Driven translocation of a polynucleotide chain through a nanopore--A continuous time Monte-Carlo study

Using continuous time Monte-Carlo method we simulated the translocation of a polynucleotide chain driven through a nanopore by an electric field. We have used two models of driven diffusion due to the electric field. The chain may have strong interaction with the pore, and depends on which end of the chain first enters the pore. Depending on this interaction, in both cases, the distribution of times for the chain to pass through the pore in our model is found to have three peaks, as observed in the experiment of Kasianowicz, Brandin, Branton and Deamer (KBBD).Comment: 26 pages, 6 figure

Statin associated necrotizing autoimmune myopathies in the Indigenous population: a case series from North Queensland

Aim: To describe clinical and histopathological features of statin associated necrotizing autoimmune myopathies (NAM) in Indigenous Australians and increase awareness of this condition amongst treating physicians. Methods: Cases were collected through the Rheumatology Department at The Townsville Hospital between March 2012 and January 2015. A chart review was performed to obtain retrospective information about each case. We detail patient demographics, presenting features, histopathological findings, autoimmune profile, treatment and outcomes. Results: 4 Indigenous Australians were identified as having a biopsy confirmed statin associated NAM. All patients had been on atorvastatin for at least 2 years and had significant proximal weakness with average CK level on presentation 16,820 U/L. Predisposing factors for myopathy included vitamin D deficiency and diabetes mellitus (all cases), with primary hypothyroidism and liver cirrhosis identified in two other cases. Two individuals were positive for the auto-antibody anti-HMGCR. Histopathological findings included muscle necrosis with varying degrees of inflammation, membrane attack complex (MAC) deposition and MHC-1 upregulation. Treatment involved various combinations of prednisolone, IVIG, methotrexate and mycophenolate. Recovery was slow but favourable in all cases with an average length of inpatient stay of 54 days. There was a significant delay in diagnosis of 1–3 months in two of the cases. Conclusions: The statin associated necrotizing autoimmune myopathies are rare but important disorders that cause significant morbidity to affected individuals. Given the prevalence of cardiovascular disease in Indigenous Australians, further research is required to facilitate earlier diagnosis and improved treatment outcomes

Statin associated necrotizing autoimmune myopathies in the Indigenous population: a case series from North Queensland

Aim: To describe clinical and histopathological features of statin associated necrotizing autoimmune myopathies (NAM) in Indigenous Australians and increase awareness of this condition amongst treating physicians. Methods: Cases were collected through the Rheumatology Department at The Townsville Hospital between March 2012 and January 2015. A chart review was performed to obtain retrospective information about each case. We detail patient demographics, presenting features, histopathological findings, autoimmune profile, treatment and outcomes. Results: 4 Indigenous Australians were identified as having a biopsy confirmed statin associated NAM. All patients had been on atorvastatin for at least 2 years and had significant proximal weakness with average CK level on presentation 16,820 U/L. Predisposing factors for myopathy included vitamin D deficiency and diabetes mellitus (all cases), with primary hypothyroidism and liver cirrhosis identified in two other cases. Two individuals were positive for the auto-antibody anti-HMGCR. Histopathological findings included muscle necrosis with varying degrees of inflammation, membrane attack complex (MAC) deposition and MHC-1 upregulation. Treatment involved various combinations of prednisolone, IVIG, methotrexate and mycophenolate. Recovery was slow but favourable in all cases with an average length of inpatient stay of 54 days. There was a significant delay in diagnosis of 1–3 months in two of the cases. Conclusions: The statin associated necrotizing autoimmune myopathies are rare but important disorders that cause significant morbidity to affected individuals. Given the prevalence of cardiovascular disease in Indigenous Australians, further research is required to facilitate earlier diagnosis and improved treatment outcomes

Interlaboratory comparison to evaluate the methodology for determination of the media filtration efficiency against nanoparticles

