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Cryogenic ion vibrational predissociation (CIVP) spectroscopy is an established and valuable technique for molecular elucidation in the gas phase. CIVP relies on tunable lasers, wherein among typical laser schemes, the application of mid-infrared continuous-wave quantum cascade laser (cw-QCL) is the most robust and elegant solution, as we have recently demonstrated. However, potential challenges arise from an inhomogeneous character across laser power tuning curves. A large laser power output could have undesired consequences, such as multiphoton absorption or saturation effects. Significant variations in laser power tuning curves could potentially alter the shape of the investigated band, particularly for diffuse bands. In this study, we have developed and introduced an automatic variable laser power attenuator designed to keep the laser power output uniform at a user-defined value across the entire available spectral range. We demonstrated the application of this attenuator in obtaining CIVP spectra of a model compound with a diffuse N-H-N band. This approach enhances the reliability of measuring diffuse bands and overall applicability of cw-QCL.
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The long-term physiological consequences of respiratory viral infections, particularly in the aftermath of the COVID-19 pandemic-termed post-acute sequelae of SARS-CoV-2 (PASC)-are rapidly evolving into a major public health concern1-3. While the cellular and molecular aetiologies of these sequelae are poorly defined, increasing evidence implicates abnormal immune responses3-6 and/or impaired organ recovery7-9 after infection. However, the precise mechanisms that link these processes in the context of PASC remain unclear. Here, with insights from three cohorts of patients with respiratory PASC, we established a mouse model of post-viral lung disease and identified an aberrant immune-epithelial progenitor niche unique to fibroproliferation in respiratory PASC. Using spatial transcriptomics and imaging, we found a central role for lung-resident CD8+ T cell-macrophage interactions in impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Specifically, IFNγ and TNF derived from CD8+ T cells stimulated local macrophages to chronically release IL-1ß, resulting in the long-term maintenance of dysplastic epithelial progenitors and lung fibrosis. Notably, therapeutic neutralization of IFNγ + TNF or IL-1ß markedly improved alveolar regeneration and pulmonary function. In contrast to other approaches, which require early intervention10, we highlight therapeutic strategies to rescue fibrotic disease after the resolution of acute disease, addressing a current unmet need in the clinical management of PASC and post-viral disease.
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A leading cause of mortality after influenza infection is the development of a secondary bacterial pneumonia. In the absence of a bacterial superinfection, prescribing antibacterial therapies is not indicated but has become a common clinical practice for those presenting with a respiratory viral illness. In a murine model, we found that antibiotic use during influenza infection impaired the lung innate immunologic defenses toward a secondary challenge with methicillin-resistant Staphylococcus aureus (MRSA). Antibiotics augment lung eosinophils, which have inhibitory effects on macrophage function through the release of major basic protein. Moreover, we demonstrated antibiotic treatment during influenza infection causes a fungal dysbiosis that drive lung eosinophilia and impair MRSA clearance. Finally, we evaluated three cohorts of hospitalized patients and found eosinophils positively correlated with antibiotic use, systemic inflammation, and worsened outcomes. Altogether, our work demonstrates a detrimental effect of antibiotic treatment during influenza infection that has harmful immunologic consequences via recruitment of eosinophils to the lungs thereby increasing the risk of developing a secondary bacterial infection.
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Avocado-derived polyhydroxylated fatty alcohols (PFAs), such as avocadene and avocadyne, have been recently identified as potent modulators of mitochondrial metabolism which selectively induce leukemia cell death and reverse pathologies associated with diet-induced obesity. However, avocadene and avocadyne bioaccessibility from avocado pulp is not reported; hence, this study aims to investigate if these PFAs are bioaccessible. Dynamic (TNO dynamic intestinal model-1 (TIM-1)) and static in vitro digestion of lyophilized Hass avocado pulp powder shows lipolytic gastrointestinal enzymes led to appreciable bioaccessibility of avocadene (55%) and avocadyne (50%). Furthermore, TIM-1 digestion of a 1:1 ratio of pure avocadene and avocadyne (avocatin B or AvoB) crystals formulated in an oil-in-water microemulsion has on average 15% higher bioaccessibility than the avocado pulp powder demonstrating both dosage forms as potential dietary sources of avocado PFAs. This research provides the impetus for further research on the nutritional significance of dietary long chain fatty alcohols.
