Miracle-dz/UniFAR-FTUs huggingface dataset:
Optimal Explicit Small-Depth Formulas for the Coin Problem

The δ-Coin Problem is the problem of distinguishing between a sequence of coin tosses that come up Heads with probability either 1+δ/2 or 1−δ/2. The computational complexity of this problem in various models has been studied in many previous works with various applications related to derandomization, hierarchy theorems, cryptography and meta-complexity. In this paper, we construct improved small-depth explicit formulas for the coin problem. Specifically, we construct explicit formulas of optimal size exp(O(d(1/δ)d−1)) and information-theoretically optimal sample complexity O(1/δ2) (the sample complexity is the number of coin tosses supplied to the formulas) for this problem, as long as 1/δ ≥ dC· d for a large enough absolute constant C. Previous constructions of size-optimal AC0 formulas for the coin problem were either randomized (and hence non-explicit) or had a much worse sample complexity of (1/δ)Ω(d). Our improved construction yields better Fixed-Depth Size Hierarchy theorems for uniform classes of small-depth circuits with AND, OR and ⊕ gates. Our techniques deviate considerably from previous explicit constructions with non-trivial sample complexity due to Limaye, Sreenivasaiah, Venkitesh and the two authors (SICOMP 2021). While the approach there was to derandomize randomized formula constructions based on results of O’Donnell and Wimmer (ICALP 2007) and Amano (ICALP 2009), we instead look to derandomize a randomized circuit construction due to Rossman and Srinivasan (Theory of Computing 2019). This leads us to the problem of constructing certain pseudorandom graphs, which we do explicitly using ideas of Viola (Computational Complexity 2014) involving an iterative use of expander graphs. The constructions of these graphs, which are related to dispersers, may be independently interesting.
On Approximability of Satisfiable k-CSPs: II

Let Σ be an alphabet and µ be a distribution on Σk for some k ≥ 2. Let α > 0 be the minimum probability of a tuple in the support of µ (denoted supp(µ)). Here, the support of µ is the set of all tuples in Σk that have a positive probability mass under µ. We treat the parameters Σ, k, µ, α as fixed and constant. We say that the distribution µ has a linear embedding if there exist an Abelian group G (with the identity element 0G) and mappings σi : Σ → G, 1 ≤ i ≤ k, such that at least one of the mappings is non-constant and for every (a1, a2, …, ak)∈ supp(µ), ∑i=1k σi(ai) = 0G. Let fi: Σn→ [−1,1] be bounded functions, such that at least one of the functions fi essentially has degree at least d, meaning that the Fourier mass of fi on terms of degree less than d is negligible, say at most δ. In particular, |E[fi]| ≤ δ. The Fourier representation is w.r. t. the marginal of µ on the ith co-ordinate, denoted (Σ, µi). If µ has no linear embedding (over any Abelian group), then is it necessarily the case that |E(x1, x2, …, xk)∼ µ⊗ n[f1(x1)f2(x2)⋯ fk(xk)] = od, δ(1), where the right hand side → 0 as the degree d → ∞ and δ → 0? In this paper, we answer this analytical question fully and in the affirmative for k=3. We also show the following two applications of the result. The first application is related to hardness of approximation. We show that for every 3-ary predicate P:Σ3 → {0,1} such that P has no linear embedding, an SDP integrality gap instance of a P-CSP instance with gap (1,s) can be translated into a dictatorship test with completeness 1 and soundness s+o(1), under certain additional conditions on the instance. The second application is related to additive combinatorics. We show that if the distribution µ on Σ3 has no linear embedding, marginals of µ are uniform on Σ, and (a,a,a)∈ supp(µ) for every a∈ Σ, then every large enough subset of Σn contains a triple (x1, x2,x3) from µ⊗ n (and in fact a significant density of such triples).
On Approximability of Satisfiable k-CSPs: III

