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Abstract SDS22 forms an inactive complex with nascent protein phosphatase PP1 and Inhibitor-3. SDS22:PP1:Inhibitor-3 is a substrate for the ATPase p97/VCP, which liberates PP1 for binding to canonical regulatory subunits. The exact role of SDS22 in PP1-holoenzyme assembly remains elusive. Here, we show that SDS22 stabilizes nascent PP1. In the absence of SDS22, PP1 is gradually lost, resulting in substrate hyperphosphorylation and a proliferation arrest. Similarly, we identify a female individual with a severe neurodevelopmental disorder bearing an unstable SDS22 mutant, associated with decreased PP1 levels. We furthermore find that SDS22 directly binds to Inhibitor-3 and that this is essential for the stable assembly of SDS22:PP1: Inhibitor-3, the recruitment of p97/VCP, and the extraction of SDS22 during holoenzyme assembly. SDS22 with a disabled Inhibitor-3 binding site co-transfers with PP1 to canonical regulatory subunits, thereby forming non-functional holoenzymes. Our data show that SDS22, through simultaneous interaction with PP1 and Inhibitor-3, integrates the major steps of PP1 holoenzyme assembly.

Background: Perfluorooctane sulfonic acid (PFOS), a widely used industrial chemical, was reported to induce memory and learning process dysfunction. Some studies tried to reveal the mechanisms that mediate these effects, but how they are produced is still unknown. Basal forebrain cholinergic neurons (BFCN) maintain cognitive function and their selective neurodegeneration induces cognitive decline, as observed in Alzheimer’s disease. PFOS was reported to disrupt cholinergic and glutamatergic transmissions and thyroid hormone action, which regulate cognitive processes and maintain BFCN viability. Objective/Methods: To evaluate PFOS neurodegenerative effects on BFCN and the mechanisms that mediate them, SN56 cells (a neuroblastoma cholinergic cell line from the basal forebrain) were treated with PFOS (0.1 µM to 40 µM) with or without thyroxine (T3; 15 nM), MK-801 (20 µM) or acetylcholine (ACh; 10 µM). Results: In the present study, we found that PFOS treatment (1 or 14 days) decreased thyroid receptor α (TRα) activity by decreasing its protein levels and increased T3 metabolism through increased deiodinase 3 (D3) levels. Further, we observed that PFOS treatment disrupted cholinergic transmission by decreasing ACh content through decreased choline acetyltransferase (ChAT) activity and protein levels and through decreasing muscarinic receptor 1 (M1R) binding and protein levels. PFOS also disrupted glutamatergic transmission by decreasing glutamate content through increased glutaminase activity and protein levels and through decreasing N-methyl-D-aspartate receptor subunit 1 (NMDAR1); effects mediated through M1R disruption. All these effects were mediated through decreased T3 activity and T3 supplementation partially restored to the normal state. Conclusions: These findings may assist in understanding how PFOS induces neurodegeneration, and the mechanisms involved, especially in BFCN, to explain the process that could lead to cognitive dysfunction and provide new therapeutic tools to treat and prevent its neurotoxic effects.

Objective To assess the predictive value of four cardiovascular (CV) risk algorithms for identifying high-risk psoriatic arthritis (PsA) patients.Methods Evaluation of patients with PsA enrolled in the Spanish prospective project CARdiovascular in RheuMAtology. Baseline data of 669 PsA patients with no history of CV events at the baseline visit, who were followed in rheumatology outpatient clinics at tertiary centres for 7.5 years, were retrospectively analysed to test the performance of the Systematic Coronary Risk Assessment (SCORE), the modified version (mSCORE) European Alliance of Rheumatology Associations (EULAR) 2015/2016, the SCORE2 algorithm (the updated and improved version of SCORE) and the QRESEARCH risk estimator version 3 (QRISK3).Results Over 4790 years of follow-up, there were 34 CV events, resulting in a linearised rate of 7.10 per 1000 person-years (95% CI 4.92 to 9.92). The four CV risk scales showed strong correlations and all showed significant associations with CV events (p

Chlorpyrifos (CPF) biocide, exposure to which is mainly produced in the human population through diet, induces several neurotoxic effects. CPF single and repeated exposure induces memory and learning disorders, although the mechanisms that produce these outcomes are complex and not well understood. CPF treatment (single and repeated) of cholinergic septal SN56 cells induced an increase in phosphorylated-P38α levels that led to WNT/β-Catenin and NGF/P75NTR/TrkA pathways disruption and cell death. These results provide new knowledge on the mechanisms that mediate CPF basal forebrain cholinergic neuronal loss induced by CPF single and repeated exposure and can help unravel the way through which this compound produces cognitive decline and develop efficient treatments against these effects.

