tauFisher predicts circadian time from a single sample of bulk and single-cell pseudobulk transcriptomic data.

As the circadian clock regulates fundamental biological processes, disrupted clocks are often observed in patients and diseased tissues. Determining the circadian time of the patient or the tissue of focus is essential in circadian medicine and research. Here we present tauFisher, a computational pipeline that accurately predicts circadian time from a single transcriptomic sample by finding correlations between rhythmic genes within the sample. We demonstrate tauFisher's performance in adding timestamps to both bulk and single-cell transcriptomic samples collected from multiple tissue types and experimental settings. Application of tauFisher at a cell-type level in a single-cell RNAseq dataset collected from mouse dermal skin implies that greater circadian phase heterogeneity may explain the dampened rhythm of collective core clock gene expression in dermal immune cells compared to dermal fibroblasts. Given its robustness and generalizability across assay platforms, experimental setups, and tissue types, as well as its potential application in single-cell RNAseq data analysis, tauFisher is a promising tool that facilitates circadian medicine and research.

miR-16-5p aggravates sepsis-associated acute kidney injury by inducing apoptosis.

Sepsis-associated acute kidney injury (S-AKI) is a common disease in pediatric intensive care units (ICU) with high morbidity and mortality. The newly discovered results indicate that microRNAs (miRNAs) play an important role in the diagnosis and treatment of S-AKI and can be used as markers for early diagnosis. In this study, the expression level of miR-16-5p was found to be significantly upregulated about 20-fold in S-AKI patients, and it also increased by 1.9 times in the renal tissue of S-AKI mice. Receiver operating characteristic (ROC) curve analysis showed that miR-16-5p had the highest predictive accuracy in the diagnosis of S-AKI (AUC = 0.9188). In vitro, the expression level of miR-16-5p in HK-2 cells treated with 10 µg/mL lipopolysaccharide (LPS) increased by more than 2 times. In addition, LPS-exposed renal tissue and HK-2 cells lead to upregulation of inflammatory cytokines IL-6, IL-1ß, TNF-a, and kidney damage molecules kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL). However, inhibition of miR-16-5p significantly mitigated LPS expose-mediated kidney injury and inflammation. Furthermore, LPS-exposed HK-2 cells increased more than 1.7-fold the expression levels of Bax and caspase-3, decreased 3.2-fold the expression level of B-cell lymphoma-2 (Bcl-2), and significantly promoted the occurrence of apoptosis. MiR-16-5p mimic further increased LPS-induced apoptosis in HK-2 cells. Nevertheless, inhibition of miR-16-5p significantly attenuated this effect. In summary, up-regulation of miR-16-5p expression can significantly aggravate renal injury and apoptosis in S-AKI, which also proves that miR-16-5p can be used as a potential biomarker to promote early identification of S-AKI.

tauFisher accurately predicts circadian time from a single sample of bulk and single-cell transcriptomic data.

As the circadian clock regulates fundamental biological processes, disrupted clocks are often observed in patients and diseased tissues. Determining the circadian time of the patient or the tissue of focus is essential in circadian medicine and research. Here we present tau-Fisher, a computational pipeline that accurately predicts circadian time from a single transcriptomic sample by finding correlations between rhythmic genes within the sample. We demonstrate tauFisher's out-standing performance in both bulk and single-cell transcriptomic data collected from multiple tissue types and experimental settings. Application of tauFisher at a cell-type level in a single-cell RNA-seq dataset collected from mouse dermal skin implies that greater circadian phase heterogeneity may explain the dampened rhythm of collective core clock gene expression in dermal immune cells compared to dermal fibroblasts. Given its robustness and generalizability across assay platforms, experimental setups, and tissue types, as well as its potential application in single-cell RNA-seq data analysis, tauFisher is a promising tool that facilitates circadian medicine and research.

How and Why the Circadian Clock Regulates Proliferation of Adult Epithelial Stem Cells.

