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"E. Lim"
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Marvel universe. Time and again
\"What mysteries await buried deep within the multitude of the Marvel Universe? During an advance scouting mission in World War II, Captain America and Bucky come across an old farmhouse where a group of concentration camp escapees are fending off recapture. Years ago, Spider-Man came back from an alien world with a fantastic new costume - a living alien symbiote looking to bond with him permanently! Anxious to find a world worthy enough to sate the mighty hunger of GALACTUS, Norrin Radd's early explorations as the Devourer's new Herald bear no fruit. When a Secret Invasion of Skrulls turns Manhattan upside down, Miles Morales must choose: do his great powers come with great responsibility? When Detective Misty Knight places the newest super-suit on the block, Daredevil, at the scene of a crime, sparks will fly - and not the good kind. What secrets has Kitty Pryde been keeping from her summer at Camp Maplebrook? And as World War II draws to a close, Sergeant Fury and his Howling Commandos face a mission unlike any other they've ever tackled!\"--Provided by publisher.
Book
Machine Learning and Portfolio Optimization
The portfolio optimization model has limited impact in practice because of estimation issues when applied to real data. To address this, we adapt two machine learning methods, regularization and cross-validation, for portfolio optimization. First, we introduce
performance-based regularization
(PBR), where the idea is to constrain the sample variances of the estimated portfolio risk and return, which steers the solution toward one associated with less estimation error in the performance. We consider PBR for both mean-variance and mean-conditional value-at-risk (CVaR) problems. For the mean-variance problem, PBR introduces a quartic polynomial constraint, for which we make two convex approximations: one based on rank-1 approximation and another based on a convex quadratic approximation. The rank-1 approximation PBR adds a bias to the optimal allocation, and the convex quadratic approximation PBR shrinks the sample covariance matrix. For the mean-CVaR problem, the PBR model is a combinatorial optimization problem, but we prove its convex relaxation, a quadratically constrained quadratic program, is essentially tight. We show that the PBR models can be cast as robust optimization problems with novel uncertainty sets and establish asymptotic optimality of both sample average approximation (SAA) and PBR solutions and the corresponding efficient frontiers. To calibrate the right-hand sides of the PBR constraints, we develop new, performance-based
k
-fold cross-validation algorithms. Using these algorithms, we carry out an extensive empirical investigation of PBR against SAA, as well as L1 and L2 regularizations and the equally weighted portfolio. We find that PBR dominates all other benchmarks for two out of three Fama–French data sets.
This paper was accepted by Yinyu Ye, optimization
.
Journal Article
Variability of the extent of the Hadley circulation in the southern hemisphere: a regional perspective
In order to understand the regional impacts of variations in the extent of the Hadley circulation in the Southern Hemisphere, regional Hadley circulations are defined in three sectors centered on the main tropical heat sources over Africa, Asia-Pacific (Maritime Continent) and the Americas. These regional circulations are defined by computing a streamfunction from the divergent component of the meridional wind. A major finding from this study is that year-to-year variability in the extent of the hemispheric Hadley circulation in the Southern Hemisphere is primarily governed by variations of the extent of the Hadley circulation in the Asia-Pacific sector, especially during austral spring and summer when there is little co-variability with the African sector, and the American sector exhibits an out of phase behavior. An expanded Hadley circulation in the Southern Hemisphere (both hemispherically and in the Asia-Pacific sector) is associated with La Niña conditions and a poleward expansion of the tropical wet zone in the Asia-Pacific sector. While La Niña also promotes expansion in the American and African sectors during austral winter, these tropical conditions tend to promote contraction in the two sectors during austral summer as a result of compensating convergence over the Americas and Africa sectors: a process driven by variations in the Walker circulation and Rossby wave trains emanating from the tropical Indian Ocean.
Journal Article
Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing
Macrophages perform diverse functions within tissues during immune responses to pathogens and injury, but molecular mechanisms by which physical properties of the tissue regulate macrophage behavior are less well understood. Here, we examine the role of the mechanically activated cation channel Piezo1 in macrophage polarization and sensing of microenvironmental stiffness. We show that macrophages lacking Piezo1 exhibit reduced inflammation and enhanced wound healing responses. Additionally, macrophages expressing the transgenic Ca
2+
reporter, Salsa6f, reveal that Ca
2+
influx is dependent on Piezo1, modulated by soluble signals, and enhanced on stiff substrates. Furthermore, stiffness-dependent changes in macrophage function, both in vitro and in response to subcutaneous implantation of biomaterials in vivo, require Piezo1. Finally, we show that positive feedback between Piezo1 and actin drives macrophage activation. Together, our studies reveal that Piezo1 is a mechanosensor of stiffness in macrophages, and that its activity modulates polarization responses.
Macrophages perform diverse functions during immune responses, but the molecular mechanisms by which physical properties of the tissue regulate macrophage behavior remain unknown. Here the authors find that Piezo1 is a mechanosensor of stiffness, and that its activity modulates macrophage polarization responses.
