulation after hypoperfusion. Our results suggest that cerebral hypoperfusion accelerates CAA, and thus promotes CMIs

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Strong interface-induced spin-orbit coupling in graphene on WS2

Interfacial interactions allow the electronic properties of graphene to be modified, as recently demonstrated by the appearance of satellite Dirac cones in the band structure of graphene on hexagonal boron nitride (hBN) substrates. Ongoing research strives to explore interfacial interactions in a broader class of materials in order to engineer targeted electronic properties. Here we show that at an interface with a tungsten disulfide (WS2) substrate, the strength of the spin-orbit interaction (SOI) in graphene is very strongly enhanced. The induced SOI leads to a pronounced low-temperature weak anti-localization (WAL) effect, from which we determine the spin-relaxation time. We find that spin-relaxation time in graphene is two-to-three orders of magnitude smaller on WS2 than on SiO2 or hBN, and that it is comparable to the intervalley scattering time. To interpret our findings we have performed first-principle electronic structure calculations, which both confirm that carriers in graphene-on-WS2 experience a strong SOI and allow us to extract a spin-dependent low-energy effective Hamiltonian. Our analysis further shows that the use of WS2 substrates opens a possible new route to access topological states of matter in graphene-based systems.Comment: Originally submitted version in compliance with editorial guidelines. Final version with expanded discussion of the relation between theory and experiments to be published in Nature Communication