L-Asparaginase (L-Asp) is an important therapeutic for childhood acute lymphoblastic leukemia (ALL). Asparaginase-associated pancreatitis (AAP) is a severe complication of L-Asp related to the dosage. We investigated the incidence of, and risk factors for, AAP in pediatric patients with ALL.

From January 2002 to December 2018, pediatric patients with ALL treated at National Taiwan University Hospital were enrolled in this study. The diagnosis of AAP was based on the criteria of the Ponte di Legno Toxicity Working Group.

Of the 353 patients enrolled in this study, 14 (4.0%) developed AAP. The incidence of AAP in ALL patients was significantly higher after treatment with the 2013 protocol compared with the 2002 protocol of the Taiwan Pediatric Oncology Group (9.5% vs. 1.3%). Multivariate analysis showed that a high peak L-Asp dose intensity (>45,000 U/m

/month) and older age at diagnosis (>6.8 years) were independently predictive of AAP development.

The incidence of acute pancreatitis in childhoojor risk factor of asparaginase-associated pancreatitis. This article demonstrated that the incidence of pancreatitis correlates with the dose-intensity of L-asparaginase, but not the accumulated dosage. Identification of patient group with high risk of pancreatitis could lead to early diagnosis and reduce the complication. This finding could aid in developing further new protocol or therapeutic strategy design to reduce treatment-related complications and improve clinical outcomes of childhood acute lymphoblastic leukemia.

Caffeine is widely used in preterm infants for apnea control. It has no effect on sleep in the only existing polysomnographic study including ten preterm infants Behavioral and polygraphic studies have conflicting results.

We studied 21 late-preterm infants at a median gestational age of 36 weeks. Polysomnography was performed twice, at baseline on day 1 and on the day after the onset of caffeine treatment (20 mg/kg loading and 5 mg/kg morning maintenance dose).

Caffeine acted short term as a breathing stimulant with reduction of apneas, improved baseline SpO

(p < 0.001), and decreased 95 percentile of end-tidal carbon dioxide level (p < 0.01). It also increased arousal frequency to SpO

desaturations of more than 5% (p < 0.001). Caffeine did not affect sleep stage distribution, sleep efficiency, frequency of sleep stage transitions, appearance of REM periods, or the high number of spontaneous arousals. The median spontaneous arousal count was 18 per hour at baseline, and 16 per hour during been investigated with only one full polysomnographic study including ten preterm infants. The study showed no effect. The current study shows that caffeine acts short term as a respiratory stimulant and increases arousal frequency to hypoxia. Although a potent central nervous system (CNS) stimulant in adults, caffeine does not seem to have similar acute CNS effect in late-preterm infants. The onset of caffeine treatment has no short-term effect on sleep stage distribution, sleep efficiency, frequency of sleep stage transitions, appearance of REM periods, or the high number of spontaneous arousals.

Coronavirus disease 2019 (COVID-19) is a pandemic that has and will continue to affect many pregnant women. Knowledge regarding the risk of vertical transmission is limited. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) real-time reverse transcriptase-polymerase chain reaction (RT-PCR) of nasopharyngeal swabs typically have been used to confirm the diagnosis among infants, but whether the virus can be detected in other biological specimens, and therefore potentially transmitted in other ways, is unknown. Positive SARS-CoV-2 RT-PCR has been reported from feces and urine from adult patients. We hypothesize that the presence of SARS-CoV-2 in infant urine and fecal samples after prenatal COVID-19 exposure is low.

We examined the presence of SARS-CoV-2 RNA using RT-PCR in urine and fecal samples among 42 infants born to SARS-CoV-2-infected mothers during different stages of pregnancy.

A urine sample was collected from 39 of 42 infants and fecal samples from all 42 infants shortly after birth. Although the majority of the women had the symptomatic disease (85.6%), we were unable to detect the presence of SARS-CoV-2 virus from any infant urine or fecal samples.

SARS-CoV-2 was not detected in infant urine or feces after maternal infection during pregnancy, providing further evidence for low rates of perinatal transmission.

SARS-CoV-2 was not detected in the urine or feces of infants of mothers with COVID-19 during various time points in pregnancy. This study provides further evidence for low rates of perinatal transmission of SARS-CoV-2. Results help to provide guidance on perinatal care practices for infants exposed to COVID-19 in utero.

SARS-CoV-2 was not detected in the urine or feces of infants of mothers with COVID-19 during various time points in pregnancy. This study provides further evidence for low rates of perinatal transmission of SARS-CoV-2. Results help to provide guidance on perinatal care practices for infants exposed to COVID-19 in utero.

Heart rate (HR) is a biomarker used to measure physiological function, health status and cardiovascular autonomic function. The purpose of this study was to determine sex- and age-specific reference values for cardiac autonomic function at rest, during maximal exercise and the recovery phase in prepubertal children.

Five hundred and twelve healthy children 7-11 years of age performed a Léger test. A heart RR-interval monitor recorded the heart data and a specific software analysed the cardiac autonomic response through HR and HR variability (HRV). It analysed HR before the test (resting HR, RHR), during the test (HR

) and HR recovery (HRR) in the first minute (HRR1) and the fifth minute (HRR5). The values are mean ± SD.

