Microfibril-associated glycoprotein 4 forms octamers that mediate interactions with elastogenic proteins and cells.

Microfibril-associated glycoprotein 4 (MFAP4) is a 36-kDa extracellular matrix glycoprotein with critical roles in organ fibrosis, chronic obstructive pulmonary disease, and cardiovascular disorders, including aortic aneurysms. MFAP4 multimerises and interacts with elastogenic proteins, including fibrillin-1 and tropoelastin, and with cells via integrins. Structural details of MFAP4 and its potential interfaces for these interactions are unknown. Here, we present a cryo-electron microscopy structure of human MFAP4. In the presence of calcium, MFAP4 assembles as an octamer, where two sets of homodimers constitute the top and bottom halves of each octamer. Each homodimer is linked together by an intermolecular disulphide bond. A C34S missense mutation prevents disulphide-bond formation between monomers but does not prevent octamer assembly. The atomic model, built into the 3.55 Å cryo-EM map, suggests that salt-bridge interactions mediate homodimer assembly, while non-polar residues form the interface between octamer halves. In the absence of calcium, an MFAP4 octamer dissociates into two tetramers. Binding studies with fibrillin-1, tropoelastin, LTBP4, and small fibulins show that MFAP4 has multiple surfaces for protein-protein interactions, most of which depend upon MFAP4 octamer assembly. The C34S mutation does not affect these protein interactions or cell interactions. MFAP4 assemblies with fibrillin-1 abrogate MFAP4 interactions with cells.

Imaging of pediatric gastrointestinal tumors: A tertiary center experience over 19 years.

PURPOSE: Gastrointestinal tract (GIT) tumors in children are rare and there is a scarcity of data on their imaging features. The purpose of this study was to determine thefrequency of various GIT tumor types in children and to identify key imaging characteristics. METHODS: This retrospective, single-center study was approved by the local ethics committee. Children with histologically proven GIT tumours (malignantand benign) who had imaging available on the institutional PACS between May 1, 2000 and Dec 31, 2019 were included. Demographic data and available imaging was reviewed by two blinded radiologists. RESULTS: In total, 90 children (45 male, mean age 9.3 ± 4.3 years) with GIT tumours were included. The final diagnoses included polyps (n = 28), lymphomas/PTLD (n = 27), neuroendocrine tumours (n = 16), adenocarcinoma (n = 6), adenoma (n = 5), gastrointestinal stromal tumor (GIST) (n = 3), inflammatory myofibroblastic tumours (n = 2) and lastly leiomyoblastoma, leiomyoma and lipoma (1 each). All GIT segments were affected, but overall the small and large bowel had most lesions. Eighty-one percent children had a single lesion while remaining 19 % had multiple lesions. The neoplastic process manifested as intra-luminal lesion (58 %) or wall thickening (42 %) on imaging. Multiple cystic areas and vascular pedicle for polyps; and hypoechogenecity of the mass or wall thickening and aneurysmal dilatation for lymphomas, were the characteristic imaging features. None of the neuroendocrine tumours affecting appendix were seen on pre-resection imaging. CONCLUSIONS: Variety of benign and malignant tumors are seen throughout the childhood. Polyps, lymphomas and appendiceal neuroendocrine tumors are common lesions. Characteristic imaging features of juvenile polyps and lymphomas on ultrasound may help narrowing the differentials, and guide further work up.

Using Deep Learning to Automate Eosinophil Counting in Pediatric Ulcerative Colitis Histopathological Images.

