gebhart/patrepeval huggingface dataset:
Bronchoscopic Advances: On the Way to the Cells (2010)

In the past 15 years, new endoscopic methods have been developed in order to improve the detection of early bronchial cancers, with autofluorescence bronchoscopy being the leading technique. However, autofluorescence bronchoscopy is hampered by the low specificity of the fluorescence defect which ranges from 25 to 50%, and its limitation to the proximal bronchial tree from which arise only half of the lung cancers that are currently diagnosed. To overcome these limitations, other techniques emerge including video/autofluorescence bronchoscopy, narrow band imaging, optical coherence tomography, and 'endomicroscopy' using confocal fluorescent laser microscopy. These emerging techniques provide new insight into bronchology, extending the field of exploration from the proximal bronchus down to the most distal part of the lungs, and from macroscopy to in vivo cellular imaging. In the near future, they may enable in vivo, minimally invasive, 'pathological grade' evaluation of abnormal bronchial or parenchymal lung tissue. Whereas promising pioneer work has recently been published, careful assessment is required before these methods find a place in the evaluation strategy of early lung cancer and other lung diseases.
Impact of sheath size and hemostasis time on radial artery patency after transradial coronary angiography and intervention in Japanese and non‐Japanese patients: A substudy from RAP and BEAT (Radial Artery Patency and Bleeding, Efficacy, Adverse evenT) randomized multicenter trial (2018)

Use of GSS6Fr was associated with a higher rate of RAO than a standard 5 Fr sheath in Japanese patients but not in non-Japanese patients. Whether improvement in post-procedural care and reduced hemostasis time could impact the incidence of RAO in Japanese patients should be further assessed.
CDK4/CDK6 Inhibitors Synergize with Midostaurin, Avapritinib, and Nintedanib in Inducing Growth Inhibition in KIT D816V+ Neoplastic Mast Cells (2022)

In most patients with advanced systemic mastocytosis (AdvSM), neoplastic mast cells (MC) express <i>KIT</i> D816V. However, despite their disease-modifying potential, KIT D816V-targeting drugs, including midostaurin and avapritinib, may not produce long-term remissions in all patients. Cyclin-dependent kinase (CDK) 4 and CDK6 are promising targets in oncology. We found that shRNA-mediated knockdown of CDK4 and CDK6 results in growth arrest in the <i>KIT</i> D816V<sup>+</sup> MC line HMC-1.2. The CDK4/CDK6 inhibitors palbociclib, ribociclib, and abemaciclib suppressed the proliferation in primary neoplastic MC as well as in all HMC-1 and ROSA cell subclones that were examined. Abemaciclib was also found to block growth in the drug-resistant MC line MCPV-1, whereas no effects were seen with palbociclib and ribociclib. Anti-proliferative drug effects on MC were accompanied by cell cycle arrest. Furthermore, CDK4/CDK6 inhibitors were found to synergize with the KIT-targeting drugs midostaurin, avapritinib, and nintedanib in inducing growth inhibition and apoptosis in neoplastic MCs. Finally, we found that CDK4/CDK6 inhibitors induce apoptosis in CD34+/CD38- stem cells in AdvSM. Together, CDK4/CDK6 inhibition is a potent approach to suppress the growth of neoplastic cells in AdvSM. Whether CDK4/CDK6 inhibitors can improve clinical outcomes in patients with AdvSM remains to be determined in clinical trials.
Integrative Genomic Analysis Identifies Isoleucine and CodY as Regulators of Listeria monocytogenes Virulence (2012)