Collectively, 91.2% of girls and 92.3% of boys were within the recommended ranges regarding RHR. The average HR

was 199 ± 10.83 b.p.m. and 96.8% of girls and 95.3% of boys were within the minimum threshold value recommended (180 b.p.m.). Boys showed lower values of RHR than girls (p &rrelation with body mass index and cardiometabolic risk.In addition to its classical role in apoptosis, accumulating evidence suggests that caspase-2 has non-apoptotic functions, including regulation of cell division. Loss of caspase-2 is known to increase proliferation rates but how caspase-2 is regulating this process is currently unclear. We show that caspase-2 is activated in dividing cells in G1-phase of the cell cycle. In the absence of caspase-2, cells exhibit numerous S-phase defects including delayed exit from S-phase, defects in repair of chromosomal aberrations during S-phase, and increased DNA damage following S-phase arrest. In addition, caspase-2-deficient cells have a higher frequency of stalled replication forks, decreased DNA fiber length, and impeded progression of DNA replication tracts. This indicates that caspase-2 protects from replication stress and promotes replication fork protection to maintain genomic stability. These functions are independent of the pro-apoptotic function of caspase-2 because blocking caspase-2-induced cell death had no effect on cell division, DNA damage-induced cell cycle arrest, or DNA damage. Thus, our data supports a model where caspase-2 regulates cell cycle and DNA repair events to protect from the accumulation of DNA damage independently of its pro-apoptotic function.Epidermal growth factor receptor (EGFR) has critical roles in epithelial cell physiology. Over-expression and over-activation of EGFR have been implicated in diverse cancers, including triple-negative breast cancers (TNBCs), prompting anti-EGFR therapies. Therefore, developing potent therapies and addressing the inevitable drug resistance mechanisms necessitates deciphering of EGFR related networks. Here, we describe Sorting Nexin 3 (SNX3), a member of the recycling retromer complex, as a critical player in the epidermal growth factor (EGF) stimulated EGFR network in TNBCs. We show that SNX3 is an immediate and sustained target of EGF stimulation initially at the protein level and later at the transcriptional level, causing increased SNX3 abundance. Using a proximity labeling approach, we observed increased interaction of SNX3 and EGFR upon EGF stimulation. We also detected colocalization of SNX3 with early endosomes and endocytosed EGF. Moreover, we show that EGFR protein levels are sensitive to SNX3 loss. Transient RNAi models of SNX3 downregulation have a temporary reduction in EGFR levels. In contrast, long-term silencing forces cells to recover and overexpress EGFR mRNA and protein, resulting in increased proliferation, colony formation, migration, invasion in TNBC cells, and increased tumor growth and metastasis in syngeneic models. Consistent with these results, low SNX3 and high EGFR mRNA levels correlate with poor relapse-free survival in breast cancer patients. Overall, our results suggest that SNX3 is a critical player in the EGFR network in TNBCs with implications for other cancers dependent on EGFR activity.Targeting the KRAS pathway is a promising but challenging approach for colorectal cancer therapy. Despite showing potent efficacy in BRAF-mutated melanoma, MEK inhibitors appeared to be tolerated by colorectal cancer cells due to their intrinsic compensatory signaling. Here, we performed genome-wide CRISPR/Cas9 screening in the presence of MEK inhibitor to identify genes that are synthetically lethal with MEK inhibition in CRC models harboring KRAS mutations. Several genes were identified as potential functional drivers, which were significantly enriched in the GRB7-mediated RTK pathway. Loss-of-function and gain-of-function assays validated that GRB7 potently rendered CRC cells primary resistance to MEK inhibitors through the RTK pathway. Mass spectrum analysis of GRB7 immunoprecipitates revealed that PLK1 was the predominant interacting kinase of GRB7. Inhibition of PLK1 suppressed downstream signaling of RTK, including FAK, STAT3, AKT, and 4EBP1. The combination of PLK1 and MEK inhibitors synergistically inhibited CRC cell proliferation and induced apoptosis in vitro and in vivo. In conclusion, we identified GRB7-PLK1 as a pivotal axis mediating RTKs, resulting in MEK inhibitor tolerance. PLK1 is therefore a promising target for synergizing MEK inhibitors in the clinical treatment of CRC patients harboring KRAS mutations.Risk assessment of allogeneic hematopoietic cell transplantation (allo-HCT) is hindered by the lack of current data on comorbidities and outcome. The EBMT identified 38,760 allo-HCT recipients with hematologic malignancies transplanted between 2010 and 2018 from matched sibling and unrelated donors with a full data set of pre-existing comorbidities. Multivariate analyses using the Cox proportional-hazards model including known risk factors for non-relapse mortality (NRM) were performed. We found that pre-existing renal comorbidity had the strongest association with NRM (hazard ratio [HR] 1.85 [95% CI 1.55-2.19]). In addition, the association of multiple pre-existing comorbidities with NRM was significant, including diabetes, infections, cardiac comorbidity, and pulmonary comorbidity. However, the HR of the association of these comorbidities with NRM was relatively low and did not exceed 1.24. Consequently, the risk of NRM was only moderately increased in patients with a high hematopoietic cell transplantation comorbidity index (HCT-CI) ≥ 3 (HR 1.34 [1.26-1.42]). In the current EBMT population, pre-existing non-renal comorbidities determined NRM after allo-HCT to a much lesser extent as compared with the underlying HCT-CI data. Improvements in management and supportive care as well as higher awareness based on the use of HCT-CI may have contributed to this favorable development.Severe Peyronie’s disease (PD) and concomitant erectile dysfunction (ED) may require plaque incision/excision and grafting (PIG) as an adjunct to penile prosthesis implantation (IPP). Currently, there is no available consensus on the best graft material to use. Our aim was to systematically review graft materials used as patches following PIG + IPP. Literature search was performed in March 2021. Only original articles in English with a series of 10 or more patients were included. Overall, a total of 17 studies were included, corresponding to a cohort of 662 patients. The mean age ranged from 45 to 65 years and most patients had curvatures >45°. Average penile lengthening ranged from 1 to 3.5 cm, average residual curvatures from 0 to 20% and decreased glans sensitivity from 0 to 20%. Eighty to 100% of patients were satisfied with cosmetic and functional results. PIG + IPP with the use of various grafts offers promising results for the treatment of patients suffering from severe PD with concomitant ED. Unfortunately, the absence of high quality and comparative studies makes it difficult to establish the optimum graft. Therefore, the level of experience of the surgical team with one or more methods should guide their choice.The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family includes nine members with aggrecan-degrading activity, i.e., ADAMTS1, 4, 5, 8, 9, 15, 16, 18, and 20. However, their systematic expression profile in knee osteoarthritis (OA) synovium and effects of cytokines and growth factors on the expression in OA synovial fibroblasts remain elusive. In this study, expression of all nine aggrecanolytic ADAMTS species was assessed by quantitative real-time PCR in OA and control normal synovial tissues. OA synovial fibroblasts were treated with interleukin-1α (IL-1α), IL-1β, tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), vascular endothelial growth factor165, and heparin-binding epidermal growth factor, and analyzed for the expression of the ADAMTS species. The signaling pathways and inhibition of ADAMTS4 expression by high-molecular-weight hyaluronan, adalimumab, tocilizumab, and signaling molecule inhibitors were studied. ADAMTS1, 4, 5, 9, and 16 were expressed in Oest that concurrent therapy with an anti-TNF-α drug and inhibitor(s) may be useful for prevention against aggrecan degradation in OA.