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OBJECTIVE: Approximately 40% of adults living with HIV experience cognitive deficits. Little is known about the risk factors for cognitive impairment and its association with myelin content in young adults living with perinatally acquired HIV (YApHIV), which is assessed in our cross-sectional study. DESIGN: A prospective, observational cohort study. METHODS: All participants underwent an 11-test cognitive battery and completed medical and social history surveys. Cognitive impairment was defined as Z scores falling at least 1.5 SD below the mean in at least two domains. Twelve participants underwent myelin water imaging. Neuroimaging data were compared to age and sex-matched HIV-uninfected controls. Regression analyses were used to evaluate for risk factors of lower cognitive domain scores and association between myelin content and cognition in YApHIV. RESULTS: We enrolled 21 virally suppressed YApHIV across two sites in the United States. Ten participants (48%) met criteria for cognitive impairment. Participants with any non-HIV related medical comorbidity scored lower across multiple cognitive domains compared to participants without comorbidities. Myelin content did not differ between YApHIV and controls after adjusting for years of education. Lower cognitive scores were associated with lower myelin content in the cingulum and corticospinal tract in YApHIV participants after correcting for multiple comparisons. CONCLUSION: Poor cognition in YApHIV may be exacerbated by non-HIV related comorbidities as noted in older adults with horizontally acquired HIV. The corticospinal tract and cingulum may be vulnerable to the legacy effect of untreated HIV in infancy. Myelin content may be a marker of cognitive reserve in YApHIV.
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BACKGROUND: There are currently no validated clinical biomarkers of postacute sequelae of SARS-CoV-2 infection (PASC). OBJECTIVE: To investigate clinical laboratory markers of SARS-CoV-2 and PASC. DESIGN: Propensity score-weighted linear regression models were fitted to evaluate differences in mean laboratory measures by prior infection and PASC index (≥12 vs. 0). (ClinicalTrials.gov: NCT05172024). SETTING: 83 enrolling sites. PARTICIPANTS: RECOVER-Adult cohort participants with or without SARS-CoV-2 infection with a study visit and laboratory measures 6 months after the index date (or at enrollment if >6 months after the index date). Participants were excluded if the 6-month visit occurred within 30 days of reinfection. MEASUREMENTS: Participants completed questionnaires and standard clinical laboratory tests. RESULTS: Among 10 094 participants, 8746 had prior SARS-CoV-2 infection, 1348 were uninfected, 1880 had a PASC index of 12 or higher, and 3351 had a PASC index of zero. After propensity score adjustment, participants with prior infection had a lower mean platelet count (265.9 × 109 cells/L [95% CI, 264.5 to 267.4 × 109 cells/L]) than participants without known prior infection (275.2 × 109 cells/L [CI, 268.5 to 282.0 × 109 cells/L]), as well as higher mean hemoglobin A1c (HbA1c) level (5.58% [CI, 5.56% to 5.60%] vs. 5.46% [CI, 5.40% to 5.51%]) and urinary albumin-creatinine ratio (81.9 mg/g [CI, 67.5 to 96.2 mg/g] vs. 43.0 mg/g [CI, 25.4 to 60.6 mg/g]), although differences were of modest clinical significance. The difference in HbA1c levels was attenuated after participants with preexisting diabetes were excluded. Among participants with prior infection, no meaningful differences in mean laboratory values were found between those with a PASC index of 12 or higher and those with a PASC index of zero. LIMITATION: Whether differences in laboratory markers represent consequences of or risk factors for SARS-CoV-2 infection could not be determined. CONCLUSION: Overall, no evidence was found that any of the 25 routine clinical laboratory values assessed in this study could serve as a clinically useful biomarker of PASC. PRIMARY FUNDING SOURCE: National Institutes of Health.
