Pursuing Inclusion and Justice While Affirming the Mental Health of Marginalized Students

This article provides best practices that instructors can use to affirm and support marginalized students’ mental health with a specific focus on students of color. Recently, campuses have witnessed renewed calls for diversity and inclusion in the wake of anti-Black violence. Advocates have called for needed structural changes. To build upon these calls for change, this article provides instructors with tools they can use in the interim to navigate questions of diversity, inclusion, and justice in the classroom. The essay centers the mental health needs of students from marginalized populations to hedge against the possibility that efforts to foster inclusion, including advocating for structural reform, contribute additional trauma to these students

Solving ARC visual analogies with neural embeddings and vector arithmetic: A generalized method

Analogical reasoning derives information from known relations and generalizes this information to similar yet unfamiliar situations. One of the first generalized ways in which deep learning models were able to solve verbal analogies was through vector arithmetic of word embeddings, essentially relating words that were mapped to a vector space (e.g., king - man + woman = __?). In comparison, most attempts to solve visual analogies are still predominantly task-specific and less generalizable. This project focuses on visual analogical reasoning and applies the initial generalized mechanism used to solve verbal analogies to the visual realm. Taking the Abstraction and Reasoning Corpus (ARC) as an example to investigate visual analogy solving, we use a variational autoencoder (VAE) to transform ARC items into low-dimensional latent vectors, analogous to the word embeddings used in the verbal approaches. Through simple vector arithmetic, underlying rules of ARC items are discovered and used to solve them. Results indicate that the approach works well on simple items with fewer dimensions (i.e., few colors used, uniform shapes), similar input-to-output examples, and high reconstruction accuracy on the VAE. Predictions on more complex items showed stronger deviations from expected outputs, although, predictions still often approximated parts of the item's rule set. Error patterns indicated that the model works as intended. On the official ARC paradigm, the model achieved a score of 2% (cf. current world record is 21%) and on ConceptARC it scored 8.8%. Although the methodology proposed involves basic dimensionality reduction techniques and standard vector arithmetic, this approach demonstrates promising outcomes on ARC and can easily be generalized to other abstract visual reasoning tasks.Comment: Data and code can be found on https://github.com/foger3/ARC_DeepLearnin

Dynamic telomerase gene suppression via network effects of GSK3 inhibition

<b>Background</b>: Telomerase controls telomere homeostasis and cell immortality and is a promising anti-cancer target, but few small molecule telomerase inhibitors have been developed. Reactivated transcription of the catalytic subunit hTERT in cancer cells controls telomerase expression. Better understanding of upstream pathways is critical for effective anti-telomerase therapeutics and may reveal new targets to inhibit hTERT expression. <b>Methodology/Principal Findings</b>: In a focused promoter screen, several GSK3 inhibitors suppressed hTERT reporter activity. GSK3 inhibition using 6-bromoindirubin-3′-oxime suppressed hTERT expression, telomerase activity and telomere length in several cancer cell lines and growth and hTERT expression in ovarian cancer xenografts. Microarray analysis, network modelling and oligonucleotide binding assays suggested that multiple transcription factors were affected. Extensive remodelling involving Sp1, STAT3, c-Myc, NFκB, and p53 occurred at the endogenous hTERT promoter. RNAi screening of the hTERT promoter revealed multiple kinase genes which affect the hTERT promoter, potentially acting through these factors. Prolonged inhibitor treatments caused dynamic expression both of hTERT and of c-Jun, p53, STAT3, AR and c-Myc. <b>Conclusions/Significance</b>: Our results indicate that GSK3 activates hTERT expression in cancer cells and contributes to telomere length homeostasis. GSK3 inhibition is a clinical strategy for several chronic diseases. These results imply that it may also be useful in cancer therapy. However, the complex network effects we show here have implications for either setting

Do large language models solve verbal analogies like children do?

Analogy-making lies at the heart of human cognition. Adults solve analogies such as \textit{Horse belongs to stable like chicken belongs to ...?} by mapping relations (\textit{kept in}) and answering \textit{chicken coop}. In contrast, children often use association, e.g., answering \textit{egg}. This paper investigates whether large language models (LLMs) solve verbal analogies in A:B::C:? form using associations, similar to what children do. We use verbal analogies extracted from an online adaptive learning environment, where 14,002 7-12 year-olds from the Netherlands solved 622 analogies in Dutch. The six tested Dutch monolingual and multilingual LLMs performed around the same level as children, with MGPT performing worst, around the 7-year-old level, and XLM-V and GPT-3 the best, slightly above the 11-year-old level. However, when we control for associative processes this picture changes and each model's performance level drops 1-2 years. Further experiments demonstrate that associative processes often underlie correctly solved analogies. We conclude that the LLMs we tested indeed tend to solve verbal analogies by association with C like children do

Biomarker proxies for reconstructing Quaternary climate and environmental change

To reconstruct past environmental changes, a range of indirect or proxy approaches can be applied to Quaternary archives. Here, we review the complementary and novel insights which have been provided by the analysis of chemical fossils (biomarkers). Biomarkers have a biological source that can be highly specific (e.g., produced by a small group of organisms) or more general. We show that biomarkers are able to quantify key climate variables (particularly water and air temperature) and can provide qualitative evidence for changes in hydrology, vegetation, human-environment interactions and biogeochemical cycling. In many settings, biomarker proxies provide the opportunity to simultaneously reconstruct multiple climate or environmental variables, alongside complementary and long-established approaches to palaeo-environmental reconstruction. Multi-proxy studies have provided rich sets of data to explore both the drivers and impacts of palaeo-environmental change. As new biomarker proxies continue to be developed and refined, there is further potential to answer emerging questions for Quaternary science and environmental change

