Lupus nephritis (LN) is a major cause death in patients with systemic lupus erythematosus. We aimed to find the differentially expressed genes (DEGs) in LN and confirm the regulatory mechanism on LN. ...The mouse model of LN was constructed by subcutaneous injection of pristane. RNA-seq screened 392 up-regulated and 447 down-regulated DEGs in LN mouse model, and KEGG analysis found that the top 20 DEGs were enriched in arachidonic acid metabolism, tryptophan metabolism, etc. The hub genes, Kynu, Spidr, Gbp3, Cbr1, Cyp4b1, and Cndp2 were identified, in which Gbp3 was selected for following study. Afterwards, the function of Gbp3 on the proliferation, inflammation, and pyroptosis of LN was verified by CCK-8, ELISA, and WB in vitro. The results demonstrated that si-Gbp3 promoted cell proliferation and inhibited the levels of inflammatory factors (IL-1β, TNF-α and IL-8) and pyroptosis-related proteins (GSDMD, Caspase-1 and NLRP3) in a cell model of LN. In constrast, Gbp3 overexpression played an opposite role. In summary, Gbp3 promoted the progression of LN via inhibiting cell proliferation and facilitating inflammation and pyroptosis.
Purpose
68
Ga-Labelled Fibroblast Activation Protein Inhibitor (
68
Ga-FAPI) has shown promise in tumour positron emission tomography (PET) imaging, including malignant pancreatic lesions. Here, we ...showed several non-malignant findings of focal
68
Ga-FAPI-04 uptake in the pancreas which were occasionally found by PET/MR. The study aimed to investigate the reasons for the focal uptake and remind caution for the diagnosis.
Methods
We retrospectively analysed imaging data of 103 patients who underwent
68
Ga-FAPI-04 PET/MR at our institute from May 22 to July 8, 2020. Seven patients had focally elevated uptake of
68
Ga-FAPI-04 in the pancreas; four of these underwent simultaneous
18
F-FDG PET/CT scans. The clinical data, PET/MR imaging features, pathological, and follow-up results were further collected and analysed.
Results
The cases showed that
68
Ga-FAPI-04 accumulation can occur in any part of the pancreas, with corresponding negative
18
F-FDG uptake. Most lesions were small with no significant changes in CT or MR signals. The SUVmax value of
68
Ga-FAPI-04 had a wide range of 3.1–9.1. All the pancreatic lesions were proven to be non-neoplastic by pathology confirmation or follow-up imaging. Lesions with uptake were identified including pancreatic pseudocysts, sites of prior pancreatitis, and foci of IgG 4-related disease.
Conclusion
Though
68
Ga-FAPI-04 demonstrates great potential for oncological diagnosis, focal
68
Ga-FAPI-04 uptake could occur in benign pancreatic lesions and should be carefully evaluated. Fortunately, combined with MR,
68
Ga-FAPI-04 PET/MR may potentially avoid the misdiagnosis of some pancreatic lesions.
Clinical Trial Registration: NCT04554719 and NCT04605939. Registered September 13, 2020 and October 25, 2020, respectively.
Spherical nucleic acids (SNAs) are composed of a nanoparticle core and a layer of densely arranged oligonucleotide shells. After the first report of SNA by Mirkin and coworkers in 1996, it has ...created a significant interest by offering new possibilities in the field of gene and drug delivery. The controlled aggregation of oligonucleotides on the surface of organic/inorganic nanoparticles improves the delivery of genes and nucleic acid–based drugs and alters and regulates the biological profiles of the nanoparticle core within living organisms. Here in this review, we present an overview of the recent progress of SNAs that has speeded up their biomedical application and their potential transition to clinical use. We start with introducing the concept and characteristics of SNAs as drug/gene delivery systems and highlight recent efforts of bioengineering SNA by imaging and treatmenting various diseases. Finally, we discuss potential challenges and opportunities of SNAs, their ongoing clinical trials, and future translation, and how they may affect the current landscape of clinical practices. We hope that this review will update our current understanding of SNA, organized oligonucleotide aggregates, for disease diagnosis and treatment.
Spherical nucleic acids are prepared by densely coated nucleic acids on the nanoparticle core. These organized nucleotide aggregates present significantly different biological properties compared to their linear counterparts, enabling advances in biosensing, bioimaging, and biomedicine.
