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COVID-19 syndrome is characterized by acute lung injury, hypoxemic respiratory failure, and high mortality. Alveolar type 2 (AT2) cells are essential for gas exchange, repair, and regeneration of distal lung epithelium. We have shown that the causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and other members of the ß-coronavirus genus induce an endoplasmic reticulum (ER) stress response in vitro; however, the consequences for host AT2 cell function in vivo are less understood. To study this, two murine models of coronavirus infection were used-mouse hepatitis virus-1 (MHV-1) in A/J mice and a mouse-adapted SARS-CoV-2 strain. MHV-1-infected mice exhibited dose-dependent weight loss with histological evidence of distal lung injury accompanied by elevated bronchoalveolar lavage fluid (BALF) cell counts and total protein. AT2 cells showed evidence of both viral infection and increased BIP/GRP78 expression, consistent with activation of the unfolded protein response (UPR). The AT2 UPR included increased inositol-requiring enzyme 1α (IRE1α) signaling and a biphasic response in PKR-like ER kinase (PERK) signaling accompanied by marked reductions in AT2 and BALF surfactant protein (SP-B and SP-C) content, increases in surfactant surface tension, and emergence of a reprogrammed epithelial cell population (Krt8+ and Cldn4+). The loss of a homeostatic AT2 cell state was attenuated by treatment with the IRE1α inhibitor OPK-711. As a proof-of-concept, C57BL6 mice infected with mouse-adapted SARS-CoV-2 demonstrated similar lung injury and evidence of disrupted surfactant homeostasis. We conclude that lung injury from ß-coronavirus infection results from an aberrant host response, activating multiple AT2 UPR stress pathways, altering surfactant metabolism/function, and changing AT2 cell state, offering a mechanistic link between SARS-CoV-2 infection, AT2 cell biology, and acute respiratory failure.NEW & NOTEWORTHY COVID-19 syndrome is characterized by hypoxemic respiratory failure and high mortality. In this report, we use two murine models to show that ß-coronavirus infection produces acute lung injury, which results from an aberrant host response, activating multiple epithelial endoplasmic reticular stress pathways, disrupting pulmonary surfactant metabolism and function, and forcing emergence of an aberrant epithelial transition state. Our results offer a mechanistic link between SARS-CoV-2 infection, AT2 cell biology, and respiratory failure.
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COVID-19 , Estrés del Retículo Endoplásmico , Endorribonucleasas , Homeostasis , Virus de la Hepatitis Murina , SARS-CoV-2 , Animales , Ratones , COVID-19/metabolismo , COVID-19/patología , COVID-19/virología , COVID-19/complicaciones , Virus de la Hepatitis Murina/patogenicidad , Endorribonucleasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/virología , Células Epiteliales Alveolares/patología , Chaperón BiP del Retículo Endoplásmico , Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Infecciones por Coronavirus/complicaciones , Surfactantes Pulmonares/metabolismo , Respuesta de Proteína Desplegada , Betacoronavirus , Insuficiencia Respiratoria/metabolismo , Insuficiencia Respiratoria/virología , Insuficiencia Respiratoria/patología , Modelos Animales de Enfermedad , eIF-2 Quinasa/metabolismo , HumanosRESUMEN
BACKGROUND: The Berlin Heart EXCOR® (BHE) can bridge children with severe heart failure to transplantation, but some are successfully weaned and spared transplantation. This study seeks to identify characteristics of children amenable to successful explantation with BHE support. METHODS: Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 guidelines were used. Five databases were screened for original, English articles measuring BHE support in patients <18 years old based on title and abstract. Exclusion criteria were applied: full-text availability, <10 total pediatric BHE patients, zero successful explantations from BHE, nonprimary literature, adult and pediatric results that could not be separated, and studies with overlapping patient information. Studies were analyzed with descriptive statistics. RESULTS: From 41 857 potential studies, 14 were analyzed with data from 58 hospitals on four continents from 1990 to 2020. There were 984 BHE patients. The most common diagnosis was dilated cardiomyopathy (n = 318, 32.3%), followed by congenital heart disease (n = 249, 25.3%). There were 85 (8.6%) children explanted with favorable outcomes. The underlying diagnosis was known in 44 (51.8%) cases: 14 (8.4%) of 166 cardiomyopathies, 17 (48.6%) of 35 myocarditis, and 12 (16.7%) of 72 with congenital heart disease were explanted. When the type of support was known, the rate of LVAD patients explanted was 21.3% (n = 19/89) and 2.4% (n = 1/42) of BiVAD patients were explanted. CONCLUSION: Explantation from BHE is not uncommon at 8.6%, but significant variation exists in the explantation data reported. Myocarditis and LVAD support may be populations suitable for weaning. Standardization of reporting measures and prospective registries may help identify patients suitable for this alternative to transplant and help develop weaning protocols.
