Background Necrotizing enterocolitis (NEC) is a leading cause of death in very low birth weight (VLBW) neonates. The overall mortality of NEC is well documented. However, those requiring surgery ...appear to have increased mortality compared with those managed medically. The objective of this study was to establish national birth-weight-based benchmarks for the mortality of surgical NEC and describe the use and mortality of laparotomy vs peritoneal drainage. Study Design There were 655 US centers that prospectively evaluated 188,703 VLBW neonates (401 to 1,500 g) between 2006 and 2010. Survival was defined as living in-hospital at 1-year or hospital discharge. Results There were 17,159 (9%) patients who had NEC, with mortality of 28%; 8,224 patients did not receive operations (medical NEC, mortality 21%) and 8,935 were operated on (mortality 35%). On multivariable regression, lower birth weight, laparotomy, and peritoneal drainage were independent predictors of mortality (p < 0.0001). In surgical NEC, a plateau mortality of around 30% persisted despite birth weights >750 g; medical NEC mortality fell consistently with increasing birth weight. For example, in neonates weighing 1,251 to 1,500 g, mortality was 27% in surgical vs 6% in medical NEC (odds ratio OR 6.10, 95% CI 4.58 to 8.12). Of those treated surgically, 6,131 (69%) underwent laparotomy only (mortality 31%), 1,283 received peritoneal drainage and a laparotomy (mortality 34%), and 1,521 had peritoneal drainage alone (mortality 50%). Conclusions Fifty-two percent of VLBW neonates with NEC underwent surgery, which was accompanied by a substantial increase in mortality. Regardless of birth weight, surgical NEC showed a plateau in mortality at approximately 30%. Laparotomy was the more frequent method of treatment (69%) and of those managed by drainage, 46% also had a laparotomy. The laparotomy alone and drainage with laparotomy groups had similar mortalities, while the drainage alone treatment cohort was associated with the highest mortality.
Machine learning (ML) profoundly improves the accuracy of the fast DU8+ hybrid density functional theory/parametric computations of nuclear magnetic resonance spectra, allowing for high throughput in ...silico validation and revision of complex alkaloids and other natural products. Of nearly 170 alkaloids surveyed, 35 structures are revised with the next-generation ML-augmented DU8 method, termed DU8ML.
The aim of a clinical classification of pulmonary hypertension (PH) is to group together different manifestations of disease sharing similarities in pathophysiologic mechanisms, clinical ...presentation, and therapeutic approaches. In 2003, during the 3rd World Symposium on Pulmonary Hypertension, the clinical classification of PH initially adopted in 1998 during the 2nd World Symposium was slightly modified. During the 4th World Symposium held in 2008, it was decided to maintain the general architecture and philosophy of the previous clinical classifications. The modifications adopted during this meeting principally concern Group 1, pulmonary arterial hypertension (PAH). This subgroup includes patients with PAH with a family history or patients with idiopathic PAH with germline mutations (e.g., bone morphogenetic protein receptor-2, activin receptor-like kinase type 1, and endoglin). In the new classification, schistosomiasis and chronic hemolytic anemia appear as separate entities in the subgroup of PAH associated with identified diseases. Finally, it was decided to place pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis in a separate group, distinct from but very close to Group 1 (now called Group 1′). Thus, Group 1 of PAH is now more homogeneous.
Light‐emitting semiconductor quantum dots (QDs) combined with magnetic resonance imaging contrast agents within a single nanoparticle platform are considered to perform as multimodal imaging probes ...in biomedical research and related clinical applications. The principles of their rational design are outlined and contemporary synthetic strategies are reviewed (heterocrystalline growth; co‐encapsulation or assembly of preformed QDs and magnetic nanoparticles; conjugation of magnetic chelates onto QDs; and doping of QDs with transition metal ions), identifying the strengths and weaknesses of different approaches. Some of the opportunities and benefits that arise through in vivo imaging using these dual‐mode probes are highlighted where tumor location and delineation is demonstrated in both MRI and fluorescence modality. Work on the toxicological assessments of QD/magnetic nanoparticles is also reviewed, along with progress in reducing their toxicological side effects for eventual clinical use. The review concludes with an outlook for future biomedical imaging and the identification of key challenges in reaching clinical applications.
