Miracle-dz/UniFAR-FTUs huggingface dataset:
Rapamycin Dampens Inflammatory Properties of Bone Marrow ILC2s in IL-33-Induced Eosinophilic Airway Inflammation

The alarmin cytokine interleukin (IL)-33 plays an important proinflammatory role in type 2 immunity and can act on type 2 innate lymphoid cells (ILC2s) and type 2 T helper (TH2) cells in eosinophilic inflammation and asthma. The mechanistic target of rapamycin (mTOR) signaling pathway drives immune responses in several inflammatory diseases, but its role in regulating bone marrow responses to IL-33 is unclear. The aim of this study was to determine the role of the mTORC1 signaling pathway in IL-33-induced bone marrow ILC2 responses and its impact on IL-33-induced eosinophilia. Wild-type mice were intranasally exposed to IL-33 only or in combination with the mTORC1 inhibitor, rapamycin, intraperitoneally. Four groups were included in the study: saline-treated (PBS)+PBS, rapamycin+PBS, PBS+IL-33 and rapamycin+IL-33. Bronchoalveolar lavage fluid (BALF), serum and bone marrow cells were collected and analyzed by differential cell count, enzyme-linked immunosorbent assay and flow cytometry. IL-33 induced phosphorylation of the mTORC1 protein rpS6 in bone marrow ILC2s both ex vivo and in vivo. The observed mTOR signal was reduced by rapamycin treatment, indicating the sensitivity of bone marrow ILC2s to mTORC1 inhibition. IL-5 production by ILC2s was reduced in cultures treated with rapamycin before stimulation with IL-33 compared to IL-33 only. Bone marrow and airway eosinophils were reduced in mice given rapamycin before IL-33-exposure compared to mice given IL-33 only. Bone marrow ILC2s responded to IL-33 in vivo with increased mTORC1 activity and rapamycin treatment successfully decreased IL-33-induced eosinophilic inflammation, possibly by inhibition of IL-5-producing bone marrow ILC2s. These findings highlight the importance of investigating specific cells and proinflammatory pathways as potential drivers of inflammatory diseases, including asthma.
Behavioral and Neural Activity-Dependent Recanalization of Plugged Capillaries in the Brain of Adult and Aged Mice

The capillaries of the brain, owing to their small diameter and low perfusion pressure, are vulnerable to interruptions in blood flow. These tiny occlusions can have outsized consequences on angioarchitecture and brain function; especially when exacerbated by disease states or accumulate with aging. A distinctive feature of the brain’s microvasculature is the ability for active neurons to recruit local blood flow. The coupling of neural activity to blood flow could play an important role in recanalizing obstructed capillaries. To investigate this idea, we experimentally induced capillary obstructions in mice by injecting fluorescent microspheres and then manipulated neural activity levels though behavioral or pharmacologic approaches. We show that engaging adult and aged mice with 12 h exposure to an enriched environment (group housing, novel objects, exercise wheels) was sufficient to significantly reduce the density of obstructed capillaries throughout the forebrain. In order to more directly manipulate neural activity, we pharmacologically suppressed or increased neuronal activity in the somatosensory cortex. When we suppressed cortical activity, recanalization was impaired given the density of obstructed capillaries was significantly increased. Conversely, increasing cortical activity improved capillary recanalization. Since systemic cardiovascular factors (changes in heart rate, blood pressure) could explain these effects on recanalization, we demonstrate that unilateral manipulations of neural activity through whisker trimming or injection of muscimol, still had significant and hemisphere specific effects on recanalization, even in mice exposed to enrichment where cardiovascular effects would be evident in both hemispheres. In summary, our studies reveal that neural activity bi-directionally regulates the recanalization of obstructed capillaries. Further, we show that stimulating brain activity through behavioral engagement (i.e., environmental enrichment) can promote vascular health throughout the lifespan.
Honey Bee Genetic Stock Determines Deformed Wing Virus Symptom Severity but not Viral Load or Dissemination Following Pupal Exposure

