Verifying Robustness of Gradient Boosted Models

Gradient boosted models are a fundamental machine learning technique. Robustness to small perturbations of the input is an important quality measure for machine learning models, but the literature lacks a method to prove the robustness of gradient boosted models. This work introduces VeriGB, a tool for quantifying the robustness of gradient boosted models. VeriGB encodes the model and the robustness property as an SMT formula, which enables state of the art verification tools to prove the model's robustness. We extensively evaluate VeriGB on publicly available datasets and demonstrate a capability for verifying large models. Finally, we show that some model configurations tend to be inherently more robust than others

Caveolae in Rabbit Ventricular Myocytes: Distribution and Dynamic Diminution after Cell Isolation

Caveolae are signal transduction centers, yet their subcellular distribution and preservation in cardiac myocytes after cell isolation are not well documented. Here, we quantify caveolae located within 100 nm of the outer cell surface membrane in rabbit single-ventricular cardiomyocytes over 8 h post-isolation and relate this to the presence of caveolae in intact tissue. Hearts from New Zealand white rabbits were either chemically fixed by coronary perfusion or enzymatically digested to isolate ventricular myocytes, which were subsequently fixed at 0, 3, and 8 h post-isolation. In live cells, the patch-clamp technique was used to measure whole-cell plasma membrane capacitance, and in fixed cells, caveolae were quantified by transmission electron microscopy. Changes in cell-surface topology were assessed using scanning electron microscopy. In fixed ventricular myocardium, dual-axis electron tomography was used for three-dimensional reconstruction and analysis of caveolae in situ. The presence and distribution of surface-sarcolemmal caveolae in freshly isolated cells matches that of intact myocardium. With time, the number of surface-sarcolemmal caveolae decreases in isolated cardiomyocytes. This is associated with a gradual increase in whole-cell membrane capacitance. Concurrently, there is a significant increase in area, diameter, and circularity of sub-sarcolemmal mitochondria, indicative of swelling. In addition, electron tomography data from intact heart illustrate the regular presence of caveolae not only at the surface sarcolemma, but also on transverse-tubular membranes in ventricular myocardium. Thus, caveolae are dynamic structures, present both at surface-sarcolemmal and transverse-tubular membranes. After cell isolation, the number of surface-sarcolemmal caveolae decreases significantly within a time frame relevant for single-cell research. The concurrent increase in cell capacitance suggests that membrane incorporation of surface-sarcolemmal caveolae underlies this, but internalization and/or micro-vesicle loss to the extracellular space may also contribute. Given that much of the research into cardiac caveolae-dependent signaling utilizes isolated cells, and since caveolae-dependent pathways matter for a wide range of other study targets, analysis of isolated cell data should take the time post-isolation into account

Heat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancer

In the colon, long-term exposure to chronic inflammation drives colitis-associated colon cancer (CAC) in patients with inflammatory bowel disease. While the causal and clinical links are well established, molecular understanding of how chronic inflammation leads to the development of colon cancer is lacking. Here we deconstruct the evolving microenvironment of CAC by measuring proteomic changes and extracellular matrix (ECM) organization over time in a mouse model of CAC. We detect early changes in ECM structure and composition, and report a crucial role for the transcriptional regulator heat shock factor 1 (HSF1) in orchestrating these events. Loss of HSF1 abrogates ECM assembly by colon fibroblasts in cell-culture, prevents inflammation-induced ECM remodeling in mice and inhibits progression to CAC. Establishing relevance to human disease, we find high activation of stromal HSF1 in CAC patients, and detect the HSF1-dependent proteomic ECM signature in human colorectal cancer. Thus, HSF1-dependent ECM remodeling plays a crucial role in mediating inflammation-driven colon cancer.R35 GM118173 - NIGMS NIH HHS; U01 TR002625 - NCATS NIH HHS; P30 CA008748 - NCI NIH HHS; FC010144 - Cancer Research UK; FC010144 - Medical Research Council; FC010144 - Wellcome TrustPublished versio

Derivation of Xeno-Free and GMP-Grade Human Embryonic Stem Cells – Platforms for Future Clinical Applications

