Miracle-dz/UniFAR-FTUs huggingface dataset:
The functional role of CST1 and CCL26 in asthma development

Abstract Background Asthma is the most common chronic disease in children with an increasing prevalence. Its development is caused by genetic and environmental factors and allergic sensitization is a known trigger. Dog allergens affect up to 30% of all children and dog dander‐sensitized children show increased expression of cystatin‐1 (CST1) and eotaxin‐3 (CCL26) in nasal epithelium. The aim of our study was to investigate the functional mechanism of CST1 and CCL26 in the alveolar basal epithelial cell line A549. Methods A549 cells were transfected with individual overexpression vectors for CST1 and CCL26 and RNA sequencing was performed to examine the transcriptomics. edgeR was used to identify differentially expressed genes (= DEG, |log2FC | ≥ 2, FDR < 0.01). The protein expression levels of A549 cells overexpressing CST1 and CCL26 were analyzed using the Target 96 inflammation panel from OLINK (antibody‐mediated proximity extension–based assay; OLINK Proteomics). Differentially expressed proteins were considered with a |log2FC| ≥ 1, p < . 05. Results The overexpression of CST1 resulted in a total of 27 DEG (1 upregulated and 26 downregulated) and the overexpression of CCL26 in a total of 137 DEG (0 upregulated and 137 downregulated). The gene ontology enrichment analysis showed a significant downregulation of type I and III interferon signaling pathway genes as well as interferon‐stimulated genes. At the protein level, overexpression of CST1 induced a significantly increased expression of CCL3, whereas CCL26 overexpression led to increased expression of HGF, and a decrease of CXCL11, CCL20, CCL3 and CXCL10. Conclusion Our results indicate that an overexpression of CST1 and CCL26 cause a downregulation of interferon related genes and inflammatory proteins. It might cause a higher disease susceptibility, mainly for allergic asthma, as CCL26 is an agonist for CCR‐3‐carrying cells, such as eosinophils and Th2 lymphocytes, mostly active in allergic asthma.
Primary care quality for older adults: Practice-based quality measures derived from a RAND/UCLA appropriateness method study

We established consensus on practice-based metrics that characterize quality of care for older primary care patients and can be examined using secondary health administrative data. We conducted a two-round RAND/UCLA Appropriateness Method (RAM) study and recruited 10 Canadian clinicians and researchers with expertise relevant to the primary care of elderly patients. Informed by a literature review, the first RAM round evaluated the appropriateness and importance of candidate quality measures in an online questionnaire. Technical definitions were developed for each endorsed indicator to specify how the indicator could be operationalized using health administrative data. In a virtual synchronous meeting, the expert panel offered feedback on the technical specifications for the endorsed indicators. Panelists then completed a second (final) questionnaire to rate each indicator and corresponding technical definition on the same criteria (appropriateness and importance). We used statistical integration to combine technical expert panelists’ judgements and content analysis of open-ended survey responses. Our literature search and internal screening resulted in 61 practice-based quality indicators for rating. We developed technical definitions for indicators endorsed in the first questionnaire (n = 55). Following the virtual synchronous meeting and second questionnaire, we achieved consensus on 12 practice-based quality measures across four Priority Topics in Care of the Elderly. The endorsed indicators provide a framework to characterize practice- and population-level encounters of family physicians delivering care to older patients and will offer insights into the outcomes of their care provision. This study presented a case of soliciting expert feedback to develop measurable practice-based quality indicators that can be examined using administrative data to understand quality of care within population-based data holdings. Future work will refine and operationalize the technical definitions established through this process to examine primary care provision for older adults in a particular context (Ontario, Canada).
Gratitude and Religiosity in Psychiatric Inpatients with Depression