First described in the early 20th century, diurnal oscillations in stem cell proliferation exist in multiple internal epithelia, including in the gastrointestinal tract, and in the epidermis. In the mouse epidermis, 3- to 4-fold more stem cells are in S-phase during the night than during the day. More recent work showed that an intact circadian clock intrinsic to keratinocytes is required for these oscillations in epidermal stem cell proliferation. The circadian clock also regulates DNA excision repair and DNA damage in epidermal stem cells in response to ultraviolet B radiation. During skin inflammation, epidermal stem cell proliferation is increased and diurnal oscillations are suspended. Here we discuss possible reasons for the evolution of this stem cell phenomenon. We argue that the circadian clock coordinates intermediary metabolism and the cell cycle in epidermal stem cells to minimize the accumulation of DNA damage from metabolism-generated reactive oxygen species. Circadian disruption, common in modern society, leads to asynchrony between metabolism and the cell cycle, and we speculate this will lead to oxidative DNA damage, dysfunction of epidermal stem cells, and skin aging.

The Effect of Resilience and Family Support Match on Psychological Distress among Women in the Menopausal Transition Based on Polynomial Regression and Response Surface Analysis.

Menopausal transition (MT) is a natural process in women from reproductive decline to aging. During this period, women present with an increased prevalence of psychological distress. The aim of this study was to investigate how resilience and family support interact to influence psychological distress among women during MT. A convenience sampling method was used to recruit 858 women during MT from Shandong Province. All participants completed the 10-item Connor-Davidson Resilience Scale, the family care degree questionnaire, and the Kessler Psychological Distress Scale. Data were analyzed by using SPSS 24.0. Response surface analysis was used for polynomial regression and response surface analysis. The results of response surface analysis show that in the case of agreement between resilience and family support, the joint effect manifested as a negative curve (inverted U shape) related to the psychological distress of women during MT. In the case of disagreement, the joint effect manifested as a negative curve (inverted U shaped) related to psychological distress. Specifically, with increased variance in the degree of resilience and family support, women experienced less psychological distress. Both resilience and family support play an important role in protecting women from psychological distress, either alone or in combination. Future intervention studies targeting women during MT should consider the coordinated actions of resilience and family support.

The M3 Muscarinic Acetylcholine Receptor Promotes Epidermal Differentiation.

The M3 muscarinic acetylcholine receptor is predominantly expressed in the basal epidermal layer where it mediates the effects of the autocrine/paracrine cytotransmitter acetylcholine. Patients with the autoimmune blistering disease pemphigus develop autoantibodies to M3 muscarinic acetylcholine receptor and show alterations in keratinocyte adhesion, proliferation, and differentiation, suggesting that M3 muscarinic acetylcholine receptor controls these cellular functions. Chmr3-/- mice display altered epidermal morphology resembling that seen in patients with pemphigus vulgaris. In this study, we characterized the cellular and molecular mechanisms through which M3 muscarinic acetylcholine receptor controls epidermal structure and function. We used single-cell RNA sequencing to evaluate keratinocyte heterogeneity and identify differentially expressed genes in specific subpopulations of epidermal cells in Chmr3-/- neonatal mice. We found that Chmr3-/- mice feature abnormal epidermal morphology characterized by accumulation of nucleated basal cells, shrinkage of basal keratinocytes, and enlargement of intercellular spaces. These morphologic changes were associated with upregulation of cell proliferation genes and downregulation of genes contributing to epidermal differentiation, extracellular matrix formation, intercellular adhesion, and cell arrangement. These findings provide, to our knowledge, previously unreported insights into how acetylcholine controls epidermal differentiation and lay a groundwork for future translational studies evaluating the therapeutic potential of cholinergic drugs in dermatology.

Governance structure affects transboundary disease management under alternative objectives.

