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His Domain Protein Tyrosine Phosphatase (HD-PTP) facilitates function of the endosomal sorting complexes required for transport (ESCRTs) during multivesicular body (MVB) formation. To uncover its role in physiological homeostasis, embryonic lethality caused by a complete lack of HD-PTP was bypassed through generation of hypomorphic mice expressing reduced protein, resulting in animals that are viable into adulthood. These mice exhibited marked lipodystrophy and decreased receptor-mediated signaling within white adipose tissue (WAT), involving multiple prominent pathways including RAS/MAPK, PI3K/AKT and RTKs such as EGFR. EGFR signaling was dissected in vitro to assess the nature of defective signaling, revealing decreased trans-autophosphorylation and downstream effector activation, despite normal EGF binding. This corresponds to decreased plasma membrane cholesterol and increased lysosomal cholesterol, likely resulting from defective endosomal maturation necessary for cholesterol trafficking and homeostasis. ESCRT components Vps4 and HRS have previously been implicated in cholesterol homeostasis, thus these findings expand knowledge on which ESCRT subunits are involved in cholesterol homeostasis and highlight a non-canonical role for HD-PTP in signal regulation and adipose tissue homeostasis.
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OBJECTIVES: To compare the image quality of 1.5T and 3T prostate MRIs of the same post-hip arthroplasty patients, with a specific focus on the degree of susceptibility artifacts. METHODS: This single-center retrospective study included post-hip arthroplasty patients who underwent 1.5T prostate MRIs between 2021 and 2023, as well as comparative 3T prostate MRIs. Three blinded abdominal radiologists retrospectively reviewed their diffusion-weighted imaging (DWI, 50 s/mm2), T2-weighted imaging (T2WI), and dynamic contrast-enhanced imaging (DCE) to evaluate the image quality. The degree of susceptibility artifacts was categorized using a three-point scale, with 3 indicating the least artifact and 1 indicating the most. Image quality was also evaluated using Prostate Imaging Quality (PI-QUAL) version 2. The median of the three raters' scores was compared between 1.5T and 3T prostate MRIs using the Wilcoxon signed-rank test. The inter-rater agreement was evaluated using the multi-rater generalized kappa. RESULTS: Twenty pairs of 1.5T and 3T prostate MRI examinations from 20 unique patients were included. The DWI susceptibility artifact score at 1.5T was significantly higher than at 3T (mean score ± standard deviation, 2.80 ± 0.41 vs. 2.35 ± 0.93, p = 0.014). In contrast, no significant differences were observed in the susceptibility artifact scores in T2WI and DCE, or in the PI-QUAL score. The inter-reader agreement in the susceptibility artifact score was moderate (multi-rater generalized kappa: 0.60) in DWI, perfect in T2WI (not applicable), and substantial (0.65) in DCE. The inter-reader agreement was fair (0.27) in the PI-QUAL score. CONCLUSION: Using 1.5T scanners may be preferable to reduce susceptibility artifacts from hip prostheses in DWI.
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Age is a major risk factor for severe coronavirus disease 2019 (COVID-19), yet the mechanisms behind this relationship have remained incompletely understood. To address this, we evaluated the impact of aging on host immune response in the blood and the upper airway, as well as the nasal microbiome in a prospective, multicenter cohort of 1031 vaccine-naïve patients hospitalized for COVID-19 between 18 and 96 years old. We performed mass cytometry, serum protein profiling, anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody assays, and blood and nasal transcriptomics. We found that older age correlated with increased SARS-CoV-2 viral abundance upon hospital admission, delayed viral clearance, and increased type I interferon gene expression in both the blood and upper airway. We also observed age-dependent up-regulation of innate immune signaling pathways and down-regulation of adaptive immune signaling pathways. Older adults had lower naïve T and B cell populations and higher monocyte populations. Over time, older adults demonstrated a sustained induction of pro-inflammatory genes and serum chemokines compared with younger individuals, suggesting an age-dependent impairment in inflammation resolution. Transcriptional and protein biomarkers of disease severity differed with age, with the oldest adults exhibiting greater expression of pro-inflammatory genes and proteins in severe disease. Together, our study finds that aging is associated with impaired viral clearance, dysregulated immune signaling, and persistent and potentially pathologic activation of pro-inflammatory genes and proteins.