Standard approaches for the assessment of Man via the Environment exposure are designed to be conservative. However, propagating these exposures into health impact assessment might lead to questionable socio-economic costs.

The objective of this study was to develop a novel tiered modelling approach to assess human exposure to lead (Pb) via the environment.

The approach starts in Tier 1 from EUSES modelling approach, modified with metal specific transfer factors. The generic Tier 2 approach uses the higher tier model GPM for air quality, and dietary exposure modelling based on EFSA’s Comprehensive Food Database, in combination with crop specific transfer factors. Tier 3 considers additional site-specific information such as proximity of inhabitants and agricultural activities in relation to industrial sites.

This tiered modelling approach was applied to a case study of 50 lead battery manufacturing and recycling sites across Europe. Data sets from general population human biomonitoring studies were used to compare the predicted additional bioburden of Pb resulting from lead battery manufacturing and recycling. The higher tier assessments were able to demonstrate a >20-fold reduction in modelled Pb exposure compared to default assumptions made in Tier 1.

Leading to better estimates for socio-economic costs in health impact assessment.

Leading to better estimates for socio-economic costs in health impact assessment.Anterior cingulate cortex (ACC) response during attentional control in the context of task-irrelevant emotional faces is a promising biomarker of cognitive behavioral therapy (CBT) outcome in patients with social anxiety disorder (SAD). However, it is unclear whether this biomarker extends to major depressive disorder (MDD) and is specific to CBT outcome. In the current study, 72 unmedicated patients with SAD (n = 39) or MDD (n = 33) completed a validated emotional interference paradigm during functional magnetic resonance imaging before treatment. Participants viewed letter strings superimposed on task-irrelevant threat and neutral faces under low perceptual load (high interference) and high perceptual load (low interference). Biomarkers comprised anatomy-based rostral ACC (rACC) and dorsal ACC (dACC) response to task-irrelevant threat (>neutral) faces under low and high perceptual load. Patients were randomly assigned to 12 weeks of CBT or supportive therapy (ST) (ClinicalTrials.gov identifier NCT03175068). Clinician-administered measures of social anxiety and depression severity were obtained at baseline and every 2 weeks throughout treatment (7 assessments total) by an assessor blinded to the treatment arm. A composite symptom severity score was submitted to latent growth curve models. Results showed more baseline rACC activity to task-irrelevant threat>neutral faces under low, but not high, perceptual load predicted steeper trajectories of symptom improvement throughout CBT or ST. Post-hoc analyses indicated this effect was driven by subgenual ACC (sgACC) activation. Findings indicate ACC activity during attentional control may be a transdiagnostic neural predictor of general psychotherapy outcome.

A non-interventional, longitudinal, retrospective follow-up study to assess CsA-induced nephrotoxicity (IN) and its reversibility after withdrawal in patients exhibiting a bilateral chronic posterior uveitis (CPU) associated with cystoid macular oedema (CMO) in at least one eye. Data from medical records between 1986 and 2013.

Primary outcome was the renal tolerance during and after CsA treatment assessed by plasma creatinine concentration and glomerular filtration rate (GFR) estimated by Chronic Kidney Disease Epidemiology (CKD-Epi) formula. Secondary outcomes were CsA through concentration, occurrence of cancers and ophthalmologic efficacy assessed by three parameters including CMO, vitreous inflammation, and best-corrected visual acuity BVCA changes.