Background: Accurate identification of inflammatory cells from mucosal histopathology images is important in diagnosing ulcerative colitis. The identification of eosinophils in the colonic mucosa has been associated with disease course. Cell counting is not only time-consuming but can also be subjective to human biases. In this study we developed an automatic eosinophilic cell counting tool from mucosal histopathology images, using deep learning. Method: Four pediatric IBD pathologists from two North American pediatric hospitals annotated 530 crops from 143 standard-of-care hematoxylin and eosin (H & E) rectal mucosal biopsies. A 305/75 split was used for training/validation to develop and optimize a U-Net based deep learning model, and 150 crops were used as a test set. The U-Net model was then compared to SAU-Net, a state-of-the-art U-Net variant. We undertook post-processing steps, namely, (1) the pixel-level probability threshold, (2) the minimum number of clustered pixels to designate a cell, and (3) the connectivity. Experiments were run to optimize model parameters using AUROC and cross-entropy loss as the performance metrics. Results: The F1-score was 0.86 (95%CI:0.79-0.91) (Precision: 0.77 (95%CI:0.70-0.83), Recall: 0.96 (95%CI:0.93-0.99)) to identify eosinophils as compared to an F1-score of 0.2 (95%CI:0.13-0.26) for SAU-Net (Precision: 0.38 (95%CI:0.31-0.46), Recall: 0.13 (95%CI:0.08-0.19)). The inter-rater reliability was 0.96 (95%CI:0.93-0.97). The correlation between two pathologists and the algorithm was 0.89 (95%CI:0.82-0.94) and 0.88 (95%CI:0.80-0.94) respectively. Conclusion: Our results indicate that deep learning-based automated eosinophilic cell counting can obtain a robust level of accuracy with a high degree of concordance with manual expert annotations.

Bicarbazole-Benzophenone Based Twisted Donor-Acceptor Derivatives as Potential Blue TADF Emitters for OLEDs.

Over the past few decades, organic light-emitting diodes (OLEDs) find applications in smartphones, televisions, and the automotive sector. However, this technology is still not perfect, and its application for lighting purposes has been slow. For further development of the OLEDs, we designed twisted donor-acceptor-type electroactive bipolar derivatives using benzophenone and bicarbazole as building blocks. Derivatives were synthesized through the reaction of 4-fluorobenzophenone with various mono-alkylated 3,3'-bicarbazoles. We have provided a comprehensive structural characterization of these compounds. The new materials are amorphous and exhibit suitable glass transition temperatures ranging from 57 to 102 °C. They also demonstrate high thermal stability, with decomposition temperatures reaching 400 °C. The developed compounds exhibit elevated photoluminescence quantum yields (PLQY) of up to 75.5% and favourable HOMO-LUMO levels, along with suitable triplet-singlet state energy values. Due to their good solubility and suitable film-forming properties, all the compounds were evaluated as blue TADF emitters dispersed in commercial 4,4'-bis(N-carbazolyl)-1,10-biphenyl (CBP) host material and used for the formation of emissive layer of organic light-emitting diodes (OLEDs) in concentration-dependent experiments. Out of these experiments, the OLED with 15 wt% of the emitting derivative 4-(9'-{2-ethylhexyl}-[3,3']-bicarbazol-9-yl)benzophenone exhibited superior performance. It attained a maximum brightness of 3581 cd/m2, a current efficacy of 5.7 cd/A, a power efficacy of 4.1 lm/W, and an external quantum efficacy of 2.7%.

The genomic and evolutionary landscapes of anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.

Bicarbazole-Benzophenone-Based Twisted Donor-Acceptor-Donor Derivatives as Blue Emitters for Highly Efficient Fluorescent Organic Light-Emitting Diodes.

This paper delves into the development of a group of twisted donor-acceptor-donor (D-A-D) derivatives incorporating bicarbazole as electron donor and benzophenone as electron acceptor for potential use as blue emitters in OLEDs. The derivatives were synthesized in a reaction of 4,4'-difluorobenzophenone with various 9-alkyl-9'H-3,3'-bicarbazoles. The materials, namely, DB14, DB23, and DB29, were designed with different alkyl side chains to enhance their solubility and film-forming properties of layers formed using the spin-coating from solution method. The new materials demonstrate high thermal stabilities with decomposition temperatures >383 °C, glass transition temperatures in the range of 95-145 °C, high blue photoluminescence quantum yields (>52%), and short decay times, which range in nanoseconds. Due to their characteristics, the derivatives were used as blue emitters in OLED devices. Some of the OLEDs incorporating the DB23 emitter demonstrated a high external quantum efficiency (EQEmax) of 5.3%, which is very similar to the theoretical limit of the first-generation devices.