Light‐emitting semiconductor quantum dots (QDs) combined with magnetic components offer appealing potential for biomedical applications. This review summarizes recent achievements in contemporary synthesis strategies identifying the strengths and weaknesses of different approaches, describes multimodal imaging of tumors in vivo, examines current understanding of the toxicity of QDs/magnetic nanoparticles, and discusses key challenges in reaching clinical applications with these materials and the perspectives for their future use in biomedical imaging.
Duality defects in E8 Burbano, Ivan M.; Kulp, Justin; Neuser, Jonas
The journal of high energy physics,
28/10, Letnik:
2022, Številka:
10
Journal Article
Recenzirano
Odprti dostop
A
bstract
We classify all non-invertible Kramers-Wannier duality defects in the
E
8
lattice Vertex Operator Algebra (i.e. the chiral (
E
8
)
1
WZW model) coming from ℤ
m
symmetries. We illustrate how ...these defects are systematically obtainable as ℤ
2
twists of invariant sub-VOAs, compute defect partition functions for small
m
, and verify our results against other techniques. Throughout, we focus on taking a physical perspective and highlight the important moving pieces involved in the calculations. Kac’s theorem for finite automorphisms of Lie algebras and contemporary results on holomorphic VOAs play a role. We also provide a perspective from the point of view of (2+1)d Topological Field Theory and provide a rigorous proof that all corresponding Tambara-Yamagami actions on holomorphic VOAs can be obtained in this manner. We include a list of directions for future studies.
EGFR-mutant lung adenocarcinomas (LUAD) display diverse clinical trajectories and are characterized by rapid but short-lived responses to EGFR tyrosine kinase inhibitors (TKIs). Through sequencing of ...79 spatially distinct regions from 16 early stage tumors, we show that despite low mutation burdens, EGFR-mutant Asian LUADs unexpectedly exhibit a complex genomic landscape with frequent and early whole-genome doubling, aneuploidy, and high clonal diversity. Multiple truncal alterations, including TP53 mutations and loss of CDKN2A and RB1, converge on cell cycle dysregulation, with late sector-specific high-amplitude amplifications and deletions that potentially beget drug resistant clones. We highlight the association between genomic architecture and clinical phenotypes, such as co-occurring truncal drivers and primary TKI resistance. Through comparative analysis with published smoking-related LUAD, we postulate that the high intra-tumor heterogeneity observed in Asian EGFR-mutant LUAD may be contributed by an early dominant driver, genomic instability, and low background mutation rates.
The Drosophila Yorkie (Yki) protein and its mammalian homolog Yes-associated protein (YAP) are potent growth promoters, and YAP overexpression is associated with multiple types of cancer 1, 2. Yki ...and YAP are transcriptional coactivators and function as downstream effectors of the Hippo tumor suppressor pathway 1–4. The regulation of Yki and YAP by the Hippo signaling pathway has been extensively investigated; however, how they regulate gene expression is poorly understood. To identify additional regulators of Yki activity, we performed a genome-wide RNAi screen in Drosophila S2 cells. In this screen, we identified the conserved protein Mask (Multiple ankyrin repeats single KH domain) as a novel promoter of Yki activity in vitro and validated this function in vivo in Drosophila. We found that Mask is required downstream of the Hippo pathway for Yki to induce target-gene expression and that Mask forms complexes with Yki. The human Mask homolog MASK1 complexes with YAP and is required for the full activity of YAP. Additionally, elevated MASK1 expression is associated with worsened outcomes for breast cancer patients. We conclude that Mask is a novel cofactor for Yki/YAP required for optimal Yki/YAP activity during development and oncogenesis.