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Remoción de Dispositivos , Insuficiencia Cardíaca , Trasplante de Corazón , Corazón Auxiliar , Humanos , Niño , Insuficiencia Cardíaca/cirugía , Insuficiencia Cardíaca/terapia , Preescolar , Adolescente , Lactante , Resultado del TratamientoRESUMEN
BACKGROUND: Patients with TB have additional nutritional requirements and thus additional costs to the household. Ni-kshay Poshan Yojana(NPY) is a Direct Benefit Transfer (DBT) scheme under the National Tuberculosis Elimination Programme(NTEP) in India which offers INR 500 monthly to all notified patients with TB for nutritional support during the period of anti-TB treatment. Five years after its implementation, we conducted the first nationwide evaluation of NPY. METHODS: In our retrospective cohort study using programmatic data of patients notified with TB in nine randomly selected Indian states between 2018 and 2022, we estimated the proportion of patients who received at least one NPY instalment and the median time to receive the first instalment. We determined the factors associated (i) with non-receipt of NPY using a generalised linear model with Poisson family and log link and (ii) with time taken to receive first NPY benefit in 2022 using quantile regression at 50th percentile. RESULTS: Overall, 3,712,551 patients were notified between 2018 and 2022. During this period, the proportion who received at least one NPY instalment had increased from 56.9% to 76.1%. Non-receipt was significantly higher among patients notified by private sector (aRR 2.10;2.08,2.12), reactive for HIV (aRR 1.69;1.64,1.74) and with missing/undetermined diabetic status (aRR 2.02;1.98,2.05). The median(IQR) time to receive the first instalment had reduced from 200(109,331) days in 2018 to 91(51,149) days in 2022. Patients from private sector(106.9;106.3,107.4days), those with HIV-reactive (103.7;101.8,105.7days), DRTB(104.6;102.6,106.7days) and missing/undetermined diabetic status (115.3;114,116.6days) experienced longer delays. CONCLUSIONS: The coverage of NPY among patients with TB had increased and the time to receipt of benefit had halved in the past five years. Three-fourths of the patients received at least one NPY instalment, more than half of whom had waited over three months to receive the first instalment. NTEP has to focus on timely transfer of benefits to enable patients to meet their additional nutritional demands, experience treatment success and avoid catastrophic expenditure.
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Diabetes Mellitus , Seropositividad para VIH , Humanos , Estudios Retrospectivos , Apoyo Nutricional , India/epidemiologíaRESUMEN
The establishment of cardiac function in the developing embryo is essential to ensure blood flow and, therefore, growth and survival of the animal. The molecular mechanisms controlling normal cardiac rhythm remain to be fully elucidated. From a forward genetic screen, we identified a unique mutant, grime, that displayed a specific cardiac arrhythmia phenotype. We show that loss-of-function mutations in tmem161b are responsible for the phenotype, identifying Tmem161b as a regulator of cardiac rhythm in zebrafish. To examine the evolutionary conservation of this function, we generated knockout mice for Tmem161b. Tmem161b knockout mice are neonatal lethal and cardiomyocytes exhibit arrhythmic calcium oscillations. Mechanistically, we find that Tmem161b is expressed at the cell membrane of excitable cells and live imaging shows it is required for action potential repolarization in the developing heart. Electrophysiology on isolated cardiomyocytes demonstrates that Tmem161b is essential to inhibit Ca2+ and K+ currents in cardiomyocytes. Importantly, Tmem161b haploinsufficiency leads to cardiac rhythm phenotypes, implicating it as a candidate gene in heritable cardiac arrhythmia. Overall, these data describe Tmem161b as a highly conserved regulator of cardiac rhythm that functions to modulate ion channel activity in zebrafish and mice.