Journal Article
Claudin-1 induces epithelial-mesenchymal transition through activation of the c-Abl-ERK signaling pathway in human liver cells
Claudins (CLDNs) are a family of integral membrane proteins central to the formation of tight junctions, structures that are involved in paracellular transport and cellular growth and differentiation, and are critical for the maintenance of cellular polarity. Recent studies have provided evidence that CLDNs are aberrantly expressed in diverse types of human cancers, including hepatocellular carcinomas (HCCs). However, little is known about how CLDN expression is involved in cancer progression. In this study, we show that CLDN1 has a causal role in the epithelial-mesenchymal transition (EMT) in human liver cells, and that the c-Abl-Ras-Raf-1-ERK1/2 signaling axis is critical for the induction of malignant progression by CLDN1. Overexpression of CLDN1 induced expression of the EMT-regulating transcription factors Slug and Zeb1, and thereby led to repression of E-cadherin, β-catenin expression, enhanced expression of N-cadherin and Vimentin, a loss of cell adhesion, and increased cell motility in normal liver cells and HCC cells. In line with these findings, inhibition of either c-Abl or ERK clearly attenuated CLDN1-induced EMT, as evidenced by a reversal of N-cadherin and E-cadherin expression patterns, and restored normal motility. Collectively, these results indicate that CLDN1 is necessary for the induction of EMT in human liver cells, and that activation of the c-Abl-Ras-Raf-1-ERK1/2 signaling pathway is required for CLDN1-induced acquisition of the malignant phenotype. The present observations suggest that CLDN1 could be exploited as a biomarker for liver cancer metastasis and might provide a pivotal point for therapeutic intervention in HCC.
Journal Article
Tropical and Extratropical Influences on the Variability of the Southern Hemisphere Wintertime Subtropical Jet
Interannual variability of the Southern Hemisphere subtropical jet (STJ) is assessed using atmospheric reanalyses during 1979–2018. The focus is on the austral winter season when the STJ is strongest and most distinct from the midlatitude eddy-driven jet (EDJ). Variations in the intensity and latitudinal position of the STJ are diagnosed using an index developed to discriminate between variations associated with the EDJ. STJ intensity and position variations are found to be tied to different mechanisms. An intensification of the STJ is associated with enhanced divergent outflow from diabatic heating over the equatorial Pacific Ocean, primarily resulting from eastern Pacific or canonical El Niño. This intensification is associated with a narrowing of the STJ and an in-place weakening of the EDJ. An equatorward-shifted STJ, however, appears to be eddy driven and is associated with an acceleration and poleward displacement of the EDJ, which projects onto the positive polarity of the southern annular mode. As has previously been reported, El Niño Modoki (or central Pacific El Niño) can act to shift the EDJ poleward during austral winter; thus, a possible pathway for changes in the position of the STJ is via tropically forced changes in the position of the EDJ. In contrast to previous studies, we also highlight a weakening and poleward shift of the STJ in association with an expansion of the Hadley circulation.
Journal Article
Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol
Aims/hypothesis
Type 2 diabetes is regarded as inevitably progressive, with irreversible beta cell failure. The hypothesis was tested that both beta cell failure and insulin resistance can be reversed by dietary restriction of energy intake.
Methods
Eleven people with type 2 diabetes (49.5 ± 2.5 years, BMI 33.6 ± 1.2 kg/m
2
, nine male and two female) were studied before and after 1, 4 and 8 weeks of a 2.5 MJ (600 kcal)/day diet. Basal hepatic glucose output, hepatic and peripheral insulin sensitivity and beta cell function were measured. Pancreas and liver triacylglycerol content was measured using three-point Dixon magnetic resonance imaging. An age-, sex- and weight-matched group of eight non-diabetic participants was studied.
Results
After 1 week of restricted energy intake, fasting plasma glucose normalised in the diabetic group (from 9.2 ± 0.4 to 5.9 ± 0.4 mmol/l;
p
= 0.003). Insulin suppression of hepatic glucose output improved from 43 ± 4% to 74 ± 5% (
p
= 0.003 vs baseline; controls 68 ± 5%). Hepatic triacylglycerol content fell from 12.8 ± 2.4% in the diabetic group to 2.9 ± 0.2% by week 8 (
p
= 0.003). The first-phase insulin response increased during the study period (0.19 ± 0.02 to 0.46 ± 0.07 nmol min
−1
m
−2
;
p
< 0.001) and approached control values (0.62 ± 0.15 nmol min
−1
m
−2
;
p
= 0.42). Maximal insulin response became supranormal at 8 weeks (1.37 ± 0.27 vs controls 1.15 ± 0.18 nmol min
−1
m
−2
). Pancreatic triacylglycerol decreased from 8.0 ± 1.6% to 6.2 ± 1.1% (
p
= 0.03).
Conclusions/interpretation
Normalisation of both beta cell function and hepatic insulin sensitivity in type 2 diabetes was achieved by dietary energy restriction alone. This was associated with decreased pancreatic and liver triacylglycerol stores. The abnormalities underlying type 2 diabetes are reversible by reducing dietary energy intake.