Honey bees exposed to Varroa mites incur substantial physical damage in addition to potential exposure to vectored viruses such as Deformed wing virus (DWV) that exists as three master variants (DWV-A, DWV-B, and DWV-C) and recombinants. Although mite-resistant bees have been primarily bred to mitigate the impacts of Varroa mites, mite resistance may be associated with increased tolerance or resistance to the vectored viruses. The goal of our study is to determine if five honey bee stocks (Carniolan, Italian, Pol-Line, Russian, and Saskatraz) differ in their resistance or tolerance to DWV based on prior breeding for mite resistance. We injected white-eyed pupae with a sublethal dose (105) of DWV or exposed them to mites and then evaluated DWV levels and dissemination and morphological symptoms upon adult emergence. While we found no evidence of DWV resistance across stocks (i.e., similar rates of viral replication and dissemination), we observed that some stocks exhibited reduced symptom severity suggestive of differential tolerance. However, DWV tolerance was not consistent across mite-resistant stocks as Russian bees were most tolerant, while Pol-Line exhibited the most severe symptoms. DWV variants A and B exhibited differential dissemination patterns that interacted significantly with the treatment group but not bee stock. Furthermore, elevated DWV-B levels reduced adult emergence time, while both DWV variants were associated with symptom likelihood and severity. These data indicate that the genetic differences underlying bee resistance to Varroa mites are not necessarily correlated with DWV tolerance and may interact differentially with DWV variants, highlighting the need for further work on mechanisms of tolerance and bee stock–specific physiological interactions with pathogen variants.
Gender Disparity and the Association Between Socioeconomic Status, Mental Health, and the Need for Long-Term Services and Support Among the Older Koreans

Background Population aging—the inevitable increase in the percentage of older adults—is occurring all around the world as the fertility rate declines and life expectancy rises. This study examined the relationship between socioeconomic status (SES), mental health, and the need for long-term services and support (LTSS) among Korean older adults. It also aimed to provide evidence-based information for South Korea's long-term support services and programs. Methods This study used the data on older adults aged over 60 years from the 2018 Korean Longitudinal Study of Aging (KLoSA). Ultimately, 5,527 older adults were included in the database (42.6% men, 57.4% women). To clarify the association between SES, mental health, and the need for LTSS among older Korean men and women, chi-squared test, t-test, and structural equation modeling (SEM) were performed. Results The SEM analysis showed that a significant, negative association was observed between SES and the need for LTSS among these older adults—the higher SES groups would generally have less need for LTSS. Mental health had a strong, negative impact on the need for LTSS—better mental health status of the older individuals would indicate a lower need for LTSS, and the effect was stronger among older men. Meanwhile, the positive relationship between SES and mental health was verified—the higher the SES of these older adults the better their mental health. Conclusions Gender- and social class-sensitive impacts of mental health on the need for LTSS were observed in this study. These findings could provide an evidence-based reference for interventions targeting different genders and social classes in Korea's long-term care system, such as the enhancement of social welfare and mental health status of the older adults.
Contemporary Trends in Global Mortality of Sepsis Among Young Infants Less Than 90 Days: A Systematic Review and Meta-Analysis

Objective Current knowledge on the global burden of infant sepsis is limited to population-level data. We aimed to summarize global case fatality rates (CFRs) of young infants with sepsis, stratified by gross national income (GNI) status and patient-level risk factors. Methods We performed a systematic review and meta-analysis on CFRs among young infants < 90 days with sepsis. We searched PubMed, Cochrane Central, Embase, and Web of Science for studies published between January 2010 and September 2019. We obtained pooled CFRs estimates using the random effects model. We performed a univariate analysis at patient-level and a meta-regression to study the associations of gestational age, birth weight, onset of sepsis, GNI, age group and culture-proven sepsis with CFRs. Results The search yielded 6314 publications, of which 240 studies (N = 437,796 patients) from 77 countries were included. Of 240 studies, 99 were conducted in high-income countries, 44 in upper-middle-income countries, 82 in lower-middle-income countries, 6 in low-income countries and 9 in multiple income-level countries. Overall pooled CFR was 18% (95% CI, 17–19%). The CFR was highest for low-income countries [25% (95% CI, 7–43%)], followed by lower-middle [25% (95% CI, 7–43%)], upper-middle [21% (95% CI, 18–24%)] and lowest for high-income countries [12% (95% CI, 11–13%)]. Factors associated with high CFRs included prematurity, low birth weight, age less than 28 days, early onset sepsis, hospital acquired infections and sepsis in middle- and low-income countries. Study setting in middle-income countries was an independent predictor of high CFRs. We found a widening disparity in CFRs between countries of different GNI over time. Conclusion Young infant sepsis remains a major global health challenge. The widening disparity in young infant sepsis CFRs between GNI groups underscore the need to channel greater resources especially to the lower income regions. Systematic Review Registration [www.crd. york.ac. uk/prospero], identifier [CRD42020164321].
The Maternal Donor of Chrysanthemum Cultivars Revealed by Comparative Analysis of the Chloroplast Genome