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Arritmias Cardíacas/genética , Frecuencia Cardíaca/genética , Proteínas de la Membrana/fisiología , Mutación , Miocitos Cardíacos/metabolismo , Proteínas de Pez Cebra/fisiología , Potenciales de Acción/genética , Animales , Animales Modificados Genéticamente , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patología , Secuencia de Bases , Calcio/metabolismo , Secuencia Conservada , Modelos Animales de Enfermedad , Embrión de Mamíferos , Embrión no Mamífero , Regulación del Desarrollo de la Expresión Génica , Genes Letales , Corazón/embriología , Corazón/fisiopatología , Transporte Iónico , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Miocitos Cardíacos/patología , Organogénesis/genética , Periodicidad , Potasio/metabolismo , Pez Cebra , Proteínas de Pez Cebra/genéticaRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic interstitial lung disease. A barrier to developing more effective therapies for IPF is the dearth of preclinical models that recapitulate the early pathobiology of this disease. Intratracheal bleomycin, the conventional preclinical murine model of IPF, fails to reproduce the intrinsic dysfunction to the alveolar epithelial type 2 cell (AEC2) that is believed to be a proximal event in the pathogenesis of IPF. Murine fibrosis models based on SFTPC (Surfactant Protein C gene) mutations identified in patients with interstitial lung disease cause activation of the AEC2 unfolded protein response and endoplasmic reticulum stress-an AEC2 dysfunction phenotype observed in IPF. Although these models achieve spontaneous fibrosis, they do so with precedent lung injury and thus are challenged to phenocopy the general clinical course of patients with IPF-gradual progressive fibrosis and loss of lung function. Here, we report a refinement of a murine Sftpc mutation model to recapitulate the clinical course, physiological impairment, parenchymal cellular composition, and biomarkers associated with IPF. This platform provides the field with an innovative model to understand IPF pathogenesis and index preclinical therapeutic candidates.
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Fibrosis Pulmonar Idiopática , Proteína C Asociada a Surfactante Pulmonar , Animales , Ratones , Células Epiteliales Alveolares/metabolismo , Progresión de la Enfermedad , Fibrosis Pulmonar Idiopática/patología , Pulmón/patología , Mutación/genética , Proteína C Asociada a Surfactante Pulmonar/genética , Proteína C Asociada a Surfactante Pulmonar/metabolismoRESUMEN
BACKGROUND: Tropomyosins are highly conserved proteins, an attribute that forms the molecular basis for their IgE antibody cross-reactivity. Despite sequence similarities, their allergenicity varies greatly between ingested and inhaled invertebrate sources. In this study, we investigated the relationship between the structural stability of different tropomyosins, their endolysosomal degradation patterns, and T-cell reactivity. METHODS: We investigated the differences between four tropomyosins-the major shrimp allergen Pen m 1 and the minor allergens Der p 10 (dust mite), Bla g 7 (cockroach), and Ani s 3 (fish parasite)-in terms of IgE binding, structural stability, endolysosomal degradation and subsequent peptide generation, and T-cell cross-reactivity in a BALB/c murine model. RESULTS: Tropomyosins displayed different melting temperatures, which did not correlate with amino acid sequence similarities. Endolysosomal degradation experiments demonstrated differential proteolytic digestion, as a function of thermal stability, generating different peptide repertoires. Pen m 1 (Tm 42°C) and Der p 10 (Tm 44°C) elicited similar patterns of endolysosomal degradation, but not Bla g 7 (Tm 63°C) or Ani s 3 (Tm 33°C). Pen m 1-specific T-cell clones, with specificity for regions highly conserved in all four tropomyosins, proliferated weakly to Der p 10, but did not proliferate to Bla g 7 and Ani s 3, indicating lack of T-cell epitope cross-reactivity. CONCLUSIONS: Tropomyosin T-cell cross-reactivity, unlike IgE cross-reactivity, is dependent on structural stability rather than amino acid sequence similarity. These findings contribute to our understanding of cross-sensitization among different invertebrates and design of suitable T-cell peptide-based immunotherapies for shrimp and related allergies.