A novel pyrazolopyrimidine ligand of human PGK1 and stress sensor DJ1 modulates the shelterin complex and telomere length regulation

Telomere signaling and metabolic dysfunction are hallmarks of cell aging. New agents targeting these processes might provide therapeutic opportunities, including chemoprevention strategies against cancer predisposition. We report identification and characterization of a pyrazolopyrimidine compound series identified from screens focused on cell immortality and whose targets are glycolytic kinase PGK1 and oxidative stress sensor DJ1. We performed structure–activity studies on the series to develop a photoaffinity probe to deconvolute the cellular targets. In vitro binding and structural analyses confirmed these targets, suggesting that PGK1/DJ1 interact, which we confirmed by immunoprecipitation. Glucose homeostasis and oxidative stress are linked to telomere signaling and exemplar compound CRT0063465 blocked hypoglycemic telomere shortening. Intriguingly, PGK1 and DJ1 bind to TRF2 and telomeric DNA. Compound treatment modulates these interactions and also affects Shelterin complex composition, while conferring cellular protection from cytotoxicity due to bleomycin and desferroxamine. These results demonstrate therapeutic potential of the compound series

BpaB, a Novel Protein Encoded by the Lyme Disease Spirochete\u27s Cp32 Prophages, Binds to Erp Operator 2 DNA

Borrelia burgdorferi produces Erp outer surface proteins throughout mammalian infection, but represses their synthesis during colonization of vector ticks. A DNA region 5′ of the start of erp transcription, Operator 2, was previously shown to be essential for regulation of expression. We now report identification and characterization of a novel erp Operator 2-binding protein, which we named BpaB. erp operons are located on episomal cp32 prophages, and a single bacterium may contain as many as 10 different cp32s. Each cp32 family member encodes a unique BpaB protein, yet the three tested cp32-encoded BpaB alleles all bound to the same DNA sequence. A 20-bp region of erp Operator 2 was determined to be essential for BpaB binding, and initial protein binding to that site was required for binding of additional BpaB molecules. A 36-residue region near the BpaB carboxy terminus was found to be essential for high-affinity DNA-binding. BpaB competed for binding to erp Operator 2 with a second B. burgdorferi DNA-binding protein, EbfC. Thus, cellular levels of free BpaB and EbfC could potentially control erp transcription levels

BpaB, a novel protein encoded by the Lyme disease spirochete’s cp32 prophages, binds to erp Operator 2 DNA

Borrelia burgdorferi produces Erp outer surface proteins throughout mammalian infection, but represses their synthesis during colonization of vector ticks. A DNA region 5′ of the start of erp transcription, Operator 2, was previously shown to be essential for regulation of expression. We now report identification and characterization of a novel erp Operator 2-binding protein, which we named BpaB. erp operons are located on episomal cp32 prophages, and a single bacterium may contain as many as 10 different cp32s. Each cp32 family member encodes a unique BpaB protein, yet the three tested cp32-encoded BpaB alleles all bound to the same DNA sequence. A 20-bp region of erp Operator 2 was determined to be essential for BpaB binding, and initial protein binding to that site was required for binding of additional BpaB molecules. A 36-residue region near the BpaB carboxy terminus was found to be essential for high-affinity DNA-binding. BpaB competed for binding to erp Operator 2 with a second B. burgdorferi DNA-binding protein, EbfC. Thus, cellular levels of free BpaB and EbfC could potentially control erp transcription levels

Stage-Specific Inhibition of MHC Class I Presentation by the Epstein-Barr Virus BNLF2a Protein during Virus Lytic Cycle

gamma-herpesvirus Epstein-Barr virus (EBV) persists for life in infected individuals despite the presence of a strong immune response. During the lytic cycle of EBV many viral proteins are expressed, potentially allowing virally infected cells to be recognized and eliminated by CD8+ T cells. We have recently identified an immune evasion protein encoded by EBV, BNLF2a, which is expressed in early phase lytic replication and inhibits peptide- and ATP-binding functions of the transporter associated with antigen processing. Ectopic expression of BNLF2a causes decreased surface MHC class I expression and inhibits the presentation of indicator antigens to CD8+ T cells. Here we sought to examine the influence of BNLF2a when expressed naturally during EBV lytic replication. We generated a BNLF2a-deleted recombinant EBV (ΔBNLF2a) and compared the ability of ΔBNLF2a and wild-type EBV-transformed B cell lines to be recognized by CD8+ T cell clones specific for EBV-encoded immediate early, early and late lytic antigens. Epitopes derived from immediate early and early expressed proteins were better recognized when presented by ΔBNLF2a transformed cells compared to wild-type virus transformants. However, recognition of late antigens by CD8+ T cells remained equally poor when presented by both wild-type and ΔBNLF2a cell targets. Analysis of BNLF2a and target protein expression kinetics showed that although BNLF2a is expressed during early phase replication, it is expressed at a time when there is an upregulation of immediate early proteins and initiation of early protein synthesis. Interestingly, BNLF2a protein expression was found to be lost by late lytic cycle yet ΔBNLF2a-transformed cells in late stage replication downregulated surface MHC class I to a similar extent as wild-type EBV-transformed cells. These data show that BNLF2a-mediated expression is stage-specific, affecting presentation of immediate early and early proteins, and that other evasion mechanisms operate later in the lytic cycle