One hundred forty-three patients were followed for renal tolerance. Underlying diseases were Birdshot retinochoroiditis (n = 67), Behçet disease (n = 9), probable sarcoidosis (n = 23), sympathetic ophthalmia (n = 3), idiopathic (n = 41). After CsA disconBone metastasis is one of the most serious complications in lung cancer patients. MicroRNAs (miRNAs) play important roles in tumour development, progression and metastasis. A previous study showed that miR-106a is highly expressed in the tissues of lung adenocarcinoma with bone metastasis, but its mechanism remains unclear. In this study, we showed that miR-106a expression is dramatically increased in lung cancer patients with bone metastasis (BM) by immunohistochemical analysis. MiR-106a promoted A549 and SPC-A1 cell proliferation, migration and invasion in vitro. The results of bioluminescence imaging (BLI), micro-CT and X-ray demonstrated that miR-106a promoted bone metastasis of lung adenocarcinoma in vivo. Mechanistic investigations revealed that miR-106a upregulation promoted metastasis by targeting tumour protein 53-induced nuclear protein 1 (TP53INP1)-mediated metastatic progression, including cell migration, autophagy-dependent death and epithelial-mesenchymal transition (EMT). Notably, autophagy partially attenuated the effects of miR-106a on promoting bone metastasis in lung adenocarcinoma. These findings demonstrated that restoring the expression of TP53INP1 by silencing miR-106a may be a novel therapeutic strategy for bone metastatic in lung adenocarcinoma.Tumor necrosis factor (TNF)-α-induced protein 8-like 2 (TIPE2) is a newly discovered negative immunoregulatory protein that is involved in various cellular immune responses to infections. However, the underlying mechanism by which TIPE2 affects the immune function of dendritic cells (DCs) is not yet understood. This study aimed to determine the correlations among DCs TIPE2 expression, autophagic activity and immune function in the context of sepsis. In addition, the signaling pathway by which TIPE2 regulates autophagy in DCs was investigated. We reported for the first time that TIPE2 overexpression (knock-in, KI) exerted an inhibitory effect on autophagy in DCs and markedly suppressed the immune function of DCs upon septic challenge both in vitro and in vivo. In addition, TIPE2 knockout (KO) in DCs significantly enhanced autophagy and improved the immune response of DCs in sepsis. Of note, we found that the transforming growth factor-β (TGF-β)-activated kinase-1 (TAK1)/c-Jun N-terminal kinase (JNK) pathway was inhibited by TIPE2 in DCs, resulting in downregulated autophagic activity. Collectively, these results suggest that TIPE2 can suppress the autophagic activity of DCs by inhibiting the TAK1/JNK signaling pathway and further negatively regulate the immune function of DCs in the development of septic complications.Globally, lung cancer remains one of the most prevalent malignant cancers. However, molecular mechanisms and functions involved in its pathogenesis have not been clearly elucidated. This study aimed to evaluate the specific regulatory mechanisms of exosomal miR-338-3p/CHL1/MAPK signaling pathway axis in non-small-cell lung cancer. Western blotting and qRT-PCR (reverse transcription-polymerase chain reaction) were used to determine the expression levels of CHL1 and exosomal miR-338-3p in NSCLC (non-small-cell lung cancer). The CHL1 gene was upregulated and downregulated to evaluate its functions in NSCLC progression. In vitro MTS and apoptotic assays were used to investigate the functions of CHL1 and exosomal miR-338-3p in NSCLC progression. The high-throughput sequencing was used to explore differently expressed exosomal miRNAs. The biological relationships between MAPK signaling pathway and CHL1 and exosomal miR-338-3p in NSCLC were predicted through bioinformatics analyses and verified by western blotting. Elevated CHL1 levels were observed in NSCLC tissues and cells. Upregulated CHL1 expression enhanced NSCLC cells’ progression by promoting tumor cells proliferation while suppressing their apoptosis. Conversely, the downregulation of the CHL1 gene inhibited NSCLC cells’ growth and promoted tumor cells’ apoptotic rate. Additionally, CHL1 activated the MAPK signaling pathway. Besides, we confirmed that miR-338-3p directly sponged with CHL1 to mediate tumor cells progression. Moreover, exosomal miR-338-3p serum levels in NSCLC patients were found to be low. BEAS-2B cells can transfer exosomal miR-338-3p to A549 cells and SK-MES-1 cells. In addition, elevated exosomal miR-338-3p levels significantly inhibited tumor cells proliferation and promoted their apoptosis by suppressing activation of the MAPK signaling pathway. Exosomal miR-338-3p suppresses tumor cells’ metastasis by downregulating the expression of CHL1 through MAPK signaling pathway inactivation.In glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH), downregulated osteogenic ability and damaged blood supply are two key pathogenic mechanisms. Studies suggested that cannabinoid receptor 2 (CB2) is expressed in bone tissue and it plays a positive role in osteogenesis. However, whether CB2 could enhance bone formation and blood supply in GC-induced ONFH remains unknown. In this study, we focused on the effect of CB2 in GC-induced ONFH and possible mechanisms in vitro and in vivo. By using GC-induced ONFH rat model, rat-bone mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) to address the interaction of CB2 in vitro and in vivo, we evaluate the osteogenic and angiogenic effect variation and possible mechanisms. Micro-CT, histological staining, angiography, calcein labeling, Alizarin red staining (ARS), alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) staining, TUNEL staining, migration assay, scratch assay, and tube formation were applied in this study. Our results showed that selective activation of CB2 alleviates GC-induced ONFH. The activation of CB2 strengthened the osteogenic activity of BMSCs under the influence of GCs by promotion of GSK-3β/β-catenin signaling pathway. Furthermore, CB2 promoted HUVECs migration and tube-forming capacities. Our findings indicated that CB2 may serve as a rational new treatment strategy against GC-induced ONFH by osteogenesis activation and maintenance of blood supply.

Prevalence of pre-pregnancy obesity and excessive gestational weight gain (GWG) are higher among women of color with low SES. Dysregulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis and its end-product, cortisol, during pregnancy is hypothesized to be associated with excessive GWG. However, past studies have produced inconsistent findings and often did not include health disparities populations. This study examined the association between pre-pregnancy body mass index (BMI), third trimester diurnal cortisol, and GWG in low-income, predominantly Hispanic women.

