Polyubiquitin chain assembly and organization determine the dynamics of protein activation and degradation

Protein degradation via ubiquitination is a major proteolytic mechanism in cells. Once a protein is destined for degradation, it is tagged by multiple ubiquitin (Ub) molecules. The synthesized polyubiquitin chains can be recognized by the 26S proteosome where proteins are degraded. These chains form through multiple ubiquitination cycles that are similar to multi-site phosphorylation cycles. As kinases and phosphatases, two opposing enzymes (E3 ligases and deubiquitinases DUBs) catalyze (de)ubiquitination cycles. Although multi-ubiquitination cycles are fundamental mechanisms of controlling protein concentrations within a cell, their dynamics have never been explored. Here, we fill this knowledge gap. We show that under permissive physiological conditions, the formation of polyubiquitin chain of length greater than two and subsequent degradation of the ubiquitinated protein, which is balanced by protein synthesis, can display bistable, switch-like responses. Interestingly, the occurrence of bistability becomes pronounced, as the chain grows, giving rise to “all-or-none” regulation at the protein levels. We give predictions of protein distributions under bistable regime awaiting experimental verification. Importantly, we show for the first time that sustained oscillations can robustly arise in the process of formation of ubiquitin chain, largely due to the degradation of the target protein. This new feature is opposite to the properties of multi-site phosphorylation cycles, which are incapable of generating oscillation if the total abundance of interconverted protein forms is conserved. We derive structural and kinetic constraints for the emergence of oscillations, indicating that a competition between different substrate forms and the E3 and DUB is critical for oscillation. Our work provides the first detailed elucidation of the dynamical features brought about by different molecular setups of the polyubiquitin chain assembly process responsible for protein degradation

Intensified Antituberculosis Therapy in Adults with Tuberculous Meningitis

BACKGROUND Tuberculous meningitis is often lethal. Early antituberculosis treatment and adjunctive treatment with glucocorticoids improve survival, but nearly one third of patients with the condition still die. We hypothesized that intensified antituberculosis treatment would enhance the killing of intracerebral Mycobacterium tuberculosis organisms and decrease the rate of death among patients. METHODS We performed a randomized, double-blind, placebo-controlled trial involving human immunodeficiency virus (HIV)-infected adults and HIV-uninfected adults with a clinical diagnosis of tuberculous meningitis who were admitted to one of two Vietnamese hospitals. We compared a standard, 9-month antituberculosis regimen (which included 10 mg of rifampin per kilogram of body weight per day) with an intensified regimen that included higher-dose rifampin (15 mg per kilogram per day) and levofloxacin (20 mg per kilogram per day) for the first 8 weeks of treatment. The primary outcome was death by 9 months after randomization. RESULTS A total of 817 patients (349 of whom were HIV-infected) were enrolled; 409 were randomly assigned to receive the standard regimen, and 408 were assigned to receive intensified treatment. During the 9 months of follow-up, 113 patients in the intensified-treatment group and 114 patients in the standard-treatment group died (hazard ratio, 0.94; 95% confidence interval, 0.73 to 1.22; P=0.66). There was no evidence of a significant differential effect of intensified treatment in the overall population or in any of the subgroups, with the possible exception of patients infected with isoniazid-resistant M. tuberculosis. There were also no significant differences in secondary outcomes between the treatment groups. The overall number of adverse events leading to treatment interruption did not differ significantly between the treatment groups (64 events in the standard-treatment group and 95 events in the intensified-treatment group, P=0.08). CONCLUSIONS Intensified antituberculosis treatment was not associated with a higher rate of survival among patients with tuberculous meningitis than standard treatment. (Funded by the Wellcome Trust and the Li Ka Shing Foundation; Current Controlled Trials number, ISRCTN61649292.)

Effect of Inclusion of Fresh or dried black soldier fly larvae in Diets on Snakehead Fish's Growth Performance and Chemical Composition (<em>Channa sp.</em>)

In snakehead fish farming, feeding represents the largest portion (accounting for 50-60%) of production cost. Thus, finding an alternative natural feed that can be replaced as full or partial inclusion in snakehead fish commercial diets is urgently needed. This study was carried out to evaluate the effect of including fresh or dried black soldier fly larvae (BSFL) in diets on the growth performance and chemical composition of snakehead fish cultured in small-scale farms. Fingerlings of snakehead (5.15 ± 0.12 g) were distributed randomly into fifteen net cages (6 m^3^) at a density of 120 fish.net cage^-1^. Including five dietary treatments named: NT1 (100% commercial feed served as a control); NT2 (100% fresh BSFL); NT3 (100% dried BSFL); NT4 (50% fresh BSFL + 50% commercial feed); and NT5 (50% dried BSFL + 50% commercial feed). Each treatment was performed in triplicate. The results showed that the inclusion of fresh BSFL in diets for the snakehead fish did not affect the survival rate (82.22 - 85.56 %), improved feed conversion ratio, increased live weight (70.9 – 103.3 g) and daily weight gain (1.09 – 1.64 g.day^-1^), and fish’s yield (1.16 – 1.73 kg.m^-2^); and did not affect the chemical composition of the fish. These findings suggest that farmers should feed snakehead fish with commercial feed plus fresh black soldier fly larvae to maintain good condition factor and enhance fish growth performance and production