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Biomarcadores , COVID-19 , Síndrome Post Agudo de COVID-19 , SARS-CoV-2 , Humanos , COVID-19/complicaciones , COVID-19/diagnóstico , COVID-19/sangre , Masculino , Femenino , Persona de Mediana Edad , Biomarcadores/sangre , Puntaje de Propensión , Anciano , Adulto , Hemoglobina Glucada/análisis , Estudios de CohortesRESUMEN
Three cyano-coordinated cobalt porphyrin dimers were synthesized and thoroughly characterized. The X-ray structure of the complexes reveals that cyanide binds in a terminal fashion in both the anti and trans isomers of ethane- and ethylene-bridged cobalt porphyrin dimers, while in the cis ethylene-bridged dimer, cyanides bind in both terminal and bridging modes. The nonconjugated ethane-bridged complex stabilizes exclusively a diamagnetic metal-centered oxidation of type CoIII(por)(CN)2 both in the solid and in solution. In contrast, the complexes with the conjugated ethylene-bridge contain signatures of both paramagnetic ligand-centered oxidation of the type CoII(porâ¢+)(CN)2 and diamagnetic metal-centered oxidation of type CoIII(por)(CN)2 with the metal-centered oxidized species being the major component in the solid state as observed in XPS, while the ligand-centered oxidized species are present in a significant amount in solution. 1H NMR spectrum in solution displays two set of signals corresponding to the simultaneous presence of both the diamagnetic and paramagnetic species. EPR and magnetic investigation reveal that there is a moderate ferromagnetic coupling between the unpaired electrons of the low-spin CoII center and the porphyrin π-cation radical in CoII(porâ¢+)(CN)2 species as well as an antiferromagnetic coupling between the two CoII(porâ¢+) units through the ethylene and CN bridges.
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PURPOSE: Many countries have developed clinical decision-making support tools, such as the smart work injury management (SWIM) system in Hong Kong, to predict rehabilitation paths and address global issues related to work injury disability. This study aims to evaluate the accuracy of SWIM by comparing its predictions on real work injury cases to those made by human case managers, specifically with regard to the duration of sick leave and the percentage of permanent disability. METHODS: The study analyzed a total of 442 work injury cases covering the period from 2012 to 2020, dividing them into non-litigated and litigated cases. The Kruskal-Wallis post hoc test with Bonferroni adjustment was used to evaluate the differences between the actual data, the SWIM predictions, and the estimations made by three case managers. The intra-class correlation coefficient was used to assess the inter-rater reliability of the case managers. RESULTS: The study discovered that the predictions made by the SWIM model and a case manager possessing approximately 4 years of experience in case management exhibited moderate reliability in non-litigated cases. Nevertheless, there was no resemblance between SWIM's predictions regarding the percentage of permanent disability and those made by case managers. CONCLUSION: The findings indicate that SWIM is capable of replicating the sick leave estimations made by a case manager with an estimated 4 years of case management experience, albeit with limitations in generalizability owing to the small sample size of case managers involved in the study. IMPLICATIONS: These findings represent a significant advancement in enhancing the accuracy of CDMS for work injury cases in Hong Kong, signaling progress in the field.
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Over the past few years, monocular depth estimation and completion have been paid more and more attention from the computer vision community because of their widespread applications. In this paper, we introduce novel physics (geometry)-driven deep learning frameworks for these two tasks by assuming that 3D scenes are constituted with piece-wise planes. Instead of directly estimating the depth map or completing the sparse depth map, we propose to estimate the surface normal and plane-to-origin distance maps or complete the sparse surface normal and distance maps as intermediate outputs. To this end, we develop a normal-distance head that outputs pixel-level surface normal and distance. Afterthat, the surface normal and distance maps are regularized by a developed plane-aware consistency constraint, which are then transformed into depth maps. Furthermore, we integrate an additional depth head to strengthen the robustness of the proposed frameworks. Extensive experiments on the NYU-Depth-v2, KITTI and SUN RGB-D datasets demonstrate that our method exceeds in performance prior state-of-the-art monocular depth estimation and completion competitors.
