2,622 research outputs found
Entropic forces drive self-organization and membrane fusion by SNARE proteins
SNARE proteins are the core of the cellâs fusion machinery and
mediate virtually all known intracellular membrane fusion reactions
on which exocytosis and trafficking depend. Fusion is catalyzed when
vesicle-associated v-SNAREs form trans-SNARE complexes (âSNAREpinsâ)
with target membrane-associated t-SNAREs, a zippering-like
process releasing âŒ65 kT per SNAREpin. Fusion requires several SNAREpins,
but how they cooperate is unknown and reports of the number
required vary widely. To capture the collective behavior on the long
timescales of fusion, we developed a highly coarse-grained model that
retains key biophysical SNARE properties such as the zippering energy
landscape and the surface charge distribution. In simulations the
âŒ65-kT zippering energy was almost entirely dissipated, with fully
assembled SNARE motifs but uncomplexed linker domains. The
SNAREpins self-organized into a circular cluster at the fusion site,
driven by entropic forces that originate in stericâelectrostatic interactions
among SNAREpins and membranes. Cooperative entropic
forces expanded the cluster and pulled the membranes together
at the center point with high force. We find that there is no critical
number of SNAREs required for fusion, but instead the fusion rate
increases rapidly with the number of SNAREpins due to increasing
entropic forces. We hypothesize that this principle finds physiological
use to boost fusion rates to meet the demanding timescales of
neurotransmission, exploiting the large number of v-SNAREs available
in synaptic vesicles. Once in an unfettered cluster, we estimate
â„15 SNAREpins are required for fusion within the âŒ1-ms
timescale of neurotransmitter release
Abrogation of LRRK2 dependent Rab10 phosphorylation with TLR4 activation and alterations in evoked cytokine release in immune cells
LRRK2 protein is expressed prominently in immune cells, cell types whose contribution to LRRK2-associated genetic Parkinson's disease (PD) is increasingly being recognised. We investigated the effect of inflammatory stimuli using RAW264.7 murine macrophage cells as model systems. A detailed time course of TLR2 and TLR4 stimulation was investigated through measuring LRRK2 phosphorylation at its specific phospho-sites, and Rab8 and Rab10 phosphorylation together with cytokine release following treatment with LPS and zymosan. LRRK2 phosphorylation at Ser935, Ser955 and Ser973 was increased significantly over untreated conditions at 4-24h in both WT-LRRK2 and T1348N-LRRK2 cell lines to similar extents although levels of Ser910 phosphorylation were maintained at higher levels throughout. Importantly we demonstrate that LPS stimulation significantly decreased phospho-Rab10 but not phospho-Rab8 levels over 4-24h in both WT-LRRK2 and T1348N-LRRK2 cell lines. The dephosphorylation of Rab10 was not attributed to its specific phosphatase, PPM1H as the levels remained unaltered with LPS treatment. MAPK phosphorylation occurred prior to LRRK2 phosphorylation which was validated by blocking TLR4 and TLR2 receptors with TAK242 or Sparstolonin B respectively. A significant decrease in basal level of TNFα release was noted in both T1348N-LRRK2 and KO-LRRK2 cell lines at 48h compared to WT-LRRK2 cell line, however LPS and zymosan treatment did not cause any significant alteration in the TNFα and IL-6 release between the three cell lines. In contrast, LPS and zymosan caused significantly lower IL-10 release in T1348N-LRRK2 and KO-LRRK2 cell lines. A significant decrease in phospho-Rab10 levels was also confirmed in human IPS-derived macrophages with TLR4 activation. Our data demonstrates for the first time that LRRK2-dependent Rab10 phosphorylation is modulated by LPS stimulation, and that cytokine release may be influenced by the status of LRRK2. These data provide further insights into the function of LRRK2 in immune response, and has relevance for understanding cellular dysfunctions when developing LRRK2-based inhibitors for clinical treatment
Ocean acidification affects fish spawning but not paternity at CO2 seeps
Fish exhibit impaired sensory function and altered behaviour at levels of ocean acidification expected to occur owing to anthropogenic carbon dioxide emissions during this century. We provide the first evidence of the effects of ocean acidification on reproductive behaviour of fish in the wild. Satellite and sneaker male ocellated wrasse (Symphodus ocellatus) compete to fertilize eggs guarded by dominant nesting males. Key mating behaviours such as dominant male courtship and nest defence did not differ between sites with ambient versus elevated CO2 concentrations. Dominant males did, however, experience significantly lower rates of pair spawning at elevated CO2 levels. Despite the higher risk of sperm competition found at elevated CO2, we also found a trend of lower satellite and sneaker male paternity at elevated CO2. Given the importance of fish for food security and ecosystem stability, this study highlights the need for targeted research into the effects of rising CO2 levels on patterns of reproduction in wild fish