Chrysanthemum (Chrysanthemum morifolium Ramat) is an important floricultural crop and medicinal herb. Modern chrysanthemum cultivars have complex genetic backgrounds because of multiple cycles of hybridization, polyploidization, and prolonged cultivation. Understanding the genetic background and hybrid origin of modern chrysanthemum cultivars can provide pivotal information for chrysanthemum genetic improvement and breeding. By now, the origin of cultivated chrysanthemums remains unclear. In this study, 36 common chrysanthemum cultivars from across the world and multiple wild relatives were studied to identify the maternal donor of modern chrysanthemum. Chloroplast (cp) genomes of chrysanthemum cultivars were assembled and compared with those of the wild relatives. The structure of cp genomes was highly conserved among cultivars and wild relatives. Phylogenetic analyses based on the assembled cp genomes showed that all chrysanthemum cultivars grouped together and shared 64 substitutions that were distinct from those of their wild relatives. These results indicated that a diverged lineage of the genus Chrysanthemum, which was most likely an extinct or un-sampled species/population, provided a maternal source for modern cultivars. These findings provide important insights into the origin of chrysanthemum cultivars, and a source of valuable genetic markers for chrysanthemum breeding programs.
Novel Stilbene-Nitroxyl Hybrid Compounds Display Discrete Modulation of Amyloid Beta Toxicity and Structure

Several neurodegenerative diseases are driven by misfolded proteins that assemble into soluble aggregates. These “toxic oligomers” have been associated with a plethora of cellular dysfunction and dysregulation, however the structural features underlying their toxicity are poorly understood. A major impediment to answering this question relates to the heterogeneous nature of the oligomers, both in terms of structural disorder and oligomer size. This not only complicates elucidating the molecular etiology of these disorders, but also the druggability of these targets as well. We have synthesized a class of bifunctional stilbenes to modulate both the conformational toxicity within amyloid beta oligomers (AβO) and the oxidative stress elicited by AβO. Using a neuronal culture model, we demonstrate this bifunctional approach has the potential to counter the molecular pathogenesis of Alzheimer’s disease in a powerful, synergistic manner. Examination of AβO structure by various biophysical tools shows that each stilbene candidate uniquely alters AβO conformation and toxicity, providing insight towards the future development of structural correctors for AβO. Correlations of AβO structural modulation and bioactivity displayed by each provides insights for future testing in vivo. The multi-target activity of these hybrid molecules represents a highly advantageous feature for disease modification in Alzheimer’s, which displays a complex, multifactorial etiology. Importantly, these novel small molecules intervene with intraneuronal AβO, a necessary feature to counter the cycle of dysregulation, oxidative stress and inflammation triggered during the earliest stages of disease progression.
Positive Effects of the Caregiver Skill Training Program on Children With Developmental Disabilities: Experiences From Serbia