A limit cycle is a self-sustained, periodic, isolated motion appearing in autonomous differential equations. As the period of a limit cycle is a priori unknown, finding it as a stationary state of a rotating ansatz is challenging. Correspondingly, its study commonly relies on numerical methodologies (e.g., brute-force time evolution, and variational shooting methods) or circumstantial evidence such as instabilities of fixed points. Alas, such approaches are (i) unable to find all solutions, as they rely on specific initial conditions, and (ii) do not provide analytical intuition about the physical origin of the limit cycles. Here, we (I) develop a multifrequency rotating ansatz with which we (II) find all limit cycles as stationary-state solutions via a semianalytical homotopy continuation. We demonstrate our approach and its performance on the Van der Pol oscillator. Moving beyond this simple example, we show that our method captures all coexisting fixed-point attractors and limit cycles in a modified nonlinear Van der Pol oscillator. Our results facilitate the systematic mapping of out-of-equilibrium phase diagrams, with implications across multiple fields of the natural sciences.

La pandemia de la COVID-19 ha cambiado drásticamente la posición de la ciencia en la sociedad para ocupar un papel protagonista. Este hecho ha podido modificar la percepción que los adolescentes tienen de ella, así como su comprensión de la construcción del conocimiento científico y su implicación en la toma de decisiones relacionadas con temas sociocientíficos. El presente trabajo explora los cambios en estos parámetros a partir de un estudio cuantitativo en el que se administra un cuestionario ad hoc a alumnos que han finalizado el primer ciclo de la ESO. Los resultados muestran un aumento de la confianza en la ciencia. Además, se ha observado que estas circunstancias han contribuido a una mejora en la comprensión de la generación de conocimiento científico en este colectivo junto con un incremento en la actitud reflexiva sobre cuestiones científicas relacionadas con la sociedad.

This article presents the design of a low-power low noise amplifier (LNA) implemented in 45 nm silicon-on-insulator (SOI) technology using the gm/ID methodology. The Ka-band LNA achieves a very low power consumption of only 1.98 mW andis the first time the gm/ID approach is applied at such a high frequency. The circuit is suitable for Ka-band applications with a central frequency of 28 GHz, as the circuit is intended to operate in the n257 frequency band defined by the 3GPP 5G new radio (NR) specification. The proposed cascode LNA uses the gm/ID methodology in an RF/MW scenario to exploit the advantages of moderate inversion region operation. The circuit occupies a total area of 1.23 mm2 excluding pads and draws 1.98 mW from a DC supply of 0.9 V. Post-layout simulation results reveal a total gain of 11.4 dB, a noise figure (NF) of 3.8 dB, and an input return loss (IRL) better than 12 dB. Compared to conventional circuits, this design obtains a remarkable figure of merit (FoM) as the LNA reports a gain and NF in line with other approaches with very low power consumption.

The vision of building computational hardware for problem optimization has spurred large efforts in the physics community. In particular, networks of Kerr parametric oscillators (KPOs) are envisioned as simulators for finding the ground states of Ising Hamiltonians. It was shown, however, that KPO networks can feature large numbers of unexpected solutions that are difficult to sample with the existing deterministic (i.e., adiabatic) protocols. In this work, we experimentally realize a system of two classical coupled KPOs, and we find good agreement with the predicted mapping to Ising states. We then introduce a protocol based on stochastic sampling of the system, and we show how the resulting probability distribution can be used to identify the ground state of the corresponding Ising Hamiltonian. This method is akin to a Monte Carlo sampling of multiple out-of-equilibrium stationary states and is less prone to become trapped in local minima than deterministic protocols.

