Drug combinations, offering increased therapeutic efficacy and reduced toxicity, play an important role in treating multiple complex diseases. Yet, our ability to identify and validate effective ...combinations is limited by a combinatorial explosion, driven by both the large number of drug pairs as well as dosage combinations. Here we propose a network-based methodology to identify clinically efficacious drug combinations for specific diseases. By quantifying the network-based relationship between drug targets and disease proteins in the human protein-protein interactome, we show the existence of six distinct classes of drug-drug-disease combinations. Relying on approved drug combinations for hypertension and cancer, we find that only one of the six classes correlates with therapeutic effects: if the targets of the drugs both hit disease module, but target separate neighborhoods. This finding allows us to identify and validate antihypertensive combinations, offering a generic, powerful network methodology to identify efficacious combination therapies in drug development.
Context. Core condensation is a critical step in the star-formation process, but it is still poorly characterized observationally. Aims. We have studied the 10 pc-long L1495/B213 complex in Taurus to ...investigate how dense cores have condensed out of the lower density cloud material. Methods. We observed L1495/B213 in C18O(1−0), N2H+(1−0), and SO(JN = 32–21) with the 14 m FCRAO telescope, and complemented the data with dust continuum observations using APEX (870 μm) and IRAM 30 m (1200 μm). Results. From the N2H+ emission, we identify 19 dense cores, some starless and some protostellar. They are not distributed uniformly, but tend to cluster with relative separations on the order of 0.25 pc. From the C18O emission, we identify multiple velocity components in the gas. We have characterized them by fitting Gaussians to the spectra and by studying the distribution of the fits in position–position–velocity space. In this space, the C18O components appear as velocity-coherent structures, and we identify them automatically using a dedicated algorithm (FIVE: Friends In VElocity). Using this algorithm, we identify 35 filamentary components with typical lengths of 0.5 pc, sonic internal velocity dispersions, and mass-per-unit length close to the stability threshold of isothermal cylinders at 10 K. Core formation seems to have occurred inside the filamentary components via fragmentation, with few fertile components with higher mass-per-unit length being responsible for most cores in the cloud. On large scales, the filamentary components appear grouped into families, which we refer to as bundles. Conclusions. Core formation in L1495/B213 has proceeded by hierarchical fragmentation. The cloud fragmented first into several pc-scale regions. Each of these regions later fragmented into velocity-coherent filaments of about 0.5 pc in length. Finally, a small number of these filaments fragmented quasi-statically and produced the individual dense cores we see today.
Many fundamental processes of life depend on the chemical energy stored in the O–O bond of dioxygen (O2), the majority of which is derived from photosynthetic H2O oxidation. Key steps in these ...processes involve Mn-, Fe-, or Cu-promoted formation or cleavage of O–O and O–H bonds, the mechanisms of which are not fully understood, especially with Mn. Metal–peroxo and high-valent metal–oxo species are proposed to be involved as intermediates. The metal ion properties that favor O–O and O–H bond formation versus cleavage have yet to be systematically explored. Herein we examine the O2 reactivity of a series of structurally related Mn(II) complexes and show that several metastable intermediates are observed, the relative stabilities of which depend on subtle differences in ligand architecture. We show that in contrast to Fe and Cu complexes, O2 binds irreversibly to Mn(II). By crystallizing an entire series of the first reported examples of Mn(III)–OOR peroxos as well as an O2-derived binuclear trans-μ-1,2-bridged Mn(III)–peroxo with varying degrees of O–O bond activation, we demonstrate that there are distinct correlations between spectroscopic, structural, and reactivity properties. Rate-limiting O–O bond cleavage is shown to afford a reactive species capable of abstracting H atoms from 2,4- t Bu2-PhOH or 1,4-cyclohexadiene, depending on the ligand substituents. The weakly coordinated N-heterocycle Mn···Npy,quino distance is shown to correlate with the peroxo O–O bond length and modulate the π overlap between the filled πv *(O–O) and Mn d xz orbitals. We also show that there is a strong correlation between the peroxo → Mn charge transfer (CT) band and the peroxo O–O bond length. The energy difference between the CT bands associated with the peroxos possessing the shortest and longest O–O bonds shows that these distances are spectroscopically distinguishable. We show that we can use this spectroscopic parameter to estimate the O–O bond length, and thus the degree of O–O bond activation, in intermediates for which there is no crystal structure, as long as the ligand environment is approximately the same.