Promocijas darbs

Darbā ir apkopota literatūra par furāna un tiofēna karbonilgrupas atvasinājumu, silatrānu un germatrānu iegūšanas metodēm. Tika sintezēti aminosililgrupu saturoši furfurola dietilacetāli, silīciju un germāniju saturoši furāna un tiofēna karbonilsavienojumi, veiktas karbonilgrupas reakcijas un iegūti jauni furil(tienil)nitroni, -aldimīni, -laktoni, -metilēn-bis-indoli, -ketoksīmi, -O-alkil- ketoksīmi, -1,5-benzodiazepīni. Sintezēti silatrāni un bis-germatrāni. Sintezēto savienojumu struktūras pierādītas ar spektrometriskajām metodēm, izpētīta un salīdzināta iegūto vielu bioloģiskā aktivitāte. Perspektīvākajām savienojumu klasēm noteikta spēja inhibēt angioģenēzi un matricas metaloproteināzes.Synthesis of furane and thiophene carbonyl group containing derivatives, silatranes and germatranes have been reviewed. Were synthesized aminosilyl group containing furfurol diethylacetals, silicon and germanium containing furane and thiophene carbonyl compounds, performed carbonyl group reactions and obtained new furyl(thienyl)nitrones, -aldimines, -lactones, -methylene-bis-indoles, -ketoximes, -O-alkylketoximes, -1,5-benzodiazepines. Were synthesized silatranes and bis-germatranes. Structure of the synthesized compounds demonstrated by spectrometrical methods and studied and compared the biological activity of substances. For the most promising compounds a certain ability to inhibit angiogenesis and matrix metalloproteinase was determine

The Asthma Control Test (ACT) as an alternative tool to Global Initiative for Asthma (GINA) guideline criteria for assessing asthma control in Vietnamese outpatients

Prevention, Population and Disease management (PrePoD

Simulation Study of an LWFA-based Electron Injector for AWAKE Run 2

The AWAKE experiment aims to demonstrate preservation of injected electron beam quality during acceleration in proton-driven plasma waves. The short bunch duration required to correctly load the wakefield is challenging to meet with the current electron injector system, given the space available to the beamline. An LWFA readily provides short-duration electron beams with sufficient charge from a compact design, and provides a scalable option for future electron acceleration experiments at AWAKE. Simulations of a shock-front injected LWFA demonstrate a 43 TW laser system would be sufficient to produce the required charge over a range of energies beyond 100 MeV. LWFA beams typically have high peak current and large divergence on exiting their native plasmas, and optimisation of bunch parameters before injection into the proton-driven wakefields is required. Compact beam transport solutions are discussed.Comment: Paper submitted to NIMA proceedings for the 3rd European Advanced Accelerator Concepts Workshop. 4 pages, 3 figures, 1 table Changes after revision: Figure 2: figures 2 and 3 of the previous version collated with plots of longitudinal electric field Line 45: E_0 = 96 GV/m Lines 147- 159: evaluation of beam loading made more accurate Lines 107 - 124: discussion of simulation geometry move

Non-coding RNA ANRIL and the number of plexiform neurofibromas in patients with NF1microdeletions

BACKGROUND: Neurofibromatosis type-1 (NF1) is caused by mutations of the NF1 gene at 17q11.2. In 95% of non-founder NF1 patients, NF1 mutations are identifiable by means of a comprehensive mutation analysis. 5-10% of these patients harbour microdeletions encompassing the NF1 gene and its flanking regions. NF1 is characterised by tumours of the peripheral nerve sheaths, the pathognomonic neurofibromas. Considerable inter- and intra-familial variation in expressivity of the disease has been observed which is influenced by genetic modifiers unrelated to the constitutional NF1 mutation. The number of plexiform neurofibromas (PNF) in NF1 patients is a highly heritable genetic trait. Recently, SNP rs2151280 located within the non-coding RNA gene ANRIL at 9p21.3, was identified as being strongly associated with PNF number in a family-based association study. The T-allele of rs2151280, which correlates with reduced ANRIL expression, appears to be associated with higher PNF number. ANRIL directly binds to the SUZ12 protein, an essential component of polycomb repressive complex 2, and is required for SUZ12 occupancy of the CDKN2A/CDKN2B tumour suppressor genes as well as for their epigenetic silencing. METHODS: Here, we explored a potential association of PNF number and PNF volume with SNP rs2151280 in 29 patients with constitutional NF1 microdeletions using the exact Cochran-Armitage test for trends and the exact Mann–Whitney–Wilcoxon test. Both the PNF number and total tumour volume in these 29 NF1 patients were assessed by whole-body MRI. The NF1 microdeletions observed in these 29 patients encompassed the NF1 gene as well as its flanking regions, including the SUZ12 gene. RESULTS: In the 29 microdeletion patients investigated, neither the PNF number nor PNF volume was found to be associated with the T-allele of rs2151280. CONCLUSION: Our findings imply that, at least in patients with NF1 microdeletions, PNF susceptibility is not associated with rs2151280. Although somatic inactivation of the NF1 wild-type allele is considered to be the PNF-initiating event in NF1 patients with intragenic mutations and patients with NF1 microdeletions, both patient groups may differ with regard to tumour progression because of the heterozygous constitutional deletion of SUZ12 present only in patients with NF1 microdeletions