Clinically compliant human embryonic stem cells (hESCs) should be developed in adherence to ethical standards, without risk of contamination by adventitious agents. Here we developed for the first time animal-component free and good manufacturing practice (GMP)-compliant hESCs. After vendor and raw material qualification, we derived xeno-free, GMP-grade feeders from umbilical cord tissue, and utilized them within a novel, xeno-free hESC culture system. We derived and characterized three hESC lines in adherence to regulations for embryo procurement, and good tissue, manufacturing and laboratory practices. To minimize freezing and thawing, we continuously expanded the lines from initial outgrowths and samples were cryopreserved as early stocks and banks. Batch release criteria included DNA-fingerprinting and HLA-typing for identity, characterization of pluripotency-associated marker expression, proliferation, karyotyping and differentiation in-vitro and in-vivo. These hESCs may be valuable for regenerative therapy. The ethical, scientific and regulatory methodology presented here may serve for development of additional clinical-grade hESCs

BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking clusterin expression in cancer associated fibroblasts with HSF1 signaling

Tumors initiate by mutations in cancer cells, and progress through interactions of the cancer cells with non-malignant cells of the tumor microenvironment. Major players in the tumor microenvironment are cancer-associated fibroblasts (CAFs), which support tumor malignancy, and comprise up to 90% of the tumor mass in pancreatic cancer. CAFs are transcriptionally rewired by cancer cells. Whether this rewiring is differentially affected by different mutations in cancer cells is largely unknown. Here we address this question by dissecting the stromal landscape of BRCA-mutated and BRCA Wild-type pancreatic ductal adenocarcinoma. We comprehensively analyze pancreatic cancer samples from 42 patients, revealing different CAF subtype compositions in germline BRCA-mutated vs. BRCA Wild-type tumors. In particular, we detect an increase in a subset of immune-regulatory clusterin-positive CAFs in BRCA-mutated tumors. Using cancer organoids and mouse models we show that this process is mediated through activation of heat-shock factor 1, the transcriptional regulator of clusterin. Our findings unravel a dimension of stromal heterogeneity influenced by germline mutations in cancer cells, with direct implications for clinical research

In vivo observation of anisotropic motion of brain water using2H double quantum filtered NMR spectroscopy

The 2H DQF NMR spectra of deuterated water molecules were measured for the first time in in vivo rat brain. The observation of the DQF signal indicates that there is a water population that exhibits anisotropic motion. The characteristics of the DQF spectra premortem and postmortem are very similar (lineshape and relaxation times). In the 1st h there is a 10–15% decrease in the signal intensity of the DQF spectra followed by a gradual but a much slower decrease in the DQF signal intensity that reaches 65–70% of its initial value after only 12 h. When the brains were kept at 4°C, a 40% decrease in the DQ signal intensity was observed only after 7 days. Mechanical chopping of the brain tissues causes an immediate loss of more that 97% of the DQ signals. The slow, temperature-sensitive decay of the signal, and its sensitivity to mechanical treatment point out that these signals originate from water molecules that interact with structural components in the brain. The characteristics of the DQF spectra depend on the amount of bulk water as exemplified by increased residual quadrupolar interaction and relaxation rates obtained when dehydrating the brain tissue

Using affinity perturbations to detect web traffic anomalies

The initial training phase of machine learning algorithms is usually computationally expensive as it involves the processing of huge matrices. Evolving datasets are challenging from this point of view because changing behavior requires updating the training. We propose a method for updating the training profile efficiently and a sliding window algorithm for online processing of the data in smaller fractions. This assumes the data is modeled by a kernel method that includes spectral decomposition. We demonstrate the algorithm with a web server request log where an actual intrusion attack is known to happen. Updating the kernel dynamically using a sliding window technique, prevents the problem of single initial training and can process evolving datasets more efficiently.peerReviewe

Susceptibility-matched envelope for the correction of EPI artifacts

Fast gradient echo sequences, such as echo planer imaging (EPI) and spiral imaging, are vulnerable to artifacts resulting from B0 inhomogeneities. A major contribution to these artifacts is the susceptibility variation across the head, which is most severe in regions adjacent to air–tissue interfaces, such as the mouth, nasal sinuses, ears and the cortex. Susceptibility artifacts can cause geometrical distortions in the image as well as loss of signal due to T2* dephasing. The extent of these artifacts increases with the main field, thus compromising the signal-to-noise ratio (SNR) benefit gained in higher fields. In the current work, inhomogeneity caused by susceptibility variations at the external boundary of the human body has been corrected by surrounding the organs with a liquid without hydrogen atoms and whose susceptibility is similar to that of the imaged organ. EPI experiments were conducted on head-sized phantom, human brain, hand and legs. This method causes minimal patient inconvenience and no interference with any function of the scanner, thus yielding a simple and efficient solution for the correction of B0 variation