466 research outputs found
Hypoxic preconditioning potentiates the trophic effects of mesenchymal stem cells on co-cultured human primary hepatocytes
The next detectors for gravitational wave astronomy
This paper focuses on the next detectors for gravitational wave astronomy
which will be required after the current ground based detectors have completed
their initial observations, and probably achieved the first direct detection of
gravitational waves. The next detectors will need to have greater sensitivity,
while also enabling the world array of detectors to have improved angular
resolution to allow localisation of signal sources. Sect. 1 of this paper
begins by reviewing proposals for the next ground based detectors, and presents
an analysis of the sensitivity of an 8 km armlength detector, which is proposed
as a safe and cost-effective means to attain a 4-fold improvement in
sensitivity. The scientific benefits of creating a pair of such detectors in
China and Australia is emphasised. Sect. 2 of this paper discusses the high
performance suspension systems for test masses that will be an essential
component for future detectors, while sect. 3 discusses solutions to the
problem of Newtonian noise which arise from fluctuations in gravity gradient
forces acting on test masses. Such gravitational perturbations cannot be
shielded, and set limits to low frequency sensitivity unless measured and
suppressed. Sects. 4 and 5 address critical operational technologies that will
be ongoing issues in future detectors. Sect. 4 addresses the design of thermal
compensation systems needed in all high optical power interferometers operating
at room temperature. Parametric instability control is addressed in sect. 5.
Only recently proven to occur in Advanced LIGO, parametric instability
phenomenon brings both risks and opportunities for future detectors. The path
to future enhancements of detectors will come from quantum measurement
technologies. Sect. 6 focuses on the use of optomechanical devices for
obtaining enhanced sensitivity, while sect. 7 reviews a range of quantum
measurement options
The impact of different DNA extraction kits and laboratories upon the assessment of human gut microbiota composition by 16S rRNA gene sequencing
Peer reviewedPublisher PD
Safety & efficacy of lifileucel (LN-144) tumor infiltrating lymphocyte therapy in metastatic melanoma patients after progression on multiple therapies – independent review committee data update
Treatment options are limited for patients with
advanced melanoma who have progressed on checkpoint
inhibitors and targeted therapies such as BRAF/MEK inhibitors
(if BRAF-V600E mutated). Adoptive cell therapy utilizing
tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable responses in heavily pretreated melanoma
patients. Safety and efficacy of lifileucel, a centrally manufactured cryopreserved autologous TIL therapy assessed by both
investigator and an independent review committee (IRC), are
presented
Orientation of the Calcium Channel β Relative to the α12.2 Subunit Is Critical for Its Regulation of Channel Activity
BACKGROUND: The Ca(v)beta subunits of high voltage-activated Ca(2+) channels control the trafficking and biophysical properties of the alpha(1) subunit. The Ca(v)beta-alpha(1) interaction site has been mapped by crystallographic studies. Nevertheless, how this interaction leads to channel regulation has not been determined. One hypothesis is that betas regulate channel gating by modulating movements of IS6. A key requirement for this direct-coupling model is that the linker connecting IS6 to the alpha-interaction domain (AID) be a rigid structure. METHODOLOGY/PRINCIPAL FINDINGS: The present study tests this hypothesis by altering the flexibility and orientation of this region in alpha(1)2.2, then testing for Ca(v)beta regulation using whole cell patch clamp electrophysiology. Flexibility was induced by replacement of the middle six amino acids of the IS6-AID linker with glycine (PG6). This mutation abolished beta2a and beta3 subunits ability to shift the voltage dependence of activation and inactivation, and the ability of beta2a to produce non-inactivating currents. Orientation of Ca(v)beta with respect to alpha(1)2.2 was altered by deletion of 1, 2, or 3 amino acids from the IS6-AID linker (Bdel1, Bdel2, Bdel3, respectively). Again, the ability of Ca(v)beta subunits to regulate these biophysical properties were totally abolished in the Bdel1 and Bdel3 mutants. Functional regulation by Ca(v)beta subunits was rescued in the Bdel2 mutant, indicating that this part of the linker forms beta-sheet. The orientation of beta with respect to alpha was confirmed by the bimolecular fluorescence complementation assay. CONCLUSIONS/SIGNIFICANCE: These results show that the orientation of the Ca(v)beta subunit relative to the alpha(1)2.2 subunit is critical, and suggests additional points of contact between these subunits are required for Ca(v)beta to regulate channel activity
The calcium channel β2 (CACNB2) subunit repertoire in teleosts
© 2008 Ebert et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens
Recognition and Degradation of Plant Cell Wall Polysaccharides by Two Human Gut Symbionts
Competition for nutrients contained in diverse types of plant cell wall-associated polysaccharides may explain the evolution of substrate-specific catabolic gene modules in common bacterial members of the human gut microbiota
Defining the Critical Hurdles in Cancer Immunotherapy
ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer
Loss of Mitogen-Activated Protein Kinase Kinase Kinase 4 (MAP3K4) Reveals a Requirement for MAPK Signalling in Mouse Sex Determination
The boygirl (byg) mouse mutant reveals that MAP3K4-mediated signaling is necessary for normal SRY expression and testis specification in the developing mouse gonad
Search for post-merger gravitational waves from the remnant of the binary neutron star merger GW170817
In Advanced LIGO, detection and astrophysical source parameter estimation of the binary black hole merger GW150914 requires a calibrated estimate of the gravitational-wave strain sensed by the detectors. Producing an estimate from each detector's differential arm length control loop readout signals requires applying time domain filters, which are designed from a frequency domain model of the detector's gravitational-wave response. The gravitational-wave response model is determined by the detector's opto-mechanical response and the properties of its feedback control system. The measurements used to validate the model and characterize its uncertainty are derived primarily from a dedicated photon radiation pressure actuator, with cross-checks provided by optical and radio frequency references. We describe how the gravitational-wave readout signal is calibrated into equivalent gravitational-wave-induced strain and how the statistical uncertainties and systematic errors are assessed. Detector data collected over 38 calendar days, from September 12 to October 20, 2015, contain the event GW150914 and approximately 16 of coincident data used to estimate the event false alarm probability. The calibration uncertainty is less than 10% in magnitude and 10 degrees in phase across the relevant frequency band 20 Hz to 1 kHz
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