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COVID-19 , Humanos , Anciano , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano de 80 o más Años , SARS-CoV-2 , Estudios Prospectivos , Multiómica , QuimiocinasRESUMEN
Age is a major risk factor for severe coronavirus disease-2019 (COVID-19), yet the mechanisms responsible for this relationship have remained incompletely understood. To address this, we evaluated the impact of aging on host and viral dynamics in a prospective, multicenter cohort of 1,031 patients hospitalized for COVID-19, ranging from 18 to 96 years of age. We performed blood transcriptomics and nasal metatranscriptomics, and measured peripheral blood immune cell populations, inflammatory protein expression, anti-SARS-CoV-2 antibodies, and anti-interferon (IFN) autoantibodies. We found that older age correlated with an increased SARS-CoV-2 viral load at the time of admission, and with delayed viral clearance over 28 days. This contributed to an age-dependent increase in type I IFN gene expression in both the respiratory tract and blood. We also observed age-dependent transcriptional increases in peripheral blood IFN-γ, neutrophil degranulation, and Toll like receptor (TLR) signaling pathways, and decreases in T cell receptor (TCR) and B cell receptor signaling pathways. Over time, older adults exhibited a remarkably sustained induction of proinflammatory genes (e.g., CXCL6) and serum chemokines (e.g., CXCL9) compared to younger individuals, highlighting a striking age-dependent impairment in inflammation resolution. Augmented inflammatory signaling also involved the upper airway, where aging was associated with upregulation of TLR, IL17, type I IFN and IL1 pathways, and downregulation TCR and PD-1 signaling pathways. Metatranscriptomics revealed that the oldest adults exhibited disproportionate reactivation of herpes simplex virus and cytomegalovirus in the upper airway following hospitalization. Mass cytometry demonstrated that aging correlated with reduced naïve T and B cell populations, and increased monocytes and exhausted natural killer cells. Transcriptional and protein biomarkers of disease severity markedly differed with age, with the oldest adults exhibiting greater expression of TLR and inflammasome signaling genes, as well as proinflammatory proteins (e.g., IL6, CXCL8), in severe COVID-19 compared to mild/moderate disease. Anti-IFN autoantibody prevalence correlated with both age and disease severity. Taken together, this work profiles both host and microbe in the blood and airway to provide fresh insights into aging-related immune changes in a large cohort of vaccine-naïve COVID-19 patients. We observed age-dependent immune dysregulation at the transcriptional, protein and cellular levels, manifesting in an imbalance of inflammatory responses over the course of hospitalization, and suggesting potential new therapeutic targets.