Current international standards dealing with efficiency test for filters and filter media focus on measurement of the minimum efficiency at the most penetrating particle size. The available knowledge and instruments provide a solid base for development of test methods to determine the effectiveness of filtration media against airborne nanoparticles down to single-digit nanometer range. An interlaboratory evaluation was performed in the framework of the European Mandate M/461 activities, within the Technical Committee 195 of European Committee for Standardization (CEN/TC195). The purpose was to develop a methodology to determine effectiveness of filtration media against air-borne particles in the 3 – 500 nm range. Five different laboratories (Camfil, ETH/Empa, Politecnico di Torino, University of Minnesota, Unifil) participate in the round robin test in order to verify the repeatability and reproducibility of the test method. The qualification of test rig and apparatus was performed prior of the filtration efficiency and air flow resistance measurement tests.Twilled dutch weave wire mesh was chosen to perform the validation filtration efficiency tests so as to ensure high uniformity of the samples being tested by each different laboratory. We present the experimental data with the discussion about their validity

A pilot controlled trial of a combination of dense cranial electroacupuncture stimulation and body acupuncture for post-stroke depression

BACKGROUND: Our previous studies have demonstrated the treatment benefits of dense cranial electroacupuncture stimulation (DCEAS), a novel brain stimulation therapy in patients with major depression, postpartum depression and obsessive-compulsive disorder. The purpose of the present study was to further evaluate the effectiveness of DCEAS combined with body acupuncture and selective serotonin reuptake inhibitors (SSRIs) in patients with post-stroke depression (PSD). METHODS: In a single-blind, randomized controlled trial, 43 patients with PSD were randomly assigned to 12 sessions of DCEAS plus SSRI plus body electroacupuncture (n = 23), or sham (non-invasive cranial electroacupuncture, n-CEA) plus SSRI plus body electroacupuncture (n = 20) for 3 sessions per week over 4 weeks. Treatment outcomes were measured using the 17-item Hamilton Depression Rating Scale (HAMD-17), the Clinical Global Impression - Severity scale (CGI-S) and Barthel Index (BI), a measure used to evaluate movement ability associated with daily self-caring activity. RESULTS: DCEAS produced a significantly greater reduction of both HAMD-17 and CGI-S as early as week 1 and CGI-S at endpoint compared to n-CEA, but subjects of n-CEA group exhibited a significantly greater improvement on BI at week 4 than DCEAS. Incidence of adverse events was not different in the two groups. CONCLUSIONS: These results indicate that DCEAS could be effective in reducing stroke patients’ depressive symptoms. Superficial electrical stimulation in n-CEA group may be beneficial in improving movement disability of stroke patients. A combination of DCEAS and body acupuncture can be considered a treatment option for neuropsychiatric sequelae of stroke. TRIAL REGISTRATION: http://www.clinicaltrials.gov, NCT01174394

Comparative Efficacy of Hemagglutinin, Nucleoprotein, and Matrix 2 Protein Gene-Based Vaccination against H5N1 Influenza in Mouse and Ferret

Efforts to develop a broadly protective vaccine against the highly pathogenic avian influenza A (HPAI) H5N1 virus have focused on highly conserved influenza gene products. The viral nucleoprotein (NP) and ion channel matrix protein (M2) are highly conserved among different strains and various influenza A subtypes. Here, we investigate the relative efficacy of NP and M2 compared to HA in protecting against HPAI H5N1 virus. In mice, previous studies have shown that vaccination with NP and M2 in recombinant DNA and/or adenovirus vectors or with adjuvants confers protection against lethal challenge in the absence of HA. However, we find that the protective efficacy of NP and M2 diminishes as the virulence and dose of the challenge virus are increased. To explore this question in a model relevant to human disease, ferrets were immunized with DNA/rAd5 vaccines encoding NP, M2, HA, NP+M2 or HA+NP+M2. Only HA or HA+NP+M2 vaccination conferred protection against a stringent virus challenge. Therefore, while gene-based vaccination with NP and M2 may provide moderate levels of protection against low challenge doses, it is insufficient to confer protective immunity against high challenge doses of H5N1 in ferrets. These immunogens may require combinatorial vaccination with HA, which confers protection even against very high doses of lethal viral challenge

A Phase 1 Study of ADI-PEG20 (Pegargiminase) Combined with Cisplatin and Pemetrexed in ASS1-Negative Metastatic Uveal Melanoma

