1,468 research outputs found
Exploiting disorder for perfect focusing
We demonstrate experimentally that disordered scattering can be used to
improve, rather than deteriorate, the focusing resolution of a lens. By using
wavefront shaping to compensate for scattering, light was focused to a spot as
small as one tenth of the diffraction limit of the lens. We show both
experimentally and theoretically that it is the scattering medium, rather than
the lens, that determines the width of the focus. Despite the disordered
propagation of the light, the profile of the focus was always exactly equal to
the theoretical best focus that we derived.Comment: 4 pages, 4 figure
The promoter polymorphism -232C/G of the PCK1 gene is associated with type 2 diabetes in a UK-resident South Asian population
Background: The PCK1 gene, encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), has previously been implicated as a candidate gene for type 2 diabetes (T2D) susceptibility. Rodent models demonstrate that over-expression of Pck1 can result in T2D development and a single nucleotide polymorphism (SNP) in the promoter region of human PCK1 (-232C/G) has exhibited significant association with the disease in several cohorts. Within the UK-resident South Asian population, T2D is 4 to 6 times more common than in indigenous white Caucasians. Despite this, few studies have reported on the genetic susceptibility to T2D in this ethnic group and none of these has investigated the possible effect of PCK1 variants. We therefore aimed to investigate the association between common variants of the PCK1 gene and T2D in a UK-resident South Asian population of Punjabi ancestry, originating predominantly from the Mirpur area of Azad Kashmir, Pakistan. \ud
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Methods: We used TaqMan assays to genotype five tagSNPs covering the PCK1 gene, including the -232C/G variant, in 903 subjects with T2D and 471 normoglycaemic controls. \ud
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Results: Of the variants studied, only the minor allele (G) of the -232C/G SNP demonstrated a significant association with T2D, displaying an OR of 1.21 (95% CI: 1.03 - 1.42, p = 0.019). \ud
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Conclusion: This study is the first to investigate the association between variants of the PCK1 gene and T2D in South Asians. Our results suggest that the -232C/G promoter polymorphism confers susceptibility to T2D in this ethnic group. \ud
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Trial registration: UKADS Trial Registration: ISRCTN38297969
Preclinical Development of ADCT-601, a Novel Pyrrolobenzodiazepine Dimer-based Antibody-drug Conjugate Targeting AXL-expressing Cancers
AXL, a tyrosine kinase receptor that is overexpressed in many solid and hematologic malignancies, facilitates cancer progression and is associated with poor clinical outcomes. Importantly, drug-induced expression of AXL results in resistance to conventional chemotherapy and targeted therapies. Together with its presence on multiple cell types in the tumor immune microenvironment, these features make it an attractive therapeutic target for AXL-expressing malignancies.
ADCT-601 (mipasetamab uzoptirine) is an AXL-targeted antibodyâdrug conjugate (ADC) comprising a humanized anti-AXL antibody site specifically conjugated using GlycoConnect technology to PL1601, which contains HydraSpace, a Val-Ala cleavable linker and the potent pyrrolobenzodiazepine (PBD) dimer cytotoxin SG3199. This study aimed to validate the ADCT-601 mode of action and evaluate its efficacy in vitro and in vivo, as well as its tolerability and pharmacokinetics.
ADCT-601 bound to both soluble and membranous AXL, and was rapidly internalized by AXL-expressing tumor cells, allowing release of PBD dimer, DNA interstrand cross-linking, and subsequent cell killing. In vivo, ADCT-601 had potent and durable antitumor activity in a wide variety of human cancer xenograft mouse models, including patient-derived xenograft models with heterogeneous AXL expression where ADCT-601 antitumor activity was markedly superior to an auristatin-based comparator ADC. Notably, ADCT-601 had antitumor activity in a monomethyl auristatin Eâresistant lung-cancer model and synergized with the PARP inhibitor olaparib in a BRCA1-mutated ovarian cancer model. ADCT-601 was well tolerated at doses of up to 6 mg/kg and showed excellent stability in vivo.