Background Intervention programs for children with developmental disabilities increasingly target caregiver training to implement effective strategies for child development. Research conducted in different countries shows that the Caregiver Skills Training Program (CST) developed by the World Health Organization and Autism Speaks could also be a recommended intervention. Methods The pre-pilot phase included seven, and the pilot phase included 29 families of children with developmental disabilities trained to implement the intervention program. The caregivers were asked to complete the Autism Treatment Evaluation Checklist at the beginning and at the end of the program. Results In the pre-pilot phase, the Wilcoxon signed-rank test determined a statistically significant improvement in Speech, Language and Communication (z = −2.99, p < 0.05) and Health/Physical/Behavior (z = −2.375, p < 0.05) after caregiver participation in the training program. In the pilot phase, the paired t-test also determined a statistically significant improvement in Speech, Language and Communication between the first (M = 24.52, SD = 5.57) and the second testing (M = 25.66, SD = 6.11), t(28) = −2.29, p < 0.05, as well as a significant improvement between the first (M = 36.62; SD = 7.15) and the second testing (M = 35.38; SD = 5.91), t(28) = 2.11, p < 0.05 in Health/Physical/Behavior. Eta squared values (0.16 and 0.14) indicate that the intervention effect was significant. No differences were determined in Sociability and Sensory/Cognitive Awareness between the first and the second testing. Conclusion The initial results of the Caregiver Skills Training Program are encouraging. For this program to be recommended as an evidence-based intervention, further research should be conducted on larger samples, controlling possible intervening variables.
Does Reorganization of Clinicopathological Information Improve Prognostic Stratification and Prediction of Chemoradiosensitivity in Sinonasal Carcinomas? A Retrospective Study on 145 Patients

Background The classification of sinonasal carcinomas (SNCs) is a conundrum. Consequently, prognosis and prediction of response to non-surgical treatment are often unreliable. The availability of prognostic and predictive measures is an unmet need, and the first logical source of information to be investigated is represented by the clinicopathological features of the disease. The hypothesis of the study was that clinicopathological information on SNC could be exploited to better predict prognosis and chemoradiosensitivity. Methods All patients affected by SNC who received curative treatment, including surgery, at the Unit of Otorhinolaryngology—Head and Neck Surgery of the University of Brescia between October 1998 and February 2019 were included in the analysis. The institutional series was reviewed and a survival analysis was performed. Machine learning and multivariable statistical methods were employed to develop, analyze, and test 3 experimental classifications (classification #1, based on cytomorphological, histomorphological, and differentiation information; classification #2, based on differentiation information; and classification #3, based on locoregional extension) of SNC, based on the inherent clinicopathological information. The association of experimental classifications with prognosis and chemoradiosensitivity was tested. Results The study included 145 patients. From a prognostic standpoint, the machine learning-generated classification of SNC provided better prediction than the current World Health Organization classification. However, the prediction of the chemoradiosensitivity of SNC was not achievable. Conclusions Reorganization of clinicopathological information, with special reference to those related to tumor differentiation, can improve the reliability of prognosis of SNC. Prediction of chemoradiosensitivity remains an unmet need and further research is required.
A New Online Dynamic Nomogram: Construction and Validation of an Assistant Decision-Making Model for Laryngeal Squamous Cell Carcinoma

