Synchronization Landscapes in Small-World-Connected Computer Networks

Motivated by a synchronization problem in distributed computing we studied a simple growth model on regular and small-world networks, embedded in one and two-dimensions. We find that the synchronization landscape (corresponding to the progress of the individual processors) exhibits Kardar-Parisi-Zhang-like kinetic roughening on regular networks with short-range communication links. Although the processors, on average, progress at a nonzero rate, their spread (the width of the synchronization landscape) diverges with the number of nodes (desynchronized state) hindering efficient data management. When random communication links are added on top of the one and two-dimensional regular networks (resulting in a small-world network), large fluctuations in the synchronization landscape are suppressed and the width approaches a finite value in the large system-size limit (synchronized state). In the resulting synchronization scheme, the processors make close-to-uniform progress with a nonzero rate without global intervention. We obtain our results by ``simulating the simulations", based on the exact algorithmic rules, supported by coarse-grained arguments.Comment: 20 pages, 22 figure

Positional variations among heterogeneous nucleosome maps give dynamical information on chromatin

Although nucleosome remodeling is essential to transcriptional regulation in eukaryotes, little is known about its genome-wide behavior. Since a number of nucleosome positioning maps in vivo have been recently determined, we examined if their comparisons might be used for obtaining a genome-wide profile of nucleosome remodeling. Using seven yeast maps, the local variability of nucleosomes, measured by the entropy, was significantly higher in a set of reported unstable nucleosomes. The binding sites of four transcription factors, known as the remodeling factors, were distinctively high both in entropy and linker ratio, whereas those of Yhp1, their potential inhibitor, showed the lowest values in both of them. Taken together, our map shows the general information of nucleosome dynamics reasonably well. The “nucleosome dynamics” map provides the new significant correlation with the degree of expression variety instead of their intensity. Furthermore, the associations with gene function and histone modification were also discussed here

The Antibody Targeting the E314 Peptide of Human Kv1.3 Pore Region Serves as a Novel, Potent and Specific Channel Blocker

Selective blockade of Kv1.3 channels in effector memory T (TEM) cells was validated to ameliorate autoimmune or autoimmune-associated diseases. We generated the antibody directed against one peptide of human Kv1.3 (hKv1.3) extracellular loop as a novel and possible Kv1.3 blocker. One peptide of hKv1.3 extracellular loop E3 containing 14 amino acids (E314) was chosen as an antigenic determinant to generate the E314 antibody. The E314 antibody specifically recognized 63.8KD protein stably expressed in hKv1.3-HEK 293 cell lines, whereas it did not recognize or cross-react to human Kv1.1(hKv1.1), Kv1.2(hKv1.2), Kv1.4(hKv1.4), Kv1.5(hKv1.5), KCa3.1(hKCa3.1), HERG, hKCNQ1/hKCNE1, Nav1.5 and Cav1.2 proteins stably expressed in HEK 293 cell lines or in human atrial or ventricular myocytes by Western blotting analysis and immunostaining detection. By the technique of whole-cell patch clamp, the E314 antibody was shown to have a directly inhibitory effect on hKv1.3 currents expressed in HEK 293 or Jurkat T cells and the inhibition showed a concentration-dependence. However, it exerted no significant difference on hKv1.1, hKv1.2, hKv1.4, hKv1.5, hKCa3.1, HERG, hKCNQ1/hKCNE1, L-type Ca2+ or voltage-gated Na+ currents. The present study demonstrates that the antibody targeting the E314 peptide of hKv1.3 pore region could be a novel, potent and specific hKv1.3 blocker without affecting a variety of closely related Kv1 channels, KCa3.1 channels and functional cardiac ion channels underlying central nervous systerm (CNS) disorders or drug-acquired arrhythmias, which is required as a safe clinic-promising channel blocker

Inhibition of HERG1 K+ channel protein expression decreases cell proliferation of human small cell lung cancer cells