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Since the adoption of guidelines for the non-invasive imaging diagnosis of hepatocellular carcinoma (HCC), the need for sampling of a lesion in cirrhosis has decreased. We aimed to retrospectively investigate the use of percutaneous imaging-guided biopsy for LI-RADS observations in cirrhosis in two large liver transplant centers. A review of the pathology database in the two Institutions (Institution A, Institution B) was conducted to identify patients that underwent percutaneous imaging-guided biopsy for a liver lesion in the interval time 01/01/2015-12/312020. Liver observations on pre-procedure contrast-enhanced CT or MRI were classified according to LI-RADS v2018. Among the 728 patients who underwent imaging guided biopsy of a liver lesion in Institution A, and among the 749 patients who underwent imaging guided biopsy of a liver lesion in Institution B, respectively 50 (6.8 %) and 16 (2.1 %) were cirrhotic with available pre-procedural contrast-enhanced CT or MRI. A total of 67 lesions were biopsied. 30/67 (45 %) biopsied observations were classified as LR-M. 55/67 (82 %) biopsies were positive for malignancy at histopathology and among them 33 (60 %) were HCC. In conclusion, a small percentage of percutaneous, imaging-guided biopsies for liver lesions are performed in cirrhosis, and more frequently for LR-M observations.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Humanos , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/cirugía , Estudios Retrospectivos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/cirugía , Imagen por Resonancia Magnética/métodos , Cirrosis Hepática/diagnóstico por imagen , Biopsia Guiada por Imagen , Medios de Contraste , Sensibilidad y EspecificidadRESUMEN
Tenofovir disoproxil fumarate (TDF) and islatravir (ISL, 4'-ethynyl-2-fluoro-2'-deoxyadensine, or MK-8591) are highly potent nucleoside reverse transcriptase inhibitors. Resistance to TDF and ISL is conferred by K65R and M184V, respectively. Furthermore, K65R and M184V increase sensitivity to ISL and TDF, respectively. Therefore, these two nucleoside analogs have opposing resistance profiles and could present a high genetic barrier to resistance. To explore resistance to TDF and ISL in combination, we performed passaging experiments with HIV-1 WT, K65R, or M184V in the presence of ISL and TDF. We identified K65R, M184V, and S68G/N mutations. The mutant most resistant to ISL was S68N/M184V, yet it remained susceptible to TDF. To further confirm our cellular findings, we implemented an endogenous reverse transcriptase assay to verify in vitro potency. To better understand the impact of these resistance mutations in the context of global infection, we determined potency of ISL and TDF against HIV subtypes A, B, C, D, and circulating recombinant forms (CRF) 01_AE and 02_AG with and without resistance mutations. In all isolates studied, we found K65R imparted hypersensitivity to ISL whereas M184V conferred resistance. We demonstrated that the S68G polymorphism can enhance fitness of drug-resistant mutants in some genetic backgrounds. Collectively, the data suggest that the opposing resistance profiles of ISL and TDF suggest that a combination of the two drugs could be a promising drug regimen for the treatment of patients infected with any HIV-1 subtype, including those who have failed 3TC/FTC-based therapies.
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Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Humanos , Tenofovir/farmacología , Tenofovir/uso terapéutico , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/uso terapéutico , VIH-1/genética , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral/genética , Mutación , Infecciones por VIH/tratamiento farmacológicoRESUMEN
PURPOSE: Radiology is a highly complex field that requires mastery over an ever-expanding body of knowledge. Spaced learning, interleaving, and retrieval practice are evidence-based learning strategies that enhance long-term retention of information. The aim of this systematic review is to assess the effectiveness of these interventions in the setting of radiology education. METHODS: The authors searched MEDLINE, Embase, PsycInfo, ERIC, and forward and backward citations for studies published between database inception and February 19, 2023. Eligibility criteria for included studies were randomized and quasi-randomized controlled trials that investigated the impact of spaced, interleaved, or retrieval practice on knowledge retention of medical trainees after education related to medical imaging as assessed by postinterventional examination scores. RESULTS: Of 1,316 records reviewed, 8 studies met eligibility criteria. Two studies investigated spaced learning, two studies interleaving, and six studies retrieval practice, including two trials that evaluated interventions incorporating both spaced learning and retrieval practice. Five of eight studies reported statistically significant differences between interventional and control groups on either immediate or delayed postinterventional examinations. CONCLUSIONS: Despite extensive evidence in support of spaced, interleaved, and retrieval practice within the broader literature, few studies have examined the effectiveness of these strategies in radiology education. Additional trials are required to evaluate the usefulness of incorporating these techniques into educational programs related to medical imaging.
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Radiología , Aprendizaje , Radiología/educaciónRESUMEN
The polarized cross-section ratio σ_{LT^{'}}/σ_{0} from hard exclusive π^{-}Δ^{++} electroproduction off an unpolarized hydrogen target has been extracted based on beam-spin asymmetry measurements using a 10.2 GeV/10.6 GeV incident electron beam and the CLAS12 spectrometer at Jefferson Lab. The study, which provides the first observation of this channel in the deep-inelastic regime, focuses on very forward-pion kinematics in the valence regime, and photon virtualities ranging from 1.5 GeV^{2} up to 7 GeV^{2}. The reaction provides a novel access to the d-quark content of the nucleon and to pâΔ^{++} transition generalized parton distributions. A comparison to existing results for hard exclusive π^{+}n and π^{0}p electroproduction is provided, which shows a clear impact of the excitation mechanism, encoded in transition generalized parton distributions, on the asymmetry.