Intracellular bacterial pathogens are metabolically adapted to grow within mammalian cells. While these adaptations are fundamental to the ability to cause disease, we know little about the relationship between the pathogen's metabolism and virulence. Here we used an integrative Metabolic Analysis Tool that combines transcriptome data with genome-scale metabolic models to define the metabolic requirements of Listeria monocytogenes during infection. Twelve metabolic pathways were identified as differentially active during L. monocytogenes growth in macrophage cells. Intracellular replication requires de novo synthesis of histidine, arginine, purine, and branch chain amino acids (BCAAs), as well as catabolism of L-rhamnose and glycerol. The importance of each metabolic pathway during infection was confirmed by generation of gene knockout mutants in the respective pathways. Next, we investigated the association of these metabolic requirements in the regulation of L. monocytogenes virulence. Here we show that limiting BCAA concentrations, primarily isoleucine, results in robust induction of the master virulence activator gene, prfA, and the PrfA-regulated genes. This response was specific and required the nutrient responsive regulator CodY, which is known to bind isoleucine. Further analysis demonstrated that CodY is involved in prfA regulation, playing a role in prfA activation under limiting conditions of BCAAs. This study evidences an additional regulatory mechanism underlying L. monocytogenes virulence, placing CodY at the crossroads of metabolism and virulence.
Protein biomarkers of amyotrophic lateral sclerosis: mass spectrometry‐based characterization of transthyretin (2007)

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease and is characterized by the progressive degeneration and death of motor neurons. Currently, established and objective molecular markers that allow for the diagnosis and monitoring of ALS are lacking. Recently, we have identified a panel of protein biomarkers for ALS using mass spectrometry‐based proteomics. One potential biomarker, transthyretin (TTR), was found to be decreased in the cerebrospinal fluid of ALS patients when compared to control subjects. We have identified specific post‐translational modifications of the TTR protein that are altered in ALS patients. Specifically, TTR adducts with cysteine (TTR‐Cys) or cysteinylglycine (TTR‐CysGly) are reduced in the ALS population and correlate with disease progression. However, ELISA specific for TTR showed no significant change in overall TTR protein levels suggesting that altered post‐translational protein modifications as opposed to total protein levels are important. We are now determining if these same TTR alterations occur within the blood plasma of ALS patients. We will also correlate the presence of TTR abnormalities to specific sub‐populations of ALS patients. Sources of research support: NIH grant ES013469 (RB) and NIH T32 EB001026 (CK)
Abstract 3564: Design, synthesis and SAR studies leading to SB1518, a novel macrocyclic JAK2/FLT3 inhibitor in phase 2 clinical trials for myelofibrosis and lymphoma (2011)

Abstract Introduction: Here we present the unique chemical structure of SB1518 and SAR studies leading to the discovery of this exciting novel JAK2/FLT3 inhibitor, currently in clinical trials for myelofibrosis and lymphoma. Methods/Results: As part of our innovative chemical strategy towards creating novel kinase scaffolds we discovered a series of unusual small molecular weight macrocycles which were optimized for selective JAK2 inhibitory potency culminating in the discovery of SB1518, which is selective for JAK2 (IC50 = 22nM) and its V617F mutant (IC50 = 19nM) over JAK1 (IC50 &amp;gt; 1µM) and JAK3 (IC50 &amp;gt; 0.5µM). FLT3 was identified as an additional kinase target (IC50 = 22nM and 6nM for its D835Y mutant) giving a broader potential in other hematological malignancies. The exciting and novel chemical structures of these compounds led us into a full lead optimization program to take full advantage of the unique nature of these molecules. SAR studies modifying the macrocyclic linker allowed unwanted protein kinase activity to be tuned out, whilst retaining a narrow spectrum of desired JAK2 kinase activity and selectivity over JAK1 and JAK3, a distinguishing feature. SB1518 and analogues were synthesized via a ring-closing metathesis (RCM) strategy: coupling of the two halves of the molecule provided a diene which was closed by RCM using either Grubbs or Zhan catalysts. SAR investigations, led by structure-based design, influenced the choice and position of a critical solubilising side-chain. Preferred compounds had improved aqueous solubility and high permeability. SB1518 is very stable both chemically and metabolically with a long half life in human microsomal preparations. With the desired balance of potency and oral pharmacokinetics, SB1518 was selected for further profiling. SB1518 demonstrated potent activity in cell lines driven by mutant JAK2 or FLT3 and was efficacious at very well tolerated oral doses in tumor models generated with these cell lines. Based on its attractive preclinical profile, SB1518 was selected for clinical development. Conclusions: Discovery of a new series of small molecule macrocycles of a unique and highly novel chemical structure are presented as inhibitors of JAK2 and FLT3 kinases. SAR studies directed us towards an optimal linker and solubilising side chain fine-tuning the molecular structure. SB1518 was selected as a development candidate with an attractive and distinguishing JAK2 selective inhibitory profile and additional activity against FLT3. SB1518 has shown encouraging clinical activity demonstrating that its attractive preclinical profile translates to the clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3564. doi:10.1158/1538-7445.AM2011-3564
Assessment of SORL1 rare variants segregation in Alzheimer disease families and in vitro models suggests diverse penetrance and oligogenic inheritance (2020)