HERG (human ether-à-go-go-related gene) K+ currents fulfill important ionic functions in cardiac and other excitable cells. In addition, HERG channels influence cell growth and migration in various types of tumor cells. The mechanisms underlying these functions are still not resolved. Here, we investigated the role of HERG channels for cell growth in a cell line (SW2) derived from small cell lung cancer (SCLC), a malignant variant of lung cancer. The two HERG1 isoforms (HERG1a, HERG1b) as well as HERG2 and HERG3 are expressed in SW2 cells. Inhibition of HERG currents by acute or sustained application of E-4031, a specific ERG channel blocker, depolarized SW2 cells by 10–15 mV. This result indicated that HERG K+ conductance contributes considerably to the maintenance of the resting potential of about −45 mV. Blockage of HERG channels by E-4031 for up to 72 h did not affect cell proliferation. In contrast, siRNA-induced inhibition of HERG1 protein expression decreased cell proliferation by about 50%. Reduction of HERG1 protein expression was confirmed by Western blots. HERG current was almost absent in SW2 cells transfected with siRNA against HERG1. Qualitatively similar results were obtained in three other SCLC cell lines (OH1, OH3, H82), suggesting that the HERG1 channel protein is involved in SCLC cell growth, whereas the ion-conducting function of HERG1 seems not to be important for cell growth

Developmental Expression of Kv Potassium Channels at the Axon Initial Segment of Cultured Hippocampal Neurons

Axonal outgrowth and the formation of the axon initial segment (AIS) are early events in the acquisition of neuronal polarity. The AIS is characterized by a high concentration of voltage-dependent sodium and potassium channels. However, the specific ion channel subunits present and their precise localization in this axonal subdomain vary both during development and among the types of neurons, probably determining their firing characteristics in response to stimulation. Here, we characterize the developmental expression of different subfamilies of voltage-gated potassium channels in the AISs of cultured mouse hippocampal neurons, including subunits Kv1.2, Kv2.2 and Kv7.2. In contrast to the early appearance of voltage-gated sodium channels and the Kv7.2 subunit at the AIS, Kv1.2 and Kv2.2 subunits were tethered at the AIS only after 10 days in vitro. Interestingly, we observed different patterns of Kv1.2 and Kv2.2 subunit expression, with each confined to distinct neuronal populations. The accumulation of Kv1.2 and Kv2.2 subunits at the AIS was dependent on ankyrin G tethering, it was not affected by disruption of the actin cytoskeleton and it was resistant to detergent extraction, as described previously for other AIS proteins. This distribution of potassium channels in the AIS further emphasizes the heterogeneity of this structure in different neuronal populations, as proposed previously, and suggests corresponding differences in action potential regulation

Histone acetylome-wide associations in immune cells from individuals with active Mycobacterium tuberculosis infection

Host cell chromatin changes are thought to play an important role in the pathogenesis of infectious diseases. Here we describe a histone acetylome-wide association study (HAWAS) of an infectious disease, on the basis of genome-wide H3K27 acetylation profiling of peripheral blood granulocytes and monocytes from persons with active Mycobacterium tuberculosis (Mtb) infection and healthy controls. We detected >2,000 differentially acetylated loci in either cell type in a Singapore Chinese discovery cohort (n = 46), which were validated in a subsequent multi-ethnic Singapore cohort (n = 29), as well as a longitudinal cohort from South Africa (n = 26), thus demonstrating that HAWAS can be independently corroborated. Acetylation changes were correlated with differential gene expression. Differential acetylation was enriched near potassium channel genes, including KCNJ15, which modulates apoptosis and promotes Mtb clearance in vitro. We performed histone acetylation quantitative trait locus (haQTL) analysis on the dataset and identified 69 candidate causal variants for immune phenotypes among granulocyte haQTLs and 83 among monocyte haQTLs. Our study provides proof-of-principle for HAWAS to infer mechanisms of host response to pathogens