In this paper we study functions on the Boolean hypercube that have the property that after applying certain random restrictions, the restricted function is correlated to a linear function with non-negligible probability. If the given function is correlated with a linear function then this property clearly holds. Furthermore, the property also holds for low-degree functions as low-degree functions become a constant function under a random restriction with a non-negligible probability. We show that this essentially is the only possible reason. More specifically, we show that the function must be correlated to a product of a linear function and a low-degree function. One of the main motivations of studying this question comes from the recent work of the authors towards understanding approximability of satisfiable Constraint Satisfaction Problems. Towards proving our structural theorem, we analyze a 2-query direct product test for the table F: [n] qn → {0,1}qn where q∈ (0,1). We show that, for every constant ε>0, if the test passes with probability ε>0, then there is a global function g: [n]→ {0,1} such that for at least δ(ε) fraction of sets, the global function g agrees with the given table on all except α(ε) many locations. The novelty of this result lies in the fact that α(ε) is independent of the set sizes. Prior to our work, such a conclusion (in fact, a stronger conclusion with α = 0) was shown by Dinur, Filmus, and Harsha albeit when the test accepts with probability 1−ε for a small constant ε>0. The setting of parameters in our direct product tests is fundamentally different compared to the previous results and hence our analysis involves new techniques, including the use of the small-set expansion property of graphs defined on multi-slices. As one application of our structural result, we give a 4-query linearity test under the p-biased distribution. More specifically, for any p∈ (1/3,2/3), we give a test that queries a given function f: {0,1}n → {0,1} at 4 locations, where the marginal distribution of each query is µp⊗ n. The test has perfect completeness and soundness 1/2+ε – in other words, for every constant ε>0, if the test passes with probability at least 1/2+ε, then the function f is correlated to a linear function under the µp⊗ n measure. This qualitatively improves the results on the linearity testing under the p-biased distribution from the previous work where the authors studied the test with soundness 1−ε, for ε close to 0.
Deep learning-driven characterization of single cell tuning in primate visual area V4 unveils topological organization

Deciphering the brain’s structure-function relationship is key to understanding the neuronal mechanisms underlying perception and cognition. The cortical column, a vertical organization of neurons with similar functions, is a classic example of primate neocortex structure-function organization. While columns have been identified in primary sensory areas using parametric stimuli, their prevalence across higher-level cortex is debated. A key hurdle in identifying columns is the difficulty of characterizing complex nonlinear neuronal tuning, especially with high-dimensional sensory inputs. Here, we asked whether area V4, a mid-level area of the macaque visual system, is organized into columns. We combined large-scale linear probe recordings with deep learning methods to systematically characterize the tuning of >1,200 V4 neurons using in silico synthesis of most exciting images (MEIs), followed by in vivo verification. We found that the MEIs of single V4 neurons exhibited complex features like textures, shapes, or even high-level attributes such as eye-like structures. Neurons recorded on the same silicon probe, inserted orthogonal to the cortical surface, were selective to similar spatial features, as expected from a columnar organization. We quantified this finding using human psychophysics and by measuring MEI similarity in a non-linear embedding space, learned with a contrastive loss. Moreover, the selectivity of the neuronal population was clustered, suggesting that V4 neurons form distinct functional groups of shared feature selectivity, reminiscent of cell types. These functional groups closely mirrored the feature maps of units in artificial vision systems, hinting at shared encoding principles between biological and artificial vision. Our findings provide evidence that columns and functional cell types may constitute universal organizing principles of the primate neocortex, simplifying the cortex’s complexity into simpler circuit motifs which perform canonical computations.
Genomic Epidemiology of Treponema pallidum and Circulation of Strains With Diminished tprK Antigen Variation Capability in Seattle, 2021–2022