Background Laryngeal squamous cell carcinoma (LSCC) is the most common type of head and neck squamous cell carcinoma. However, there are currently no reliable biomarkers for the diagnosis and prognosis of LSCC. Thus, this study aimed to identify the independent risk factors and develop and validate a new dynamic web-based nomogram that can predict auxiliary laryngeal carcinogenesis. Methods Data on the medical history of 221 patients who were recently diagnosed with LSCC and 359 who were recently diagnosed with benign laryngeal lesions (BLLs) at the First Affiliated Hospital of Anhui Medical University were retrospectively reviewed. Using the bootstrap method, 580 patients were divided in a 7:3 ratio into a training cohort (LSCC, 158 patients; BLL, 250 patients) and an internal validation cohort (LSCC, 63 patients; BLL, 109 patients). In addition, a retrospective analysis of 31 patients with LSCC and 54 patients with BLL from Fuyang Hospital affiliated with Anhui Medical University was performed as an external validation cohort. In the training cohort, the relevant indices were initially screened using univariate analysis. Then, least absolute shrinkage and selection operator logistic analysis was used to evaluate the significant potential independent risk factors (P<0.05); a dynamic online diagnostic nomogram, whose discrimination was evaluated using the area under the ROC curve (AUC), was constructed, while the consistency was evaluated using calibration plots. Its clinical application was evaluated by performing a decision curve analysis (DCA) and validated by internal validation of the training set and external validation of the validation set. Results Five independent risk factors, sex (odds ratio [OR]: 6.779, P<0.001), age (OR: 9.257, P<0.001), smoking (OR: 2.321, P=0.005), red blood cell width distribution (OR: 2.698, P=0.001), albumin (OR: 0.487, P=0.012), were screened from the results of the multivariate logistic analysis of the training cohort and included in the LSCC diagnostic nomogram. The nomogram predicted LSCC with AUC values of 0.894 in the training cohort, 0.907 in the internal testing cohort, and 0.966 in the external validation cohort. The calibration curve also proved that the nomogram predicted outcomes were close to the ideal curve, the predicted outcomes were consistent with the real outcomes, and the DCA curve showed that all patients could benefit. This finding was also confirmed in the validation cohort. Conclusion An online nomogram for LSCC was constructed with good predictive performance, which can be used as a practical approach for the personalized early screening and auxiliary diagnosis of the potential risk factors and assist physicians in making a personalized diagnosis and treatment for patients.
Development and Verification of a Prognostic Ferroptosis-Related Gene Model in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is the subtype with the worst prognosis of breast cancer. Ferroptosis, a novel iron-dependent programmed cell death, has an increasingly important role in tumorigenesis and development. However, there is still a lack of research on the relationship between ferroptosis-related genes and the prognosis of TNBC. In this study, we obtained the gene expression profile of TNBC patients and matched clinical data from The Cancer Genome Atlas (TCGA) database. Univariate Cox analysis was used to screen out ferroptosis-related genes associated with TNBC prognosis. Then, the least absolute shrinkage and selection operator (LASSO) regression analysis was employed to establish a prognostic prediction model. A 15-ferroptosis-related gene prognostic prediction model was developed, which classified patients into low-risk (LR) or high-risk (HR) groups. Kaplan-Meier analysis results showed that the prognosis of the LR group was better. The receiver operating characteristic (ROC) curve also confirmed the satisfactory predictive ability of this model. Evaluation of the immune microenvironment of TNBC patients in the HR and LR group suggested these 15 ferroptosis-related genes might affect the prognosis of TNBC by regulating the tumor microenvironment. Our prognostic model can provide a theoretical basis for accurate prognosis prediction of TNBC in clinical practice.
Comparison of the Gut Microbiota in Healthy Infants With Different Delivery Modes and Feeding Types: A Cohort Study

To compare the gut microbiota of healthy infants based on specific interactions of delivery modes and feeding types, we recruited 62 healthy babies who were followed up for 2 years from our previous cohort study of 91 infants (the rest were lost to follow-up). They were exclusively fed breast milk or specific formulas for more than 4 months after birth. The fecal bacterial composition was tested at 40 days, 3 months, and 6 months of age. Solid foods were introduced from 4 to 6 months of age and thus did not affect the microbiota before 4 months of age. According to the different delivery modes (i.e., vaginal delivery, VD, or cesarean section delivery, CS) and feeding types (i.e., breast-fed, br, or formula-fed, fo), the infants were assigned to four different groups, namely, the VD-br, VD-fo, CS-br, and CS-fo groups. We found that at 40 days of age, the α diversity (reported as the Shannon index) was lower in the br infants than in the fo infants. At 3 months of age, the α diversity was significantly lower in the CS-br group, although significant differences were not observed after solid food introduction. Bifidobacterium represented the most predominant genus in all groups at all time points, followed by Enterobacteriaceae. At 40 days of age, the abundance of Bifidobacterium was much higher in the CS-br group than in the CS-fo group but did not differ between the VD-br and VD-fo groups. The differences in Bifidobacterium disappeared at 3 and 6 months of age among the different groups. At 40 days of age, the abundance of Streptococcus and Enterococcus was much lower in the br infants than in the CS-fo group. At 3 months of age, Enterococcus was significantly lower in the CS-br group than in the fo infants, although for infants delivered by VD, the difference between feeding types was not significant. The specific interaction of delivery modes and feeding types has a large impact on the infants' gut microbiota. Breastfeeding and VD may decrease the potential adverse effects of formula feeding or CS delivery on gut microbiota, thus leading to a more stable and beneficial gut environment for infants.