3D N=6 Gauged Supergravity: Admissible Gauge Groups, Vacua and RG Flows
We study N=6 gauged supergravity in three dimensions with scalar manifolds
for in great details. We
classify some admissible non-compact gauge groups which can be consistently
gauged and preserve all supersymmetries. We give the explicit form of the
embedding tensors for these gauge groups as well as study their scalar
potentials on the full scalar manifold for each value of along with
the corresponding vacua. Furthermore, the potentials for the compact gauge
groups, for ,
identified previously in the literature are partially studied on a submanifold
of the full scalar manifold. This submanifold is invariant under a certain
subgroup of the corresponding gauge group. We find a number of supersymmetric
AdS vacua in the case of compact gauge groups. We then consider holographic RG
flow solutions in the compact gauge groups and
for the k=4 case. The solutions
involving one active scalar can be found analytically and describe operator
flows driven by a relevant operator of dimension 3/2. For non-compact gauge
groups, we find all types of vacua namely AdS, Minkowski and dS, but there is
no possibility of RG flows in the AdS/CFT sense for all gauge groups considered
here.Comment: 43 pages, no figures references added, typoes corrected and more
information adde
Participatory analysis for adaptation to climate change in Mediterranean agricultural systems: possible choices in process design (versĂŁo Pre Print)
There is an increasing call for local measures to adapt to climate change, based on foresight analyses in collaboration with actors. However, such analyses involve many challenges, particularly because the actors concerned may not consider climate change to be an urgent concern. This paper examines the methodological choices made by three research teams in the design and implementation of participatory foresight analyses to explore agricultural and water management options for adaptation to climate change. Case studies were conducted in coastal areas of France, Morocco, and Portugal where the groundwater is intensively used for irrigation, the aquifers are at risk or are currently overexploited, and a serious agricultural crisis is underway. When designing the participatory processes, the researchers had to address four main issues: whether to avoid or prepare dialogue between actors whose relations may be limited or tense; how to select participants and get them involved; how to facilitate discussion of issues that the actors may not initially consider to be of great concern; and finally, how to design and use scenarios. In each case, most of the invited actors responded and met to discuss and evaluate a series of scenarios. Strategies were discussed at different levels, from farming practices to aquifer management. It was shown that such participatory analyses can be implemented in situations which may initially appear to be unfavourable. This was made possible by the flexibility in the methodological choices, in particular the possibility of framing the climate change issue in a broader agenda for discussion with the actors
Initiation of Psychotropic Medication after Partner Bereavement: A Matched Cohort Study
Background
Recent changes to diagnostic criteria for depression in DSM-5 remove the bereavement exclusion, allowing earlier diagnosis following bereavement. Evaluation of the potential effect of this change requires an understanding of existing psychotropic medication prescribing by non-specialists after bereavement.
Aims
To describe initiation of psychotropic medication in the first year after partner bereavement.
Methods
In a UK primary care database, we identified 21,122 individuals aged 60 and over with partner bereavement and no psychotropic drug use in the previous year. Prescribing (anxiolytic/hypnotic, antidepressant, antipsychotic) after bereavement was compared to age, sex and practice matched controls.
Results
The risks of receiving a new psychotropic prescription within two and twelve months of bereavement were 9.5% (95% CI 9.1 to 9.9%) and 17.9% (17.3 to 18.4%) respectively; an excess risk of initiation in the first year of 12.4% compared to non-bereaved controls. Anxiolytic/hypnotic and antidepressant initiation rates were highest in the first two months. In this period, the hazard ratio for initiation of anxiolytics/hypnotics was 16.7 (95% CI 14.7 to 18.9) and for antidepressants was 5.6 (4.7 to 6.7) compared to non-bereaved controls. 13.3% of those started on anxiolytics/hypnotics within two months continued to receive this drug class at one year. The marked variation in background family practice prescribing of anxiolytics/hypnotics was the strongest determinant of their initiation in the first two months after bereavement.