Metastatic uveal melanoma (UM) is a devastating disease with few treatment options. We evaluated the safety, tolerability and preliminary activity of arginine depletion using pegylated arginine deiminase (ADI-PEG20; pegargiminase) combined with pemetrexed (Pem) and cisplatin (Cis) chemotherapy in a phase 1 dose-expansion study of patients with argininosuccinate synthetase (ASS1)-deficient metastatic UM. Eligible patients received up to six cycles of Pem (500 mg/m2 ) and Cis (75 mg/m2 ) every three weeks plus weekly intramuscular ADI (36 mg/m2 ), followed by maintenance ADI until progression (NCT02029690). Ten of fourteen ASS1-deficient patients with UM liver metastases and a median of one line of prior immunotherapy received ADIPemCis. Only one ≥ grade 3 adverse event of febrile neutropenia was reported. Seven patients had stable disease with a median progression-free survival of 3.0 months (range, 1.3-8.1) and a median overall survival of 11.5 months (range, 3.2-36.9). Despite anti-ADI-PEG20 antibody emergence, plasma arginine concentrations remained suppressed by 18 weeks with a reciprocal increase in plasma citrulline. Tumour rebiopsies at progression revealed ASS1 re-expression as an escape mechanism. ADIPemCis was well tolerated with modest disease stabilisation in metastatic UM. Further investigation of arginine deprivation is indicated in UM including combinations with immune checkpoint blockade and additional antimetabolite strategies

Structure-based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1

The treatment of Human African Trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important and pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp. has been identified as a candidate target and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from T. brucei (J. Med. Chem. 2010, 53, 221-229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. 8 compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development

A novel Hsp90 inhibitor AT13387 induces senescence in EBV-positive nasopharyngeal carcinoma cells and suppresses tumor formation

Background: Nasopharyngeal carcinoma (NPC) is an epithelial malignancy strongly associated with Epstein-Barr virus (EBV). AT13387 is a novel heat shock protein 90 (Hsp90) inhibitor, which inhibits the chaperone function of Hsp90 and reduces expression of Hsp90-dependent client oncoproteins. This study aimed to evaluate both the in vitro and in vivo antitumor effects of AT13387 in the EBV-positive NPC cell line C666-1.Results: Our results showed that AT13387 inhibited C666-1 cell growth and induced cellular senescence with the downregulation of multiple Hsp90 client oncoproteins EGFR, AKT, CDK4, and restored the protein expression of negative cell cycle regulator p27. We also studied the ability of AT13387 to restore p27 expression by downregulation of AKT and the p27 ubiquitin mediator, Skp2, using AKT inhibitor and Skp2 siRNA. In the functional study, AT13387 inhibited cell migration with downregulation of a cell migration regulator, HDAC6, and increased the acetylation and stabilization of α-tubulin. We also examined the effect of AT13387 on putative cancer stem cells (CSC) by 3-D tumor sphere formation assay. AT13387 effectively reduced both the number and size of C666-1 tumor spheres with decreased expression of NPC CSC-like markers CD44 and SOX2. In the in vivo study, AT13387 significantly suppressed tumor formation in C666-1 NPC xenografts.Conclusion: AT13387 suppressed cell growth, cell migration, tumor sphere formation and induced cellular senescence on EBV-positive NPC cell line C666-1. Also, the antitumor effect of AT13387 was demonstrated in an in vivo model. This study provided experimental evidence for the preclinical value of using AT13387 as an effective antitumor agent in treatment of NPC. © 2013 Chan et al.; licensee BioMed Central Ltd.published_or_final_versio

Forest-Fire Model with Resistant Trees

The role of forest heterogeneity in the long-term, large-scale dynamics of forest fires is investigated by means of a cellular automata model and mean field approximation. Heterogeneity was conceived as trees (or acres of forest) with distinct strengths of resistance to burn. The scaling analysis of fire-size and fire-lifetime frequency distributions in the non-interacting fire steady-state limit indicates the breakdown of the power-law behavior whenever the resistance strength parameter R exceeds a certain value. For higher resistant strength, exponential behavior characterizes the frequency distributions, while power-law like behavior was observed for the lower resistant case in the same manner as reported in the literature for a homogeneous counterpart model. For the intermediate resistance strength, however, it may be described either by a stretched exponential or by a power-law plot whenever the fraction of recovering empty cells by susceptible trees not-exceeds or exceeds a certain threshold respectively, also suggesting a dynamical percolation transition with respect to the stationary forest density.Comment: 14 pages, 4 figures; J. Stat. Mech. (2011) P0602