BACKGROUND: The development of public health policy is inextricably linked with governance structure. In our increasingly globalized world, human migration and infectious diseases often span multiple administrative jurisdictions that might have different systems of government and divergent management objectives. However, few studies have considered how the allocation of regulatory authority among jurisdictions can affect disease management outcomes. METHODS: Here we evaluate the relative merits of decentralized and centralized management by developing and numerically analyzing a two-jurisdiction SIRS model that explicitly incorporates migration. In our model, managers choose between vaccination, isolation, medication, border closure, and a travel ban on infected individuals while aiming to minimize either the number of cases or the number of deaths. RESULTS: We consider a variety of scenarios and show how optimal strategies differ for decentralized and centralized management levels. We demonstrate that policies formed in the best interest of individual jurisdictions may not achieve global objectives, and identify situations where locally applied interventions can lead to an overall increase in the numbers of cases and deaths. CONCLUSIONS: Our approach underscores the importance of tailoring disease management plans to existing regulatory structures as part of an evidence-based decision framework. Most importantly, we demonstrate that there needs to be a greater consideration of the degree to which governance structure impacts disease outcomes.

The circadian clock and diseases of the skin.

Organisms have an evolutionarily conserved internal rhythm that helps them anticipate and adapt to daily changes in the environment. Synchronized to the light-dark cycle with a period of around 24 hours, the timing of the circadian clock is set by light-triggering signals sent from the retina to the suprachiasmatic nucleus. Other inputs, including food intake, exercise, and temperature, also affect clocks in peripheral tissues, including skin. Here, we review the intricate interplay between the core clock network and fundamental physiological processes in skin such as homeostasis, regeneration, and immune- and stress responses. We illustrate the effect of feeding time on the skin circadian clock and skin functions, a previously overlooked area of research. We then discuss works that relate the circadian clock and its disruption to skin diseases, including skin cancer, sunburn, hair loss, aging, infections, inflammatory skin diseases, and wound healing. Finally, we highlight the promise of circadian medicine for skin disease prevention and management.

An Extremely Rare Epithelioid Sarcoma Arising from the Infratemporal Fossa: A Case Report and Literature Review.

INTRODUCTION: Epithelioid sarcoma (ES) is a rare histopathological type of soft tissue sarcoma. They are subcutaneous soft tissue masses that tend to arise in extremity sites (the classic type, formerly referred to as distal type) or proximal midline region of the body (the proximal type), such as the perineum, genital tract, and pelvis. The head and neck regions are rarely affected by ES, but the infratemporal fossa (ITF) is extremely rare. ES involving the ITF has not been reported before in literature. In this paper, the imaging features of ES were reviewed in detail, and the anatomical structure and epidemiology of ITF were briefly introduced. SOURCES: We performed a systematic search from 3 databases, CNKI(China National Knowledge Internet), FMRS(Foreign Medical Literature Retrieval Service, Shenzhen METSTR Technology CO., Led. China), and PubMed, to obtain literature from January 1970 to July 2020. Epithelioid sarcoma, head and neck regions, infratemporal fossa, diagnostic imaging, anatomy, MRI, and CT were used as keywords for advanced retrieval. A study had to be found eligible for inclusion to be closely related to ES and/or ITF. A total of 129 related pieces of literature were retrieved successfully, of which 37 were closely related to this study. The case report in this article is from the Affiliated Hospital of North Sichuan Medical College. The present study was approved by the institutional review board of the Affiliated Hospital of North Sichuan Medical College and a written informed consent for the publication of the case was obtained from the patient. CASE PRESENTATION: A 33-year-old man accidentally found a slowly growing, painless mass in the left cheek more than a month ago. On plain computed tomography (CT) scan of the outpatient department, an oval slightly low-density mass with well-defined and uniform boundary in the infratemporal fossa was revealed, and on the contrast-enhanced scan, it was homogeneous and moderately enhanced. Initially, the CT appearance favored benign lesions. However, the possibility of a malignant tumor can not be excluded completely. Finally, the patient was referred to the inpatient department a tumor arose from IF and underwent a selective operation. The tumor was completely removed. Histologic findings were compatible with epithelioid sarcoma. Post-operatively, the patient received 2 cycles of radiotherapy, and there was no evidence of recurrence after 6 months follow- up. CONCLUSION: The imaging manifestations of ES are various. The anatomic structure of ITF is complex and the pathological types are various. It should be very careful in the qualitative diagnosis of tumors from the ITF, and advanced imaging techniques will be useful in imaging diagnosis.