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BACKGROUND: Serial measurement of virological and immunological biomarkers in patients admitted to hospital with COVID-19 can give valuable insight into the pathogenic roles of viral replication and immune dysregulation. We aimed to characterise biomarker trajectories and their associations with clinical outcomes. METHODS: In this international, prospective cohort study, patients admitted to hospital with COVID-19 and enrolled in the Therapeutics for Inpatients with COVID-19 platform trial within the Accelerating COVID-19 Therapeutic Interventions and Vaccines programme between Aug 5, 2020 and Sept 30, 2021 were included. Participants were included from 108 sites in Denmark, Greece, Poland, Singapore, Spain, Switzerland, Uganda, the UK, and the USA, and randomised to placebo or one of four neutralising monoclonal antibodies: bamlanivimab (Aug 5 to Oct 13, 2020), sotrovimab (Dec 16, 2020, to March 1, 2021), amubarvimab-romlusevimab (Dec 16, 2020, to March 1, 2021), and tixagevimab-cilgavimab (Feb 10 to Sept 30, 2021). This trial included an analysis of 2149 participants with plasma nucleocapsid antigen, anti-nucleocapsid antibody, C-reactive protein (CRP), IL-6, and D-dimer measured at baseline and day 1, day 3, and day 5 of enrolment. Day-90 follow-up status was available for 1790 participants. Biomarker trajectories were evaluated for associations with baseline characteristics, a 7-day pulmonary ordinal outcome, 90-day mortality, and 90-day rate of sustained recovery. FINDINGS: The study included 2149 participants. Participant median age was 57 years (IQR 46-68), 1246 (58·0%) of 2149 participants were male and 903 (42·0%) were female; 1792 (83·4%) had at least one comorbidity, and 1764 (82·1%) were unvaccinated. Mortality to day 90 was 172 (8·0%) of 2149 and 189 (8·8%) participants had sustained recovery. A pattern of less favourable trajectories of low anti-nucleocapsid antibody, high plasma nucleocapsid antigen, and high inflammatory markers over the first 5 days was observed for high-risk baseline clinical characteristics or factors related to SARS-CoV-2 infection. For example, participants with chronic kidney disease demonstrated plasma nucleocapsid antigen 424% higher (95% CI 319-559), CRP 174% higher (150-202), IL-6 173% higher (144-208), D-dimer 149% higher (134-165), and anti-nucleocapsid antibody 39% lower (60-18) to day 5 than those without chronic kidney disease. Participants in the highest quartile for plasma nucleocapsid antigen, CRP, and IL-6 at baseline and day 5 had worse clinical outcomes, including 90-day all-cause mortality (plasma nucleocapsid antigen hazard ratio (HR) 4·50 (95% CI 3·29-6·15), CRP HR 3·37 (2·30-4·94), and IL-6 HR 5·67 (4·12-7·80). This risk persisted for plasma nucleocapsid antigen and CRP after adjustment for baseline biomarker values and other baseline factors. INTERPRETATION: Patients admitted to hospital with less favourable 5-day biomarker trajectories had worse prognosis, suggesting that persistent viral burden might drive inflammation in the pathogenesis of COVID-19, identifying patients that might benefit from escalation of antiviral or anti-inflammatory treatment. FUNDING: US National Institutes of Health.
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Biomarcadores , COVID-19 , Hospitalización , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/mortalidad , COVID-19/sangre , Estudios Prospectivos , Masculino , Femenino , Biomarcadores/sangre , Persona de Mediana Edad , SARS-CoV-2/inmunología , Anciano , Hospitalización/estadística & datos numéricos , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Anticuerpos Monoclonales Humanizados/uso terapéutico , Interleucina-6/sangre , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Pandemias , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/virología , Neumonía Viral/inmunología , Neumonía Viral/sangre , Neumonía Viral/mortalidad , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/virología , Resultado del TratamientoRESUMEN
Conditional protein degradation tags (degrons) are usually >100 amino acids long or are triggered by small molecules with substantial off-target effects, thwarting their use as specific modulators of endogenous protein levels. We developed a phage-assisted continuous evolution platform for molecular glue complexes (MG-PACE) and evolved a 36-amino acid zinc finger (ZF) degron (SD40) that binds the ubiquitin ligase substrate receptor cereblon in complex with PT-179, an orthogonal thalidomide derivative. Endogenous proteins tagged in-frame with SD40 using prime editing are degraded by otherwise inert PT-179. Cryo-electron microscopy structures of SD40 in complex with ligand-bound cereblon revealed mechanistic insights into the molecular basis of SD40's activity and specificity. Our efforts establish a system for continuous evolution of molecular glue complexes and provide ZF tags that overcome shortcomings associated with existing degrons.