In this paper, a microwave monolithic integrated circuit (MMIC) high-power amplifier (HPA) for Ku-band active radar applications based on gallium nitride on silicon (GaN-on-Si) is presented. The design is based on a three-stage architecture and was implemented using the D01GH technology provided by OMMIC foundry. Details on the architecture definition and design process to maximize delivered power are provided along with stability and thermal analyses. To optimize the amplifier performance, an asymmetry was included at the output combiner. Experimental results show that the HPA achieves a 39.5 dBm pulsed-mode output power, a peak linear gain of 23 dB, a drain efficiency of 27%, and good input/output matching in the 16–19 GHz frequency range. The chip area is 5 × 3.5 mm2 and for the measurements was mounted on a custom-made module. These results demonstrate that GaN-on-Si-based Solid-State Power Amplifiers (SSPAs) can be used for the implementation of Ku-band active radars.

Environmental pollutants’ (EPs) amount and diversity have increased in recent years due to anthropogenic activity. Several neurodegenerative diseases (NDs) are theorized to be related to EPs, as their incidence has increased in a similar way to human EPs exposure and they reproduce the main ND hallmarks. EPs induce several neurotoxic effects, including accumulation and gradual deposition of misfolded toxic proteins, producing neuronal malfunction and cell death. Cells possess different mechanisms to eliminate these toxic proteins, including heat shock proteins (HSPs) and the proteasome system. The accumulation and deleterious effects of toxic proteins are induced through HSPs and disruption of proteasome proteins’ homeostatic function by exposure to EPs. A therapeutic approach has been proposed to reduce accumulation of toxic proteins through treatment with recombinant HSPs/proteasome or the use of compounds that increase their expression or activity. Our aim is to review the current literature on NDs related to EP exposure and their relationship with the disruption of the proteasome system and HSPs, as well as to discuss the toxic effects of dysfunction of HSPs and proteasome and the contradictory effects described in the literature. Lastly, we cover the therapeutic use of developed drugs and recombinant proteasome/HSPs to eliminate toxic proteins and prevent/treat EP-induced neurodegeneration.

A comparison between a fully integrated Doherty power amplifier (DPA) and outphasing power amplifier (OPA) for fifth Generation (5G) wireless communications is presented in this paper. Both amplifiers are integrated using pHEMT transistors from the OMMIC’s 100 nm GaN-on-Si technology (D01GH). After a theoretical analysis, the design and layout of both circuits are presented. The DPA uses an asymmetric configuration where the main amplifier is biased in class AB and the auxiliary amplifier is biased in class C, while the OPA uses two amplifiers biased in class B. In the comparative analysis, it has been observed that the OPA presents a better performance in terms of maximum power added efficiency (PAE), while the DPA provides higher linearity and efficiency at 7.5 dB output back-off (OBO). At a 1 dB compression point, the OPA exhibits an output power of 33 dBm with a maximum PAE of 58.3% compared to 44.2% for the DPA for an output power of 35 dBm, and at 7.5 dB OBO, the DPA achieves a PAE of 38.5%, while the OPA achieves 26.1%. The area has been optimized using absorbing adjacent component techniques, resulting in an area of 3.26 mm2 for the DPA and 3.18 mm2 for the OPA.

The widely used plasticizer bisphenol-A (BPA) is well-known for producing neurodegeneration and cognitive disorders, following acute and long-term exposure. Although some of the BPA actions involved in these effects have been unraveled, they are still incompletely known. Basal forebrain cholinergic neurons (BFCN) regulate memory and learning processes and their selective loss, as observed in Alzheimer’s disease and other neurodegenerative diseases, leads to cognitive decline. In order to study the BPA neurotoxic effects on BFCN and the mechanisms through which they are induced, 60-day old Wistar rats were used, and a neuroblastoma cholinergic cell line from the basal forebrain (SN56) was used as a basal forebrain cholinergic neuron model. Acute treatment of rats with BPA (40 µg/kg) induced a more pronounced basal forebrain cholinergic neuronal loss. Exposure to BPA, following 1- or 14-days, produced postsynaptic-density-protein-95 (PSD95), synaptophysin, spinophilin, and N-methyl-D-aspartate-receptor-subunit-1 (NMDAR1) synaptic proteins downregulation, an increase in glutamate content through an increase in glutaminase activity, a downregulation in the vesicular-glutamate-transporter-2 (VGLUT2) and in the WNT/β-Catenin pathway, and cell death in SN56 cells. These toxic effects observed in SN56 cells were mediated by overexpression of histone-deacetylase-2 (HDAC2). These results may help to explain the synaptic plasticity, cognitive dysfunction, and neurodegeneration induced by the plasticizer BPA, which could contribute to their prevention.