These preclinical results warrant further evaluation of ADCT-601 in the clinic
Scaling Laws in Human Language
Zipf's law on word frequency is observed in English, French, Spanish,
Italian, and so on, yet it does not hold for Chinese, Japanese or Korean
characters. A model for writing process is proposed to explain the above
difference, which takes into account the effects of finite vocabulary size.
Experiments, simulations and analytical solution agree well with each other.
The results show that the frequency distribution follows a power law with
exponent being equal to 1, at which the corresponding Zipf's exponent diverges.
Actually, the distribution obeys exponential form in the Zipf's plot. Deviating
from the Heaps' law, the number of distinct words grows with the text length in
three stages: It grows linearly in the beginning, then turns to a logarithmical
form, and eventually saturates. This work refines previous understanding about
Zipf's law and Heaps' law in language systems.Comment: 6 pages, 4 figure
An Exact Fluctuating 1/2-BPS Configuration
This work explores the role of thermodynamic fluctuations in the two
parameter giant and superstar configurations characterized by an ensemble of
arbitrary liquid droplets or irregular shaped fuzzballs. Our analysis
illustrates that the chemical and state-space geometric descriptions exhibit an
intriguing set of exact pair correction functions and the global correlation
lengths. The first principle of statistical mechanics shows that the possible
canonical fluctuations may precisely be ascertained without any approximation.
Interestingly, our intrinsic geometric study exemplifies that there exist exact
fluctuating 1/2-BPS statistical configurations which involve an ensemble of
microstates describing the liquid droplets or fuzzballs. The Gaussian
fluctuations over an equilibrium chemical and state-space configurations
accomplish a well-defined, non-degenerate, curved and regular intrinsic
Riemannian manifolds for all physically admissible domains of black hole
parameters. An explicit computation demonstrates that the underlying chemical
correlations involve ordinary summations, whilst the state-space correlations
may simply be depicted by standard polygamma functions. Our construction
ascribes definite stability character to the canonical energy fluctuations and
to the counting entropy associated with an arbitrary choice of excited boxes
from an ensemble of ample boxes constituting a variety of Young tableaux.Comment: Minor changes, added references, 30 pages, 4 figures, PACS numbers:
04.70.-s: Physics of black holes; 04.70.-Bw: Classical black holes; 04.50.Gh
Higher-dimensional black holes, black strings, and related objects; 04.60.Cf
Gravitational aspects of string theory, accepted for publication in JHE
A novel pathway producing dimethylsulphide in bacteria is widespread in soil environments
The volatile compound dimethylsulphide (DMS) is important in climate regulation, the sulphur cycle and signalling to higher organisms. Microbial catabolism of the marine osmolyte dimethylsulphoniopropionate (DMSP) is thought to be the major biological process generating DMS. Here we report the discovery and characterisation of the first gene for DMSP-independent DMS production in any bacterium. This gene, mddA, encodes a methyltransferase that methylates methanethiol (MeSH) and generates DMS. MddA functions in many taxonomically diverse bacteria including sediment-dwelling pseudomonads, nitrogen-fixing bradyrhizobia and cyanobacteria, and mycobacteria, including the pathogen Mycobacterium tuberculosis. The mddA gene is present in metagenomes from varied environments, being particularly abundant in soil environments, where it is predicted to occur in up to 76% of bacteria. This novel pathway may significantly contribute to global DMS emissions, especially in terrestrial environments, and could represent a shift from the notion that DMSP is the only significant precursor of DMS
Altruism can proliferate through group/kin selection despite high random gene flow
The ways in which natural selection can allow the proliferation of
cooperative behavior have long been seen as a central problem in evolutionary
biology. Most of the literature has focused on interactions between pairs of
individuals and on linear public goods games. This emphasis led to the
conclusion that even modest levels of migration would pose a serious problem to
the spread of altruism in group structured populations. Here we challenge this
conclusion, by analyzing evolution in a framework which allows for complex
group interactions and random migration among groups. We conclude that
contingent forms of strong altruism can spread when rare under realistic group
sizes and levels of migration. Our analysis combines group-centric and
gene-centric perspectives, allows for arbitrary strength of selection, and
leads to extensions of Hamilton's rule for the spread of altruistic alleles,
applicable under broad conditions.Comment: 5 pages, 2 figures. Supplementary material with 50 pages and 26
figure
Sociological and Communication-Theoretical Perspectives on the Commercialization of the Sciences
Both self-organization and organization are important for the further
development of the sciences: the two dynamics condition and enable each other.