Background Gratitude and religiousness/spirituality are increasingly recognized resources that have potential influence on psychological states such as depression. However, only few studies have investigated this relationship in psychiatric patients. Objective The present study examined gratitude in psychiatric inpatients with depression, exploring its relevance, course, and interaction with psychopathological and religious measures. Both general and religious gratitude will be evaluated. Methods A total of 212 inpatients with depression completed a questionnaire both at the beginning and the end of treatment. Gratitude was measured with a general gratitude scale using the Gratitude Questionnaire and a religion-specific measure assessing gratitude to God as part of the Structure of Religiosity Test. The Beck Depression Inventory was used to evaluate depressive symptoms. General religiosity was assessed using the Centrality of Religiosity Scale. Results Scores on the general and religious gratitude measures were in the upper range of these scales at baseline and demonstrated a significant increase during the hospital stay. Negative associations were found between general gratitude and depressive symptoms both on admission and at discharge (r = −0.505 and r = −0.478, respectively). General as well as religious gratitude was associated with the centrality of religiosity (r = 0.384 and r = 0.546, respectively). Religiosity accounted for approximately 10% of the variance in general gratitude on admission. Conclusions Gratitude is highly prevalent in psychiatric patients with depression, and that may serve as a resource for these individuals. Both general and religious gratitude are associated with religiosity, which may also serve as a resource to these patients.
Temporal Dynamics, Discovery, and Emergence of Human-Transmissible RNA Viruses

Abstract Transmissibility, the ability to spread within host populations, is a prerequisite for a pathogen to have epidemic or pandemic potential. Here, we estimate the phylogenies of human infectivity and transmissibility using 1,408 genome sequences from 743 distinct RNA virus species/types in 59 genera. By repeating this analysis using data sets censored by virus discovery date, we explore how temporal changes in the known diversity of RNA viruses—especially recent increases in recognized nonhuman viruses—have altered these phylogenies. Over time, we find significant increases in the proportion of RNA virus genera estimated to have a nonhuman-infective ancestral state, in the fraction of distinct human virus lineages that are purely human-transmissible or strictly zoonotic (compared to mixed lineages), and in the number of human viruses with nearest relatives known not to infect humans. Our results are consistent with viruses that are capable of spreading in human populations commonly emerging from a nonhuman reservoir. This is more likely in lineages that already contain human-transmissible viruses but is rare in lineages that contain only strictly zoonotic viruses.
Analysis of the successfulness of wolverine (Gulo gulo) depredation control in Västerbotten County

During the last five years, permitted quota of wolverine to be removed by depredation control have not been filled in the County of Vasterbotten. Few hunting attempts have been successful. Because of this, issues regarding the depredation of reindeer may not be solved. The aim of this study was to evaluate the successfulness of hunting of wolverines for depredation control in Vasterbotten County. Results from this study show that interviewees viewed depredation control as a positive management tool, but that possibilities for hunting were rather limited. The critical factor for a successful outcome of wolverine hunting was to find fresh tracks. However, possibilities for finding tracks were limited by weather and snow conditions. All hunting methods used were looked upon as being effective if they were conducted when weather and snow conditions were suitable. Hunting with dogs worked well during fall when there was little snow. Hunting by helicopter and snowmobile were most preferred in January, which also was the month where most wolverines where shot. Five out of seven interviewees were positive towards implementing quota harvest of wolverine in the future, if the hunting would be executed by moose hunters during the regular hunting season.
Disynaptic Inhibitory Cerebellar Control Over Caudal Medial Accessory Olive

The olivocerebellar system, which is critical for sensorimotor performance and learning, functions through modules with feedback loops. The main feedback to the inferior olive comes from the cerebellar nuclei (CN), which are predominantly GABAergic and contralateral. However, for the subnucleus d of the caudomedial accessory olive (cdMAO), a crucial region for oculomotor and upper body movements, the source of GABAergic input has yet to be identified. Here, we demonstrate the existence of a disynaptic inhibitory projection from the medial CN (MCN) to the cdMAO via the superior colliculus (SC) by exploiting retrograde, anterograde, and transsynaptic viral tracing at the light microscopic level as well as anterograde classical and viral tracing combined with immunocytochemistry at the electron microscopic level. Retrograde tracing in Gad2-Cre mice reveals that the cdMAO receives GABAergic input from the contralateral SC. Anterograde transsynaptic tracing uncovered that the SC neurons receiving input from the contralateral MCN provide predominantly inhibitory projections to contralateral cdMAO, ipsilateral to the MCN. Following ultrastructural analysis of the monosynaptic projection about half of the SC terminals within the contralateral cdMAO are GABAergic. The disynaptic GABAergic projection from the MCN to the ipsilateral cdMAO mirrors that of the monosynaptic excitatory projection from the MCN to the contralateral cdMAO. Thus, while completing the map of inhibitory inputs to the olivary subnuclei, we established that the MCN inhibits the cdMAO via the contralateral SC, highlighting a potential push–pull mechanism in directional gaze control that appears unique in terms of laterality and polarity among olivocerebellar modules.
Heart rate variability is reduced in COVID‐19 survivors and associated with physical activity and fatigue