This paper presents a novel and compact vector modulator (VM) architecture implemented in 130 nm SiGe BiCMOS technology. The design is suitable for use in receive phased arrays for the gateways of major low Earth orbit (LEO) constellations that operate in the 17.8 to 20.2 GHz frequency range. The proposed architecture uses four variable gain amplifiers (VGA) that are active at any given time and are switched to generate the four quadrants. Compared to conventional architectures, this structure is more compact and produces double the output amplitude. The design offers 6-bit phase control for 360°, and the total root mean square (RMS) phase and gain errors are 2.36° and 1.46 dB, respectively. The design occupies an area of 1309.4 μm × 1783.8 μm (including pads).

The implementation of a 0.38 V K-band low-power fully differential low-noise amplifier (LNA) in a 45 nm silicon-on-insulator (SOI) process is presented. The proposed architecture employs a two-stage approach with transformer-based interstage matching networks to minimize circuit area. The proposed LNA covers the frequency range from 20.3 to 24.1 GHz, it achieves a noise figure (NF) as low as 2.2 dB, and a gain of 12.9 dB, with a power consumption of 11.7 mW from a 0.38 V DC supply in a very compact area (0.15 mm2) excluding pads. Non-linearity simulations show the proposed circuit achieves a Po1dB of −7.3 dBm, and an OIP3 (Output Third Order Intercept) of 7 dBm. The transformers allow improved area use since they are simultaneously used as matching networks, RF chokes to bias the active devices, baluns at the input and output terminals to convert the single-ended signal into differential mode, and vice versa, and facilitates the interconnection with the upcoming stages. We used a state-of-the-art tool that generates the desired inductances to perform impedance matching for a given frequency and coupling factor value. A comparison with similar works proves the proposed LNA achieves a very low NF and the lowest power consumption reported in a differential circuit.

A 1.4-dB Noise Figure (NF) four-stage K-band Monolithic Microwave Integrated Circuit (MMIC) Low-Noise Amplifier (LNA) in UMS 100 nm GaAs pHEMT technology is presented. The proposed circuit is designed to cover the 5G New Release n258 frequency band (24.25–27.58 GHz). Momentum EM post-layout simulations reveal the circuit achieves a minimum NF of 1.3 dB, a maximum gain of 34 dB, |S11| better than –10 dB from 23 GHz to 29 GHz, a P1dB of –18 dBm and an OIP3 of 24.5 dBm. The LNA draws a total current of 59.1 mA from a 2 V DC supply and results in a chip size of 3300 × 1800 µm2 including pads. We present a design methodology focused on the selection of the active device size and DC bias conditions to obtain the lowest NF when source degeneration is applied. The design procedure ensures a minimum NF design by selecting a device which facilitates a simple input matching network implementation and obtains a reasonable input return loss thanks to the application of source degeneration. With this approach the input matching network is implemented with a shunt stub and a transmission line, therefore minimizing the contribution to the NF achieved by the first stage. Comparisons with similar works demonstrate the developed circuit is very competitive with most of the state-of-the-art solutions.

Pump-probe method is commonly used for studying ultrafast molecular dynamics. Here, the authors discuss alternative approach of using time-dependent ultrafast light emission from excited molecules coupled to a plasmonic nanocavity instead of using probe pulse.

In this paper, a wide-band distributed model that can approximate the behaviour of square and octagonal inductors, both with and without tapering, is presented. This paper also presents a novel way of accurately modelling the lateral coupling in the substrate. The presented model can be applied to any foundry process, and its validity has been demonstrated using a novel technology, the D01GH GaN process developed by OMMIC, which has a high resistivity substrate. To do so, seventeen inductors have been designed and manufactured. The proposed model has been verified against EM simulations and measurements of the designed inductors. Comparisons show that the model can correctly estimate the behaviour of the inductor, improving the results of the EM simulations for most cases. The root mean square (RMS) error calculated across the samples when estimating the inductance is 0.0565. The RMS error for the quality factor results (2.2727) is also adequate, although there is more deviation when comparing the results with the measurements.