•We propose the first dial-a-ride problem that considers service consistency.•Two formulations are proposed and solved by a tailored Branch-and-Cut algorithm.•A simple metaheuristic generates ...near-optimal solutions in a short amount of time.•An extensive numerical analysis with more than 1000 instances is presented.•Transporting users with 2 drivers is a good compromise between consistency and cost.
Dial-a-ride services provide disabled and elderly people with a personalized mode of transportation to preserve their mobility. Typically, several users with different pickup and dropoff locations are transported on a vehicle simultaneously. The focus in dial-a-ride problems (DARPs) is mainly on minimizing routing cost. Service quality has been taken into account in the models by imposing time windows and limiting the maximum ride time of each user. We extend the classical DARP by an additional feature of service quality referred to as driver consistency. Customers of dial-a-ride services are often sensitive to changes in their daily routine. This aspect includes the person who is providing the transportation service, i.e., the driver of the vehicle. Our problem, called the driver consistent dial-a-ride problem (DC-DARP), considers driver consistency by bounding the maximum number of different drivers that transport a user over a multi-period planning horizon.
We propose different formulations of the problem and examine their efficiency when applied in a Branch-and-Cut fashion. Additionally, we develop a large neighborhood search algorithm that generates near-optimal solutions in a short amount of time.
Over 1000 instances are generated with close reference to real world scenarios. Extensive computational experiments are conducted in order to assess the quality of the solution approaches and to provide insights into the new problem. Results reveal that the cost of offering driver consistency varies greatly in magnitude. Depending on the instance, the cost of assigning one driver to each user can be up to 27.98% higher compared to a low-cost solution. However, routing cost increases by not more than 5.80% if users are transported by at least two drivers.
Human immunodeficiency virus (HIV) persists in peripheral blood mononuclear cells despite sustained, undetectable plasma viremia resulting from long-term antiretroviral therapy. However, the source ...of persistentHIVin such infected individuals remains unclear. Given recent data suggesting high levels of viral replication and profound depletion of CD4+ T cells in gut-associated lymphoid tissue (GALT) of animals infected with simian immunodeficiency virus and HIV-infected humans, we sought to determine the level of CD4+ T cell depletion as well as the degree and extent of HIV persistence in the GALT of infected individuals who had been receiving effective antiviral therapy for prolonged periods of time. We demonstrate incomplete recoveries of CD4+ T cells in the GALT of aviremic, HIV-infected individuals who had received up to 9.9 years of effective antiretroviral therapy. In addition, we demonstrate higher frequencies of HIV infection in GALT, compared with PBMCs, in these aviremic individuals and provide evidence for cross-infection between these 2 cellular compartments. Together, these data provide a possible mechanism for the maintenance of viral reservoirs revolving around theGALTof HIV-infected individuals despite long-term viral suppression and suggest that theGALTmayplay a major role in the persistence of HIV in such individuals.
NASA's periodic selection of astronauts is a highly selective process accepting applications from the general population, wherein the mechanics of selection are not made public. This research was an ...effort to determine if biases (specifically age) exist in the process and, if so, at which points they might manifest. Two sets of analyses were conducted. The first utilized data requested via the Freedom of Information Act (FOIA) on NASA astronaut applicants for the 2009 and 2013 selection years. Using a series of multinomial and logistic regressions, the data were analyzed to uncover whether age of the applicants linearly or nonlinearly affected their likelihood of receiving an invitation, as well as their likelihood of being selected into the astronaut program. The second used public data on age at selection and age at other career milestones for every astronaut selected from 1959 to 2013 to analyze trends in age over time using ordinary least-squares (OLS) regression and Pearson's correlation. The results for the FOIA data revealed a nonlinear relationship between age and receiving an interview, as well as age and selection into the astronaut program, but the most striking observation was the loss of age diversity at each stage of selection. Applicants younger or older than approximately 40 years were significantly less likely to receive invitations for interviews and were significantly less likely to be selected as an astronaut. Analysis of the public-source data for all selections since the beginning of the astronaut program revealed significant age trends over time including a gradual increase in selectee age and decreased tenure at NASA after last flight, with average age at retirement steady over the entire history of the astronaut program at approximately 48 years.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Traumatic brain injury (TBI) is a leading global cause of death and disability. Here we demonstrate in an experimental mouse model of TBI that mild forms of brain trauma cause severe deficits in ...meningeal lymphatic drainage that begin within hours and last out to at least one month post-injury. To investigate a mechanism underlying impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics. We demonstrate that increased ICP can contribute to meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction before TBI leads to increased neuroinflammation and negative cognitive outcomes. Finally, we report that rejuvenation of meningeal lymphatic drainage function in aged mice can ameliorate TBI-induced gliosis. These findings provide insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.