Status and Challenges of Blue OLEDs: A Review.

Organic light-emitting diodes (OLEDs) have outperformed conventional display technologies in smartphones, smartwatches, tablets, and televisions while gradually growing to cover a sizable fraction of the solid-state lighting industry. Blue emission is a crucial chromatic component for realizing high-quality red, green, blue, and yellow (RGBY) and RGB white display technologies and solid-state lighting sources. For consumer products with desirable lifetimes and efficiency, deep blue emissions with much higher power efficiency and operation time are necessary prerequisites. This article reviews over 700 papers covering various factors, namely, the crucial role of blue emission for full-color displays and solid-state lighting, the performance status of blue OLEDs, and the systematic development of fluorescent, phosphorescent, and thermally activated delayed fluorescence blue emitters. In addition, various challenges concerning deep blue efficiency, lifetime, and approaches to realizing deeper blue emission and higher efficacy for blue OLED devices are also described.

High-Fat Diet Has a Protective Sex-Dependent Effect on Aortic Aneurysm Severity in a Marfan Syndrome Mouse Model.

BACKGROUND: Marfan syndrome (MFS) is a genetic disorder caused by mutations in fibrillin-1 and is characterized by thoracic aortic aneurysms and other complications. Previous studies revealed sexual dimorphisms in formation of aortic aneurysm in patients with MFS. The current study aimed to investigate the combined role of a high-fat diet (HFD) and biological sex in aortic disease using the mgR/mgR MFS mouse model. METHODS: Male and female mgR/mgR mice, as well as wild-type (WT) littermate mice, were fed a control diet (CD [10% fat]) or HFD (60% fat) from 4 to 12 weeks of age. Key aortic disease parameters analyzed included the diameter of the aortic wall; elastic fibre fragmentation; proteoglycan content; mRNA levels of Mmp12, Col1a1, Col3a1, and Fbn1; and fibrillin-1 deposition in the aortic wall. RESULTS: HFD-fed female mgR/mgR mice had significantly reduced aortic diameters (35%), elastic fibre fragmentation (56%), pathologically enhanced proteoglycans (45%), and expression of Mmp12 (64%), Col1a1 (41%), and Col3a1 (43%) compared with male mgR/mgR mice on HFD. Fibrillin-1 deposition and Fbn1 mRNA levels were unaffected. The data reveal a protective effect of HFD in female mice. In contrast, CD did not exert any protective effects. CONCLUSIONS: This study demonstrates a specific sexual dimorphism in MFS mice, with HFD exerting an explicit protective effect on severity of aortic disease in female mice. These preclinical data may be useful for developing nutritional recommendations for individuals with MFS in the longer term.

Bifunctional Bicarbazole-Benzophenone-Based Twisted Donor-Acceptor-Donor Derivatives for Deep-Blue and Green OLEDs.