Background
Uncertainty surrounding COVID-19 regarding rapid progression to acute respiratory distress syndrome and unusual clinical characteristics make discharge from a monitored setting ...challenging. A clinical risk score to predict 14-day occurrence of hypoxia, ICU admission, and death is unavailable.
Objective
Derive and validate a risk score to predict suitability for discharge from a monitored setting among an early cohort of patients with COVID-19.
Design
Model derivation and validation in a retrospective cohort. We built a manual forward stepwise logistic regression model to identify variables associated with suitability for discharge and assigned points to each variable. Event-free patients were included after at least 14 days of follow-up.
Participants
All adult patients with a COVID-19 diagnosis between March 1, 2020, and April 12, 2020, in 10 hospitals in Massachusetts, USA.
Main Measures
Fourteen-day composite predicting hypoxia, ICU admission, and death. We calculated a risk score for each patient as a predictor of suitability for discharge evaluated by area under the curve.
Key Results
Of 2059 patients with COVID-19, 1326 met inclusion. The 1014-patient training cohort had a mean age of 58 years, was 56% female, and 65% had at least one comorbidity. A total of 255 (25%) patients were suitable for discharge. Variables associated with suitability for discharge were age, oxygen saturation, and albumin level, yielding a risk score between 0 and 55. At a cut point of 30, the score had a sensitivity of 83% and specificity of 82%. The respective
c
-statistic for the derivation and validation cohorts were 0.8939 (95% CI, 0.8687 to 0.9192) and 0.8685 (95% CI, 0.8095 to 0.9275). The score performed similarly for inpatients and emergency department patients.
Conclusions
A 3-item risk score for patients with COVID-19 consisting of age, oxygen saturation, and an acute phase reactant (albumin) using point of care data predicts suitability for discharge and may optimize scarce resources.
Aims/hypothesis
Berardinelli–Seip congenital lipodystrophy type 2 (BSCL2) is an autosomal recessive disorder characterised by lipodystrophy and insulin resistance. BSCL2 is caused by loss-of-function ...mutations in the
Seipin
gene (also known as
Bscl2
). Deletion of this gene in mice induces insulin resistance, glucose intolerance and a loss of adipose tissue. This study evaluated the effects of genetic deletion of
Seipin
on islet beta cell function.
Methods
We examined seipin expression in islet cells and measured glucose profiles, insulin synthesis, glucose-stimulated insulin secretion (GSIS), islet expression of peroxisome proliferator-activated receptor γ (PPARγ), levels of
Pdx-1
,
Nkx6.1
,
Glut2
(also known as
Slc2a2
) and proinsulin mRNA, nuclear translocation of pancreatic duodenal homeobox 1 (PDX-1), islet numbers, and beta cell mass and proliferation in male and female
Seipin
-knockout homozygous (
Seipin
−/−
) and heterozygous (
Seipin
+/−
) mice.
Results
Male and female
Seipin
−/−
mice displayed glucose intolerance, insulin resistance, hyperinsulinaemia and a lack of adipose tissue. By contrast, male but not female
Seipin
+/−
mice showed glucose intolerance without adipose tissue loss or insulin resistance. Seipin was highly expressed in islet beta cells in wild-type mice. Expression of islet PPARγ was reduced in male
Seipin
−/−
and
Seipin
+/−
mice but not in female
Seipin
−/−
or
Seipin
+/−
mice. Treatment of male
Seipin
+/−
mice with rosiglitazone corrected the glucose intolerance. Male
Seipin
+/−
mice displayed a decrease in islet insulin concentration and GSIS with low expression of
Pdx-1
,
Nkx6.1
,
Glut2
and proinsulin, and a decline in PDX-1 nuclear translocation; these changes were rescued by rosiglitazone administration. Male
Seipin
−/−
mice showed obvious, but rosiglitazone-sensitive, increases in islet insulin concentration, islet number and beta cell mass and proliferation, with a notable decline in GSIS. Ovariectomised female
Seipin
+/−
mice displayed glucose intolerance and deficits in insulin synthesis and secretion, with a decline in islet PPARγ level; these deleterious effects were reversed by administration of oestradiol or rosiglitazone.