Factores de riesgo de lesión de las arterias coronarias en niños con enfermedad de Kawasaki / Risk factors for coronary artery lesions in children with Kawasaki disease

Introducción. La enfermedad de Kawasaki (EK) es una vasculitis sistémica inespecífica que suele presentarse en los niños; la lesión de las arterias coronarias (LAC) es la complicación más grave.Objetivos. Nuestro objetivo fue investigar los factores de riesgo de LAC en niños con EK.Materiales y métodos. Se incluyó a niños con EK según los criterios diagnósticos, hospitalizados entre enero de 2014 y diciembre de 2017. Se realizaron análisis univariado y multivariado de regresión logística para investigar las relaciones entre LAC y género, edad, diagnóstico clínico, velocidad de sedimentación globular (VSG), recuento de trombocitos, concentración de hemoglobina, concentración de proteína C-reactiva, recuento de leucocitos, momento de inicio de la administración de inmunoglobulina intravenosa (IgIV) y duración de la fiebre.Resultados. Se dividió a los 982 niños con EK en un grupo con LAC (n = 104) y otro sin LAC (n = 878), según una ecocardiografía Doppler color. La tasa de incidencia de LAC fue del 10,6 % (104/982). En el análisis univariado, se observó una diferencia significativa entre ambos grupos en cuanto al género, la VSG, el recuento de trombocitos, el momento de inicio de la administración de IgIV y la duración de la fiebre (p < 0,05). Según el análisis multivariado de regresión logística, el sexo masculino, una VSG elevada y la administración tardía de IgIV fueron factores de riesgo independientes de EK complicada con LAC.Conclusiones. El sexo masculino, una VSG elevada y la administración tardía de IgIV fueron factores de riesgo independientes de EK complicada con LAC.

Introduction. Kawasaki disease (KD) is a non-specific systemic vasculitic disease that frequently occurs among children, and coronary artery lesion (CAL) is the most serious complication.Objectives. We aimed to study the risk factors for CAL in children with KD.Materials and methods. KD children in accordance with diagnostic criteria, who were hospitalized from January 2014 to December 2017, were selected as subjects. Univariate and multivariate logistic regression analyses were conducted to explore the relationships between CAL and gender, age, clinical diagnosis, erythrocyte sedimentation rate (ESR), platelet count, hemoglobin level, C reactive protein level, white blood cell count, initiation time of IVIG administration and duration of fever.Results. The enrolled 982 KD children were divided into a CAL group (n = 104) and an NCAL group (n = 878) according to cardiac color Doppler ultrasonography. The incidence rate of CAL was 10.6 % (104/982). Univariate analysis showed that the two groups had significantly different gender, ESR, platelet count, initiation time of IVIG administration and duration of fever (P < 0.05). Multivariate logistic regression analysis revealed that male gender, elevated ESR and delayed use of IVIG were independent risk factors for KD complicated with CAL.Conclusions:Male gender, increased ESR and delayed use of IVIG were independent risk factors for KD complicated with CA

Risk factors for coronary artery lesions in children with Kawasaki disease. / Factores de riesgo de lesión de las arterias coronarias en niños con enfermedad de Kawasaki.