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Alérgenos , Tropomiosina , Animales , Reacciones Cruzadas , Inmunoglobulina E , Ratones , Linfocitos TRESUMEN
Adhesiveness of the endometrial epithelium to an embryo plays a critical role in the initiation of pregnancy. Loss or gain of adhesiveness also dictates the potential of endometrial epithelial cells to metastasize, an event that can result from certain genetic insults. A proteomics-based exploration of the "adhesiveness" these epithelial cells was employed that could identify targets that could disrupt embryo-endometrium interactions and/or metastasis of endometrial cancer cells. The present study defined the surfactomes of two human endometrial epithelial cell lines known for their differential adhesiveness to embryonic cells. Comparative, two-dimensional electrophoretic analysis of the surfactomes of RL95-2 (exhibiting higher adhesiveness to the embryonic cell line JAr) and HEC-1A (exhibiting reduced adhesiveness to JAr cells) revealed 55 differentially enriched proteins. Of these, 10 proteins were identified by MALDI-TOF/TOF or LC-MS/MS. TUBB2C, ADAMTS3, and elongation factor beta were more abundant on the HEC-1A cell surface whereas HSP27, HSPA9, GP96, CRT, Tapasin-ERP57, PDI, and ß-actin were more abundant on the RL95-2 cell surface. Nano LC-MS/MS was also employed to generate a more comprehensive surfactomes of RL95-2 and HEC-1A. The study also demonstrated a pro-adhesive role of CRT and HSPA9 and an anti-adhesive role of TUBB2C populations found on the cell surface. In brief, this study identifies the cell-surface protein complements of two human endometrial epithelial cell lines, and reveals the role of three proteins in heterotypic cell adhesion.
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Implantación del Embrión/fisiología , Endometrio/citología , Células Epiteliales/citología , Proteínas de la Membrana/análisis , Trofoblastos/citología , Adhesión Celular/fisiología , Línea Celular Transformada , Línea Celular Tumoral , Coriocarcinoma/patología , Cromatografía Liquida/métodos , Electroforesis en Gel Bidimensional , Femenino , Proteínas de Choque Térmico/análisis , Proteínas de Choque Térmico/fisiología , Humanos , Masculino , Proteínas de la Membrana/fisiología , Nanotecnología , Neoplasias de la Próstata/patología , Proteómica , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Esferoides Celulares , Propiedades de Superficie , Neoplasias Uterinas/patologíaRESUMEN
A neonate born of third-degree consanguineous marriage presented on day 12 of life with congestive cardiac failure. A male sibling died at 3 months of age, cause of which was not known. He was treated with decongestive measures and multiple inotropes. 2D Echocardiogram revealed severe Left ventricular dysfunction with prominent trabeculations and deep recesses in the left ventricle suggestive of Left ventricular non-compaction. He was also found to have horse-shoe kidney. Considering the presence of cardiac left ventricular non compaction, horse-shoe kidney and family history of neonatal death and pregnancy loss clinical exome sequencing was done. It detected a homozygous missense variant in exon 6 of the AGK gene suggestive of Senger's syndrome. Baby was on regular follow-up and was thriving well on diuretics, sacubitril-valsartan and weekly levosimendan infusions. At 8 months of age, cardiac transplantation was successfully done and baby has been doing well post-transplantation. LVNC in children is rare with an estimated incidence of 0.11 per 100,000, the highest incidence being during infancy. Senger's syndrome is autosomal recessive in inheritance. Senger's syndrome associated with Left ventricular non compaction has been reported only once in literature so far. Renal manifestations in the form of horse shoe kidney like in our index baby has not been reported previously with Senger's syndrome.