Abstract Reduced heart rate variability (HRV) and fatigue are common after COVID‐19 infection and both are potentially influenced by physical activity (PA). We compared resting HRV, PA from accelerometers and questionnaires, and self‐reported fatigue in 41 COVID‐19 survivors (~8 months postinfection, 38 ± 17 years) with 41 matched controls. Differences in HRV were observed on acceleration capacity (p = 0.041), deceleration capacity (p = 0.032), high‐frequency peak frequency (p = 0.019), absolute low‐frequency power (p = 0.042), relative very low‐frequency power (p = 0.012), SD2 (from Poincare plot; p = 0.047), and DFA2 (slope of long‐term detrended fluctuation analysis; p = 0.004). Fatigue was greater in COVID‐19 survivors (p < 0.001) with no differences in PA. Moderate‐vigorous physical activity (MVPA) (Standardized Beta = −0.427, p = 0.003) and steps per day (Standardized Beta = −0.402, p = 0.007) were associated with DFA2 in COVID‐19 survivors after controlling for age, sex, and body fat percentage. Fatigue was correlated to less MVPA (Spearman's rho = 0.342, p = 0.031) and fewer steps per day (rho = 0.329, p = 0.038) in COVID‐19 survivors, and was indirectly linked to HRV through these PA mediators (Estimate = −0.20; p = 0.040). We present a model showing the complex relations between HRV, PA, and fatigue that provides the foundation for strategies to improve outcomes and rehabilitation after COVID‐19 infection.
Tumor-draining lymph nodes: opportunities, challenges, and future directions in colorectal cancer immunotherapy

Tumor-draining lymph nodes (TDLNs) are potential immunotherapy targets that could expand the population of patients with colorectal cancer (CRC) who may benefit from immunotherapy. Currently, pathological detection of tumor cell infiltration limits the acquisition of immune information related to the resected lymph nodes. Understanding the immune function and metastatic risk of specific stages of lymph nodes can facilitate better discussions on the removal or preservation of lymph nodes, as well as the timing of immunotherapy. This review summarized the contribution of TDLNs to CRC responses to immune checkpoint blockade therapy, local immunotherapy, adoptive cell therapy, and cancer vaccines, and discussed the significance of these findings for the development of diagnostics based on TDLNs and the potential implications for guiding immunotherapy after a definitive diagnosis. Molecular pathology and immune spectrum diagnosis of TDLNs will promote significant advances in the selection of immunotherapy options and predicting treatment efficacy.
Antarctic climate and vegetation during the Neogene : a geochemical and modelling approach