Nowadays, mega-constellations of Low Earth Orbit (LEO) satellites have become increasingly important to provide high-performance Internet access with global coverage. This paper provides an updated comparison of four of the largest LEO mega-constellations: Telesat, SpaceX, OneWeb and Amazon. It describes the gateway design workflow from the patch antenna to phased array analysis. Patch antennas are developed for both transmission and reception after a thorough examination of the four systems. The results of electromagnetic simulation using Advanced Design Software (ADS) Momentum are shown, including their radiation pattern. Finally, a model of the gateway phased array using SystemVue is obtained using hexagonal, circular, and square arrays. According to the required effective isotropic radiated power (EIRP) and gain, the antenna sizes for the four constellations are estimated. As an example, for SpaceX constellation, a reception antenna with 8910 radiating elements using a hexagonal distribution with a gain of 46.9 dB and a sensitivity of −113.1 dBm was obtained.

In this paper, a wide-band noise-canceling (NC) current conveyor (CC)-based CMOS low-noise amplifier (LNA) is presented. The circuit employs a CC-based approach to obtain wide-band input matching without the need for bulky inductances, allowing broadband performance with a very small area used. The NC technique is applied by subtracting the input transistor’s noise contribution to the output and achieves a noise figure (NF) reduction from 4.8 dB to 3.2 dB. The NC LNA is implemented in a UMC 65-nm CMOS process and occupies an area of only 160 × 80 μm2. It achieves a stable frequency response from 0 to 6.2 GHz, a maximum gain of 15.3 dB, an input return loss (S11) < −10 dB, and a remarkable IIP3 of 7.6 dBm, while consuming 18.6 mW from a ±1.2 V DC supply. Comparisons with similar works prove the effectiveness of this new implementation, showing that the circuit obtains a noteworthy performance trade-off.

Wireless sensor network (WSN) applications are under extensive research and development due to the need to interconnect devices with each other. To reduce latency while keeping very low power consumption, the implementation of a wake-up receiver (WuR) is of particular interest. In WuR implementations, meeting high performance metrics is a design challenge, and the obtention of high-sensitivity, high data rate, low-power-consumption WuRs is not a straightforward procedure. The focus of our proposals is centered on power consumption and area reduction to provide high integrability and maintain a low cost-per-node, while we simultaneously improve circuit sensitivity. Firstly, we present a two-stage design based on a feedback technique and improve the area use, power consumption and sensitivity of the circuit by adding a current-reuse approach. The first solution is composed of a feedback amplifier, two op-amps plus a low-pass filter. The circuit achieves a sensitivity of –63.2 dBm with a power consumption of 6.77 µA and an area as low as 398 × 266 µm2. With the current-reuse feedback amplifier, the power consumption is halved in the second circuit (resulting in 3.63 µA), and the resulting circuit area is as low as 262 × 262 µm2. Thanks to the nature of the circuit, the sensitivity is improved to –75 dBm. This latter proposal is particularly suitable in applications where a fully integrated WuR is desired, providing a reasonable sensitivity with a low power consumption and a very low die footprint, therefore facilitating integration with other components of the WSN node. A thorough discussion of the most relevant state-of-the-art solutions is presented, too, and the two developed solutions are compared to the most relevant contributions available in the literature.

Abstract Biogenesis and function of microRNAs can be influenced by genetic variants in the pri-miRNA sequences leading to phenotypic variability. This study aims to identify single nucleotide polymorphisms (SNPs) affecting the expression levels of bone-related mature microRNAs and thus, triggering an osteoporotic phenotype. An association analysis of SNPs located in pri-miRNA sequences with bone mineral density (BMD) was performed in the OSTEOMED2 cohort (n = 2183). Functional studies were performed for assessing the role of BMD-associated miRNAs in bone cells. Two SNPs, rs6430498 in the miR-3679 and rs12512664 in the miR-4274, were significantly associated with femoral neck BMD. Further, we measured these BMD-associated microRNAs in trabecular bone from osteoporotic hip fractures comparing to non-osteoporotic bone by qPCR. Both microRNAs were found overexpressed in fractured bone. Increased matrix mineralization was observed after miR-3679-3p inhibition in human osteoblastic cells. Finally, genotypes of rs6430498 and rs12512664 were correlated with expression levels of miR-3679 and miR-4274, respectively, in osteoblasts. In both cases, the allele that generated higher microRNA expression levels was associated with lower BMD values. In conclusion, two osteoblast-expressed microRNAs, miR-3679 and miR-4274, were associated with BMD; their overexpression could contribute to the osteoporotic phenotype. These findings open new areas for the study of bone disorders.