Abstract Background SORL1 rare (allele frequency &lt;1%) loss‐of‐function (LOF) and missense predicted damaging (Mis3) variants have first been identified in early‐onset Alzheimer disease (EOAD, onset before 66 years) patients with a positive family history. However, segregation data in families are still missing to assess the actual pattern of inheritance. Since then, we and others have shown an increased burden of SORL1 rare LOF and Mis3 variants in EOAD patients, whatever the family history, and in late onset AD patients, with a lower effect size. In addition, although the interpretation of the biological effect of LOF variants is rather straightforward, no formal evidence of a functional effect of Mis3 variants can be inferred from bioinformatics predictions only. Method We gathered data from French families with a rare LOF or Mis3 variant and developed a cellular model to assess the role of SORL1 missense variants. Result We studied 20 families with a LOF variant (mean age at onset (AAO) in probands, 55.4 years, range: [48‐65]). Seventeen showed a positive family history. Mean AAO in affected relatives was 66.3 (range: [50‐80]). One patient carried two LOF compound heterozygous variants. DNA was available in 18 relatives: 5/6 affected relatives carried the familial variant (AAO = [61‐78]) while 3/12 unaffected were also carriers, aged 42, 71 and 95, respectively. Strikingly, 57% affected carriers were APOE4+ including one homozygous, who was also a carrier of a LOF rare ABCA7 risk variant. We developed a functional assay using CRISPR/Cas9 introduction of variants in iPSCs. We succeeded in introducing a homozygous LOF variant showing increased levels of Aβ in the supernatant. We are now inducing neuronal differentiation and introducing missense variants to better sort missense variants for penetrance studies and understand mechanisms. Interestingly, in one family with a Mis3 variant associated with increased Aβ secretion, the proband was APOE4+ and carried a LOF rare ABCA7 risk variant. Additional families and variants are currently being studied. Conclusion Our data support incomplete penetrance and oligogenic determinism in SORL1 families, making genetic counseling difficult. The development of cellular models will help us understand how and which missense variants result in reduced SORL1 functions.
Renal afferent arteriolar and tubuloglomerular feedback reactivity in mice with conditional deletions of adenosine 1 receptors (2012)

Adenosine 1 receptors (A1AR) have been shown in previous experiments to play a major role in the tubuloglomerular feedback (TGF) constrictor response of afferent arterioles (AA) to increased loop of Henle flow. Overexpression studies have pointed to a critical role of vascular A1AR, but it has remained unclear whether selective deletion of A1AR from smooth muscle cells is sufficient to abolish TGF responsiveness. To address this question, we have determined TGF response magnitude in mice in which vascular A1AR deletion was achieved using the loxP recombination approach with cre recombinase being controlled by a smooth muscle actin promoter (SmCre/A1ARff). Effective vascular deletion of A1AR was affirmed by absence of vasoconstrictor responses to adenosine or cyclohexyl adenosine (CHA) in microperfused AA. Elevation of loop of Henle flow from 0 to 30 nl/min caused a 22.1 ± 3.1% reduction of stop flow pressure in control mice and of 7.2 ± 1.5% in SmCre/A1ARff mice (P < 0.001). Maintenance of residual TGF activity despite absence of A1AR-mediated responses in AA suggests participation of extravascular A1AR in TGF. Support for this notion comes from the observation that deletion of A1ARff by nestin-driven cre causes an identical TGF response reduction (7.3 ± 2.4% in NestinCre/A1ARff vs. 20.3 ± 2.7% in controls), whereas AA responsiveness was reduced but not abolished. A1AR on AA smooth muscle cells are primarily responsible for TGF activation, but A1AR on extravascular cells, perhaps mesangial cells, appear to contribute to the TGF response.
Investigating the relationship between expressivity and synchronization in ensemble performance: an exploratory study (2013)