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Deeply virtual Compton scattering (DVCS) allows one to probe generalized parton distributions describing the 3D structure of the nucleon. We report the first measurement of the DVCS beam-spin asymmetry using the CLAS12 spectrometer with a 10.2 and 10.6 GeV electron beam scattering from unpolarized protons. The results greatly extend the Q^{2} and Bjorken-x phase space beyond the existing data in the valence region and provide 1600 new data points measured with unprecedented statistical uncertainty, setting new, tight constraints for future phenomenological studies.
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We report results of Λ hyperon production in semi-inclusive deep-inelastic scattering off deuterium, carbon, iron, and lead targets obtained with the CLAS detector and the Continuous Electron Beam Accelerator Facility 5.014 GeV electron beam. These results represent the first measurements of the Λ multiplicity ratio and transverse momentum broadening as a function of the energy fraction (z) in the current and target fragmentation regions. The multiplicity ratio exhibits a strong suppression at high z and an enhancement at low z. The measured transverse momentum broadening is an order of magnitude greater than that seen for light mesons. This indicates that the propagating entity interacts very strongly with the nuclear medium, which suggests that propagation of diquark configurations in the nuclear medium takes place at least part of the time, even at high z. The trends of these results are qualitatively described by the Giessen Boltzmann-Uehling-Uhlenbeck transport model, particularly for the multiplicity ratios. These observations will potentially open a new era of studies of the structure of the nucleon as well as of strange baryons.
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We report the first measurements of deep inelastic scattering spin-dependent azimuthal asymmetries in back-to-back dihadron electroproduction in the deep inelastic scattering process. In this reaction, two hadrons are produced in opposite hemispheres along the z axis in the virtual photon-target nucleon center-of-mass frame, with the first hadron produced in the current-fragmentation region and the second in the target-fragmentation region. The data were taken with longitudinally polarized electron beams of 10.2 and 10.6 GeV incident on an unpolarized liquid-hydrogen target using the CLAS12 spectrometer at Jefferson Lab. Observed nonzero sinΔÏ modulations in epâe^{'}pπ^{+}X events, where ΔÏ is the difference of the azimuthal angles of the proton and pion in the virtual photon and target nucleon center-of-mass frame, indicate that correlations between the spin and transverse momenta of hadrons produced in the target- and current-fragmentation regions may be significant. The measured beam-spin asymmetries provide a first access in dihadron production to a previously unexplored leading-twist spin- and transverse-momentum-dependent fracture function. The fracture functions describe the hadronization of the target remnant after the hard scattering of a virtual photon off a quark in the target particle and provide a new avenue for studying nucleonic structure and hadronization.
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BACKGROUND: Diabetes Mellitus (DM) and its associated immune dysfunction are well-studied risk factors for adverse surgical outcomes. The literature regarding endoscopic sinus surgery (ESS) is less robust and there have been conflicting reports on post-operative complications and surgical results in this patient population. The purpose of this study was to analyze the impact of diabetes mellitus on outcomes after ESS via rates of post-operative medical intervention in the first 6 months after surgery. METHODS: This was a retrospective cohort study of 176 subjects who underwent ESS from 2015 to 2019 at a single institution by 2 fellowship-trained rhinologists. Subjects were divided into 2 groups, those with a documented Hemoglobin A1c (HbA1c) >6.5 or diagnosis of DM and those with HbA1C < 6.5. Patient age, demographics, 6-month preoperative HbA1c, surgical status and extent, and 6-monthpostoperative need for steroids and/or antibiotics were collected. RESULTS: Out of n = 176 total patients, n = 39 (22.2%) were categorized into the DM group, which were older (46.4 vs 53.8 years, P = .004) and higher proportion of white patients (89.7% vs 68.6%, P = .008). There were no significant differences between the 2 groups in proportion of revision surgery, surgical extent, and post-operative use of antibiotics or steroids. When including all variables in binary logistic regression for use of postoperative antibiotics or steroids, the only significant variable predicting these outcomes was the extent of surgical resection including sphenoid sinus (P = .001, OR [95% CI] = 4.02 [1.73-9.34]) or frontal sinus (P < .001, OR [95% CI = 9.86 [4.00-24.33]). CONCLUSIONS: Patients with DM do not appear to have worse post-operative outcomes outside of the initial 6-month postoperative period.
