Sialylation of MUC4β N-glycans by ST6GAL1 orchestrates human airway epithelial cell differentiation associated with type-2 inflammation

Although type-2-induced (T2-induced) epithelial dysfunction is likely to profoundly alter epithelial differentiation and repair in asthma, the mechanisms for these effects are poorly understood. A role for specific mucins, heavily N-glycosylated epithelial glycoproteins, in orchestrating epithelial cell fate in response to T2 stimuli has not previously been investigated. Levels of a sialylated MUC4 beta isoform were found to be increased in airway specimens from asthmatic patients in association with T2 inflammation. We hypothesized that IL-13 would increase sialylation of MUC4 beta, thereby altering its function and that the beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) would regulate the sialylation. Using human biologic specimens and cultured primary human airway epithelial cells (HAECs), we demonstrated that IL-13 increases ST6GAL1-mediated sialylation of MUC4 beta and that both were increased in asthma, particularly in sputum supernatant and/or fresh isolated HAECs with elevated T2 biomarkers. ST6GAL1-induced sialylation of MUC4 beta altered its lectin binding and secretion. Both ST6GAL1 and MUC4 beta inhibited epithelial cell proliferation while promoting goblet cell differentiation. These in vivo and in vitro data provide strong evidence for a critical role for ST6GAL1-induced sialylation of MUC4 beta in epithelial dysfunction associated with T2-high asthma, thereby identifying specific sialylation pathways as potential targets in asthma.NIH [R01 HL069174]; National Heart, Lung, and Blood Institute [R01 HL064937, R01 HL069116, P01 HL103453, R01 HL69167, U01 HL109086, U10 HL109152, R21 AI122071]; National Institute of Allergy and Infectious Diseases [P01 AI106684]; Nikon A1 [NIH 1S10OD019973-01]This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Frontally mediated inhibitory processing and white matter microstructure: age and alcoholism effects

RationaleThe NOGO P3 event-related potential is a sensitive marker of alcoholism, relates to EEG oscillation in the δ and θ frequency ranges, and reflects activation of an inhibitory processing network. Degradation of white matter tracts related to age or alcoholism should negatively affect the oscillatory activity within the network.ObjectiveThis study aims to evaluate the effect of alcoholism and age on δ and θ oscillations and the relationship between these oscillations and measures of white matter microstructural integrity.MethodsData from ten long-term alcoholics to 25 nonalcoholic controls were used to derive P3 from Fz, Cz, and Pz using a visual GO/NOGO protocol. Total power and across trial phase synchrony measures were calculated for δ and θ frequencies. DTI, 1.5 T, data formed the basis of quantitative fiber tracking in the left and right cingulate bundles and the genu and splenium of the corpus callosum. Fractional anisotropy and diffusivity (λL and λT) measures were calculated from each tract.ResultsNOGO P3 amplitude and δ power at Cz were smaller in alcoholics than controls. Lower δ total power was related to higher λT in the left and right cingulate bundles. GO P3 amplitude was lower and GO P3 latency was longer with advancing age, but none of the time-frequency analysis measures displayed significant age or diagnosis effects.ConclusionsThe relation of δ total power at CZ with λT in the cingulate bundles provides correlational evidence for a functional role of fronto-parietal white matter tracts in inhibitory processing

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

An Indigenous Archaeological Perspective on the Use of Artificial Intelligence in Reconstructing Chumash History

The development and use of Artificial Intelligence (AI) natural language models such as ChatGPT have raised questions about the applications and risks to academia, research, and privacy. What is currently not being explored is the use of ChatGPT in shaping public understanding of indigenous histories. As we have seen, public opinion is often shaped by a single source of information, and this source is often not vetted for accuracy or credibility. Assuming ChatGPT to be one of those sources, I explore the knowledge and perspectives communicated in synthesizing the last 13,000 years of Chumash occupation in the Santa Barbara Channel Region of California and juxtapose this information with the archaeological record to evaluate the model’s knowledge of our cultural history. I specifically explore the relationships between my ancestors and their environment, the development and maintenance of our cross-channel exchange network, shifts in diet through time, and changes in sociopolitical organization within the context of climate change. I also explore the potential risks of increased looting of Chumash cultural sites by assessing ChatGPT’s ability to provide geographic information on archaeological sites

Ceasing Production in Favor of Consumption: Diachronic Analysis of the Rincon Point (CA-VEN-62) Microlithic Assemblage

This thesis focuses on the diachronic analysis of microlithic tools over the late Middle to proto-Historic occupation of the Chumash village Shuku, or Rincon Point. Based on criteria put forth by Arnold (1987, 1990), two separate VEN-62 lithic assemblages were re-evaluated for the presence of microblades, microdrills, microlithic cores, and flake drills. Frequency and density values for artifact type and material composition were calculated for Middle, Transitional, Late, and proto-Historic period deposits. In order to explore the legitimacy of mainland microlithic production after the Middle period, the Rincon Point data is then juxtaposed with sites located on the northern Channel Islands and coastal mainland. The results of this research suggest the Chumash living at Shuku acquired small amounts of microliths via cross-channel exchange and minimal on-site production throughout all chronological phases