To date, few data on how the COVID-19 pandemic and restrictions affected children's physical activity in Europe have been published. This study examined the prevalence and correlates of physical ...activity and screen time from a large sample of European children during the COVID-19 pandemic to inform strategies and provide adequate mitigation measures. An online survey was conducted using convenience sampling from 15 May to 22 June, 2020. Parents were eligible if they resided in one of the survey countries and their children aged 6-18 years. 8395 children were included (median age IQR, 13 10-15 years; 47% boys; 57.6% urban residents; 15.5% in self-isolation). Approximately two-thirds followed structured routines (66.4% 95%CI, 65.4-67.4), and more than half were active during online P.E. (56.6% 95%CI, 55.5-57.6). 19.0% (95%CI, 18.2-19.9) met the WHO Global physical activity recommendation. Total screen time in excess of 2 h/day was highly prevalent (weekdays: 69.5% 95%CI, 68.5-70.5; weekend: 63.8% 95%CI, 62.7-64.8). Playing outdoors more than 2 h/day, following a daily routine and being active in online P.E. increased the odds of healthy levels of physical activity and screen time, particularly in mildly affected countries. In severely affected countries, online P.E. contributed most to meet screen time recommendation, whereas outdoor play was most important for adequate physical activity. Promoting safe and responsible outdoor activities, safeguarding P.E. lessons during distance learning and setting pre-planned, consistent daily routines are important in helping children maintain healthy active lifestyle in pandemic situation. These factors should be prioritised by policymakers, schools and parents.
Highlights
To our knowledge, our data provide the first multi-national estimates on physical activity and total screen time in European children roughly two months after COVID-19 was declared a global pandemic.
Only 1 in 5 children met the WHO Global physical activity recommendations.
Under pandemic conditions, parents should set pre-planned, consistent daily routines and integrate at least 2-hours outdoor activities into the daily schedule, preferable on each day. Schools should make P.E. lessons a priority. Decision makers should mandate online P.E. be delivered by schools during distance learning. Closing outdoor facilities for PA should be considered only as the last resort during lockdowns.
Network communities help the functional organization and evolution of complex networks. However, the development of a method, which is both fast and accurate, provides modular overlaps and partitions ...of a heterogeneous network, has proven to be rather difficult.
Here we introduce the novel concept of ModuLand, an integrative method family determining overlapping network modules as hills of an influence function-based, centrality-type community landscape, and including several widely used modularization methods as special cases. As various adaptations of the method family, we developed several algorithms, which provide an efficient analysis of weighted and directed networks, and (1) determine persvasively overlapping modules with high resolution; (2) uncover a detailed hierarchical network structure allowing an efficient, zoom-in analysis of large networks; (3) allow the determination of key network nodes and (4) help to predict network dynamics.
The concept opens a wide range of possibilities to develop new approaches and applications including network routing, classification, comparison and prediction.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lipoproteins of Bacterial Pathogens Kovacs-Simon, A; Titball, R.W; Michell, S.L
Infection and Immunity,
02/2011, Letnik:
79, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Bacterial lipoproteins are a set of membrane proteins with many different functions. Due to this broad-ranging functionality, these proteins have a considerable significance in many phenomena, from ...cellular physiology through cell division and virulence. Here we give a general overview of lipoprotein biogenesis and highlight examples of the roles of lipoproteins in bacterial disease caused by a selection of medically relevant Gram-negative and Gram-positive pathogens: Mycobacterium tuberculosis, Streptococcus pneumoniae, Borrelia burgdorferi, and Neisseria meningitidis. Lipoproteins have been shown to play key roles in adhesion to host cells, modulation of inflammatory processes, and translocation of virulence factors into host cells. As such, a number of lipoproteins have been shown to be potential vaccines. This review provides a summary of some of the reported roles of lipoproteins and of how this knowledge has been exploited in some cases for the generation of novel countermeasures to bacterial diseases.
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