Background Syphilis incidence continues to increase dramatically in the United States and yet little is known about Treponema pallidum (TP) genomic epidemiology within American metropolitan areas. Methods We performed whole genome sequencing and tprK deep sequencing of 28 TP-containing specimens collected mostly from remnant Aptima swabs from 24 individuals from Seattle Sexual Health Clinic during 2021-2022. Results All 12 individuals infected with Nichols lineage strains were MSM, while a specific SS14 cluster (average 0.33 SNPs) included 1 MSW and five women. All TP strains sequenced were azithromycin resistant via 23S rRNA A2058G mutation. Identical TP genomic sequences were found in pharyngeal and rectal swab specimens taken from the same individuals concurrently. tprK sequences were less variable between patient-matched specimens and between epidemiologically-linked clusters. We detected a 528 bp deletion in the tprK donor site locus, eliminating nine tprK donor sites, in TP genomes of three individuals with secondary syphilis, associated with diminution of overall tprK sequence diversity. Conclusions We developed an end-to-end workflow for public health genomic surveillance of TP from remnant Aptima swab specimens. With its high rate of gene conversion, tprK sequencing may assist in linking cases beyond routine TP genome sequencing. TP strains with deletions in tprK donor sites currently circulate and are associated with diminished antigenic diversity of the TprK putative outer membrane protein.
Sex differences in binge alcohol drinking and the behavioral consequences of protracted withdrawal in

Background Binge alcohol drinking is a risk factor linked to numerous disease states including alcohol use disorder (AUD). While men binge drink more alcohol than women, this demographic gap is quickly shrinking, and preclinical studies demonstrate that females consistently consume more alcohol than males. Further, women are at increased risk for the co-expression of AUD with neuropsychiatric diseases such as anxiety and mood disorders. However, little is understood about chronic voluntary alcohol drinking and its long-term effects on behavior in females. Here, we sought to characterize sex differences in chronic binge drinking and the effects of protracted alcohol withdrawal on anxiety-and affective-related behaviors in males and females. Methods We assessed binge alcohol drinking patterns in male and female C57BL/6J mice using a modified Drinking in the Dark (DID) paradigm in which mice received home cage access to one bottle of 10% or 20% alcohol (EtOH) or water for 2 hrs per day on Days 1-3 and to two bottles (EtOH/H2O + H2O) for 24 hrs on Day 4 for eight weekly cycles. Mice were then tested for the effects of protracted abstinence on avoidance, affective
Persistent hepatitis B virus and HIV coinfections in dually humanized mice engrafted with human liver and immune system

Chronic hepatitis B (CHB), caused by hepatitis B virus (HBV), remains a major medical problem. HBV has a high propensity for progressing to chronicity and can result in severe liver disease, including fibrosis, cirrhosis, and hepatocellular carcinoma. CHB patients frequently present with viral coinfection, including human immunodeficiency virus type (HIV) and hepatitis delta virus. About 10% of chronic HIV carriers are also persistently infected with HBV, which can result in more exacerbated liver disease. Mechanistic studies of HBV‐induced immune responses and pathogenesis, which could be significantly influenced by HIV infection, have been hampered by the scarcity of immunocompetent animal models. Here, we demonstrate that humanized mice dually engrafted with components of a human immune system and a human liver supported HBV infection, which was partially controlled by human immune cells, as evidenced by lower levels of serum viremia and HBV replication intermediates in the liver. HBV infection resulted in priming and expansion of human HLA‐restricted CD8+ T cells, which acquired an activated phenotype. Notably, our dually humanized mice support persistent coinfections with HBV and HIV, which opens opportunities for analyzing immune dysregulation during HBV and HIV coinfection, and preclinical testing of novel immunotherapeutics.
The androgen receptor does not directly regulate the transcription of DNA damage response genes

The clinical success of combined androgen deprivation therapy (ADT) and radiation therapy (RT) in prostate cancer (PCa) created interest in understanding the mechanistic links between androgen receptor (AR) signaling and the DNA damage response (DDR). Convergent data have led to a model where AR both regulates, and is regulated by, the DDR. Integral to this model is that the AR regulates the transcription of DDR genes both at steady state and in response to ionizing radiation (IR). In this study, we sought to determine which immediate transcriptional changes are induced by IR in an AR-dependent manner. Using PRO-seq to quantify changes in nascent RNA transcription in response to IR, the AR antagonist enzalutamide, or the combination of the two, we find that enzalutamide treatment significantly decreased expression of canonical AR target genes but had no effect on DDR gene sets in PCa cells. Surprisingly, we also found that the AR is not a primary regulator of DDR genes either in response to IR or at steady state in asynchronously growing PCa cells. Our data indicate that the clinical benefit of ADT and RT is not due to the direct regulation of DDR gene transcription by AR.
Novel metrics reveal new structure and unappreciated heterogeneity in C. elegans development

