Reciprocal copy number variations (CNVs) of 16p11.2 are associated with a wide spectrum of neuropsychiatric and neurodevelopmental disorders. Here, we use human induced pluripotent stem cells ...(iPSCs)-derived dopaminergic (DA) neurons carrying CNVs of 16p11.2 duplication (16pdup) and 16p11.2 deletion (16pdel), engineered using CRISPR-Cas9. We show that 16pdel iPSC-derived DA neurons have increased soma size and synaptic marker expression compared to isogenic control lines, while 16pdup iPSC-derived DA neurons show deficits in neuronal differentiation and reduced synaptic marker expression. The 16pdel iPSC-derived DA neurons have impaired neurophysiological properties. The 16pdel iPSC-derived DA neuronal networks are hyperactive and have increased bursting in culture compared to controls. We also show that the expression of RHOA is increased in the 16pdel iPSC-derived DA neurons and that treatment with a specific RHOA-inhibitor, Rhosin, rescues the network activity of the 16pdel iPSC-derived DA neurons. Our data suggest that 16p11.2 deletion-associated iPSC-derived DA neuron hyperactivation can be rescued by RHOA inhibition.
Machine learning offers the potential to revolutionize the inverse design of complex nanophotonic components. Here, we propose a novel variant of this formalism specifically suited for the design of ...resonant nanophotonic components. Typically, the first step of an inverse design process based on machine learning is training a neural network to approximate the non-linear mapping from a set of input parameters to a given optical system’s features. The second step starts from the desired features, e.g. a transmission spectrum, and propagates back through the trained network to find the optimal input parameters. For resonant systems, this second step corresponds to a gradient descent in a highly oscillatory loss landscape. As a result, the algorithm often converges into a local minimum. We significantly improve this method’s efficiency by adding the Fourier transform of the desired spectrum to the optimization procedure. We demonstrate our method by retrieving the optimal design parameters for desired transmission and reflection spectra of Fabry–Pérot resonators and Bragg reflectors, two canonical optical components whose functionality is based on wave interference. Our results can be extended to the optimization of more complex nanophotonic components interacting with structured incident fields.
Ventilator sharing is one option to emergently increase ventilator capacity during a crisis but has been criticized for its inability to adjust for individual patient needs. Newer ventilator sharing ...designs use valves and restrictors to control pressures for each patient. A key component of these designs is an inline Positive End Expiratory Pressure (PEEP) Valve but these are not readily available. Creating an inline PEEP valve by converting a standard bag-valve-mask PEEP valve is possible with the addition of a 3D printed collar.
This was a feasibility study assessing the performance and safety of a method for converting a standard PEEP valve into an inline PEEP valve. A collar was designed and printed that covers the exhaust ports of the valve and returns exhaled gases to the ventilator.
The collar piece was simple to print and easily assembled with the standard PEEP valve. In bench testing it successfully created differential pressures in 2 simulated expiratory limbs without leaking to the atmosphere at pressures greater than 60 cm of H2O.
Our novel inline PEEP valve design shows promise as an option for building a safer ventilator sharing system.
Metasurfaces allow for agile manipulation of incoming light using a single layer of resonators. Despite recent progress, it remains difficult to generate new spectral components using nonlinear ...surfaces, because of the limited interaction length of a pulse traveling through a single surface. Time-dependent surfaces offer an exciting alternative to overcome this limitation, but a self-consistent framework to describe this mechanism is lacking. Based on an analytical model and finite-difference time-domain numerical simulations, we obtain physical insight into the frequency-shifting process that occurs when broadband electromagnetic pulses interact with time-varying surfaces. In particular, we find that there is an intriguing relationship between the bandwidth of the incident pulse, the targeted frequency shift, and the number of Lorentzian resonators that need to be implemented. We also demonstrate that in certain parameter regimes, pulse distortion and a deviation of pulse amplitude cannot be avoided. These results are independent of the mechanism that generates the time dependence. They are also independent of the frequency, the geometry, size, and material of the unit cell, but they are rather a direct result of the subtle interplay between time-dependent Lorentzian resonances.
The COVID-19 pandemic has resulted in an increased need for ventilators. The potential to ventilate more than one patient with a single ventilator, a so-called split ventilator setup, provides an ...emergency solution. Our hypothesis is that ventilation can be individualized by adding a flow restrictor to limit tidal volumes, add PEEP, titrate FiO
2
and monitor ventilation. This way we could enhance optimization of patient safety and clinical applicability. We performed bench testing to test our hypothesis and identify limitations. We performed a bench testing in two test lungs: (1) determine lung compliance (2) determine volume, plateau pressure and PEEP, (3) illustrate individualization of airway pressures and tidal volume with a flow restrictor, (4a) illustrate that PEEP can be applied and individualized (4b) create and measure intrinsic PEEP (4c and d) determine PEEP as a function of flow restriction, (5) individualization of FiO
2
. The lung compliance varied between 13 and 27 mL/cmH
2
O. Set ventilator settings could be applied and measured. Extrinsic PEEP can be applied except for settings with a large expiratory time. Volume and pressure regulation is possible between 70 and 39% flow restrictor valve closure. Flow restriction in the tested circuit had no effect on the other circuit or on intrinsic PEEP. FiO
2
could be modulated individually between 0.21 and 0.8 by gradually adjusting the additional flow, and minimal affecting FiO
2
in the other circuit. Tidal volumes, PEEP and FiO
2
can be individualized and monitored in a bench testing of a split ventilator. In vivo research is needed to further explore the clinical limitations and outcomes, making implementation possible as a last resort ventilation strategy.