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Degrones , Evolución Molecular Dirigida , Proteolisis , Ubiquitina-Proteína Ligasas , Dedos de Zinc , Microscopía por Crioelectrón , Talidomida/química , Ubiquitina-Proteína Ligasas/química , Ubiquitinación , Degrones/genética , Dedos de Zinc/genética , Quimera Dirigida a la Proteólisis , Evolución Molecular Dirigida/métodos , HumanosRESUMEN
Neuromodulators transform animal behaviors. Recent research has demonstrated the importance of both sustained and transient change in neuromodulators, likely due to tonic and phasic neuromodulator release. However, no method could simultaneously record both types of dynamics. Fluorescence lifetime of optical reporters could offer a solution because it allows high temporal resolution and is impervious to sensor expression differences across chronic periods. Nevertheless, no fluorescence lifetime change across the entire classes of neuromodulator sensors was previously known. Unexpectedly, we find that several intensity-based neuromodulator sensors also exhibit fluorescence lifetime responses. Furthermore, we show that lifetime measures in vivo neuromodulator dynamics both with high temporal resolution and with consistency across animals and time. Thus, we report a method that can simultaneously measure neuromodulator change over transient and chronic time scales, promising to reveal the roles of multi-time scale neuromodulator dynamics in diseases, in response to therapies, and across development and aging.
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Envejecimiento , Neurotransmisores , Animales , Neurotransmisores/metabolismoRESUMEN
Using transient inhibition of DNA mismatch repair during a permissive stage of development, we demonstrate highly efficient prime editing of mouse embryos with few unwanted, local byproducts (average 58% precise edit frequency, 0.5% on-target error frequency across 13 substitution edits at 8 sites), enabling same-generation phenotyping of founders. Whole-genome sequencing reveals that mismatch repair inhibition increases off-target indels at low-complexity regions in the genome without any obvious phenotype in mice.
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This case report discusses posterior segment characteristics in a patient aged 24 years with low vision and a history of Gaucher disease.
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Enfermedad de Gaucher , Humanos , Enfermedad de Gaucher/diagnóstico , Enfermedad de Gaucher/tratamiento farmacológicoRESUMEN
Background: Breast-conserving surgery with synchronous 50-kV X-ray intraoperative radiation therapy (TARGIT-IORT) is a convenient form of partial breast irradiation; however, the existing literature supports a wide range of local control rates. Objectives: We investigated the treatment effectiveness and toxic effects of TARGIT-IORT in a patient cohort aged 64 years or older with low-risk breast cancer. Design: Retrospective analysis. Methods: Patients who received breast-conserving surgery with synchronous TARGIT-IORT at a single institution from 2016 to 2019 were reviewed. Additional whole breast irradiation was recommended at the discretion of the treating radiation oncologist. Baseline patient demographics and treatment details were recorded. Acute and chronic toxicities, measured using the Common Terminology Criteria for Adverse Events version 3.0 or 4.0 and breast cosmetic outcomes, using the Harvard Cosmesis score, were recorded. Locoregional recurrence, distant metastasis, and overall survival were recorded, and 5-year rates were estimated using the Kaplan-Meier method. Results: 61 patients were included with a median follow-up of 3.5 years and median age of 72 years. Eight (13%) patients received additional whole breast irradiation, and fifty-four (89%) received adjuvant hormone therapy. There were no local, regional, or distance recurrences. One patient died of complications from COVID-19 infection. Grade 2 + acute and chronic toxicities were observed in 6 (12%) and 7 (14%) patients, respectively. One patient experienced a grade 3 acute toxicity. Cosmetic outcome was "excellent" or "good" in 45 (92%) patients. Conclusions: Breast TARGIT-IORT was well tolerated and conferred excellent disease control in this cohort of patients with low-risk breast cancer. While continued follow-up is required, TARGIT-IORT may be an appropriate treatment option for this population.
