A Theory of Emergent In-Context Learning as Implicit Structure Induction

Scaling large language models (LLMs) leads to an emergent capacity to learn in-context from example demonstrations. Despite progress, theoretical understanding of this phenomenon remains limited. We argue that in-context learning relies on recombination of compositional operations found in natural language data. We derive an information-theoretic bound showing how in-context learning abilities arise from generic next-token prediction when the pretraining distribution has sufficient amounts of compositional structure, under linguistically motivated assumptions. A second bound provides a theoretical justification for the empirical success of prompting LLMs to output intermediate steps towards an answer. To validate theoretical predictions, we introduce a controlled setup for inducing in-context learning; unlike previous approaches, it accounts for the compositional nature of language. Trained transformers can perform in-context learning for a range of tasks, in a manner consistent with the theoretical results. Mirroring real-world LLMs in a miniature setup, in-context learning emerges when scaling parameters and data, and models perform better when prompted to output intermediate steps. Probing shows that in-context learning is supported by a representation of the input's compositional structure. Taken together, these results provide a step towards theoretical understanding of emergent behavior in large language models

N-Methylmesoporphyrin IX Fluorescence As A Reporter Of Strand Orientation In Guanine Quadruplexes

Guanine quadruplexes (GQ) are four-stranded DNA structures formed by guanine-rich DNA sequences. The formation of GQs inhibits cancer cell growth, although the detection of GQs invivo has proven difficult, in part because of their structural diversity. The development of GQ-selective fluorescent reporters would enhance our ability to quantify the number and location of GQs, ultimately advancing biological studies of quadruplex relevance and function. N-methylmesoporphyrin IX (NMM) interacts selectively with parallel-stranded GQs; in addition, its fluorescence is sensitive to the presence of DNA, making this ligand a possible candidate for a quadruplex probe. In the present study, we investigated the effect of DNA secondary structure on NMM fluorescence. We found that NMM fluorescence increases by about 60-fold in the presence of parallel-stranded GQs and by about 40-fold in the presence of hybrid GQs. Antiparallel GQs lead to lower than 10-fold increases in NMM fluorescence. Single-stranded DNA, duplex, or i-motif, induce no change in NMM fluorescence. We conclude that NMM shows promise as a turn-on\u27 fluorescent probe for detecting quadruplex structures, as well as for differentiating them on the basis of strand orientation

Non uniform digitizer for alias-free sampling of wideband analog signals

Non uniform digitizer for alias-free sampling of wideband analog signal

Hypertrophic cardiomyopathy and ultra-endurance running - two incompatible entities?

Regular and prolonged exercise is associated with increased left ventricular wall thickness that can overlap with hypertrophic cardiomyopathy (HCM). Differentiating physiological from pathological hypertrophy has important implications, since HCM is the commonest cause of exercise-related sudden cardiac death in young individuals. Most deaths have been reported in intermittent 'start-stop' sports such as football (soccer) and basketball. The theory is that individuals with HCM are unable to augment stroke volume sufficiently to meet the demands of endurance sports and are accordingly 'selected-out' of participation in such events. We report the case of an ultra-endurance athlete with 25 years of > 50 km competitive running experience, with genetically confirmed HCM; thereby demonstrating that these can be two compatible entities

MELK Promotes Melanoma Growth by Stimulating the NF-kappaB Pathway

Melanoma accounts for more than 80% of skin cancer-related deaths, and current therapies provide only short-term benefit to patients. Here, we show in melanoma cells that maternal embryonic leucine zipper kinase (MELK) is transcriptionally upregulated by the MAPK pathway via transcription factor E2F1. MELK knockdown or pharmacological inhibition blocked melanoma growth and enhanced the effectiveness of BRAFV600E inhibitor against melanoma cells. To identify mediators of MELK function, we performed stable isotope labeling with amino acids in cell culture (SILAC) and identified 469 proteins that had downregulated phosphorylation after MELK inhibition. Of these proteins, 139 were previously reported as substrates of BRAF or MEK, demonstrating that MELK is an important downstream mediator of the MAPK pathway. Furthermore, we show that MELK promotes melanoma growth by activating NF-kappaB pathway activity via Sequestosome 1 (SQSTM1/p62). Altogether, these results underpin an important role for MELK in melanoma growth downstream of the MAPK pathway

Investigation Of The Interactions Between Pt(II) And Pd(II) Derivatives Of 5,10,15,20-Tetrakis (N-Methyl-4-Pyridyl) Porphyrin And G-Quadruplex DNA