Organic light-emitting diodes (OLEDs) have played a vital role in showing tremendous technological advancements for a better lifestyle, due to their display and lighting technologies in smartphones, tablets, television, and automotive industries. Undoubtedly, OLED is a mainstream technology and, inspired by its advancements, we have designed and synthesized the bicarbazole-benzophenone-based twisted donor-acceptor-donor (D-A-D) derivatives, namely DB13, DB24, DB34, and DB43, as bi-functional materials. These materials possess high decomposition temperatures (>360 °C) and glass transition temperatures (~125 °C), a high photoluminescence quantum yield (>60%), wide bandgap (>3.2 eV), and short decay time. Owing to their properties, the materials were utilized as blue emitters as well as host materials for deep-blue and green OLEDs, respectively. In terms of the blue OLEDs, the emitter DB13-based device outperformed others by showing a maximum EQE of 4.0%, which is close to the theoretical limit of fluorescent materials for a deep-blue emission (CIEy = 0.09). The same material also displayed a maximum power efficacy of 45 lm/W as a host material doped with a phosphorescent emitter Ir(ppy)3. Furthermore, the materials were also utilized as hosts with a TADF green emitter (4CzIPN) and the device based on DB34 displayed a maximum EQE of 11%, which may be attributed to the high quantum yield (69%) of the host DB34. Therefore, the bi-functional materials that are easily synthesized, economical, and possess excellent characteristics are expected to be useful in various cost-effective and high-performance OLED applications, especially in displays.

Beyond IBD: the genetics of other early-onset diarrhoeal disorders.

Diarrhoeal disorders in childhood extend beyond the inflammatory bowel diseases. Persistent and severe forms of diarrhoea can occur from birth and are associated with significant morbidity and mortality. These disorders can affect not only the gastrointestinal tract but frequently have extraintestinal manifestations, immunodeficiencies and endocrinopathies. Genomic analysis has advanced our understanding of these conditions and has revealed precision-based treatment options such as potentially curative haematopoietic stem cell transplant. Although many new mutations have been discovered, there is frequently no clear genotype-phenotype correlation. The functional effects of gene mutations can be studied in model systems such as patient-derived organoids. This allows us to further characterise these disorders and advance our understanding of the pathophysiology of the intestinal mucosa. In this review, we will provide an up to date overview of genes involved in diarrhoeal disorders of early onset, particularly focussing on the more recently described gene defects associated with protein loosing enteropathy.

Use of a combined transient elastography and biochemical strategy to determine liver fibrosis in pediatric intestinal failure.

BACKGROUND & AIMS: Non-invasive monitoring of intestinal failure (IF) associated liver disease is an ongoing challenge in children with IF. Our objective was to develop a combined algorithm of clinical, transient elastography (TE) and biochemical parameters to identify liver fibrosis in this population. METHODS: A retrospective cohort study of IF patients followed by our intestinal rehabilitation program between November 2015 to October 2019. Patients with a liver biopsy and TE were included. Demographic and liver function tests were collected. Fibrosis on liver biopsies was graded using the modified Scheuer score. Decision tree based algorithms classified low (F0-F1) versus high (F2-F4) fibrosis scores based on a combination of TE, biochemical and demographic parameters, using 6-fold classification error, sensitivity and specificity cross-validation (CV) scores. RESULTS: 42 patients (74% male, median age 7.6 (4.6; 42.7) months) were evaluated. Median length of PN therapy was 182 (121; 556) days. High fibrosis was present in 40.5% with a median TE of 12.1 (6.7; 12.9) kPa in high fibrosis children. An algorithm, based on cut-off values for TE of 11.3 kPa and AST of 40 U/L, and grouping of the underlying etiology resulted in a correct classification of 88.1% of the pathology scores; with sensitivity 0.82 (95% CI 0.57; 0.96), specificity 0.92 (95% CI 0.74; 0.99), positive predictive value 0.88 (95% CI 0.64; 0.96) and negative predictive value 0.88 (95% CI 0.73; 0.96). The CV classification error was 28.6%, CV sensitivity 72.2% and CV specificity 75.5%. CONCLUSIONS: This algorithm shows promising results that could simplify non-invasive monitoring of liver fibrosis in children with IF. Validation in additional IF cohorts is needed.

Precision cut intestinal slices, a novel model of acute food allergic reactions.