High throughput experimental approaches are increasingly allowing for the quantitative description of cellular and organismal phenotypes. Distilling these large volumes of complex data into meaningful measures that can drive biological insight remains a central challenge. In the quantitative study of development, for instance, one can resolve phenotypic measures for single cells onto their lineage history, enabling joint consideration of heritable signals and cell fate decisions. Most attempts to analyze this type of data, however, discard much of the information content contained within lineage trees. In this work we introduce a generalized metric, which we term the branch distance, that allows us to compare any two embryos based on phenotypic measurements in individual cells. This approach aligns those phenotypic measurements to the underlying lineage tree, providing a flexible and intuitive framework for quantitative comparisons between, for instance, Wild-Type (WT) and mutant developmental programs. We apply this novel metric to data on cell-cycle timing from over 1300 WT and RNAi-treated Caenorhabditis elegans embryos. Our new metric revealed surprising heterogeneity within this data set, including subtle batch effects in WT embryos and dramatic variability in RNAi-induced developmental phenotypes, all of which had been missed in previous analyses. Further investigation of these results suggests a novel, quantitative link between pathways that govern cell fate decisions and pathways that pattern cell cycle timing in the early embryo. Our work demonstrates that the branch distance we propose, and similar metrics like it, have the potential to revolutionize our quantitative understanding of organismal phenotype.
Whole Transcriptome and Functional Analyses Identify Novel Genes Involved in Meiosis and Fertility in Drosophila melanogaster

Reproductive success requires the development of viable oocytes and the accurate segregation of chromosomes during meiosis. Failure to segregate chromosomes properly can lead to infertility, miscarriages, or developmental disorders. A variety of factors contribute to accurate chromosome segregation and oocyte development, such as spindle assembly and sister chromatid cohesion. However, many proteins required for meiosis remain unknown. In this study, we aimed to identify and characterize novel meiotic and fertility genes using the genome of Drosophila melanogaster. To accomplish this goal, genes upregulated within meiotically active tissues were identified. About 200 genes with no known function were silenced using RNA interference (RNAi), and the effects on meiosis and fertility were assessed. We identified 65 genes that when silenced caused infertility and/or high levels of chromosomal nondisjunction. The vast majority of these genes have human and mouse homologs that are also poorly studied. Through this screening process, we identified novel genes that are crucial for meiosis and oocyte development but have not been extensively studied in human or model organisms. Understanding the function of these genes will be an important step towards the understanding of their biological significance during reproduction. Author Summary In this study, we aimed to identify and characterize novel meiotic and fertility genes within the genome of Drosophila melanogaster. We identified 65 genes that when silenced caused infertility and/or high levels of chromosomal nondisjunction. The vast majority of these genes have human and mouse homologs that are also poorly studied. Through this screening process, we identified novel genes that are crucial for meiosis and oocyte development, making them strong candidates for future studies to characterize their functions.
Numerical and Theoretical Studies of Physics Beyond the Standard Model