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Higher rates of obesity in rural compared to urban districts suggest environmental differences that affect student health. This study examined urban-rural differences in districts' local wellness policies (LWPs) and LWP implementation environments. Cross-sectional data from two assessments in Texas were analyzed. In assessment one, each district's LWP was reviewed to see if 16 goals were included. In assessment two, an audit was conducted to identify the presence of a wellness plan (a document with recommendations for implementing LWPs), triennial LWP assessment, and school health advisory councils (SHACs) on the district website. Rural districts' LWPs had a smaller number of total goals (B = -2.281, p = 0.014), nutrition education goals (B = -0.654, p = 0.005), and other school-based activity goals (B = -0.675, p = 0.001) in their LWPs, compared to urban districts. Rural districts also had lower odds of having a wellness plan (OR = 0.520, 95% CI = 0.288-0.939), p = 0.030) and a SHAC (OR = 0.201, 95% CI = 0.113-0.357, p < 0.001) to support LWP implementation, compared to urban districts. More resources may be needed to create effective SHACs that can help develop and implement LWPs in rural areas. Important urban-rural differences exist in Texas LWPs and LWP implementation environments.
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Política de Salud , Promoción de la Salud , Humanos , Estudios Transversales , Educación en Salud , Instituciones Académicas , Servicios de Salud Escolar , Política NutricionalRESUMEN
BACKGROUND: Ni-kshay Poshan Yojana (NPY), a direct benefit transfer scheme under the National Tuberculosis Elimination Program (NTEP) in India, provides a monthly benefit of INR500 for nutritional support of persons with TB (PwTB). OBJECTIVES: To determine the proportion of PwTB receiving atleast one NPY instalment and pattern of utilisation; to ascertain factors associated with NPY non-receipt and association of NPY receipt with TB treatment outcome. METHODS: In our cross-sectional study, we used multi-stage sampling to select PwTB whose treatment outcome was declared between May 2022 and February 2023. A cluster-adjusted, generalized linear model was used to identify factors associated with the non-receipt of NPY and determine association between NPY receipt and TB treatment outcome. RESULTS: Among 3201 PwTB, 2888 (92.7%; 95% CI 89.8%, 94.8%) had received at least one NPY instalment, and 1903 (64.2%; 95% CI 58.9%, 69.2%) self-reported receipt of benefit. The median (IQR) time to receipt of first instalment was 105 (60,174) days. Non-receipt was significantly higher among PwTB from states with low TB score (aPR = 2.34; 95%CI 1.51, 3.62), who do not have bank account (aPR = 2.48; 95%CI 1.93, 3.19) and with unknown/missing diabetic status (aPR = 1.69; 95%CI 1.11, 2.55). Unfavorable treatment outcomes were associated with non-receipt of NPY (aPR 4.93; 95%CI 3.61,6.75) after adjusting for potential confounders. CONCLUSION: Majority of the PwTB received atleast one NPY instalment, but they experience significant delays. Most of the recipients utilised NPY for nutrition. Longitudinal follow-up studies are required to study the impact of NPY on treatment outcomes.
Main findings: Five years since implementation, almost ninety percent of persons with tuberculosis in India had received at least one benefit under Ni-kshay Poshan Yojana, most of whom utilise it for nutrition.Added knowledge: Persons with tuberculosis in India experience a median delay of over three months to receive the first instalment of the benefit.Global health impact for policy and action: Ensuring timely credit of benefits is crucial to enable its utilisation by persons with tuberculosis for better nutrition and favourable treatment outcomes.
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Tuberculosis , Humanos , India , Masculino , Femenino , Estudios Transversales , Adulto , Tuberculosis/tratamiento farmacológico , Persona de Mediana Edad , Antituberculosos/uso terapéutico , Adulto Joven , Adolescente , Resultado del Tratamiento , Programas Nacionales de SaludRESUMEN
Alveolar epithelial type II (AT2) cell dysfunction is implicated in the pathogenesis of familial and sporadic idiopathic pulmonary fibrosis (IPF). We previously described that expression of an AT2 cell exclusive disease-associated protein isoform (SP-CI73T) in murine and patient-specific induced pluripotent stem cell (iPSC)-derived AT2 cells leads to a block in late macroautophagy and promotes time-dependent mitochondrial impairments; however, how a metabolically dysfunctional AT2 cell results in fibrosis remains elusive. Here using murine and human iPSC-derived AT2 cell models expressing SP-CI73T, we characterize the molecular mechanisms governing alterations in AT2 cell metabolism that lead to increased glycolysis, decreased mitochondrial biogenesis, disrupted fatty acid oxidation, accumulation of impaired mitochondria, and diminished AT2 cell progenitor capacity manifesting as reduced AT2 self-renewal and accumulation of transitional epithelial cells. We identify deficient AMP-kinase signaling as a key upstream signaling hub driving disease in these dysfunctional AT2 cells and augment this pathway to restore alveolar epithelial metabolic function, thus successfully alleviating lung fibrosis in vivo.