Introduction: Kawasaki disease (KD) is a nonspecific systemic vasculitic disease that frequently occurs among children, and coronary artery lesion (CAL) is the most serious complication. Objectives: We aimed to study the risk factors for CAL in children with KD. Materials and methods: KD children in accordance with diagnostic criteria, who were hospitalized from January 2014 to December 2017, were selected as subjects. Univariate and multivariate logistic regression analyses were conducted to explore the relationships between CAL and gender, age, clinical diagnosis, erythrocyte sedimentation rate (ESR), platelet count, hemoglobin level, C reactive protein level, white blood cell count, initiation time of IVIG administration and duration of fever. Results: The enrolled 982 KD children were divided into a CAL group (n = 104) and an NCAL group (n = 878) according to cardiac color Doppler ultrasonography. The incidence rate of CAL was 10.6 % (104/982). Univariate analysis showed that the two groups had significantly different gender, ESR, platelet count, initiation time of IVIG administration and duration of fever (P < 0.05). Multivariate logistic regression analysis revealed that male gender, elevated ESR and delayed use of IVIG were independent risk factors for KD complicated with CAL. Conclusions: Male gender, increased ESR and delayed use of IVIG were independent risk factors for KD complicated with CAL.

Introducción. La enfermedad de Kawasaki (EK) es una vasculitis sistémica inespecífica que suele presentarse en los niños; la lesión de las arterias coronarias (LAC) es la complicación más grave. Objetivos. Nuestro objetivo fue investigar los factores de riesgo de LAC en niños con EK. Materiales y métodos. Se incluyó a niños con EK según los criterios diagnósticos, hospitalizados entre enero de 2014 y diciembre de 2017. Se realizaron análisis univariado y multivariado de regresión logística para investigar las relaciones entre LAC y género, edad, diagnóstico clínico, velocidad de sedimentación globular (VSG), recuento de trombocitos, concentración de hemoglobina, concentración de proteína C-reactiva, recuento de leucocitos, momento de inicio de la administración de inmunoglobulina intravenosa (IgIV) y duración de la fiebre. Resultados. Se dividió a los 982 niños con EK en un grupo con LAC (n = 104) y otro sin LAC (n = 878), según una ecocardiografía Doppler color. La tasa de incidencia de LAC fue del 10,6 % (104/982). En el análisis univariado, se observó una diferencia significativa entre ambos grupos en cuanto al género, la VSG, el recuento de trombocitos, el momento de inicio de la administración de IgIV y la duración de la fiebre (p < 0,05). Según el análisis multivariado de regresión logística, el sexo masculino, una VSG elevada y la administración tardía de IgIV fueron factores de riesgo independientes de EK complicada con LAC. Conclusiones. El sexo masculino, una VSG elevada y la administración tardía de IgIV fueron factores de riesgo independientes de EK complicada con LAC.

Resveratrol protects against asthma-induced airway inflammation and remodeling by inhibiting the HMGB1/TLR4/NF-κB pathway.

The aim of the present study was to explore the protective role of resveratrol (RES) in asthma-induced airway inflammation and remodeling, as well as its underlying mechanism. An asthma rat model was induced by ovalbumin (OVA) treatment. Rats were randomly assigned into sham, asthma, 10 µmol/l RES and 50 µmol/l RES groups. The amount of inflammatory cells in rat bronchoalveolar lavage fluid (BALF) was detected. Pathological lesions in lung tissues were accessed by hematoxylin and eosin (H&E), and Masson's trichrome staining. Levels of inflammatory factors in lung homogenate were detected via ELISA. The blood serum of asthmatic and healthy children was also collected for analysis. Reverse transcription-quantitative polymerase chain reaction was performed to detect high mobility group box 1 (HMGB1), Τoll-like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MyD88) and NF-κB expression in asthmatic and healthy children, as well as rats of the different groups. H&E staining demonstrated that multiple inflammatory cell infiltration into the rat airway epithelium of the asthma group occurred whilst the 50 µmol/l RES group displayed alleviated pathological lesions. Masson staining indicated that there was an increased airway collagen deposition area in the asthma and 10 µmol/l RES groups compared with the 50 µmol/l RES group. The number of inflammatory cells in BALF extracted from rats of the asthma and 10 µmol/l RES groups was higher compared with the 50 µmol/l RES group. Treatment with 50 µmol/l RES significantly decreased the thicknesses of the airway wall and smooth muscle. ELISA results illustrated that interleukin (IL)-1, IL-10 and tumor necrosis factor-α (TNF-α) levels were elevated, whereas IL-12 level was reduced in lung tissues of the asthma and 10 µmol/l RES groups whilst the 50 µmol/l RES group demonstrated the opposite trend. HMGB1, TLR4, MyD88 and NF-κB mRNA levels were remarkably elevated in rats of the asthma and 10 µmol/l RES groups compared with the 50 µmol/l RES group. Serum levels of IL-1, IL-10 and TNF-α were elevated, whereas IL-12 was reduced in asthmatic children compared with healthy children. The present results demonstrated that a large dose of RES alleviated asthma-induced airway inflammation and airway remodeling by inhibiting the release of inflammatory cytokines via the HMGB1/TLR4/NF-κB pathway.