The Standard Model of particle interactions triumphed when the discovery of the Higgs boson was announced by the CMS and ATLAS collaboration at the Large Hadron Collider July 4th, 2012. The Standard Model has been very successful, but has limitations as well as some aesthetic problems. Many of these problems are related to the Higgs field. By replacing the Higgs sector of the Standard Model with a new strongly coupled sector some of these problems can be solved. These new strong interactions are referred to as Technicolor interactions. In this thesis we present results from lattice studies of two concrete Technicolor models, the SO(4) fundamental Minimal Walking Technicolor (MWT) model and the SU(3) sextet MWT. After motivating this type of models by discussing some experimental constraints, we present results from our numerical investigations of their spectra. Our results disfavor the existence of an infrared fixed point in either model. This thesis also contain a presentation of our attempt to accelerate Monte Carlo simulations of lattice gauge theories, by performing the calculations on graphics processing units (GPUs). We discuss several optimizations and test the performance using as test cases SU(2) gauge theories with Wilson fermions transforming in the fundamental and adjoint representation.
RIP140 regulates HES1 oscillatory expression and mitogenic activity in colon cancer cells

Background The transcription factor RIP140 (Receptor Interacting Protein of 140 kDa) regulates intestinal homeostasis and tumorigenesis through the Wnt signaling. In this study, we have investigated its effect on the Notch/HES1 signaling pathway. Methods The impact on HES1 expression and activity was evaluated in colorectal cancer (CRC) cell lines and in transgenic mice, invalidated or not for the Rip140 gene in the intestinal epithelium. A tumor microarray and transcriptomic data sets were used to investigate RIP140 and HES1 expression in relation with patient survival. Statistical comparisons were performed with Mann-Whitney or Kruskal-Wallis or Chi2 tests. Results In CRC cells, RIP140 positively regulated HES1 gene expression at the transcriptional level via an RBPJ/NICD-mediated mechanism. In support of these in vitro data, RIP140 and HES1 expression significantly correlated in mouse intestine and in a cohort of CRC samples, analyzed by immunohistochemistry, thus supporting the positive regulation of HES1 gene expression by RIP140. Interestingly, when the Notch pathway is fully activated, RIP140 exerted a strong inhibition of HES1 gene transcription controlled by the level of HES1 itself. Moreover, RIP140 directly interacts with HES1 and reversed its mitogenic activity in human CRC cells. In line with this observation, HES1 levels were associated with a better patient survival only when tumors expressed high levels of RIP140. Conclusions Our data identify RIP140 as a key regulator of the Notch/HES1 signaling pathway with a dual effect on HES1 gene expression at the transcriptional level and a strong impact on colon cancer cell proliferation.
Resolving the unsolved: Comprehensive assessment of tandem repeats at scale

Tandem repeat (TR) variation is associated with gene expression changes and over 50 rare monogenic diseases. Recent advances in sequencing have enabled accurate, long reads that can characterize the full-length sequence and methylation profile of TRs. However, despite these advances in sequencing technology, computational methods to fully profile tandem repeats across the genome do not exist. To address this gap, we introduce tools for tandem repeat genotyping (TRGT), visualization and an accompanying TR database. TRGT accurately resolves the length and sequence composition of TR regions in the human genome. Assessing 937,122 TRs, TRGT showed a Mendelian concordance of 99.56%, allowing a single repeat unit difference. In six samples with known repeat expansions, TRGT detected all repeat expansions while also identifying methylation signals, mosaicism, and providing finer resolution of repeat length. Additionally, we release a database with allele sequences and methylation levels for 937,122 TRs across 100 genomes.
ZKSQL: Verifiable and Efficient Query Evaluation with Zero-Knowledge Proofs

Individuals and organizations are using databases to store personal information at an unprecedented rate. This creates a quandary for data providers. They are responsible for protecting the privacy of individuals described in their database. On the other hand, data providers are sometimes required to provide statistics about their data instead of sharing it wholesale with strong assurances that these answers are correct and complete such as in regulatory filings for the US SEC and other goverment organizations. We introduce a system, ZKSQL , that provides authenticated answers to ad-hoc SQL queries with zero-knowledge proofs. Its proofs show that the answers are correct and sound with respect to the database's contents and they do not divulge any information about its input records. This system constructs proofs over the steps in a query's evaluation and it accelerates this process with authenticated set operations. We validate the efficiency of this approach over a suite of TPC-H queries and our results show that ZKSQL achieves two orders of magnitude speedup over the baseline.