The development of wake-up receivers (WuR) has recently received a lot of interest from both academia and industry researchers, primarily because of their major impact on the improvement of the performance of wireless sensor networks (WSNs). In this paper, we present the development of three different radiofrequency envelope detection (RFED) based WuRs operating at the 868 MHz industrial, scientific and medical (ISM) band. These circuits can find application in densely populated WSNs, which are fundamental components of Internet-of-Things (IoT) or Internet-of-Everything (IoE) applications. The aim of this work is to provide circuits with high integrability and a low cost-per-node, so as to facilitate the implementation of sensor nodes in low-cost IoT applications. In order to demonstrate the feasibility of implementing a WuR with commercially available off-chip components, the design of an RFED WuR in a PCB mount is presented. The circuit is validated in a real scenario by testing the WuR in a system with a pattern recognizer (AS3933), an MCU (MSP430G2553 from TI), a transceiver (CC1101 from TI) and a T/R switch (ADG918). The WuR has no active components and features a sensitivity of about −50 dBm, with a total size of 22.5 × 51.8 mm2. To facilitate the integration of the WuR in compact systems and low-cost applications, two designs in a commercial UMC 65 nm CMOS process are also explored. Firstly, an RFED WuR with integrated transformer providing a passive voltage gain of 18 dB is demonstrated. The circuit achieves a sensitivity as low as −62 dBm and a power consumption of only 528 nW, with a total area of 634 × 391 μm2. Secondly, so as to reduce the area of the circuit, a design of a tuned-RF WuR with integrated current-reuse active inductor is presented. In this case, the WuR features a sensitivity of −55 dBm with a power consumption of 43.5 μW and a total area of 272 × 464 μm2, obtaining a significant area reduction at the expense of higher power consumption. The alternatives presented show a very low die footprint with a performance in line with most of the state-of-the-art contributions, making the topologies attractive in scenarios where high integrability and low cost-per-node are necessary.

This paper presents a procedure to analyse the effects of radiation in an IEEE 802.15.4 RF receiver for wireless sensor networks (WSNs). Specifically, single-event transients (SETs) represent one of the greatest threats to the adequate performance of electronic communication devices in high-radiation environments. The proposed procedure consists in injecting current pulses in sensitive nodes of the receiver and analysing how they propagate through the different circuits that form the receiver. In order to perform this analysis, a Complementary Metal Oxide Semiconductor (CMOS) low-IF receiver has been designed using a 0.18 μm technology from the foundry UMC. In order to analyse the effect of single-event transients in this receiver, it has been studied how current pulses generated in the low-noise amplifier propagate down the receiver chain. The effect of the different circuits that form the receiver on this kind of pulse has been studied prior to the analysis of the complete receiver. First, the effect of SETs in low-noise amplifiers was analysed. Then, the propagation of pulses through mixers was studied. The effect of filters in the analysed current pulses has also been studied. Regarding the analysis of the designed RF receiver, an amplitude and phase shift was observed under the presence of SETs.

In cavity optomechanics, nonlinear interactions between an optical field and a mechanical resonator mode enable a variety of unique effects in classical and quantum measurement and information processing. Here, we describe nonlinear optomechanical coupling in the membrane-in-the-middle (MIM) system in a way that allows direct comparison to the intrinsic optomechanical nonlinearity in a standard, single-cavity optomechanical system. We find that the enhancement of nonlinear optomechanical coupling in the MIM system as predicted by Ludwig et al (2012 Phys. Rev. Lett. 109 063601) is limited to the degree of sideband resolution of the system. Moreover, we show that the selectivity of the MIM system of nonlinear over linear transduction has the same limit as in a single cavity system. These findings put constraints on the experiments in which it is advantageous to use an MIM system. We discuss dynamical backaction effects in this system and find that these effects per cavity photon are exactly as strong as in a single cavity system, while allowing for reduction of the required input power. We propose using the nonlinear enhancement and reduced input power in realistic MIM systems towards parametric squeezing and heralding of phonon pairs, and evaluate the limits to the magnitude of both effects.

La Enfermedad Ósea de Paget (EOP) es la enfermedad metabólica ósea más frecuente después de la osteoporosis. Aunque suele cursar de manera asintomática, es importante pensar en ella en pacientes que consultan por dolor óseo, deformidad ósea, o en pacientes con elevación de Fosfatasa Alcalina sin hepatopatía. Presentamos el caso de una pacientes con EOP afectando al radio, una localización extremadamente infrecuente de esta enfermedad.