Comunicacio presentada al International Symposium on Performance Science (ISPS), celebrat a Viena (Austria) els dies 28 a 31 d'agost de 2013.
Design of Perforated Membrane for Low-Noise Capacitive MEMS Accelerometers (2019)

We propose a design method for a thick membrane with several thousand perforations suitable for low-noise capacitive micro-electro-mechanical systems (MEMS) accelerometers. Although we have already reported that a membrane with two-step perforations shows good noise performance, it is difficult to simulate mechanical noise using a conventional method because the large number of perforations complicates the membrane structure. In this work, we assumed that the number of perforations is infinite and that there are symmetric planes between them. This assumption greatly reduces computational complexity because the simulation model is simplified in the region around a perforation. We fabricated MEMS resonators with a two-step perforated membrane and evaluated the accuracy of the simulation results. The measured Q values of the fabricated resonators were in good agreement with the calculated results. Using this design method, we optimized the structure of a membrane with two-step perforations and fabricated capacitive MEMS accelerometers that showed excellent low-noise performance (less than 15 ng/Hz <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">1/2</sup> ) and low-power consumption (20 mW).
Five-year follow-up observation of HIV prevalence in serodiscordant couples (2015)

HIV-negative partners in serodiscordant couples were at risk of HIV infection if the index partner did not receive any intervention. It is strongly advised that existing interventions are used, such as couples consultations, condom use, and antiretroviral treatment, to minimize the risk of HIV transmission.
Rate-Splitting Assisted Massive Machine-Type Communications in Cell-Free Massive MIMO (2022)

This letter focuses on integrating rate-splitting multiple-access (RSMA) with time-division-duplex Cell-free Massive MIMO (multiple-input multiple-output) for massive machine-type communications. Due to the large number of devices, their sporadic access behaviour and limited coherence interval, we assume a random access strategy with all active devices utilizing the same pilot for uplink channel estimation. This gives rise to a highly pilot-contaminated scenario, which inevitably deteriorates channel estimates. Motivated by the robustness of RSMA towards imperfect channel state information, we propose a novel RSMA-assisted downlink transmission framework for cell-free massive MIMO. On the basis of the downlink achievable spectral efficiency of the common and private streams, we devise a heuristic common precoder design and propose a novel max-min power control method for the proposed RSMA-assisted scheme. Numerical results show that RSMA effectively mitigates the effect of pilot contamination in the downlink and achieves a significant performance gain over a conventional cell-free massive MIMO network.
Anisotropies in Stereo Depth Thresholds of Spatial Patterns and the Stereo Aperture Problem (1992)

Does a pattern's orientation affect stereoacuity? Do vertical disparities play a role in stereopsis? Furthermore, is retinal disparity encoded by changes in spatial position or spatial phase? The latter implies a "stereo aperture problem" -- only disparities perpendicular to the pattern's orientation are encoded. We found stereoacuities are worse for oblique patterns than for vertical patterns, but are worse for horizontal patterns. Moreover, for oblique patterns (unlike vertical or horizontal patterns), vertical disparity can be as effective as horizontal disparity. Results for vertical and oblique patterns suggest spatial phase encoding of disparity. In contrast, results for horizontal patterns suggest spatial postition encoding of disparity.
A piezoelectric micromachined ultrasonic transducer array for parametric loudspeakers (2013)