During the mid- to late Neogene (20 - 2.5 million years ago), episodic retreat of the Antarctic Ice Sheet (AIS) coincided with periods of higher-than-present atmospheric CO2, indicating ice sheet sensitivity to climatic conditions similar to those projected for the coming decades. Understanding Antarctic climate and vegetation during such a period of AIS retreat is crucial for our fundamental understanding of high latitude environments in warmer-than-present climate scenarios. This thesis presents a detailed geochemical study of sediments and plant fossils from the terrestrial Sirius Group of Oliver Bluffs, Transantarctic Mountains, located at 85 °S today and during the Neogene. Biomarker analysis of the sediments show strong evidence for a warmer Antarctica, where summer temperatures reached 5 °C. These relatively favourable conditions sup- ported a low diversity mixed vegetation. In contrast to the macrofossil record, there is geochemical evidence for conifers, suggesting that Antarctic vegetation was strongly controlled by local environmental variability. The warmer conditions are associated with a dynamic carbon cycle, evidenced by anomalously high and variable atmospheric 13C and possibly linked to atmospheric CO2 levels. Precipitation isotopes are reconstructed from plant compound isotope analysis of the fossils, and indicate markedly different hydrological cycling. This result is supported by climate modelling experiments which suggest that Antarctic hydrological cycling is most strongly governed by the extent of the ice sheet rather than by greenhouse gas radiative forcing. This thesis presents a new approach to exploring Antarctic climate and vegetation and provides important novel information on this crucial region of the world.
Genome-wide analyses reveal the contribution of somatic variants to the immune landscape of multiple cancer types

It has been well established that cancer cells can evade immune surveillance by mutating themselves. Understanding genetic alterations in cancer cells that contribute to immune regulation could lead to better immunotherapy patient stratification and identification of novel immune-oncology (IO) targets. In this report, we describe our effort of genome-wide association analyses across 22 TCGA cancer types to explore the associations between genetic alterations in cancer cells and 74 immune traits. Results showed that the tumor microenvironment (TME) is shaped by different gene mutations in different cancer types. Out of the key genes that drive multiple immune traits, top hit KEAP1 in lung adenocarcinoma (LUAD) was selected for validation. It was found that KEAP1 mutations can explain more than 10% of the variance for multiple immune traits in LUAD. Using public scRNA-seq data, further analysis confirmed that KEAP1 mutations activate the NRF2 pathway and promote a suppressive TME. The activation of the NRF2 pathway is negatively correlated with lower T cell infiltration and higher T cell exhaustion. Meanwhile, several immune check point genes, such as CD274 (PD-L1), are highly expressed in NRF2-activated cancer cells. By integrating multiple RNA-seq data, a NRF2 gene signature was curated, which predicts anti-PD1 therapy response better than CD274 gene alone in a mixed cohort of different subtypes of non-small cell lung cancer (NSCLC) including LUAD, highlighting the important role of KEAP1-NRF2 axis in shaping the TME in NSCLC. Finally, a list of overexpressed ligands in NRF2 pathway activated cancer cells were identified and could potentially be targeted for TME remodeling in LUAD.
Assessment of postoperative circulating tumour DNA to predict early recurrence in patients with stage I–III right-sided colon cancer: prospective observational study

Abstract Background Right-sided colon cancer (RCC) differs in mutation profile and risk of recurrence compared to distal colon cancer. Circulating tumour DNA (ctDNA) present after surgery can identify patients with residual disease after curative surgery and predict risk of early recurrence. Methods This is a prospective observational biomarker trial with exploration of ctDNA in 50 non-metastatic RCC patients for which oncological right-sided colectomy was performed. Blood samples were collected preoperatively, within 1 month post surgery, 3 months (not mandatory), 6 months and every 6 months thereafter. Plasma cell free DNA and/or tumour was investigated for cancer-related mutations by the next-generation sequencing (NGS) panel AVENIO surveillance specifically designed for ctDNA analysis. Detected mutations were quantified using digital droplet PCR (ddPCR) for follow-up. Recurrence-free survival was explored. Results 50 patients were recruited. Somatic cancer-related mutations were detected in 47/50 patients. ddPCR validated results from NGS for 27/34 (plasma) and 72/72 samples (tumour). Preoperative ctDNA was detected in 31/47 of the stage I/III patients and the majority of ctDNA positive patients showed reduction of ctDNA after surgery (27/31). ctDNA-positive patients at first postoperative sample had high recurrence risk compared to patients without measurable ctDNA (adjusted hazard ratio: 172.91; 95% c.i.: 8.70 to 3437.24; P: 0.001). Conclusion ctDNA was detectable in most patients with non-metastatic RCC before surgery. Positive postoperative ctDNA was strongly associated with early recurrence. Detectable postoperative ctDNA is a prognostic factor with high (100%) positive predictive value for recurrence in this cohort of non-metastatic RCC. Clinical Trial Registration ClinicalTrials.gov ID: NCT03776591
Efficacy of non-pharmacological interventions for primary dysmenorrhoea: a systematic review and Bayesian network meta-analysis.