Paget disease of bone (PDB) is a focal bone disorder affecting the skeleton segmentally. The main alteration resides in osteoclasts that increase in size, number and activity. Many osteoclasts have cytoplasmic inclusions that have been associated with protein aggregates, increasing the evidences of a possible deregulation of autophagy in the development of the PDB. Autophagy starts with encapsulation of the target into a double-membrane-bound structure called an "autophagosome." It has been reported that at least 18 ATG genes (autophagy-related genes) are involved in autophagosome formation. We have studied the distribution of genotypes of the ATG2B rs3759601, ATG16L1 rs2241880, ATG10 rs1864183 and ATG5 rs2245214 polymorphisms in a Spanish cohort of subjects with PDB and compared with healthy subjects. Our results show that being a carrier of the C allele of the ATG16L1 rs2241880 and the G allele of ATG5 rs2245214 polymorphisms were associated with an increased risk of developing PDB, whereas being a carrier of the T allele of ATG10 rs1864183 polymorphism decreased the risk of suffering the disease in our series. This is the first report that shows an association between autophagy and Paget Disease of Bone and requires further confirmation in other series.

The reversible phosphorylation of the alpha-subunit of eukaryotic translation initiation factor 2 (eIF2alpha) is a well-characterized mechanism of translational control in response to a wide variety of cellular stresses, including viral infection. Beside PKR, the eIF2alpha kinase GCN2 participates in the cellular response against viral infection by RNA viruses with central nervous system tropism. PKR has also been involved in the antiviral response against HIV-1, although this antiviral effect is very limited due to the distinct mechanisms evolved by the virus to counteract PKR action. Here we report that infection of human cells with HIV-1 conveys the proteolytic cleavage of GCN2 and that purified HIV-1 and HIV-2 proteases produce direct proteolysis of GCN2 in vitro, abrogating the activation of GCN2 by HIV-1 RNA. Transfection of distinct cell lines with a plasmid encoding an HIV-1 cDNA clone competent for a single round of replication resulted in the activation of GCN2 and the subsequent eIF2alpha phosphorylation. Moreover, transfection of GCN2 knockout cells or cells with low levels of phosphorylated eIF2alpha with the same HIV-1 cDNA clone resulted in a marked increase of HIV-1 protein synthesis. Also, the over-expression of GCN2 in cells led to a diminished viral protein synthesis. These findings suggest that viral RNA produced during HIV-1 infection activates GCN2 leading to inhibition of viral RNA translation, and that HIV-1 protease cleaves GCN2 to overcome its antiviral effect.

Adequate vitamin D levels are necessary for good vascular health. 1,25-dihydroxycholecalciferol activates CYP3A4, an enzyme of the cytochrome P450 system, which metabolizes atorvastatin to its main metabolites. The objective of this study was to evaluate the response of cholesterol and triglycerides to atorvastatin according to vitamin D levels. Sixty-three patients with acute myocardial infarction treated with low and high doses of atorvastatin were included. Levels of total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol were measured at baseline and at 12 months of follow-up. Baseline levels of 25-hydroxyvitamin D (25-OHD) were classified as deficient (50 nmol/L). In patients with 25-OHD 50 nmol/L) had a good response to atorvastatin. We suggest that vitamin D concentrations >30 nmol/L may be required for atorvastatin to reduce lipid levels in patients with acute myocardial infarction.

We develop a quantum mechanical formalism to treat the strong coupling between an electromagnetic mode and a vibrational excitation of an ensemble of organic molecules. By employing a Bloch–Redfield–Wangsness approach, we show that the influence of dephasing-type interactions, i.e., elastic collisions with a background bath of phonons, critically depends on the nature of the bath modes. In particular, for long-range phonons corresponding to a common bath, the dynamics of the ‘bright state’ (the collective superposition of molecular vibrations coupling to the cavity mode) is effectively decoupled from other system eigenstates. For the case of independent baths (or short-range phonons), incoherent energy transfer occurs between the bright state and the uncoupled dark states. However, these processes are suppressed when the Rabi splitting is larger than the frequency range of the bath modes, as achieved in a recent experiment (Shalabney et al 2015 Nat. Commun. http://dx.doi.org/10.1038/ncomms6981 6 http://dx.doi.org/10.1038/ncomms6981 ). In both cases, the dynamics can thus be described through a single collective oscillator coupled to a photonic mode, making this system an ideal candidate to explore cavity optomechanics at room temperature.