Influence of pollutants on activity of aerosol cloud condensation nuclei (CCN) during pollution and post-rain periods in Guangzhou, southern China.

Atmospheric pollutions have an important impact on aerosol, condensation nuclei (CN) and cloud condensation nuclei (CCN) loadings near the ground through disturbing particle size, number, chemical composition and reactions, mixing state, hygroscopicity, and so on. Aerosols and CCN were measured in urban Guangzhou during pollution and post-rain periods to examine effects of particulate pollutants on aerosol CCN activity and compare their mechanisms between summer and winter. In contrast with different levels of pollutions, particle matter (PM2.5) and number (CN) and CCN almost showed an opposite trend to aerosol activity (CCN/CN). In summer, new particle formation (NPF) events triggered by photochemical reactions (e.g. O3) always occurred in no-pollution daytime, and increased significantly CN and CCN as a dominant contributor to secondary aerosols. Under pollution conditions, the gas-to-particle transition driven by photochemical reactions guided the formation and aging processes of particles in daytime, especially in changing soluble species, whereas atmospheric oxidation and heterogeneous reactions dominated at night. In winter, stagnant weather conditions, high pollutant levels and relatively high RH were in favor of particle growing and aging through enhancing secondary particle formation and heterogeneous reactions. The wet scavenging of precipitation reduced greatly CCN amount by scouring pre-existing particles in winter, and during post-rain period the photochemical reactions did not promote the burst of secondary particle formation in the absence of ozone, compared with summer. The results may provide insights into the relationship between aerosol moisture absorption and pollution that may be useful for improving air quality.

Comparison of aerosol and cloud condensation nuclei between wet and dry seasons in Guangzhou, southern China.

Cloud condensation nuclei (CCN), condensation nuclei (CN) and aerosol chemical composition were measured simultaneously at an urban site of Guangzhou from July to August 2015 and in January 2016, and the seasonal variations of aerosol activated fractions (NCCN/NCN) as well as their relevant influence factors were further studied accordingly. NCN is generally higher in winter (dry season), whereas NCCN and NCCN/NCN are mostly higher in summer (wet season) instead. In particular, NCCN and NCCN/NCN are much lower at smaller supersaturation levels (SS<0.2) in winter. In spite of similar diurnal variations for NCCN and NCN, NCCN/NCN indicates an opposite tendency, relatively lower at midday, dusk and before midnight. Other than the size of particles as well as their chemical composition, some other factors, such as mass, gas precursors, pollutant transportation, meteorological conditions, etc., also contribute to the variations of NCCN and NCCN/NCN. Particles from the local source or local-oceanic combination source cast influence on CN and CCN significantly, while the pollutants originating from and crossing over distant polluted areas contribute largely to CCN/CN. NCN and NCCN are relatively higher under pollution-free conditions in summertime and polluted conditions in wintertime, but NCCN/NCN is just the opposite. On various polluted conditions, aerosol CCN activities are greatly discrepant between summer and winter, especially during mist or heavy haze periods. The results imply that anthropogenic pollutants exert critical impacts on aerosol CCN activation.