Conclusion
Almost one in five older people received a new psychotropic drug prescription in the year after bereavement. The early increase and trend in antidepressant use after bereavement suggests some clinicians did not adhere to the bereavement exclusion, with implications for its recent removal in DSM-5. Family practice variation in use of anxiolytics/hypnotics suggests uncertainty over their role in bereavement with the potential for inappropriate long term use
Uncovering the overlapping community structure of complex networks in nature and society
Many complex systems in nature and society can be described in terms of
networks capturing the intricate web of connections among the units they are
made of. A key question is how to interpret the global organization of such
networks as the coexistence of their structural subunits (communities)
associated with more highly interconnected parts. Identifying these a priori
unknown building blocks (such as functionally related proteins, industrial
sectors and groups of people) is crucial to the understanding of the structural
and functional properties of networks. The existing deterministic methods used
for large networks find separated communities, whereas most of the actual
networks are made of highly overlapping cohesive groups of nodes. Here we
introduce an approach to analysing the main statistical features of the
interwoven sets of overlapping communities that makes a step towards uncovering
the modular structure of complex systems. After defining a set of new
characteristic quantities for the statistics of communities, we apply an
efficient technique for exploring overlapping communities on a large scale. We
find that overlaps are significant, and the distributions we introduce reveal
universal features of networks. Our studies of collaboration, word-association
and protein interaction graphs show that the web of communities has non-trivial
correlations and specific scaling properties.Comment: The free academic research software, CFinder, used for the
publication is available at the website of the publication:
http://angel.elte.hu/clusterin
The Reform of Employee Compensation in Chinaâs Industrial Enterprises
Although employee compensation reform in Chinese industrial sector has been discussed in the literature, the real changes in compensation system and pay practices have received insufficient attention and warrant further examination. This paper briefly reviews the pre- and post-reform compensation system, and reports the results of a survey of pay practices in the four major types of industrial enterprises in China. The research findings indicate that the type of enterprise ownership has little influence on general compensation practices, adoption of profit-sharing plans, and subsidy and allowance packages. In general, pay is linked more to individual performance and has become an important incentive to Chinese employees. However, differences are found across the enterprise types with regard to performance-related pay. Current pay practices are positively correlated to overall effectiveness of the enterprise
Magnetic Field Evolution in Accreting White Dwarfs
We discuss the evolution of the magnetic field of an accreting white dwarf.
We first show that the timescale for ohmic decay in the liquid interior is 8 to
12 billion years for a dipole field, and 4 to 6 billion years for a quadrupole
field. We then compare the timescales for ohmic diffusion and accretion at
different depths in the star, and for a simplified field structure and
spherical accretion, calculate the time-dependent evolution of the global
magnetic field at different accretion rates. In this paper, we neglect mass
loss by classical nova explosions and assume the white dwarf mass increases
with time. In this case, the field structure in the outer layers of the white
dwarf is significantly modified for accretion rates above the critical rate
(1-5) x 10^(-10) solar masses per year. We consider the implications of our
results for observed systems. We propose that accretion-induced magnetic field
changes are the missing evolutionary link between AM Her systems and
intermediate polars. The shorter ohmic decay time for accreting white dwarfs
provides a partial explanation of the lack of accreting systems with 10^9 G
fields. In rapidly accreting systems such as supersoft X-ray sources,
amplification of internal fields by compression may be important for Type Ia
supernova ignition and explosion. Finally, spreading matter in the polar cap
may induce complexity in the surface magnetic field, and explain why the more
strongly accreting pole in AM Her systems has a weaker field. We conclude with
speculations about the field evolution when classical nova explosions cause the
white dwarf mass to decrease with time.Comment: To appear in MNRAS (15 pages, 10 figures); minor revision
N-acetyltransferase 2 (NAT2) gene polymorphisms in Parkinson's disease
BACKGROUND: Parkinson's disease (PD) is a movement disorder caused by the degeneration of dopaminergic neurons in the substantia nigra of the midbrain. The molecular basis of this neural death is unknown, but genetic predisposition and environmental factors may cause the disease. Sequence variations in N-acetyltransferase 2 (NAT2) gene leading to slow acetylation process have been associated with PD, but results are contradictory. METHODS: We analyzed three NAT2 genetic variations, c.481C>T, c.590G>A (p.R197Q) and c.857G>A (p.G286E), which are known to result in a slow acetylator phenotype. Using validated PCR-RFLP assays, we genotyped 243 healthy unrelated Caucasian control subjects and 124 PD patients for these genetic variations. Further, we have undertaken a systematic review of NAT2 studies on PD and we incorporated our results in a meta-analysis consisting of 10 studies, 1,206 PD patients and 1,619 control subjects. RESULTS: Overall, we did not find significant differences in polymorphic acetylation genotypes in PD and control subjects. In the meta-analysis of slow acetylators from 10 studies and representing 604/1206 PD vs. 732/1619 control subjects, a marginally significant odds ratio (OR) of 1.32 (95% CI 1.12â1.54, p < 0.05) was obtained. Re-analysis of the data to exclude the only two studies showing positive association of slow acetylators to PD, resulted in a non-significant OR (1.07, 95% CI 0.9â1.28). Furthermore, meta-analysis of studies for c.590G>A, where both allele and genotype frequencies in PD vs. control subjects were analyzed, did not give significant summary odds ratios as well. CONCLUSION: We found little evidence for differences in polymorphic acetylation genotypes in PD and control subjects. Results of the meta-analyses did not also provide conclusive evidence for an overall association of NAT2 slow acetylator genotypes to PD
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