The MADRES study is an ongoing prospective cohort study of primarily Hispanic, low-income pregnant women and their children in Los Angeles, California. Data from 176 participants were included in this study. Total cortisol secretion (area under the curve, AUC) was quantified using four salivary cortisol samples (awakening, 30 min after awakening, afternoon, and bedtime) that were collected at home on one day during the third trimester of pregnancy. Moderation of the association between total cortisol and GWG by pre-pregnancy BMI was tested using multiple linear regression with a multiplicative interaction term.

There was no association between total cortisol secretion and GWG overall (p = 0.82), but the association between total cortisol and GWG was stronger for women with class 1 pre-pregnancy obesity compared to women with normal pre-pregnancy BMI (interaction term p = 0.04).

Results suggest that obesity status before pregnancy may be exacerbating the physiological impact of cortisol on GWG.

Results suggest that obesity status before pregnancy may be exacerbating the physiological impact of cortisol on GWG.

There are limited data comparing the relative associations of various BMI metrics with adiposity and cardiometabolic risk factors in youth.

Examine correlations of 7 different BMI metrics with adiposity, cardiometabolic risk factors, and biomarkers (i.e. blood pressure, waist circumference, cholesterol, leptin, insulin, high molecular weight adiponectin, high-sensitivity c-reactive protein (hsCRP)).

This was a cross-sectional analysis of youth in all BMI categories. BMI metrics BMI z-score (BMIz), extended BMIz (ext.BMIz), BMI percentile (BMIp), percent of the BMI 95th percentile (%BMI

), percent of the BMI median (%BMI

), triponderal mass index (TMI), and BMI (BMI). Correlations between these BMI metrics and adiposity, visceral adiposity, cardiometabolic risk factors and biomarkers were summarized using Pearson’s correlations.