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BACKGROUND: Globally, occupational hazards are a concern, especially in waste management. With 31.2% of its population in urban areas, India is confronted with escalating waste management challenges. People worldwide generate about two-thirds of a kilogram of waste daily. Effective solid waste management is crucial due to population growth, changing waste patterns, and rapid urbanisation. It profoundly impacts environmental, resident, and worker health. Rag picking is an informal profession undertaken by a marginalised population of the society, which involves collecting waste from trash cans, streets, and household waste. To assess the burden and the pattern of morbidity, and the occupational factors associated with it, as well as their health-seeking behaviour, the present study was carried out among women rag pickers in Mumbai, India. METHODOLOGY: A cross-sectional descriptive study was conducted through a mixed-method approach in Mumbai's Chembur and Govandi areas, focusing on women rag pickers aged 15 to 49 years. The research was conducted over a period of three months, during which a total of 150 female rag pickers from individual families were identified and included in the study through purposive sampling. The structured questionnaires gathered quantitative data on socio-demographics, health-seeking behaviour, morbidity, and monthly expenses. The qualitative data were collected through focus group discussions with rag pickers, analysing themes related to rag picking as occupational preference and substance usage factors. Ethical approval from the institute and informed consent from each participant were obtained prior to data collection. RESULTS: Among the cohort of 150 women rag pickers, 67.3% were aged between 15 and 30 years, with 82% belonging to the lower socio-economic class. A notable 43.4% of these women engaged in significant tobacco use, primarily through oral consumption, while about 56.7% of their family members exhibited high substance use, including pan, tobacco, and alcohol. In terms of health-seeking behaviour, 51% refrained from seeking treatment for minor ailments, 29% resorted to home remedies or self-medication, and 20% sought care at hospitals. A morbidity analysis over the past three months revealed prevalent health issues, informing potential interventions. Examination of monthly expenditure patterns unveiled an average income of 9000 INR (130 USD), with a significant 61% allocation towards food and grocery expenses. Qualitative insights indicated that the preference for rag picking was driven by limited alternatives and substance use was influenced by peers and served as a means to cope with stress. These findings underscore distinct health-seeking behaviours, and the unique needs of women rag pickers, providing valuable guidance for targeted policies to enhance their well-being. CONCLUSION: These findings underscore the need for targeted interventions to improve the well-being and socio-economic conditions of women rag pickers in India. Universal healthcare coverage, community-based initiatives, and social inclusion are vital for addressing their unique challenges and enhancing their quality of life.
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T cells recognize tumor-derived mutated peptides presented on MHC by tumors. The recognition of these neo-epitopes leads to rejection of tumors, an event that is critical for successful cancer immunosurveillance. Determination of tumor-rejecting neo-epitopes in human tumors has proved difficult, though recently developed systems approaches are becoming increasingly useful at evaluating their immunogenicity. We have used the differential aggretope index to determine the neo-epitope burden of sarcomas and observed a conspicuously titrated antigenic landscape, ranging from the highly antigenic osteosarcomas to the low antigenic leiomyosarcomas and liposarcomas. We showed that the antigenic landscape of the tumors inversely reflected the historical T cell responses in the tumor-bearing patients. We predicted that highly antigenic tumors with poor antitumor T cell responses, such as osteosarcomas, would be responsive to T cell-based immunotherapy regimens and demonstrated this in a murine osteosarcoma model. Our study presents a potentially novel pipeline for determining antigenicity of human tumors, provides an accurate predictor of potential neo-epitopes, and will be an important indicator of which cancers to target with T cell-enhancing immunotherapy.