BACKGROUND: Food allergy affects up to 10% of the pediatric population. Despite ongoing efforts, treatment options remain limited. Novel models of food allergy are needed to study response patterns downstream of IgE-crosslinking and evaluate drugs modifying acute events. Here, we report a novel human ex vivo model that displays acute, allergen-specific, IgE-mediated smooth muscle contractions using precision cut intestinal slices (PCIS). METHODS: PCIS were generated using gut tissue samples from children who underwent clinically indicated surgery. Viability and metabolic activity were assessed from 0 to 24 h. Distribution of relevant cell subsets was confirmed using single nucleus RNA sequencing. PCIS were passively sensitized using plasma from peanut allergic donors or peanut-sensitized non-allergic donors, and exposed to various stimuli including serotonin, histamine, FcɛRI-crosslinker, and food allergens. Smooth muscle contractions and mediator release functioned as readouts. A novel program designed to measure contractions was developed to quantify responses. The ability to demonstrate the impact of antihistamines and immunomodulation from peanut oral immunotherapy (OIT) was assessed. RESULTS: PCIS viability was maintained for 24 h. Cellular distribution confirmed the presence of key cell subsets including mast cells. The video analysis tool reliably quantified responses to different stimulatory conditions. Smooth muscle contractions were allergen-specific and reflected the clinical phenotype of the plasma donor. Tryptase measurement confirmed IgE-dependent mast cell-derived mediator release. Antihistamines suppressed histamine-induced contraction and plasma from successful peanut OIT suppressed peanut-specific PCIS contraction. CONCLUSION: PCIS represent a novel human tissue-based model to study acute, IgE-mediated food allergy and pharmaceutical impacts on allergic responses in the gut.

Solution-processable organic light-emitting diodes utilizing electroluminescent perylene tetraester-based columnar liquid crystals.

Herein, we reveal a homologous series of liquid crystals involving perylene tetraesters as the core connected to the four trialkoxyphenyl units at the periphery using the triazole moiety as the linker. A thorough analysis using differential scanning calorimetry, polarized optical microscopy, and small- and wide-angle X-ray scattering studies confirm that all the mesogens 1a-c hold a stable enantiotropic columnar mesophase. Suitable molecular orbital levels and excellent material photophysical and thermal properties encouraged the study of their electroluminescent properties. Due to this, a well designed solution-processable organic light emitting diode device structure is configured as ITO (125 nm)/poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) (35 nm)/host: x wt% emitter (x = 0.5, 1.0, 3.0, 5.0) (20 nm)/2,2'2''-(1,3,5-benzinetriyl)tris(1-phenyl-1-H-benzimidazole) (TPBi) (40 nm)/lithium fluoride (LiF) (1 nm)/aluminium (Al) (200 nm) using compounds 1a-c as emitters. 4,4',4''-Tris[phenyl(m-tolyl)amino]triphenylamine (m-MTDATA) and 4,4'-bis(N-carbazolyl)-1,1'-biphenyl (CBP) were chosen as two different host materials. The current density-voltage-luminance and current efficacy-luminance-power efficacy plots suggest that m-MTDATA is a better host than CBP. Amongst, device based on 1 wt% emitter 1c doped in the m-MTDATA host matrix displayed the best performance, with a maximum power efficacy of 17.2 lm W-1, current efficacy of 18.5 cd A-1, and external quantum efficiency of 6.3%.

Digital quantitative tissue image analysis of hypoxia in resected pancreatic ductal adenocarcinomas.

Background: Tumor hypoxia is theorized to contribute to the aggressive biology of pancreatic ductal adenocarcinoma (PDAC). We previously reported that hypoxia correlated with rapid tumor growth and metastasis in patient-derived xenografts. Anticipating a prognostic relevance of hypoxia in patient tumors, we developed protocols for automated semi-quantitative image analysis to provide an objective, observer-independent measure of hypoxia. We further validated this method which can reproducibly estimate pimonidazole-detectable hypoxia in a high-through put manner. Methods: We studied the performance of three automated image analysis platforms in scoring pimonidazole-detectable hypoxia in resected PDAC (n = 10) in a cohort of patients enrolled in PIMO-PANC. Multiple stained tumor sections were analyzed on three independent image-analysis platforms, Aperio Genie (AG), Definiens Tissue Studio (TS), and Definiens Developer (DD), which comprised of a customized rule set. Results: The output from Aperio Genie (AG) had good concordance with manual scoring, but the workflow was resource-intensive and not suited for high-throughput analysis. TS analysis had high levels of variability related to misclassification of cells class, while the customized rule set of DD had a high level of reliability with an intraclass coefficient of more than 85%. Discussion: This work demonstrates the feasibility of developing a robust, high-performance pipeline for an automated, quantitative scoring of pimonidazole-detectable hypoxia in patient tumors.