Kitozanski umetci za periodontitis: Utjecaj količine lijeka, plastifikatora i umrežavanja na oslobađanje metronidazola in vitro

Chitosan based metronidazole (MZ) inserts were fabricated by the casting method and characterized with respect to mass and thickness uniformity, metronidazole loading and in vitro metronidazole release kinetics. The fabricated inserts exhibited satisfactory physical characteristics. The mass of inserts was in the range of 5.63 ± 0.42 to 6.04 ± 0.89 mg. The thickness ranged from 0.46 ± 0.06 to 0.49 ± 0.08 mm. Metronidazole loading was in the range of 0.98 ± 0.09 to 1.07 ± 0.07 mg except for batch CM3 with MZ loading of 2.01 ± 0.08 mg. The inserts exhibited an initial burst release at the end of 24 h, irrespective of the drug to polymer ratio, plasticizer content or cross-linking. However, further drug release was sustained over the next 6 days. Cross-linking with 10% (m/m) of glutaraldehyde inhibited the burst release by ~30% and increased the mean dissolution time (MDT) from 0.67 to 8.59 days. The decrease in drug release was a result of reduced permeability of chitosan due to cross-linking.Umetci metronidazola na bazi kitozana napravljeni su kasting metodom. Proučavana je ujednačenost mase i debljine, količina ljekovite tvari i kinetika oslobađanja metronidazola in vitro. Fizičke karakteristike umetaka bile su zadovoljavajuće: masa je bila u rasponu 5,63 ± 0,42 – 6,04 ± 0,89 mg, debljina od 0.46 ± 0.06 – 0.49 ± 0.08 mm with, količina metronidazola od 0,98 ± 0,09 – 1,07 ± 0,07 mg. Nakon 24 h iz svih umetaka, neovisno o omjeru ljekovite tvari i polimera, količini plastifikatora ili umrežavanju, dio metronidazola se naglo oslobodio. Međutim, daljnje oslobađanje je bilo polagano tijekom 6 dana. Umrežavanje s 10% (m/m) otopinom glutaraldehida spriječilo je naglo oslobađanje za ~30% i povećalo je srednje vrijeme oslobađanja (MDT) s 0,67 na 8,59 dana. Smanjenje u oslobađanju ljekovite tvari posljedica je smanjenja permeabilnosti umreženog kitozana

Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021

Background: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050. Methods: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8–63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0–45·0] in 2050) and south Asia (31·7% [29·2–34·1] to 15·5% [13·7–17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4–40·3) to 41·1% (33·9–48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6–25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5–43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5–17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7–11·3) in the high-income super-region to 23·9% (20·7–27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5–6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2–26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [–0·6 to 3·6]). Interpretation: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions

Active memory controller

Inability to hide main memory latency has been increasingly limiting the performance of modern processors. The problem is worse in large-scale shared memory systems, where remote memory latencies are hundreds, and soon thousands, of processor cycles. To mitigate this problem, we propose an intelligent memory and cache coherence controller (AMC) that can execute Active Memory Operations (AMOs). AMOs are select operations sent to and executed on the home memory controller of data. AMOs can eliminate a significant number of coherence messages, minimize intranode and internode memory traffic, and create opportunities for parallelism. Our implementation of AMOs is cache-coherent and requires no changes to the processor core or DRAM chips. In this paper, we present the microarchitecture design of AMC, and the programming model of AMOs. We compare AMOs\u27 performance to that of several other memory architectures on a variety of scientific and commercial benchmarks. Through simulation, we show that AMOs offer dramatic performance improvements for an important set of data-intensive operations, e.g., up to 50x faster barriers, 12x faster spinlocks, 8.5x-15x faster stream/array operations, and 3x faster database queries. We also present an analytical model that can predict the performance benefits of using AMOs with decent accuracy. The silicon cost required to support AMOs is less than 1% of the die area of a typical high performance processor, based on a standard cell implementation