G-quadruplexes are non-canonical DNA structures formed by guanine-rich DNA sequences that are implicated in cancer and aging. Understanding how small molecule ligands interact with quadruplexes is essential both to the development of novel anticancer therapeutics and to the design of new quadruplex-selective probes needed for elucidation of quadruplex biological functions. In this work, UV–visible, fluorescence, and circular dichroism spectroscopies, fluorescence resonance energy transfer (FRET) melting assays, and resonance light scattering were used to investigate how the Pt(II) and Pd(II) derivatives of the well-studied 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP4) interact with quadruplexes formed by the human telomeric DNA, Tel22, and by the G-rich sequences from oncogene promoters. Our results suggest that Pt- and PdTMPyP4 interact with Tel22 via efficient π–π stacking with a binding affinity of 106–107 M−1. Under porphyrin excess, PtTMPyP4 aggregates using Tel22 as a template; the aggregates reach maximum size at [PtTMPyP4]/[Tel22] ~8 and dissolve at [PtTMPyP4]/[Tel22] ≤ 2. FRET assays reveal that both porphyrins are excellent stabilizers of human telomeric DNA, with stabilization temperature of 30.7 ± 0.6 °C for PtTMPyP4 and 30.9 ± 0.4 °C for PdTMPyP4 at [PtTMPyP4]/[Tel22] = 2 in K+ buffer, values significantly higher as compared to those for TMPyP4. The porphyrins display modest selectivity for quadruplex vs. duplex DNA, with selectivity ratios of 150 and 330 for Pt- and PdTMPyP4, respectively. This selectivity was confirmed by observed ‘light switch’ effect: fluorescence of PtTMPyP4 increases significantly in the presence of a variety of DNA secondary structures, yet the strongest effect is produced by quadruplex DNA

Survey of Obstetrician-Gynecologists in the United States About Toxoplasmosis

Background: Although the incidence of toxoplasmosis is low in the United States, up to 6000 congenital cases occur annually. In September 1998, the Centers for Disease Control and Prevention held a conference about toxoplasmosis; participants recommended a survey of the toxoplasmosis-related knowledge and practices of obstetrician-gynecologists and the development of professional educational materials for them. Methods: In the fall of 1999, surveys were mailed to a 2% random sample of American College of Obstetricians and Gynecologists (ACOG) members and to a demographically representative group of ACOGmembers known as the Collaborative Ambulatory Research Network (CARN). Responses were not significantly different for the random and CARN groups for most questions (p value shown when different). Results: Among 768 US practicing ACOG members surveyed, 364 (47%) responded. Seven per cent (CARN 10%, random 5%) had diagnosed one or more case(s) of acute toxoplasmosis in the past year. Respondents were well-informed about how to prevent toxoplasmosis. However, only 12% (CARN 11%, random 12%) indicated that a positive Toxoplasma IgM test might be a false–positive result, and only 11% (CARN 14%, random 9%) were aware that the Food and Drug Administration sent an advisory to all ACOG members in 1997 stating that some Toxoplasma IgM test kits have high false–positive rates. Most of those surveyed (CARN 70%, random 59%; X(2) p < 0.05) were opposed to universal screening of pregnant women. Conclusions: Many US obstetrician-gynecologists will encounter acute toxoplasmosis during their careers, but they are frequently uncertain about interpretation of the laboratory tests for the disease. Most would not recommend universal screening of pregnant women

BTDAzo: A Photoswitchable TRPC5 Channel Activator

Photoswitchable reagents can be powerful tools for high-precision biological control. TRPC5 is a Ca2+-permeable cation channel with distinct tissue-specific roles, from synaptic function to hormone regulation. Reagents giving spatiotemporally-resolved control over TRPC5 activity may be key to understanding and harnessing its biology. Here we develop the first photoswitchable TRPC5-modulator, BTDAzo, to address this goal. BTDAzo can photocontrol TRPC5 currents in cell culture, as well as controlling endogenous TRPC5-based neuronal Ca2+ responses in mouse brain slices. BTDAzos are also the first reported azo-benzothiadiazines, an accessible and conveniently derivatised azoheteroarene with strong two-colour photoswitching. BTDAzo ' s ability to control TRPC5 across relevant channel biology settings makes it suitable for a range of dynamically reversible photoswitching studies in TRP channel biology, with the aim to decipher the various biological roles of this centrally important ion channel