Commercial and public considerations can interact and "interpenetrate" in
historical organization; different codes of communication are then
"recombined." However, self-organization in the symbolically generalized codes
of communication can be expected to operate at the global level. The Triple
Helix model allows for both a neo-institutional appreciation in terms of
historical networks of university-industry-government relations and a
neo-evolutionary interpretation in terms of three functions: (i) novelty
production, (i) wealth generation, and (iii) political control. Using this
model, one can appreciate both subdynamics. The mutual information in three
dimensions enables us to measure the trade-off between organization and
self-organization as a possible synergy. The question of optimization between
commercial and public interests in the different sciences can thus be made
empirical.Comment: Science & Education (forthcoming
The design, evaluation, and reporting on non- pharmacological, cognition- oriented treatments for older adults: Results of a survey of experts
IntroductionCognitive decline and dementia significantly affect independence and quality of life in older adults; therefore, it is critical to identify effective cognition- oriented treatments (COTs; eg, cognitive training, rehabilitation) that can help maintain or enhance cognitive functioning in older adults, as well as reduce dementia risk or alleviate symptoms associated with pathological processes.MethodsThe Cognitive Intervention Design Evaluation and Reporting (CIDER), a working group from the Non- Pharmacological Interventions Professional Interest Area (NPI- PIA) of the Alzheimerâs Association conducted as survey in 2017 with experts in COTs worldwide. The surveyâs aims were three- fold: (1) determine the common attitudes, beliefs, and practices of experts involved in the COTs research targeting older people; (2) identify areas of relative agreement and disagreement among experts in the field; and (3) offer a critical review of the literature, including recommendations for future research.ResultsThe survey identified several areas of agreements among experts on critical features of COTs, and on study design and outcome measures. Nevertheless, there were some areas with relative disagreement. Critically, expert opinions were not always supported by scientific evidence, suggesting that methodologic improvements are needed regarding design, implementation, and reporting of COTs. There was a clear consensus that COTs provide benefits and should be offered to cognitively unimpaired older adults, mild cognitive impairment (MCI), and mild dementia, but opinions differed for moderate and severe dementia. In addition, there is no consensus on the potential role of COTs in dementia prevention, indicating that future research should prioritize this aspect.DiscussionEvidence of COTs in older adults is encouraging, but additional evidence is needed to enhance dementia prevention. Consensus building and guidelines in the field are critical to improve and accelerate the development of high- quality evidence for COTs in cognitively unimpaired older adults, and those with MCI and dementia.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155935/1/trc212024_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155935/2/trc212024.pd
The smart grid as commons: exploring alternatives to infrastructure financialisation
This paper explores a tension between financialisation of electricity infrastructures and efforts to bring critical urban systems into common ownership. Focusing on the emerging landscape of electricity regulation and e-mobility in the United Kingdom (UK), it examines how electricity grid ownership has become financialised, and why the economic assumptions that enabled this financialisation are being called into question. New technologies, such as smart electricity meters and electric vehicles, provide cities with new tools to tackle poor air quality and greenhouse gas emissions. Electricity grids are key enabling infrastructures but the companies that run them do not get rewarded for improving air quality or tackling climate change. UK government regulation of electricity grids both enables financialisation and forecloses opportunities to manage the infrastructure for wider environmental and public benefit. Nonetheless, the addition of smart devices to this network - the âsmart gridâ â opens up an opportunity for common ownership of the infrastructure. Transforming the smart grid into commons necessitates deep structural reform to the entire architecture of infrastructure regulation in the UK
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