OBJECTIVES To assess the relative benefits of various non-pharmacological interventions on treating primary dysmenorrhoea within a network meta-analysis. STUDY DESIGN Systematic review and Bayesian network meta-analysis. INCLUSION CRITERIA Randomised controlled trial involving patient with primary dysmenorrhoea and received non-pharmacological interventions. DATA SOURCES Four databases (Medline, Embase, Cochrane Library and Web of Science) were searched from inception to October first, 2022. RISK-OF-BIAS ROB ASSESSMENT RoB 2.0 assessment tools was used to assess the risk of bias in the included studies. SYNTHESIS OF RESULTS Conventional meta-analysis was conducted by pairwise comparison between non-pharmacological therapy and control treatment. The Bayesian network meta-analysis was conducted by the Aggregate Data Drug Information System Software based on the consistency or inconsistency model, and rank probability was used to indicate the priority of non-pharmacological therapy. RESULTS 33 studies involving eight non-pharmacological interventions were included. With regard to conventional meta-analysis, we selected Visual Analogue Scale (VAS) as primary outcome to evaluate the pain intensity. The result showed that eight interventions (Exercise, Herb, Acupuncture, Aromatherapy, Transcutaneous Electrical Nerve Stimulation, Topical heat, Acupressure, Yoga) displayed positive effect on reduction of menstrual pain compared with placebo or no treatment. A Bayesian network meta-analysis revealed that exercise -3.20 (95% CI -4.01 to -2.34), acupuncture -2.90 (95% CI -3.97 to -2.85) and topical heat -2.97 (95% CI -4.66 to -1.29) probably resulted in a reduction in pain intensity (VAS) . CONCLUSIONS Non-pharmacological interventions may result in a reduction or slight reduction in pain intensity compared with no treatment or placebo. Specifically, exercise and acupuncture are considered as potentially effective non-pharmacological treatments in short-term treatment. Indeed, larger and better methodological quality research is needed. TRIAL REGISTRATION NUMBER CRD42022351021.
Epidemiology and Clinical Characteristics of Human Metapneumovirus Infections in Hospitalized Children in Two Consecutive Postpandemic Years

We assessed human metapneumovirus infections in children hospitalized between 2011 and 2023 and compared the strongest pre- and postpandemic seasons. After the COVID-19 pandemic, we observed offseason cases and loss of the alternating pattern of the human metapneumovirus season magnitude. Incidence rate ratio of 0- to 11-month-old versus 12- to 23-month-old children was 2.1 (95% CI: 1.0–4.8) before and 1.3 (95% CI: 0.6–2.9) after the pandemic.
Exploring human rare disease variants from a multidimensional perspective illuminates receptor – G protein coupling diversity

G protein-coupled receptors (GPCRs) are transmembrane proteins capable of detecting signals as diverse as odours, neurotransmitters, and hormones. Upon activation, receptor signalling converges onto four Gα protein subtypes to regulate intracellular responses. Therefore, variation in a single Gα protein gene can potentially impact the function of numerous receptors. In this work, we have performed a multidimensional study of rare disease mutations in Gαs, a prototypical Gα protein. By integrating data from 3D structures, GPCR / G protein functional pairings, transcriptomics, biophysics, and molecular dynamics with systems pharmacology modelling, our results reveal why mutations impairing receptor / Gαs coupling result in highly specific context-based signalling defects. Furthermore, we show that mutations leading to the same rare disease can alter different signal transduction steps, highlighting the importance of patient-specific treatment strategies. By closely dissecting G protein coupling, our study provides a blueprint to interrogate GPCR pathway signalling diversity in different (patho)physiological contexts.