► Mask is required for tissue growth and activation of Yki target genes in Drosophila ► Mask forms complexes with the Hippo pathway effector Yki ► Human MASK complexes with YAP and is required for full YAP activity in mammalian cells ► Mask expression levels correlate with worsened outcomes for breast cancer patients
This manuscript reports preliminary results obtained by combining estimates of two or three (among seven) quantitative ultrasound (QUS) parameters in a model-free, multi-parameter classifier to ...differentiate breast carcinomas from fibroadenomas (the most common benign solid tumor). Forty-three patients scheduled for core biopsy of a suspicious breast mass were recruited. Radiofrequency echo signal data were acquired using clinical breast ultrasound systems equipped with linear array transducers. The reference phantom method was used to obtain system-independent estimates of the specific attenuation (ATT), the average backscatter coefficients, the effective scatterer diameter (ESD) and an effective scatterer diameter heterogeneity index (ESDHI) over regions of interest within each mass. In addition, the envelope amplitude signal-to-noise ratio (SNR), the Nakagami shape parameter, m, and the maximum collapsed average (maxCA) of the generalized spectrum were also computed. Classification was performed using the minimum Mahalanobis distance to the centroids of the training classes and tested against biopsy results. Classification performance was evaluated with the area under the receiver operating characteristic (ROC) curve. The best performance with a two-parameter classifier used the ESD and ESDHI and resulted in an area under the ROC curve of 0.98 (95% confidence interval CI: 0.95-1.00). Classification performance improved with three parameters (ATT, ESD and ESDHI) yielding an area under the ROC curve of 0.999 (0.995-1.000). These results suggest that system-independent QUS parameters, when combined in a model-free classifier, are a promising tool to characterize breast tumors. A larger study is needed to further test this idea.
Mutations in the gene encoding the protein kinase CDKL5 cause a debilitating neurodevelopmental disease termed CDKL5 disorder. The impact of these mutations on CDKL5 function is poorly understood ...because the substrates and cellular processes controlled by CDKL5 are unclear. Here, we describe a quantitative phosphoproteomic screening which identified MAP1S, CEP131 and DLG5—regulators of microtubule and centrosome function—as cellular substrates of CDKL5. Antibodies against MAP1S phospho‐Ser900 and CEP131 phospho‐Ser35 confirmed CDKL5‐dependent phosphorylation of these targets in human cells. The phospho‐acceptor serine residues in MAP1S, CEP131 and DLG5 lie in the motif RPXSA, although CDKL5 can tolerate residues other than Ala immediately C‐terminal to the phospho‐acceptor serine. We provide insight into the control of CDKL5 activity and show that pathogenic mutations in CDKL5 cause a major reduction in CDKL5 activity in vitro and in cells. These data reveal the first cellular substrates of CDKL5, which may represent important biomarkers in the diagnosis and treatment of CDKL5 disorder, and illuminate the functions of this poorly characterized kinase.
Synopsis
CDKL5 kinase is mutated in a neurodevelopmental disease termed CDKL5 disorder but the cellular targets and functions of CDKL5 are unclear. A phosphoproteomic screen to identify cellular targets of CDKL5 now addresses this gap.
CDKL5 phosphorylates MAP1S, CEP131, and DLG5, proteins involved in regulation of microtubules and centrosomes.
In all three substrates, the phosphorylated serine lies in an RPXSA motif, with in vitro analysis showing certain amino acids other than Ala also tolerated C‐terminal to the phosphoacceptor serine.
CDKL5 activity is controlled by tyrosine auto‐phosphorylation in its T‐loop.
Pathogenic CDKL5 mutations cause severe reduction in kinase activity towards MAP1S and CEP131 in cells and in vitro.
Identification of phosphorylation targets reveals a sequence preference for the neurodevelopmental disease‐linked CDKL5, and that pathogenic mutations decrease activity towards microtubule‐ and centrosome‐associated substrates.
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