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Osteosarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Ratones , Animales , Epítopos , Monitorización Inmunológica , Sarcoma/terapia , Osteosarcoma/genética , Osteosarcoma/terapia , InmunoterapiaRESUMEN
Idiopathic Pulmonary Fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2α, and its cognate receptor FPr (Ptfgr) are implicated as a TGFß1 independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (IER - SftpcI73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene. Tamoxifen treated IER-SftpcI73T mice develop an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. IER-SftpcI73T mice crossed to a Ptgfr null (FPr-/-) line showed attenuated weight loss and gene dosage dependent rescue of mortality compared to FPr+/+ cohorts. IER-SftpcI73T/FPr-/- mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single cell RNA sequencing, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts which were reprogrammed to an "inflammatory/transitional" cell state in a PGF2α/FPr dependent manner. Collectively, the findings provide evidence for a role for PGF2α signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung remodeling.
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BACKGROUND: India has been implementing active case-finding (ACF) for TB among marginalised and vulnerable (high-risk) populations since 2017. The effectiveness of ACF cycle(s) is dependent on the use of appropriate screening and diagnostic tools and meeting quality indicators. OBJECTIVES: To determine the number of ACF cycles implemented in 2021 at national, state (n = 36) and district (n = 768) level and quality indicators for the first ACF cycle. METHODS: In this descriptive study, aggregate TB program data for each ACF activity that was extracted was further aggregated against each ACF cycle at the district level in 2021. One ACF cycle was the period identified to cover all the high-risk populations in the district. Three TB ACF quality indicators were calculated: percentage population screened (≥10%), percentage tested among screened (≥4.8%) and percentage diagnosed among tested (≥5%). We also calculated the number needed to screen (NNS) for diagnosing one person with TB (≤1538). RESULTS: Of 768 TB districts, ACF data for 111 were not available. Of the remaining 657 districts, 642 (98%) implemented one, and 15 implemented two to three ACF cycles. None of the districts or states met all three TB ACF quality indicators' cut-offs. At the national level, for the first ACF cycle, 9.3% of the population were screened, 1% of the screened were tested and 3.7% of the tested were diagnosed. The NNS was 2824: acceptable (≤1538) in institutional facilities and poor for population-based groups. Data were not consistently available to calculate the percentage of i) high-risk population covered, ii) presumptive TB among screened and iii) tested among presumptive. CONCLUSION: In 2021, India implemented one ACF cycle with sub-optimal ACF quality indicators. Reducing the losses between screening and testing, improving data quality and sensitising stakeholders regarding the importance of meeting all ACF quality indicators are recommended.
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Análisis de Datos Secundarios , Tuberculosis , Humanos , Tuberculosis/diagnóstico , Tuberculosis/epidemiología , Tuberculosis/prevención & control , Exactitud de los Datos , Instituciones de Salud , India/epidemiologíaRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2α, and its cognate receptor FPr (Ptgfr) are implicated as a TGF-ß1-independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (IER-SftpcI73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene. Tamoxifen-treated IER-SftpcI73T mice developed an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. IER-SftpcI73T mice crossed to a Ptgfr-null (FPr-/-) line showed attenuated weight loss and gene dosage-dependent rescue of mortality compared with FPr+/+ cohorts. IER-SftpcI73T/FPr-/- mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single-cell RNA-Seq, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts, which were reprogrammed to an "inflammatory/transitional" cell state in a PGF2α /FPr-dependent manner. Collectively, the findings provide evidence for a role for PGF2α signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung remodeling.
