An Exact Kernel Equivalence for Finite Classification Models

We explore the equivalence between neural networks and kernel methods by deriving the first exact representation of any finite-size parametric classification model trained with gradient descent as a kernel machine. We compare our exact representation to the well-known Neural Tangent Kernel (NTK) and discuss approximation error relative to the NTK and other non-exact path kernel formulations. We experimentally demonstrate that the kernel can be computed for realistic networks up to machine precision. We use this exact kernel to show that our theoretical contribution can provide useful insights into the predictions made by neural networks, particularly the way in which they generalize.Comment: TAG-ML at ICML 2023 in Proceedings. 8 pages, 6 figures, proofs in Appendi

Faster algorithms for learning convex functions

W911NF2110246 - Department of Defense/ARO; CCF-2007350 - National Science Foundation; CCF-1955981 - National Science Foundationhttps://proceedings.mlr.press/v162/siahkamari22a/siahkamari22a.pdfFirst author draf

Sources, mechanisms, and timescales of sediment delivery to a New England salt marsh

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Baranes, H., Woodruff, J., Geyer, W., Yellen, B., Richardson, J. & Griswold, F. Sources, mechanisms, and timescales of sediment delivery to a New England salt marsh. Journal of Geophysical Research: Earth Surface, 127, (2022): e2021JF006478, https://doi.org/10.1029/2021jf006478.he availability and delivery of an external clastic sediment source is a key factor in determining salt marsh resilience to future sea level rise. However, information on sources, mechanisms, and timescales of sediment delivery are lacking, particularly for wave-protected mesotidal estuaries. Here we show that marine sediment mobilized and delivered during coastal storms is a primary source to the North and South Rivers, a mesotidal bar-built estuary in a small river system impacted by frequent, moderate-intensity storms that is typical to New England (United States). On the marsh platform, deposition rates, clastic content, and dilution of fluvially-sourced contaminated sediment by marine material all increase down-estuary toward the inlet, consistent with a predominantly marine-derived sediment source. Marsh clastic deposition rates are also highest in the storm season. We observe that periods of elevated turbidity in channels and over the marsh are concurrent with storm surge and high wave activity offshore, rather than with high river discharge. Flood tide turbidity also exceeds ebb tide turbidity during storm events. Timescales of storm-driven marine sediment delivery range from 2.5 days to 2 weeks, depending on location within the estuary; therefore the phasing of storm surge and waves with the spring-neap cycle determines how effectively post-event suspended sediment is delivered to the marsh platform. This study reveals that sediment supply and the associated resilience of New England mesotidal salt marshes involves the interplay of coastal and estuarine processes, underscoring the importance of looking both up- and downstream to identify key drivers of environmental change.The project described in this publication was in part supported by Grant or Cooperative Agreement No. G20AC00071 from the U.S. Geological Survey and a Department of Interior Northeast Climate Adaptation Science Center graduate fellowship awarded to H.E.B (G12AC00001)

Translational control of recombinant human acetylcholinesterase accumulation in plants

<p>Abstract</p> <p>Background</p> <p>Codon usage differences are known to regulate the levels of gene expression in a species-specific manner, with the primary factors often cited to be mRNA processing and accumulation. We have challenged this conclusion by expressing the human acetylcholinesterase coding sequence in transgenic plants in its native GC-rich sequence and compared to a matched sequence with (dicotyledonous) plant-optimized codon usage and a lower GC content.</p> <p>Results</p> <p>We demonstrate a 5 to 10 fold increase in accumulation levels of the "synaptic" splice variant of human acetylcholinesterase in <it>Nicotiana benthamiana </it>plants expressing the optimized gene as compared to the native human sequence. Both transient expression assays and stable transformants demonstrated conspicuously increased accumulation levels. Importantly, we find that the increase is not a result of increased levels of acetylcholinesterase mRNA, but rather its facilitated translation, possibly due to the reduced energy required to unfold the sequence-optimized mRNA.</p> <p>Conclusion</p> <p>Our findings demonstrate that codon usage differences may regulate gene expression at different levels and anticipate translational control of acetylcholinesterase gene expression in its native mammalian host as well.</p

Changes in readthrough acetylcholinesterase expression modulate amyloid-beta pathology