Journal Article
Prediction models used in the progression of chronic kidney disease: A scoping review
To provide a review of prediction models that have been used to measure clinical or pathological progression of chronic kidney disease (CKD).
Scoping review.
Medline, EMBASE, CINAHL and Scopus from the year 2011 to 17th February 2022.
All English written studies that are published in peer-reviewed journals in any country, that developed at least a statistical or computational model that predicted the risk of CKD progression.
Eligible studies for full text review were assessed on the methods that were used to predict the progression of CKD. The type of information extracted included: the author(s), title of article, year of publication, study dates, study location, number of participants, study design, predicted outcomes, type of prediction model, prediction variables used, validation assessment, limitations and implications.
From 516 studies, 33 were included for full-text review. A qualitative analysis of the articles was compared following the extracted information. The study populations across the studies were heterogenous and data acquired by the studies were sourced from different levels and locations of healthcare systems. 31 studies implemented supervised models, and 2 studies included unsupervised models. Regardless of the model used, the predicted outcome included measurement of risk of progression towards end-stage kidney disease (ESKD) of related definitions, over given time intervals. However, there is a lack of reporting consistency on details of the development of their prediction models.
Researchers are working towards producing an effective model to provide key insights into the progression of CKD. This review found that cox regression modelling was predominantly used among the small number of studies in the review. This made it difficult to perform a comparison between ML algorithms, more so when different validation methods were used in different cohort types. There needs to be increased investment in a more consistent and reproducible approach for future studies looking to develop risk prediction models for CKD progression.
Journal Article
DNA metabarcoding of insects and allies: an evaluation of primers and pipelines
Metabarcoding, the coupling of DNA-based species identification and high-throughput sequencing, offers enormous promise for arthropod biodiversity studies but factors such as cost, speed and ease-of-use of bioinformatic pipelines, crucial for making the leapt from demonstration studies to a real-world application, have not yet been adequately addressed. Here, four published and one newly designed primer sets were tested across a diverse set of 80 arthropod species, representing 11 orders, to establish optimal protocols for Illumina-based metabarcoding of tropical Malaise trap samples. Two primer sets which showed the highest amplification success with individual specimen polymerase chain reaction (PCR, 98%) were used for bulk PCR and Illumina MiSeq sequencing. The sequencing outputs were subjected to both manual and simple metagenomics quality control and filtering pipelines. We obtained acceptable detection rates after bulk PCR and high-throughput sequencing (80–90% of input species) but analyses were complicated by putative heteroplasmic sequences and contamination. The manual pipeline produced similar or better outputs to the simple metagenomics pipeline (1.4 compared with 0.5 expected:unexpected Operational Taxonomic Units). Our study suggests that metabarcoding is slowly becoming as cheap, fast and easy as conventional DNA barcoding, and that Malaise trap metabarcoding may soon fulfill its potential, providing a thermometer for biodiversity.
Journal Article
c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells
Uncovering the mechanisms that govern the maintenance of stem-like cancer cells is critical for developing therapeutic strategies for targeting these cells. Constitutive activation of c-Jun N-terminal kinase (JNK) has been reported in gliomas and correlates with histological grade. Here, we found that JNK signaling is crucial for the maintenance of ‘stemness’ in glioma cells. Sphere-cultured glioma cells showed more phosphorylation of JNK compared with serum-containing monolayer cultures. Importantly, blockade of JNK signaling with SP600125 or small interfering RNAs targeting JNK1 or JNK2 significantly reduced the CD133
+
/Nestin
+
population and suppressed sphere formation, colony formation in soft agar, and expression of stem cell markers in sphere-cultured glioma cells. Intriguingly, sphere-cultured glioma cells exhibited enhanced expression of Notch-2, but not Notch-1, -3 or -4, and JNK inhibition almost completely abrogated this increase. Blocking the phosphoinoside 3-kinase (PI3K)/Akt pathway with LY294002 or si-Akt also suppressed the self-renewal of sphere-cultured glioma cells. PI3K, but not Akt, had a role as an upstream kinase in JNK1/2 activation. In addition, treatment with si-JNK greatly increased etoposide- and ionizing radiation (IR)-induced cell death in glioma spheres. Consistent with glioma cell lines, glioma stem-like cells isolated from primary patient glioma cells also had a higher activity of JNK and Notch-2 expression. Importantly, inhibition of JNK2 led to a decrease of Notch-2 expression and suppressed the CD133
+
/Nestin
+
cell population in patient-derived primary glioma cells. Finally, downregulation of JNK2 almost completely suppressed intracranial tumor formation by glioma cells in nude mice. Taken together, these data demonstrate that JNK signaling is crucial for the maintenance of self-renewal and tumorigenicity of glioma stem-like cells and drug/IR resistance, and can be considered a promising target for eliminating stem-like cancer cells in gliomas.
Journal Article