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Dinoprost , Fibrosis Pulmonar Idiopática , Ratones , Animales , Dinoprost/metabolismo , Fibroblastos/metabolismo , Fibrosis Pulmonar Idiopática/patología , Fibrosis , Dinámica PoblacionalAsunto(s)
Alérgenos/inmunología , Antígenos Dermatofagoides/inmunología , Proteínas de Artrópodos/inmunología , Hipersensibilidad Inmediata/diagnóstico , Inmunoglobulina E/inmunología , Tropomiosina/inmunología , Biomarcadores/sangre , Reacciones Cruzadas , Femenino , Humanos , Hipersensibilidad Inmediata/inmunología , Inmunoglobulina E/sangre , Lactante , Masculino , Hipersensibilidad a los Mariscos/diagnóstico , Hipersensibilidad a los Mariscos/inmunologíaRESUMEN
Shrimp is one of the predominant causes of food allergy among adults, often presenting with severe reactions. Current in vitro diagnostics are based on quantification of patient specific-IgE (sIgE) to shrimp extract. Tropomyosin is the known major shrimp allergen, but IgE sensitisation to other allergens is poorly characterised. In this study, the binding of IgE to various shrimp allergens, additional to tropomyosin, was investigated using sera from 21 subjects who had clinical reactions to one or more shellfish species. Total shrimp-sIgE was quantified using ImmunoCAP, while allergen-sIgEs were quantified using immunoblotting and mass spectrometry, and immuno-PCR to recombinant shrimp tropomyosin. Sixty-two percent of subjects (13/21) were positive to shrimp by ImmunoCAP. IgE from 43% of subjects (9/21) bound tropomyosin, while an additional 29% of subjects (6/21) demonstrated IgE-binding solely to other shrimp allergens, including sarcoplasmic calcium-binding protein, arginine kinase and hemocyanin. Furthermore, IgE sensitisation to other shrimp allergens was demonstrated in 50% of subjects (4/8) who were ImmunoCAP negative. The lack of standardised shrimp allergens and inadequacy of current extracts for shrimp allergy diagnosis is highlighted by this study. Comprehensive knowledge of less studied allergens and their inclusion in component-resolved diagnostics will improve diagnostic accuracy, benefitting the wider population suffering from shellfish allergy.
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Alérgenos/inmunología , Artemia/inmunología , Hipersensibilidad a los Alimentos/diagnóstico , Hipersensibilidad a los Alimentos/inmunología , Adulto , Animales , Arginina Quinasa/inmunología , Proteínas de Unión al Calcio/inmunología , Femenino , Hemocianinas/inmunología , Humanos , Inmunoglobulina E/inmunología , Masculino , Persona de Mediana Edad , Alimentos Marinos , Tropomiosina/inmunología , Adulto JovenRESUMEN
Endothelial cells form a critical component of the coronary vasculature, yet the factors regulating their development remain poorly defined. Here we reveal a novel role for the transmembrane protein CRIM1 in mediating cardiac endothelial cell development. In the absence of Crim1 in vivo, the coronary vasculature is malformed, the number of endothelial cells reduced, and the canonical BMP pathway dysregulated. Moreover, we reveal that CRIM1 can bind IGFs, and regulate IGF signalling within endothelial cells. Finally, loss of CRIM1 from human cardiac endothelial cells results in misregulation of endothelial genes, predicted by pathway analysis to be involved in an increased inflammatory response and cytolysis, reminiscent of endothelial cell dysfunction in cardiovascular disease pathogenesis. Collectively, these findings implicate CRIM1 in endothelial cell development and homeostasis in the coronary vasculature.
Asunto(s)
Receptores de Proteínas Morfogenéticas Óseas/genética , Receptores de Proteínas Morfogenéticas Óseas/metabolismo , Vasos Coronarios/citología , Células Endoteliales/metabolismo , Homeostasis , Animales , Proteínas Morfogenéticas Óseas/metabolismo , Supervivencia Celular/genética , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Ratones Noqueados , Mutación , Transducción de SeñalRESUMEN
The regulation of growth factor localization, availability and activity is critical during embryogenesis to ensure appropriate organogenesis. This process is regulated through the coordinated expression of growth factors and their cognate receptors, as well as via proteins that can bind, sequester or localize growth factors to distinct locations. One such protein is the transmembrane protein Crim1. This protein has been shown to be expressed broadly within the developing embryo, and to regulate organogenesis within the eye, kidney and placenta. Mechanistically, Crim1 has been revealed to mediate organogenesis via its interaction with growth factors including TGFßs, BMPs, VEGFs and PDFGs. More recently, Crim1 has been shown to influence cardiac development, providing further insights into the function of this protein. This review will provide an overview of the role of Crim1 in organogenesis, largely focusing on how this protein regulates growth factor signaling in the nascent heart. Moreover, we will address the challenges ahead relating to further elucidating how Crim1 functions during development.