Alzheimer's disease has long been known to involve cholinergic deficits, but the linkage between cholinergic gene expression and the Alzheimer's disease amyloid pathology has remained incompletely understood. One known link involves synaptic acetylcholinesterase (AChE-S), shown to accelerate amyloid fibrils formation. Here, we report that the ‘Readthrough' AChE-R splice variant, which differs from AChE-S in its 26 C-terminal residues, inversely exerts neuroprotective effects from amyloid β (Aβ) induced toxicity. In vitro, highly purified AChE-R dose-dependently suppressed the formation of insoluble Aβ oligomers and fibrils and abolished Aβ toxicity to cultured cells, competing with the prevalent AChE-S protein which facilitates these processes. In vivo, double transgenic APPsw/AChE-R mice showed lower plaque burden, fewer reactive astrocytes and less dendritic damage than single APPsw mice, inverse to reported acceleration of these features in double APPsw/AChE-S mice. In hippocampi from Alzheimer's disease patients (n = 10), dentate gyrus neurons showed significantly elevated AChE-R mRNA and reduced AChE-S mRNA. However, immunoblot analyses revealed drastic reductions in the levels of intact AChE-R protein, suggesting that its selective loss in the Alzheimer's disease brain exacerbates the Aβ-induced damages and revealing a previously unforeseen linkage between cholinergic and amyloidogenic event

Using protein geometry to optimize cytotoxicity and the cytokine window of a ROR1 specific T cell engager

T cell engaging bispecific antibodies have shown clinical proof of concept for hematologic malignancies. Still, cytokine release syndrome, neurotoxicity, and on-target-off-tumor toxicity, especially in the solid tumor setting, represent major obstacles. Second generation TCEs have been described that decouple cytotoxicity from cytokine release by reducing the apparent binding affinity for CD3 and/or the TAA but the results of such engineering have generally led only to reduced maximum induction of cytokine release and often at the expense of maximum cytotoxicity. Using ROR1 as our model TAA and highly modular camelid nanobodies, we describe the engineering of a next generation decoupled TCE that incorporates a “cytokine window” defined as a dose range in which maximal killing is reached but cytokine release may be modulated from very low for safety to nearly that induced by first generation TCEs. This latter attribute supports pro-inflammatory anti-tumor activity including bystander killing and can potentially be used by clinicians to safely titrate patient dose to that which mediates maximum efficacy that is postulated as greater than that possible using standard second generation approaches. We used a combined method of optimizing TCE mediated synaptic distance and apparent affinity tuning of the TAA binding arms to generate a relatively long but persistent synapse that supports a wide cytokine window, potent killing and a reduced propensity towards immune exhaustion. Importantly, this next generation TCE induced significant tumor growth inhibition in vivo but unlike a first-generation non-decoupled benchmark TCE that induced lethal CRS, no signs of adverse events were observed

word~river literary review (2009)

wordriver is a literary journal dedicated to the poetry, short fiction and creative nonfiction of adjuncts and part-time instructors teaching in our universities, colleges, and community colleges. Our premier issue was published in Spring 2009. We are always looking for work that demonstrates the creativity and craft of adjunct/part-time instructors in English and other disciplines. We reserve first publication rights and onetime anthology publication rights for all work published. We define adjunct instructors as anyone teaching part-time or full-time under a semester or yearly contract, nationwide and in any discipline. Graduate students teaching under part-time contracts during the summer or who have used up their teaching assistant time and are teaching with adjunct contracts for the remainder of their graduate program also are eligible.https://digitalscholarship.unlv.edu/word_river/1002/thumbnail.jp

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors

Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12–cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.United States. National Institutes of Health (HG002668)United States. National Institutes of Health (CA109901

Asian-variant intravascular lymphoma in the African race

Intravascular Large B-cell lymphoma (IVLBCL) is an exceptionally rare form of non-Hodgkin lymphoma (NHL) distinguished by the preferential growth of neoplastic cells within blood vessel lumen. Challenging to detect and deemed disseminated at diagnosis, this condition is characterized by a highly aggressive, inconspicuous course with a high mortality rate. We describe the case of a 48 year-old African-American female presenting with a two month history of low-grade fevers and malaise. Laboratory data was notable for anemia, thrombocytopenia, elevated liver function tests, and hematuria. An extensive work-up for infectious, rheumatologic and malignant causes was negative. Her symptoms progressed and within two weeks, she was admitted for disseminated intravascular coagulation (DIC). Her course was complicated by diffuse pulmonary hemorrhage and ultimately, care was withdrawn. Autopsy identified widespread CD-20 positive intravascular large B-cell lymphoma with significant hepatosplenic involvement, characteristic of the Asian variant IVLBCL. This case uniquely highlights development of the Asian variant IVLBVL in a previously undescribed race. Identified by its intraluminal vascular growth pattern, IVLBCL generally spares lymphatic channels. Diagnosis and differentiation of this condition from other hematological malignancies via skin, visceral and bone marrow biopsy is imperative as anthracycline-containing chemotherapies may significantly improve clinical outcomes. This article outlines the common presentation, natural course, and treatment options of IVLBCL, along with the histopathology, immunohistochemistry, and chromosomal aberrations common to this condition