A parametric array is a nonlinear conversion process that can generate a highly directional sound beam with a small aperture. Since parametric sound generation requires high-intensity ultrasound for nonlinear interaction, efficient sound generation is an important issue in the practical use of parametric loudspeakers. In this study, a piezoelectric micromachined ultrasonic transducer array was investigated in order to generate directional audible sound with a parametric array. A piezoelectric micromachined ultrasonic transducer, with a micron-thick radiating plate, was verified to generate ultrasound with high-efficiency in air. Two types of unit transducers with different resonance frequencies (f1 = 100 kHz, and f2 = 110 kHz) were arranged in the transducer array to extend the frequency bandwidth. The electroacoustic efficiency of the transducer was measured to 71% at its resonance frequency. The ±3dB-frequency bandwidth of the transducer array was 17 kHz. The spatial distributions of the difference frequency wave were measured and compared with the computed data in the audible frequency range. The fabricated transducer array consumed 1 W of electric power while generating a 10 kHz-difference frequency wave with sound pressure level of 80 dB.
Assay for lignin breakdown based on lignin films: insights into the Fenton reaction with insoluble lignin (2015)

This paper reports a multiplexed assay for degradation of lignin, and insights into the Fenton reaction with insoluble lignin.
Studying Ultrafast Magnetization Dynamics with Ultrafast Extreme Ultraviolet Light (2014)

By using laser-based high harmonic EUV sources, we make several advances in uncovering new understanding of correlated charge and spin dynamics on few femtosecond timescales, and in developing new element-specific capabilities for probing magnetic materials.
Long-range Quantum Cryptography: Amplified Quantum Key Distribution (AQKD) (2014)

Recently, Takeoka, Guha and Wilde have established a new (loose) upper bound on the secret key capacity of a pure-loss bosonic channel that is several times larger than an error-free BB84 QKD channel with same transmittance. This suggests that new QKD protocols may exist with higher secret key rates and effective ranges larger than the metro-area limits of BB84 QKD over optical fiber. In this paper we illustrate such a possibility with a new protocol called Amplified Quantum Key Distribution (AQKD), which will be compatible with the optical amplification typically encountered on inter-city fiber spans. We analyze one instantiation of AQKD, in which the transmitter enclave contains an optical amplifier (OA), with security against passive optical tapping. For this scenario AQKD is shown to: give three times the secret key rate of BB84 at spans up to 100km, increasing to more than a ten-fold gain at 140km; and double the maximum single-span optical fiber transmission range to inter-city distances (300km). Essential to these performance gains is a new information-theoretic protocol post-processing stage called generalized advantage distillation (GAD). AQKD could be implemented with commercial off-the-shelf (COTS) hardware as an augmentation of present-day BB84 QKD. AQKD avoids the expense, complexity and resource duplication of "trusted relay" approaches to QKD range extension. We expect AQKD to be compatible with fiber spans containing intermediate OAs, which will facilitate its deployment as an overlay on existing fiber networks.
Serial 3D Imaging Mass Spectrometry at Its Tipping Point (2015)

Since biology is by and large a 3-dimensional phenomenon, it is hardly surprising that 3D imaging has had a significant impact on many challenges in the life sciences. Imaging mass spectrometry (MS) is a spatially resolved label-free analytical technique that recently maturated into a powerful tool for in situ localization of hundreds of molecular species. Serial 3D imaging MS reconstructs 3D molecular images from serial sections imaged with mass spectrometry. As such, it provides a novel 3D imaging modality inheriting the advantages of imaging MS. Serial 3D imaging MS has been steadily developing over the past decade, and many of the technical challenges have been met. Essential tools and protocols were developed, in particular to improve the reproducibility of sample preparation, speed up data acquisition, and enable computationally intensive analysis of the big data generated. As a result, experimental data is starting to emerge that takes advantage of the extra spatial dimension that 3D imaging MS offers. Most studies still focus on method development rather than on exploring specific biological problems. The future success of 3D imaging MS requires it to find its own niche alongside existing 3D imaging modalities through finding applications that benefit from 3D imaging and at the same time utilize the unique chemical sensitivity of imaging mass spectrometry. This perspective critically reviews the challenges encountered during the development of serial-sectioning 3D imaging MS and discusses the steps needed to tip it from being an academic curiosity into a tool of choice for answering biological and medical questions.