Multifunctional Scaffolds for Selective Protein-Protein Inhibition

Protein-protein interactions (PPIs) play an important role in numerous biological processes. Consequently, modulating PPIs is fundamental for understanding and manipulating mechanisms that govern many diseases. Among the wide range of topographies that PPIs display, the α-helix is the most common secondary structure in nature and thus represents a good generic template for inhibitor design.1 Some of the most relevant approaches in this field are the proteomimetic approach, which recapitulate the key binding residues of an α-helix on a non-peptidic scaffold; and the constrained peptides, which aim to reproduce the helical structure by stabilising a helical peptide. Both approaches have generated potent inhibitors of a great diversity of α-helix mediated PPIs. However, developing a better understanding of the key features that govern the modulation of protein recognition is necessary to further advance the field and fully exploit each class of foldamer. In that context, we developed functionalised aromatic oligoamide backbones to mimic residues located on multiple faces of an -helix to target the ER/co-activator PPI. The novel scaffolds are based on bis-benzamide and N-(4-aminophenyl)terephthalamidic acid backbones functionalised with isobutyl groups to reproduce the key side chains of the co-activator α-helix. Conformational studies in combination with molecular modeling and docking analysis provide evidence that the new oligomers can adopt conformations that mimic the residues at i, i+3 and i+4 positions of the native co-activator α-helix. In addition, the rules that govern molecular recognition of protein surfaces were further investigated through the optimisation of the oligobenzamide hybrid scaffold using a structure-activity relationship (SAR) study. A library of compound analogues has been synthesised incorporating five variable sites. The modifications focused on size, polarity and stereochemistry to obtain more potent and selective proteomimetic inhibitors of the p53/hDM2 and Mcl-1/NOXA B PPIs. Finally, using existing methodologies a 3-O-alkylated proteomimetic scaffold and hydrocarbon stapling peptide strategy, have been used to design inhibitors of the Asf1/H3 interaction. The application of both approaches allowed the different inhibitor designs to be directly compared when targeting the same PPI

Neonatal hearing screening in high-risk patients with otoacoustic emissions: evaluation of results

Resumen Objetivo: evaluar la efectividad del programa de tamizaje auditivo del Homic en pacientes de alto riesgo de hipoacusia neurosensorial, el cual está basado en la realización de otoemisiones acústicas Diseño: estudio de cohorte retrospectiva, en el que se incluirán a los pacientes mayores de 12 meses de edad nacidos en el Hospital Militar central (HMC) entre enero de 2009 y diciembre de 2012; a quienes por condiciones de alto riesgo de hipoacusia neurosensorial se les realizó antes de los 6 meses de edad otoemisiones acústicas como prueba de tamizaje auditivo. A esta población, se le realizara diagnostico auditivo por medio del método diagnostico Gold Standart el cual es el “cross cheking”. Resultados: Se estudiaron los factores de riesgo para hipoacusia neurosensorial encontrando que el peso al nacer ≤1500 gr. Se relacionó con hipoacusia en un 16%. El 5.6% tiene antecedente familiar de hipoacusia neurosensorial en primer y segundo grado de consanguinidad. La infección congénita (TORCHS: toxoplasmosis, sífilis, rubéola, citomegalovirus, o herpes) como factor de riesgo se presentó en el 2.4% únicamente con la presencia de Toxoplasmosis, de los cuales 2 oídos presentaron cofosis. Conclusiones: La sensibilidad de las Otoemisiones acusticas para sospechar hipoacusia neurosensorial fue del 82.5%. La especificidad estimada en nuestro estudio fue de 90.9%Hospital Militar CentralObjective: To evaluate the effectiveness of auditory screening program Central Military Hospital in patients at high risk of sensorineural hearing loss, which is based on the realization of otoacoustic emissions. Design: Retrospective cohort study, in which over 12 months of age born patients in the Central Military Hospital (HOMIC) between January 2009 and December 2012 were included; who by conditions of high risk of sensorineural hearing loss was performed before 6 months of age otoacoustic emissions and hearing screening test. Total population was 125 patients. We evaluated each ear separately for a total of 250 measurements, this population was conducted auditory diagnosis through cross cheking diagnosis method were analyzed. Results: Risk factors for sensorineural hearing loss were studied. We found that birth weight ≤1500 g. It was associated with hearing loss by 16%. 5.6% have a family history of sensorineural hearing loss in first and second degree of consanguinity. Congenital infection (TORCHS: toxoplasmosis, syphilis, rubella, cytomegalovirus, or herpes) as a risk factor occurred in 2.4% only in the presence of Toxoplasmosis, of which 2 ears presented deafness. Conclusions: The otoacoustic emissions are effective as hearing screening test in Military Central Hospital in patients at high risk of Sensorineural hearing loss. The sensitivity of otoacoustic emissions to suspect sensorineural hearing loss was 82.5%. The estimated specificity in our study was 90.9

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Energy Estimation of Cosmic Rays with the Engineering Radio Array of the Pierre Auger Observatory

The Auger Engineering Radio Array (AERA) is part of the Pierre Auger Observatory and is used to detect the radio emission of cosmic-ray air showers. These observations are compared to the data of the surface detector stations of the Observatory, which provide well-calibrated information on the cosmic-ray energies and arrival directions. The response of the radio stations in the 30 to 80 MHz regime has been thoroughly calibrated to enable the reconstruction of the incoming electric field. For the latter, the energy deposit per area is determined from the radio pulses at each observer position and is interpolated using a two-dimensional function that takes into account signal asymmetries due to interference between the geomagnetic and charge-excess emission components. The spatial integral over the signal distribution gives a direct measurement of the energy transferred from the primary cosmic ray into radio emission in the AERA frequency range. We measure 15.8 MeV of radiation energy for a 1 EeV air shower arriving perpendicularly to the geomagnetic field. This radiation energy -- corrected for geometrical effects -- is used as a cosmic-ray energy estimator. Performing an absolute energy calibration against the surface-detector information, we observe that this radio-energy estimator scales quadratically with the cosmic-ray energy as expected for coherent emission. We find an energy resolution of the radio reconstruction of 22% for the data set and 17% for a high-quality subset containing only events with at least five radio stations with signal.Comment: Replaced with published version. Added journal reference and DO