Ceasing Production in Favor of Consumption: Diachronic Analysis of the Rincon Point (CA-VEN-62) Microlithic Assemblage

This thesis focuses on the diachronic analysis of microlithic tools over the late Middle to proto-Historic occupation of the Chumash village Shuku, or Rincon Point. Based on criteria put forth by Arnold (1987, 1990), two separate VEN-62 lithic assemblages were re-evaluated for the presence of microblades, microdrills, microlithic cores, and flake drills. Frequency and density values for artifact type and material composition were calculated for Middle, Transitional, Late, and proto-Historic period deposits. In order to explore the legitimacy of mainland microlithic production after the Middle period, the Rincon Point data is then juxtaposed with sites located on the northern Channel Islands and coastal mainland. The results of this research suggest the Chumash living at Shuku acquired small amounts of microliths via cross-channel exchange and minimal on-site production throughout all chronological phases

Progeria and its Association with Cerebrovascular Disease, First Report of a Case in the National Literature of Colombia

El síndrome de progeria de Hutchinson-Gilford (SPHG) es un síndrome de envejecimiento prematuro, progresivo y poco frecuente con morbilidad temprana debido a enfermedades cardiovasculares y cerebrovasculares. Los síntomas clínicos son muy diversos, incluyendo síntomas inespecíficos como retraso del crecimiento, esclerodermia, alopecia y osteoporosis, así como hipertensión y enfermedades cardiovasculares que se presentan en la infancia y la adolescencia debido al envejecimiento vascular acelerado, es causado por una mutación esporádica de una sola base de LMNA, que da como resultado una forma anormal de la proteína lamina A de la membrana interna, también conocida como progerina. La progerina se expresa en tipos de células que son fundamentales para la función y estructura vascular, como las células del músculo liso vascular, las células endoteliales y los fibroblastos adventiciales. La presencia del síndrome genera un riesgo elevado para desarrollar eventos cerebrovasculares entre otras comorbilidades. Presentamos a continuación un caso de un masculino de 21 años de edad proveniente de Santander Colombia con diagnóstico de Progeria y con 2 eventos cerebrovasculares lacunares. Se trata de un masculino de la tercera década de la vida con cuadro clínico de 2 ingresos hospitalarios por enfermedad cerebrovascular cursando con hemiparesia motora izquierda, Rankin modificado de 1, en los estudios del protocolo CASCADE se descartaron fuentes embolicas, aterotrombóticas y de hipercoagulabilidad. Se evidencio infarto lacunar en resonancia cerebral a nivel del hemisferio derecho e izquierdo. Los infartos lacunares se expresan por cuatro síndromes lacunares estereotipados: hemiparesia motora pura, síndrome sensitivo puro, paresia crural con ataxia homolateral, que más tarde se llamaría hemiparesia atáxica o ataxia-hemiparesia, y disartria mano torpe. El paciente presenta un evento tipo hemiparesia motora pura izquierda con minimas limitaciones actualmente. El presente caso es anecdótico y sería el primer reporte en la literatura Colombiana de este tipo de asociación con la progeria.Hutchinson-Gilford progeria syndrome (HGPS) is a rare, progressive, premature aging syndrome with early morbidity due to cardiovascular and cerebrovascular diseases. The clinical symptoms are very diverse, including non-specific symptoms such as growth retardation, scleroderma, alopecia and osteoporosis, as well as hypertension and cardiovascular diseases that occur in childhood and adolescence due to accelerated vascular aging, is caused by a sporadic mutation of a LMNA single base, resulting in an abnormal form of the inner membrane protein lamin A, also known as progerin. Progerin is expressed in cell types that are essential for vascular function and structure, such as vascular smooth muscle cells, endothelial cells, and adventitial fibroblasts. The presence of the syndrome generates a high risk of developing cerebrovascular events among other comorbidities. We present below a case of a 21-year-old male from Santander Colombia with a diagnosis of Progeria and 2 lacunar cerebrovascular events. This is a male in his third decade of life with a clinical picture of 2 hospital admissions for cerebrovascular disease presenting with left motor hemiparesis, modified Rankin of 1, in the CASCADE protocol studies, embolic, atherothrombotic and hypercoagulability sources were ruled out. A lacunar infarction was evidenced in brain resonance at the level of the right and left hemisphere. Lacunar infarcts are expressed by four stereotyped lacunar syndromes: pure motor hemiparesis, pure sensory syndrome, femoral paresis with ipsilateral ataxia, later called ataxic hemiparesis or ataxia-hemiparesis, and clumsy hand dysarthria. The patient presents a pure left motor hemiparesis-type event with currently minimal limitations. This case is anecdotal and would be the first report in the Colombian literature of this type of association with progeria