Conclusions/interpretation
Heterozygous deletion of
Seipin
in islet beta cells impacts on insulin synthesis and secretion through reduced PPARγ expression. This leads to glucose intolerance and is relieved by oestradiol, which rescues PPARγ expression.
Abstract
Basal cell carcinoma (BCC) is the most common cancer with a rising incidence among white-skinned individuals. A number of epidemiological studies have suggested that obesity and serum ...25-hydroxy-vitamin D (25(OH)D) levels may affect the arising of BCC. To address this, we selected 443 and 96 single nucleotide polymorphisms (SNPs) associated with body mass index (BMI) and serum level of 25(OH)D from large-scale genome-wide association studies (GWAS), respectively. The univariable and multivariable two-sample Mendelian randomization (MR) analyses were conducted with a series of sensitivity analyses to ensure the results were reliable and reproducible. The results of univariable two-sample MR analysis showed that higher BMI was related to lower risk for BCC (Odds ratio(OR) = 0.90; 95% confidence interval (CI),0.81,0.99;
p
= 0.02). In addition, this causal effect of BMI on BCC still remained (OR = 0.88; 95%CI,− 0.22, − 0.03, p-value = 0.008) after adjusting for 25(OH)D level in the multivariable MR analysis. However, the results suggested that 25(OH)D level was not associated with BCC(OR = 1.02; 95%CI, 0.94,1.09, p-value = 0.67). In conclusion, similar to the conclusions of retrospective observational studies, the MR results indicate that high BMI is an independent protective factor for BCC. Meanwhile, vitamin D levels may not be causally associated with the risk of basal cell carcinoma and increasing vitamin D supplementation is unlikely to reduce the risk.
Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening cardiovascular disorder lacking effective clinical pharmacological therapies. The underlying molecular mechanisms of TAAD still ...remain elusive with participation of versatile cell types and components including endothelial cells (ECs), smooth muscle cells (SMCs), fibroblasts, immune cells, and the extracellular matrix (ECM). The main pathological features of TAAD include SMC dysfunction, phenotypic switching, and ECM degradation, which is closely associated with inflammation and immune cell infiltration. Among various types of immune cells, macrophages are a distinct participator in the formation and progression of TAAD. In this review, we first highlight the important role of inflammation and immune cell infiltration in TAAD. Furthermore, we discuss the role of macrophages in TAAD from the aspects of macrophage origination, classification, and functions. On the basis of experimental and clinical studies, we summarize key regulators of macrophages in TAAD. Finally, we review how targeting macrophages can reduce TAAD in murine models. A better understanding of the molecular and cellular mechanisms of TAAD may provide novel insights into preventing and treating the condition.Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening cardiovascular disorder lacking effective clinical pharmacological therapies. The underlying molecular mechanisms of TAAD still remain elusive with participation of versatile cell types and components including endothelial cells (ECs), smooth muscle cells (SMCs), fibroblasts, immune cells, and the extracellular matrix (ECM). The main pathological features of TAAD include SMC dysfunction, phenotypic switching, and ECM degradation, which is closely associated with inflammation and immune cell infiltration. Among various types of immune cells, macrophages are a distinct participator in the formation and progression of TAAD. In this review, we first highlight the important role of inflammation and immune cell infiltration in TAAD. Furthermore, we discuss the role of macrophages in TAAD from the aspects of macrophage origination, classification, and functions. On the basis of experimental and clinical studies, we summarize key regulators of macrophages in TAAD. Finally, we review how targeting macrophages can reduce TAAD in murine models. A better understanding of the molecular and cellular mechanisms of TAAD may provide novel insights into preventing and treating the condition.