Data from 371 children and adolescents ages 8-21 years old were included in our analysis 52% were female; 20.2% with Class I obesity, 20.5% with Class II, and 14.3% with Clasobesity and severe obesity in both clinical and research settings. BMIp consistently had the lowest correlations. Future research should evaluate the longitudinal stability of various BMI metrics and their relative associations with medium to long-term changes in adiposity and cardiometabolic outcomes in the context of intervention trials.Phenotypic and genetic divergence are shaped by the homogenizing effects of gene flow and the differentiating processes of genetic drift and local adaptation. Herein, we examined the mechanisms that underlie phenotypic (size and color) and genetic divergence in 35 populations (535 individuals) of the poison frog Epipedobates anthonyi along four elevational gradients (0-1800 m asl) in the Ecuadorian Andes. We found phenotypic divergence in size and color despite relatively low genetic divergence at neutral microsatellite loci. Genetic and phenotypic divergence were both explained by landscape resistance between sites (isolation-by-resistance, IBR), likely due to a cold and dry mountain ridge between the northern and southern elevational transects that limits dispersal and separates two color morphs. Moreover, environmental differences among sites also explained genetic and phenotypic divergence, suggesting isolation-by-environment (IBE). When northern and southern transects were analyzed separately, genetic divergence was predicted either by distance (isolation-by-distance, IBD; northern) or environmental resistance between sites (IBR; southern). In contrast, phenotypic divergence was primarily explained by environmental differences among sites, supporting the IBE hypothesis. These results indicate that although distance and geographic barriers are important drivers of population divergence, environmental variation has a two-fold effect on population divergence. On the one hand, landscape resistance between sites reduces gene flow (IBR), while on the other hand, environmental differences among sites exert divergent selective pressures on phenotypic traits (IBE). Our work highlights the importance of studying both genetic and phenotypic divergence to better understand the processes of population divergence and speciation along ecological gradients.Necrotic cell death represents a major pathogenic mechanism of Mycobacterium tuberculosis (Mtb) infection. It is increasingly evident that Mtb induces several types of regulated necrosis but how these are interconnected and linked to the release of pro-inflammatory cytokines remains unknown. Exploiting a clinical cohort of tuberculosis patients, we show here that the number and size of necrotic lesions correlates with IL-1β plasma levels as a strong indicator of inflammasome activation. Our mechanistic studies reveal that Mtb triggers mitochondrial permeability transition (mPT) and subsequently extensive macrophage necrosis, which requires activation of the NLRP3 inflammasome. NLRP3-driven mitochondrial damage is dependent on proteolytic activation of the pore-forming effector protein gasdermin D (GSDMD), which links two distinct cell death machineries. Intriguingly, GSDMD, but not the membranolytic mycobacterial ESX-1 secretion system, is dispensable for IL-1β secretion from Mtb-infected macrophages. Thus, our study dissects a novel mechanism of pathogen-induced regulated necrosis by identifying mitochondria as central regulatory hubs capable of delineating cytokine secretion and lytic cell death.Previous studies demonstrated that cGAS pathway is related to the inflammation amplification in a variety of autoimmune diseases. Lysine acetyltransferase family (KATs) can regulate the nuclear transcription or cytoplasmic activation of cGAS through different mechanisms. However, its role and related immunity patterns in systemic lupus erythematosus (SLE) have not been explored. In this study, RNA-seq and scRNA-seq profiling were performed for peripheral blood mononuclear cells (PBMCs) from patients with SLE. R packages were used for bioinformatic analysis. Cell culture, RT-PCR, western blotting, immunofluorescence, immunohistochemistry, and ELISA were used to explore gene expression in vitro or clinical specimens. Plasmid transfection and mass spectrometry were used to detect protein modifications. Eight acetyltransferase and deacetylase family members with significantly differential expression in SLE were found. Among them, KAT2A was abnormally upregulated and positively correlated with disease activity index. Further, KAT2A-cGAS pathway was aberrantly expressed in specific immune cell subsets in SLE. In vitro studies showed KAT2A modulated cGAS through increasing expression and post-translational modification. Our research provides novel insights for accurately positioning specific immune-cell subgroups in which KAT2A-cGAS reaction mainly works and KAT2A regulation patterns.Autophagy-mediated lipotoxicity plays a critical role in the progression of diabetic nephropathy (DN), but the precise mechanism is not fully understood. Whether lipophagy, a selective type of autophagy participates in renal ectopic lipid deposition (ELD) and lipotoxicity in the kidney of DN is unknown. Here, decreased lipophagy, increased ELD and lipotoxcity were observed in tubular cells of patients with DN, which were accompanied with reduced expression of AdipoR1 and p-AMPK. Similar results were found in db/db mice, these changes were reversed by AdipoRon, an adiponectin receptor activator that promotes autophagy. Additionally, a significantly decreased level of lipophagy was observed in HK-2 cells, a human proximal tubular cell line treated with high glucose, which was consistent with increased lipid deposition, apoptosis and fibrosis, while were partially alleviated by AdipoRon. However, these effects were abolished by pretreatment with ULK1 inhibitor SBI-0206965, autophagy inhibitor chloroquine and enhanced by AMPK activator AICAR. These data suggested by the first time that autophagy-mediated lipophagy deficiency plays a critical role in the ELD and lipid-related renal injury of DN.Lithium is a first-line treatment for bipolar disorder, where it acts as a mood-stabilizing agent. Although its precise mechanism remains unclear, neuroimaging studies have shown that lithium accumulates in the hippocampus and that chronic use amongst bipolar disorder patients is associated with larger hippocampal volumes. Here, we tested the chronic effects of low (0.75 mM) and high (2.25 mM) doses of lithium on human hippocampal progenitor cells and used immunocytochemistry to investigate the effects of lithium on cell parameters implicated in neurogenesis. Corresponding RNA-sequencing and gene-set enrichment analyses were used to evaluate whether genes affected by lithium in our model overlap with those regulating the volume of specific layers of the dentate gyrus. We observed that high-dose lithium treatment in human hippocampal progenitors increased the generation of neuroblasts (P ≤ 0.01), neurons (P ≤ 0.01), and glia (P ≤ 0.001), alongside the expression of genes, which regulate the volume of the molecular layer of the dentate gyrus. This study provides empirical support that adult hippocampal neurogenesis and gliogenesis are mechanisms that could contribute to the effects of lithium on human hippocampal volume.Chemotherapy-induced intestinal mucositis (CIM) is a common adverse reaction to antineoplastic treatment with few appropriate, specific interventions. We aimed to identify the role of the G protein coupled estrogen receptor (GPER) in CIM and its mechanism. Adult male C57BL/6 mice were intraperitoneally injected with 5-fluorouracil to establish the CIM model. The selective GPER agonist G-1 significantly inhibited weight loss and histological damage in CIM mice and restored mucosal barrier dysfunction, including improving the expression of ZO-1, increasing the number of goblet cells, and decreasing mucosal permeability. Moreover, G-1 treatment did not alter the antitumor effect of 5-fluorouracil. In the CIM model, G-1 therapy reduced the expression of proapoptotic protein and cyclin D1 and cyclin B1, reversed the changes in the number of TUNEL+ cells, Ki67+ and bromodeoxyuridine+ cells in crypts. The selective GPER antagonist G15 eliminated all of the above effects caused by G-1 on CIM, and application of G15 alone increased the severity of CIM. GPER was predominantly expressed in ileal crypts, and G-1 inhibited the DNA damage induced by 5-fluorouracil in vivo and vitro, as confirmed by the decrease in the number of γH2AX+ cells in the crypts and the comet assay results. Referring to the data from GEO dataset we verified GPER activation restored ERK1/2 activity in CIM and 5-fluorouracil-treated IEC-6 cells. Once the effects of G-1 on ERK1/2 activity were abolished with the ERK1/2 inhibitor PD0325901, the effects of G-1 on DNA damage both in vivo and in vitro were eliminated. Correspondingly, all of the manifestations of G-1 protection against CIM were inhibited by PD0325901, such as body weight and histological changes, the mucosal barrier, the apoptosis and proliferation of crypt cells. In conclusion, GPER activation prevents CIM by inhibiting crypt cell DNA damage in an ERK1/2-dependent manner, suggesting GPER might be a target preventing CIM.The clinical presentation of late-life depression is highly heterogeneous and likely influenced by the co-presence of somatic diseases. Using a network approach, this study aims to explore how depressive symptoms are interconnected with each other, as well as with different measures of somatic disease burden in older adults. We examined cross-sectional