Measurement of the Radiation Energy in the Radio Signal of Extensive Air Showers as a Universal Estimator of Cosmic-Ray Energy

We measure the energy emitted by extensive air showers in the form of radio emission in the frequency range from 30 to 80 MHz. Exploiting the accurate energy scale of the Pierre Auger Observatory, we obtain a radiation energy of 15.8 \pm 0.7 (stat) \pm 6.7 (sys) MeV for cosmic rays with an energy of 1 EeV arriving perpendicularly to a geomagnetic field of 0.24 G, scaling quadratically with the cosmic-ray energy. A comparison with predictions from state-of-the-art first-principle calculations shows agreement with our measurement. The radiation energy provides direct access to the calorimetric energy in the electromagnetic cascade of extensive air showers. Comparison with our result thus allows the direct calibration of any cosmic-ray radio detector against the well-established energy scale of the Pierre Auger Observatory.Comment: Replaced with published version. Added journal reference and DOI. Supplemental material in the ancillary file

Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke

During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke. Ibanez et al. perform a multi-ancestry meta-analysis to investigate the genetic architecture of early stroke outcomes. Two of the eight genome-wide significant loci identified-ADAM23 and GRIA1-are involved in synaptic excitability, suggesting that excitotoxicity contributes to neurological instability after ischaemic stroke.Peer reviewe

Association of Candidate Gene Polymorphisms With Chronic Kidney Disease: Results of a Case-Control Analysis in the Nefrona Cohort

Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Despite classical clinical risk factors for CKD and some genetic risk factors have been identified, the residual risk observed in prediction models is still high. Therefore, new risk factors need to be identified in order to better predict the risk of CKD in the population. Here, we analyzed the genetic association of 79 SNPs of proteins associated with mineral metabolism disturbances with CKD in a cohort that includes 2, 445 CKD cases and 559 controls. Genotyping was performed with matrix assisted laser desorption ionizationtime of flight mass spectrometry. We used logistic regression models considering different genetic inheritance models to assess the association of the SNPs with the prevalence of CKD, adjusting for known risk factors. Eight SNPs (rs1126616, rs35068180, rs2238135, rs1800247, rs385564, rs4236, rs2248359, and rs1564858) were associated with CKD even after adjusting by sex, age and race. A model containing five of these SNPs (rs1126616, rs35068180, rs1800247, rs4236, and rs2248359), diabetes and hypertension showed better performance than models considering only clinical risk factors, significantly increasing the area under the curve of the model without polymorphisms. Furthermore, one of the SNPs (the rs2248359) showed an interaction with hypertension, being the risk genotype affecting only hypertensive patients. We conclude that 5 SNPs related to proteins implicated in mineral metabolism disturbances (Osteopontin, osteocalcin, matrix gla protein, matrix metalloprotease 3 and 24 hydroxylase) are associated to an increased risk of suffering CKD

First X-ray polarization measurement confirms the low black-hole spin in LMC X-3

X-ray polarization is a powerful tool to investigate the geometry of accreting material around black holes, allowing independent measurements of the black hole spin and orientation of the innermost parts of the accretion disk. We perform the X-ray spectro-polarimetric analysis of an X-ray binary system in the Large Magellanic Cloud, LMC X-3, that hosts a stellar-mass black hole, known to be persistently accreting since its discovery. We report the first detection of the X-ray polarization in LMC X-3 with the Imaging X-ray Polarimetry Explorer, and find the average polarization degree of 3.2% +- 0.6% and a constant polarization angle -42 deg +- 6 deg over the 2-8 keV range. Using accompanying spectroscopic observations by NICER, NuSTAR, and the Neil Gehrels Swift observatories, we confirm previous measurements of the black hole spin via the X-ray continuum method, a ~ 0.2. From polarization analysis only, we found consistent results with low black-hole spin, with an upper limit of a < 0.7 at a 90% confidence level. A slight increase of the polarization degree with energy, similar to other black-hole X-ray binaries in the soft state, is suggested from the data but with a low statistical significance.Comment: 14 pages, 8 figures, submitted to Ap

The first X-ray polarimetric observation of the black hole binary LMC X-1

We report on an X-ray polarimetric observation of the high-mass X-ray binary LMC X-1 in the high/soft state, obtained by the Imaging X-ray Polarimetry Explorer (IXPE) in October 2022. The measured polarization is below the minimum detectable polarization of 1.1 per cent (at the 99 per cent confidence level). Simultaneously, the source was observed with the NICER, NuSTAR and SRG/ART-XC instruments, which enabled spectral decomposition into a dominant thermal component and a Comptonized one. The low 2-8 keV polarization of the source did not allow for strong constraints on the black-hole spin and inclination of the accretion disc. However, if the orbital inclination of about 36 degrees is assumed, then the upper limit is consistent with predictions for pure thermal emission from geometrically thin and optically thick discs. Assuming the polarization degree of the Comptonization component to be 0, 4, or 10 per cent, and oriented perpendicular to the polarization of the disc emission (in turn assumed to be perpendicular to the large scale ionization cone orientation detected in the optical band), an upper limit to the polarization of the disc emission of 1.0, 0.9 or 0.9 per cent, respectively, is found (at the 99 per cent confidence level).Comment: 12 pages, 9 figures, 4 tables. Accepted for publication in MNRA