Insomnia is one of the most prevalent and burdensome mental disorders worldwide, affecting between 10-20% of adults and up to 48% of the geriatric population. It is further associated with substance ...usage and dependence, as well other psychiatric disorders. In this study, we combined electronic health record (EHR) derived phenotypes and genotype information to conduct a genome wide analysis of insomnia in a 18,055 patient cohort. Diagnostic codes were used to identify 3,135 patients with insomnia. Our genome-wide association study (GWAS) identified one novel genomic risk locus on chromosome 8 (lead SNP rs17052966, p = 4.53 × 10
, odds ratio = 1.28, se = 0.04). The heritability analysis indicated that common SNPs accounts for 7% (se = 0.02, p = 0.015) of phenotypic variation. We further conducted a large-scale meta-analysis of our results and summary statistics of two recent insomnia GWAS and 13 significant loci were identified. The genetic correlation analysis yielded a strong positive genetic correlation between insomnia and alcohol use (rG = 0.56, se = 0.14, p < 0.001), nicotine use (rG = 0.50, se = 0.12, p < 0.001) and opioid use (rG = 0.43, se = 0.18, p = 0.02) disorders, suggesting a significant common genetic risk factors between insomnia and substance use.
•Diversity-predictor associations differed between species groups and ecoregions.•Annual average and seasonality in temperature and precipitation and human footprint were the strongest ...predictors.•Lower explained diversity variances in the mesic than xeric ecoregions.•Curbing human impacts destabilizing long-term climate regimes is vital to terrestrial mammal conservation efforts.
Understanding the interactions between abiotic (environmental and anthropogenic) factors and species diversity and distribution patterns is fundamental to improving the ecological representativeness of biodiversity management tools such as protected areas (PAs). However, significant knowledge gaps remain about how species’ ecological and evolutionary opportunities are associated with abiotic factors, especially in biodiversity-rich but economically ill-equipped countries such as Kenya. Here, we explored the interactions of terrestrial mammal diversity patterns and abiotic factors across species groups and ecoregions in Kenya. We coupled data on terrestrial mammal occurrences, phylogeny, functional traits, and environmental predictors in Kenya to derive multiple diversity indices, encompassing species richness and phylogenetic and functional richness, and mean pairwise and nearest taxon distances. We explored the interactions of these indices with several abiotic factors using multivariate regression analyses while adjusting for spatial autocorrelation. The results showed weak correlations between species richness versus the phylogenetic and functional diversity indices. The best-fit models explained variable proportions of diversity indices between species groups and ecoregions and consistently retained annual temperature and precipitation averages and seasonality and human footprint as the strongest predictors. Compared to the species-poor xeric northern and eastern Kenya regions, the predictors had weak associations with diversity variances in the species-rich mesic western and central Kenya regions, similar to focal species groups compared to ordinal classifications and the combined species pool. These findings illustrate that climate and human footprint interplay determine multiple facets of terrestrial mammal diversity patterns in Kenya. Accordingly, curbing human activities degrading long-term climatic regimes is vital to ensuring the ecological integrity of terrestrial mammal communities and should be integrated into biodiversity management frameworks. For a holistic representation of critical conservation areas, biodiversity managements should also prioritize terrestrial mammal phylogenetic and functional attributes besides species richness.
This mini-review delves into the realm of Langerhans cell histiocytosis (LCH) in children, focusing on its skeletal involvement. By synthesizing pertinent literature, we sought to provide a ...comprehensive understanding of LCH's clinical and radiographic spectrum. Our study then demonstrates the diagnostic prowess of whole-body
Tc-methyl diphosphonate (MDP) scintigraphy in LCH cases, underscoring its value in tandem with existing knowledge.
Our approach involved an extensive literature review that contextualized LCH within the current medical landscape. Subsequently, we presented a case series featuring five pediatric instances of skeletal LCH, one accompanied by soft tissue infiltration. The principal aim was to illuminate the diagnostic and staging potential of whole-body
Tc-MDP scintigraphy, augmenting existing insights.
Through meticulous literature synthesis, we highlighted pediatric LCH's protean clinical manifestations and radiological variability. Aligning with this spectrum, our case series underscored the role of
Tc-MDP scintigraphy in diagnosing and staging LCH. Among the five pediatric cases, one demonstrated concurrent soft tissue involvement. This aligns with the multifaceted nature of LCH presentations.
Pediatric LCH can present with a wide range of clinical and radiologic features. By amalgamating our cases with extant literature, we stress the necessity of a multimodal strategy.
Tc-MDP scintigraphy emerged as an indispensable tool for accurate staging and soft tissue detection. Our findings collectively advocate for a holistic approach to managing LCH, ensuring informed therapeutic decisions for optimal patient outcomes.
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