data on 2860 individuals aged 60+ from the Swedish National Study on Aging and Care in Kungsholmen, Stockholm. The severity of sixteen depressive symptoms was clinically assessed with the Comprehensive Psychopathological Rating Scale. We combined data from individual clinical assessment and health-registers to construct eight system-specific disease clusters (cardiovascular, neurological, gastrointestinal, metabolic, musculoskeletal, respiratory, sensory, and unclassified), along with a measure of overall somatic burden. The interconnection among depressive symptoms, and with disease clusters was explored through networks based on Spearman partial correlations. Bridge centrality index and network loadings were employed to identify depressive symptoms directly connecting disease clusters and depression. Sadness, pessimism, anxiety, and suicidal thoughts were the most interconnected symptoms of the depression network, while somatic symptoms of depression were less interconnected. In the network integrating depressive symptoms with disease clusters, suicidal thoughts, reduced appetite, and cognitive difficulties constituted the most consistent bridge connections. The same bridge symptoms emerged when considering an overall measure of somatic disease burden. Suicidal thoughts, reduced appetite, and cognitive difficulties may play a key role in the interconnection between late-life depression and somatic diseases. If confirmed in longitudinal studies, these bridging symptoms could constitute potential targets in the prevention of late-life depression.Lipopolysaccharide (LPS) as an important inflammatory mediator activates the innate/adaptive immune system. The existence of LPS in pancreatic ductal adenocarcinoma (PDAC) has been reported, however, its biological function in PDAC remains unclear. Here, we demonstrated that circulating and tumoral LPS was significantly increased by intestinal leakage in the orthotopic murine PDAC model, and LPS administration promoted T cell infiltration but exhaustion paradoxically in the subcutaneous murine PDAC model. By bioinformatic analysis, Toll-like receptor 4 (TLR4), LPS receptor, was further found to enrich in immune tolerance signaling in PDAC tissues. Then, a significant positive correlation was found between TLR4 and programmed death ligand-1 (PD-L1) in clinical PDAC tissues, as well as serum LPS and tumoral PD-L1. Meanwhile, LPS stimulation in vitro and in vivo obviously upregulated tumor PD-L1 expression, and effectively promoted cancer cells resistance to T cell cytotoxicity. Mechanistically, the activation of TLR4/MyD88/AKT/NF-κB cascade was found to participate in LPS mediated PD-L1 transcription via binding to its promoter regions, which was enhanced by crosstalk between NF-κB and AKT pathways. Finally, PD-L1 blockade could significantly reverse LPS-induced immune escape, and synergized with LPS treatment. Taken together, LPS can remodel tumor microenvironment, and synergize with PD-L1 blockade to suppress tumor growth, which may be a promising comprehensive strategy for PDAC.F-box and leucine-rich repeat protein 10 (FBXL10) has been reported to play a regulatory role in the initiation and development of breast cancer. Bioinformatics analyses revealed that FBXL10 may involve in the process of cytoskeleton organization. This research aimed to investigate the function of FBXL10 in epithelial-mesenchymal transition (EMT) and metastasis of breast cancer, and tried to reveal the molecular mechanism involved in this issue. Functional experiments in vitro revealed that FBXL10 promoted the migration and invasion of breast cancer cells through inhibiting E-cadherin expression and inducing EMT. Mechanical studies revealed that FBXL10 could specifically interact with SNAI1, but not Slug or ZEB1. And it promoted the transcriptional repression activity of SNAI1 on CDH1 in breast cancer cells. Furthermore, FBXL10 had a positive role for the deacetylation of SNAI1 by facilitating the interaction between SNAI1 and HDAC1, a dominating deacetylase of SNAI1. And the deacetylated SNAI1 showed a more suppressive ability to inhibit the transcription of E-cadherin. Moreover, mouse models were also conducted to confirm the effect of FBXL10 on the lung metastasis of breast cancer in vivo. Totally, our data revealed that FBXL10 served as a pro-metastatic factor in breast cancer via repressing the expression of E-cadherin and inducing EMT. It may provide a novel regulatory axis in the EMT of breast cancer.Between adolescence and adulthood, the brain critically undergoes maturation and refinement of synaptic and neural circuits that shape cognitive processing. Adolescence also represents a vulnerable period for the onset of symptoms in neurodevelopmental psychiatric disorders. Despite the wide use of rodent models to unravel neurobiological mechanisms underlying neurodevelopmental disorders, there is a surprising paucity of rigorous studies focusing on normal cognitive-developmental trajectories in such models. Here, we sought to behaviorally capture maturational changes in cognitive trajectories during adolescence and into adulthood in male and female mice using distinct behavioral paradigms. C57 BL/6J mice (4.5, 6, and 12 weeks of age) were assessed on three behavioral paradigms drug-induced locomotor hyperactivity, prepulse inhibition, and a novel validated version of a visuospatial paired-associate learning touchscreen task. We show that the normal maturational trajectories of behavioral performance on these paradigms are dissociable. Responses in drug-induced locomotor hyperactivity and prepulse inhibition both displayed a 'U-shaped’ developmental trajectory; lower during mid-adolescence relative to early adolescence and adulthood. In contrast, visuospatial learning and memory, memory retention, and response times indicative of motivational processing progressively improved with age. Our study offers a framework to investigate how insults at different developmental stages might perturb normal trajectories in cognitive development. We provide a brain maturational approach to understand resilience factors of brain plasticity in the face of adversity and to examine pharmacological and non-pharmacological interventions directed at ameliorating or rescuing perturbed trajectories in neurodevelopmental and neuropsychiatric disorders.BACKGROUND Uvular necrosis is an uncommon complication of esophagogastroduodenoscopy. It usually presents with sore throat, fever, foreign-body sensation, and odynophagia following esophagogastroduodenoscopy. It occurs due to impairment of local circulation, which is caused by impingement of the uvula between the endoscope and the hard palate. It may also arise from excessive suctioning of the area surrounding the uvula. We present a case of uvular necrosis following esophagogastroduodenoscopy and describe current strategies to prevent this rare complication. CASE REPORT A 19-year-old man presented with a 4-day history of odynophagia, severe sore throat, and foreign-body sensation that started within 24 h after esophagogastroduodenoscopy. Uvular necrosis was observed on physical examination. The patient was treated conservatively with nonsteroidal anti-inflammatory drugs and antibiotics, and his symptoms resolved completely. CONCLUSIONS We believe that this is the sixth reported case of uvular necrosis following an uncomplicated diagnostic esophagogastroduodenoscopy in a young patient. Esophagogastroduodenoscopy is a routine procedure performed by gastroenterologists. Uvular necrosis can occur as a rare complication of esophagogastroduodenoscopy; therefore, it is important to monitor patients for odynophagia and abnormal foreign-body sensation following the procedure for at least 72 h. Uvular necrosis should be suspected if odynophagia persists after this period despite adequate treatment with conventional analgesics. Prompt diagnosis and management can relieve the patient’s symptoms, given that uvular necrosis is a self-limiting complication with a good prognosis.BACKGROUND Many psychological problems arising from patients undergoing aesthetic repair of teeth should be considered. However, there are no published studies on the relationship between anxiety/depression and perfectionism in patients with aesthetic repair of anterior teeth. MATERIAL AND METHODS A total of 640 patients receiving aesthetic repair of anterior teeth were assessed using the Corah dental anxiety scale (CDAS), a self-rating anxiety scale (SAS), a self-rating depression scale (SDS), and the Chinese version of the Frost Multidimensional Perfectionism Psychological Scale (CFMPS). Statistical analyses included use of the independent-samples t test, correlation analysis, and multiple stepwise regression analysis. RESULTS We found that 156 patients with a high dental anxiety disorder had significantly greater SAS and SDS scores than those without a high dental anxiety disorder. There were significant differences between these patients and the non-high dental anxiety group, based on 3 dimensions of the CFMPS concern over mistakes (CM), doubt about action (DA), and organization (OR). Patients with dental anxiety had a significant positive correlation with SAS in the categories CM and DA, with SDS in the categories CM and DA, and with personal standard (PS); OR was negatively correlated with SAS and SDS scores. Regression analysis showed that the CM and OR dimension scores of CFMPS and age had strong predictive effects on SAS scores, while CM, DA, PS dimension scores, and age were strong predictors of SDS scores. CONCLUSIONS The incidence of dental anxiety prior to anterior tooth repair treatment is high, and patients with dental anxiety have a significant tendency toward pursuing perfectionism.