We here present a stepping stone towards a deeper understanding of convolutional neural networks (CNNs) in the form of a theory of learning in linear CNNs. Through analyzing the gradient descent ...equations, we discover that the evolution of the network during training is determined by the interplay between the dataset structure and the convolutional network structure. We show that linear CNNs discover the statistical structure of the dataset with non-linear, ordered, stage-like transitions, and that the speed of discovery changes depending on the relationship between the dataset and the convolutional network structure. Moreover, we find that this interplay lies at the heart of what we call the ``dominant frequency bias'', where linear CNNs arrive at these discoveries using only the dominant frequencies of the different structural parts present in the dataset. We furthermore provide experiments that show how our theory relates to deep, non-linear CNNs used in practice. Our findings shed new light on the inner working of CNNs, and can help explain their shortcut learning and their tendency to rely on texture instead of shape.
Optical devices lie at the heart of most of the technology we see around us. When one actually wants to make such an optical device, one can predict its optical behavior using computational ...simulations of Maxwell's equations. If one then asks what the optimal design would be in order to obtain a certain optical behavior, the only way to go further would be to try out all of the possible designs and compute the electromagnetic spectrum they produce. When there are many design parameters, this brute force approach quickly becomes too computationally expensive. We therefore need other methods to create optimal optical devices. An alternative to the brute force approach is inverse design. In this paradigm, one starts from the desired optical response of a material and then determines the design parameters that are needed to obtain this optical response. There are many algorithms known in the literature that implement this inverse design. Some of the best performing, recent approaches are based on Deep Learning. The central idea is to train a neural network to predict the optical response for given design parameters. Since neural networks are completely differentiable, we can compute gradients of the response with respect to the design parameters. We can use these gradients to update the design parameters and get an optical response closer to the one we want. This allows us to obtain an optimal design much faster compared to the brute force approach. In my thesis, I use Deep Learning for the inverse design of the Fabry-Pérot resonator. This system can be described fully analytically and is therefore ideal to study.
Highlights • CMV mutations emergence and persistence must be followed in transplanted patients. • UL97 L595S mutation is one of the more frequent mutations conferring GCV resistance. • Sanger and ...Next-Generation Sequencing technologies must be compared for a routine use. • Compared to Sanger, NGS allowed a deeper discrimination of UL97 L595S evolution. • Along with entropy, NGS contributed to gain deeply insight into UL97 variability.
The reported association of mTOR-inhibitor (mTORi) treatment with a lower incidence of cytomegalovirus (CMV) infection in kidney transplant recipients (KTR) who are CMV seropositive (R+) remains ...unexplained.
The incidence of CMV infection and T-cell profile was compared between KTRs treated with mTORis and mycophenolic acid (MPA), and
mTORi effects on T-cell phenotype and functions were analyzed.
In KTRs who were R+ and treated with MPA, both
and
T cells displayed a more dysfunctional phenotype (PD-1+, CD85j+) at day 0 of transplantation in the 16 KTRs with severe CMV infection, as compared with the 17 KTRs without or with spontaneously resolving CMV infection. In patients treated with mTORis (
=27), the proportion of PD-1+ and CD85j+
and
T cells decreased, when compared with patients treated with MPA (
=44), as did the frequency and severity of CMV infections. mTORi treatment also led to higher proportions of late-differentiated and cytotoxic
T cells and IFN
-producing and cytotoxic
T cells.
, mTORis increased proliferation, viability, and CMV-induced IFN
production of T cells and decreased PD-1 and CD85j expression in T cells, which shifted the T cells to a more efficient EOMES
Hobit
profile. In
T cells, the mTORi effect was related to increased TCR signaling.
Severe CMV replication is associated with a dysfunctional T-cell profile and mTORis improve T-cell fitness along with better control of CMV. A dysfunctional T-cell phenotype could serve as a new biomarker to predict post-transplantation infection and to stratify patients who should benefit from mTORi treatment.
Proportion of CMV Seropositive Kidney Transplant Recipients Who Will Develop a CMV Infection When Treated With an Immunosuppressive Regimen Including Everolimus and Reduced Dose of Cyclosporine Versus an Immunosuppressive Regimen With Mycophenolic Acid and Standard Dose of Cyclosporine A (EVERCMV), NCT02328963.
The reported association of mTOR-inhibitor (mTORi) treatment with a lower incidence of cytomegalovirus (CMV) infection in CMV-seropositive (R+) kidney transplant recipients (KTR) remains unexplained. ...The incidence of CMV infection and T-cell profile was compared between mTORi- treated and mycophenolic acid (MPA)-treated KTR, and mTORi effects on T-cell phenotype and functions analyzed. In MPA-treated R+ KTR, both αβ and γδ T-cells displayed a more dysfunctional phenotype (PD-1+, CD85j+) at day 0 of transplantation in the 16 KTR with severe CMV infection when compared to the 17 KTR without or with spontaneously resolving CMV infection. In mTORi-treated patients (n= 27), the proportion of PD-1+ and CD85j+ αβ and γδ T cells decreased when compared to MPA-treated patients (n=44), as well as the frequency and severity of CMV infections. mTORi treatment also led to higher proportions of latedifferentiated and cytotoxic γδ T cells, and IFNγ-producing and cytotoxic αβ T cells. , mTORi increased proliferation, viability, and CMV-induced IFNγ production of T cells and (decreased PD-1 and CD85j expression in T cells that shifted to a more efficient EOMES Hobit profile. In γδ T cells the mTORi effect was related to increased TCR signaling. Severe CMV replication is associated with a dysfunctional T-cell profile and mTORi improve T-cell fitness in association with better control of CMV. A dysfunctional Tcell phenotype could provide a new biomarker to predict post-transplantation infection and to stratify patients who should benefit from mTORi treatment.
PDF