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The rovibrational spectra of freely rotating gas phase molecules are often plagued by spectral congestion due to the high density of rotational peaks. The congestion is especially severe at higher infrared frequencies due to the large numbers of overlapping overtones and combination bands that form polyads. As a result, rovibrational peaks in the near-infrared region of the spectrum are seldom assigned. This work describes how two-dimensional (2D) rovibrational spectroscopy can use the coupling between vibrational modes to isolate rovibrational bands that would otherwise remain overlapped and congested. Multidimensional spectroscopic techniques that make use of the large number of cross-peaks that form rich 2D rovibrational patterns are explored. Propyne is used to demonstrate 2D methods for identifying the frequencies and symmetries of coupled vibrations and for assigning rotational quantum numbers, even in regions that are heavily congested.
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Efferocytosis is a process whereby apoptotic cells are cleared to maintain tissue homeostasis. In the lungs, efferocytosis has been implicated in several acute and chronic inflammatory diseases. A long-standing method to study efferocytosis in vivo is to instill apoptotic cells into the lungs to evaluate macrophage uptake. However, this approach provides nonphysiologic levels of cells to the airspaces, where there is preferential access to the alveolar macrophages. To circumvent this limitation, we developed a new method to study efferocytosis of damaged alveolar type 2 (AT2) epithelial cells in vivo. A reporter mouse that expresses TdTomato in AT2 epithelial cells was injured with influenza (strain PR8) to induce apoptosis of AT2 cells. We were able to identify macrophages that acquire red fluorescence after influenza injury, indicating efferocytosis of AT2 cells. Furthermore, evaluation of macrophage populations led to the surprising finding that lung interstitial macrophages were the primary efferocyte in vivo. In summary, we present a novel finding that the interstitial macrophage, not the alveolar macrophage, primarily mediates clearance of AT2 cells in the lungs after influenza infection. Our method of studying efferocytosis provides a more physiologic approach in evaluating the spatiotemporal dynamics of apoptotic cell clearance in vivo and opens new avenues to study the mechanisms by which efferocytosis regulates inflammation.
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Eferocitosis , Gripe Humana , Proteína Fluorescente Roja , Animales , Ratones , Humanos , Macrófagos , EpitelioRESUMEN
PURPOSE: There are mixed and limited data regarding radiation therapy (RT) tolerance in carriers of a germline pathogenic or likely pathogenic (P/LP) ATM variant. We investigated RT-related toxic effects in carriers of an ATM variant who received treatment for breast cancer. METHODS AND MATERIALS: We identified 71 patients treated with adjuvant RT for breast cancer who were carriers of a variant in ATM: 15 were classified as P/LP and 56 classified as variants of unknown significance (VUS). We additionally identified 205 consecutively treated patients during a similar timeframe who were either confirmed ATM wild type or had no prior genetic testing. RT plans were reviewed. Acute and chronic toxic effects were evaluated using Common Terminology Criteria for Adverse Events version 4.0 criteria. Fisher's exact tests for count data were performed to compare toxic effects between the cohorts (P/LP vs VUS vs control). Wilcoxon rank-sum testing was performed to assess for differences in patient characteristics. RESULTS: The median toxicity follow-up was 19.4 months; median follow-up for the subcohorts was 13.3 months (P/LP), 12.6 months (VUS), and 23.3 months (control). There were no significant differences in radiation plan heterogeneity, receipt of a boost, or size of breast/chest wall planning target volume. There was greater use of hypofractionated RT in the control cohort (P = .023). After accounting for patient- and treatment-related factors that may affect toxic effects, we found no significant differences with respect to acute dermatitis, hyperpigmentation, moist desquamation, breast/chest wall pain, or breast edema. Additionally, we found no significant differences with respect to chronic breast/chest wall pain, induration, telangiectasia, or cosmetic outcome. CONCLUSIONS: RT as part of the management of breast cancer was well tolerated in carriers of a P/LP ATM variant, with toxic effect profiles that were similar to those seen in patients without known ATM mutations. High rates of excellent or good cosmesis were observed in carriers of a P/LP ATM variant who underwent breast conservation.