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Diabetes Mellitus , Humanos , Estudios Retrospectivos , Hemoglobina Glucada , Diabetes Mellitus/epidemiología , Endoscopía/métodos , Periodo Posoperatorio , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiologíaRESUMEN
We present the first measurement of dihadron angular correlations in electron-nucleus scattering. The data were taken with the CLAS detector and a 5.0 GeV electron beam incident on deuterium, carbon, iron, and lead targets. Relative to deuterium, the nuclear yields of charged-pion pairs show a strong suppression for azimuthally opposite pairs, no suppression for azimuthally nearby pairs, and an enhancement of pairs with large invariant mass. These effects grow with increased nuclear size. The data are qualitatively described by the gibuu model, which suggests that hadrons form near the nuclear surface and undergo multiple scattering in nuclei.These results show that angular correlation studies can open a new way to elucidate how hadrons form and interact inside nuclei.
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A critical challenge during volcanic emergencies is responding to rapid changes in eruptive behaviour. Actionable advice, essential in times of rising uncertainty, demands the rapid synthesis and communication of multiple datasets with prognoses. The 2020-2021 eruption of La Soufrière volcano exemplifies these challenges: a series of explosions from 9-22 April 2021 was preceded by three months of effusive activity, which commenced with a remarkably low level of detected unrest. Here we show how the development of an evolving conceptual model, and the expression of uncertainties via both elicitation and scenarios associated with this model, were key to anticipating this transition. This not only required input from multiple monitoring datasets but contextualisation via state-of-the-art hazard assessments, and evidence-based knowledge of critical decision-making timescales and community needs. In addition, we share strategies employed as a consequence of constraints on recognising and responding to eruptive transitions in a resource-constrained setting, which may guide similarly challenged volcano observatories worldwide.
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Desastres , Erupciones VolcánicasRESUMEN
A collection of 30 Phytophthora cactorum and 12 P. pseudotsugae (subclade 1a) strains isolated from several recent surveys across California was phylogenetically compared to a worldwide collection of 112 conspecific strains using sequences from three barcoding loci. The surveys baited P. cactorum from soil and water across a wide variety of forested ecosystems with a geographic range of more than 1000 km. Two cosmopolitan lineages were identified within the widespread P. cactorum, one being mainly associated with strawberry production and the other more closely associated with apple orchards, oaks and ornamental trees. Two other well-sampled P. cactorum lineages, including one that dominated Californian restoration outplantings, were only found in the western United States, while a third was only found in Japan. Coastal California forest isolates of both Phytophthora species exhibited considerable diversity, suggesting both may be indigenous to the state. Many isolates with sequence accessions deposited as P. cactorum were determined to be P. hedraiandra and P. ×serendipita, with one hybrid lineage appearing relatively common across Europe and Asia. This study contains the first report of P. pseudotsugae from the state of California and one of the only reports of that species since its original description.