Hepatic ultrastructural features distinguish paediatric Wilson disease from NAFLD and autoimmune hepatitis.

BACKGROUND AND AIMS: Wilson disease (WD) has diverse presentations that frequently mimic other liver diseases. Distinguishing WD from non-alcoholic fatty liver disease (NAFLD) and autoimmune hepatitis (AIH), can be difficult and has critical implications for medical management. This study aimed to examine the utility of histological features of WD in children compared to those with NAFLD and AIH. METHODS: A review of liver biopsy slides was performed in children with a clinical and/or genetic diagnosis of WD, seen at the Hospital for Sick Children between 1981 and 2019 and compared to controls with NAFLD and AIH. 37 children with WD and 37 disease controls (20 NAFLD; 17 AIH) were included. Three pathologists, blind to clinical details and diagnosis, reviewed all liver biopsies to reach consensus. Clinical and histopathologic features were compared between groups. RESULTS: Most WD cases displayed steatosis or steatohepatitis on histology (34/37), active AIH-pattern in 1 and inactive cirrhosis in 2 cases. Electron microscopy (EM) findings of mitochondrial abnormalities including dilated tips of cristae, pleomorphism, membrane duplication and dense matrix were more frequent in the WD group as compared to disease controls (p < 0.0001). In WD, dilated tips of mitochondrial cristae had a sensitivity of 91% and specificity of 86%, best among EM features. CONCLUSIONS: Light microscopic findings display considerable overlap among children with WD, NAFLD and AIH. Ultrastructural findings of mitochondrial abnormalities are important to distinguish WD from NAFLD and AIH. EM examination should be considered essential in the diagnostic work-up of paediatric liver biopsies.

Correction: Luminescent columnar discotics as highly efficient emitters in pure deep-blue OLEDs with an external quantum efficiency of 4.7.

Correction for 'Luminescent columnar discotics as highly efficient emitters in pure deep-blue OLEDs with an external quantum efficiency of 4.7%' by Joydip De et al., Soft Matter, 2022, DOI: 10.1039/d1sm01558c.

Magnetic resonance imaging of neonatal hemochromatosis.

Neonatal hemochromatosis is a rare condition that causes neonatal liver failure, frequently resulting in fetal loss or neonatal death. It is thought that most cases of neonatal hemochromatosis are caused by gestational alloimmune liver disease (GALD), with neonatal hemochromatosis being a phenotype of GALD rather than a disease process. Extrahepatic siderosis in the pancreas, myocardium, thyroid and minor salivary gland is a characteristic feature of neonatal hemochromatosis. There is also sparing of the reticuloendothelial system with no iron deposition in the spleen. Hepatic and extrahepatic siderosis seen in neonatal hemochromatosis is from iron dysregulation secondary to liver damage rather than iron deposition causing the liver damage. The presence of extrahepatic siderosis in the pancreas and thyroid is diagnostic of neonatal hemochromatosis and can be detected noninvasively by multi-echo gradient recalled echo (GRE) T2*-weighted sequence of MRI within hours of birth. This helps to expedite the treatment in the form of intravenous immunoglobulin and exchange transfusion, which improves the survival in these babies. The finding of hepatic siderosis is nonspecific and does not help in the diagnosis of neonatal hemochromatosis because it is seen with other causes of advanced liver disease.