In a woman’s life, pregnancy is a unique experience accompanied by significant physiological, biochemical, and psychological changes that can affect mental health status. Participation in preventive activities during pregnancy has an impact on better emotional state after childbirth.

The therapeutic effects of listening to music on the health of mother and child have been proven in numerous studies. Listening to music during pregnancy contributes to a better sense of well – being and less pronounced symptoms of postpartum depression. Scientific evidence confirms the effects of music therapy on the level of stress and anxiety in pregnant women, but also calmer children and better emotional bonding. The application of GIM therapy – music – induced imagination – also provides significant results in strengthening psychological resilience.

Music therapy is a simple, non – pharmacological and safe method that significantly contributes to mental health in pregnancy and after childbirth. The application of music therapy has a scientific potential that offers many ideas for the development of medical – music research.

Music therapy is a simple, non – pharmacological and safe method that significantly contributes to mental health in pregnancy and after childbirth. The application of music therapy has a scientific potential that offers many ideas for the development of medical – music research.

As a contribution to the dimensional classification of mental disorders, which in the next edition of the American Psychiatric Association (APA) could dominate over the categorical, and in general, due to the impact of anger on the behavior of individuals in our society, it seems important to examine and analyze dimensions that represent risk factors for occurrence and development of anger disorders. Aim, to examine gender differences in the expression of the adaptive and maladaptive dimensions of perfectionism and anger (state and trait, as well as the anger expression and control) and to examine whether the dimensions of perfectionism are statistically significant predictors of anger.

This study included a total of 600 primary and secondary school students (305 girls and 295 boys), 12 to 18 years old. Data were collected using a Socio-demographic Features Questionnaire for general information onto the Adaptive/ Maladaptive Perfectionism Scale (AMPS), Child-Adolescent Perfectionism Scale (CAPS), and Statdiagnostic system to prevent comorbidity of mental disorders and provide more clinically relevant information about each individual. The instrument which is used to measure anger in this study (STAXI-2 C/A; Brunner & Spielberger 2009) was for the first time applied in Bosnia and Herzegovina. The results of this research are a contribution to its validation.

Nursing is a profession frequently organized around shift work in order to guarantee the continuity of care throughout the 24 hours. However, working in shifts is coupled with the desynchronization of circadian rhythms and may result in adverse effects on nurses’ health. Our previous work has demonstrated the presence of increased stress levels, reduced coping abilities and diminished life enjoyment in shift work nurses in comparison to those working only in accordance with the daily schedule. Here we aimed to appraise the effects of shift work on their overall health status.

We used a comparative cross-sectional approach on a sample of 157 hospital nursing professionals at the University Clinical Hospital Mostar. Study subjects were divided into two groups a total of 51% study subjects were included in a specific type of shift work (i.e., 12-hour day shift / 24 hours off / 12-hour night shift / 48 hours off), while the remaining 49% adhered to the conventional 7-hour daily schedule. The instrument used w issues.

Radiologist workload had increased significantly within the past three decades. In 2006-2007, the average annual workload per FTE radiologist was 14,900 procedures, an increase of 7% since 2002-2003 and 34.0% since 1991-1992. Annual RVUs per FTE radiologist were 10 200, an increase of 10% since 2002-2003 and 70.3% since 1991-1992.

The study included worksheets data of three radiology specialists in their first three years as specialists. Data were collected and analyzed retrospectively for the period frame January 1

to September 21

2018. The total data of imaging procedures by one radiologist had been collected and then separated by different imaging procedures as followed.

Average total number of imaging procedures per radiologist was 2785. Separately, there were 850 bone X ray images, 550 chest X rays, 250 ultrasound examinations, 860 CTs and 256 MRIs. Daily average of analyzed imaging procedures per radiologist was as followed 7.4 bone X ray images, 4.8 chest X rays, 2.2 ultrasounds, 7.5 CTs and 2.