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High precision measurements of the polarized electron beam-spin asymmetry in semi-inclusive deep inelastic scattering (SIDIS) from the proton have been performed using a 10.6 GeV incident electron beam and the CLAS12 spectrometer at Jefferson Lab. We report here a high precision multidimensional study of single π^{+} SIDIS data over a large kinematic range in Bjorken x, fractional energy, and transverse momentum of the hadron as well as photon virtualities Q^{2} ranging from 1-7 GeV^{2}. In particular, the structure function ratio F_{LU}^{sinÏ}/F_{UU} has been determined, where F_{LU}^{sinÏ} is a twist-3 quantity that can reveal novel aspects of emergent hadron mass and quark-gluon correlations within the nucleon. The data's impact on the evolving understanding of the underlying reaction mechanisms and their kinematic variation is explored using theoretical models for the different contributing transverse momentum dependent parton distribution functions.
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In the few years leading up to this research, CLEAPSS noticed a small but steadily increasing number of calls from UK schools regarding a red-brown discolouration on the surface of the foil of their radium source. There were no reports of this type of discolouration on foils of other radionuclides. CLEAPSS and the University of Liverpool collaborated to investigate the nature and cause of this discolouration and the likelihood that the foils were becoming unsafe. The evidence indicates that the discolouration is principally caused by some combination of silicon, sulfur and possibly lead from within the foil diffusing into the face layer. There is no indication currently that the face layers are fragmenting on these foils, but the longer-term integrity of the discoloured foils now becomes questionable. Given the age of the foils and the radiotoxicity of radium, the recommendation from this research is that discoloured foils should be taken out of service and disposed.
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Radio (Elemento) , Instituciones Académicas , Reino UnidoRESUMEN
Nerve growth factor (NGF), a critical mediator of nociception, is a novel analgesic therapeutic target. Bedinvetmab, a canine monoclonal antibody (mAb), binds NGF and inhibits its interaction with tropomyosin receptor kinase A (trkA) and p75 neurotrophin receptor (p75NTR) receptors. The objective of three integrated laboratory studies was to demonstrate the safety of bedinvetmab in adult laboratory Beagle dogs. Daily health, veterinary, clinical pathology, systemic exposure, and anti-drug antibody evaluations were performed. Study 1 additionally included electrocardiography, neurologic, and ophthalmic assessments, and radiographic monitoring of joints of the appendicular skeleton. Study 2 evaluated T-lymphocyte-dependent immune function. Study 3 evaluated the safety of short-term concurrent administration of carprofen, a nonsteroidal anti-inflammatory drug (NSAID), with bedinvetmab. Studies 1 and 3 included terminal pathology and histopathology evaluations. Study designs and procedures included directed complementary morphologic and functional evaluations of a literature- and in vitro-based list of potential safety issues related to the NGF signaling pathway and characteristics engineered into this mAb. Screening-level general procedures evaluated effects associated with mAbs that target and inhibit soluble agonist cytokines. There were no treatment-related adverse changes in clinical evaluations, clinical neurological and ophthalmic examinations, joints, immune morphology or function, and no effects of short-term concurrent NSAID usage. Treatment-emergent immunogenicity was not observed. Bedinvetmab (1 mg/kg SC monthly; 3× and 10× dose multiples) was well tolerated in normal laboratory Beagle dogs for 6 months and with 2 weeks' concurrent NSAID administration.
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Laboratorios , Factor de Crecimiento Nervioso , Animales , Anticuerpos Monoclonales/efectos adversos , Perros , Receptor de Factor de Crecimiento Nervioso , Transducción de SeñalRESUMEN
The observation of beam spin asymmetries in two-pion production in semi-inclusive deep inelastic scattering off an unpolarized proton target is reported. The data presented here were taken in the fall of 2018 with the CLAS12 spectrometer using a 10.6 GeV longitudinally spin-polarized electron beam delivered by CEBAF at JLab. The measured asymmetries provide the first opportunity to extract the parton distribution function e(x), which provides information about the interaction between gluons and quarks, in a collinear framework that offers cleaner access than previous measurements. The asymmetries also constitute the first ever signal sensitive to the helicity-dependent two-pion fragmentation function G_{1}^{â¥}. A clear sign change is observed around the ρ mass that appears in model calculations and is indicative of the dependence of the produced pions on the helicity of the fragmenting quark.