Fold-Transversal Clifford Gates for Quantum Codes

We generalize the concept of folding from surface codes to CSS codes by considering certain dualities within them. In particular, this gives a general method to implement logical operations in suitable LDPC quantum codes using transversal gates and qubit permutations only. To demonstrate our approach, we specifically consider a [[30, 8, 3]] hyperbolic quantum code called Bring's code. Further, we show that by restricting the logical subspace of Bring's code to four qubits, we can obtain the full Clifford group on that subspace

Machine Learning and Big Data for Neuro-Diagnostics: Opportunities and Challenges for Clinical Translation

In this report, we examine some developments in neurodiagnostics that make use of machine learning and other algorithms, with a particular focus on the potentials and challenges for clinical translation. As the ultimate aim of development of diagnostic algorithms is for their use in the diagnosis and treatment of patients, we focus particularly on the possibilities and challenges of clinical translation. We draw attention to the challenges faced in relating probabilistic predictions derived from such algorithms to individualised clinical interventions, and we highlight the importance of trust in the relationships that enable clinical translation of technologies – trust between researchers, clinicians, patients, and regulators

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Functionalizing tandem mass tags for streamlining click-based quantitative chemoproteomics.

Mapping the ligandability or potential druggability of all proteins in the human proteome is a central goal of mass spectrometry-based covalent chemoproteomics. Achieving this ambitious objective requires high throughput and high coverage sample preparation and liquid chromatography-tandem mass spectrometry analysis for hundreds to thousands of reactive compounds and chemical probes. Conducting chemoproteomic screens at this scale benefits from technical innovations that achieve increased sample throughput. Here we realize this vision by establishing the silane-based cleavable linkers for isotopically-labeled proteomics-tandem mass tag (sCIP-TMT) proteomic platform, which is distinguished by early sample pooling that increases sample preparation throughput. sCIP-TMT pairs a custom click-compatible sCIP capture reagent that is readily functionalized in high yield with commercially available TMT reagents. Synthesis and benchmarking of a 10-plex set of sCIP-TMT reveal a substantial decrease in sample preparation time together with high coverage and high accuracy quantification. By screening a focused set of four cysteine-reactive electrophiles, we demonstrate the utility of sCIP-TMT for chemoproteomic target hunting, identifying 789 total liganded cysteines. Distinguished by its compatibility with established enrichment and quantification protocols, we expect sCIP-TMT will readily translate to a wide range of covalent chemoproteomic applications

sCIP-ing towards streamlined chemoproteomics

Mapping the ligandability or potential druggability of all proteins in the human proteome is a central goal of mass spectrometry-based chemoproteomics. Achieving this ambitious objective requires high throughput and high coverage sample preparation and LC-MS/MS analysis for hundreds to thousands of reactive compounds and chemical probes. Conducting chemoproteomic screens at this scale benefits from technical innovations that achieve increased sample throughput. Multiplexed analysis using commercially available amine-reactive isobaric reagents (e.g. tandem mass tags or TMT) is a favored strategy to decrease instrument acquisition time. These reagents are ideally suited for protein-based quantification applications, with efficient capping and pooling of peptides after sequence specific digestion. The added enrichment steps in nearly all chemoproteomic sample preparation workflows reveals a still largely untapped opportunity for isobaric labeling, namely incorporation of the TMT label into the chemoproteomic enrichment handle for early sample pooling and increased sample preparation throughput. Here we realize this vision by establishing the silane-based Cleavable Linkers for Isotopically-labeled Proteomics (sCIP)-TMT proteomic platform. sCIP-TMT pairs a custom click-compatible sCIP capture reagent that is readily functionalized in high yield with commercially available TMT tags. Synthesis and benchmarking of a 10-plex set of sCIP-TMT reveals a 1.5-fold decrease in sample preparation time together with high coverage and high accuracy quantification. By screening a focused library of cysteine-reactive electrophiles, we demonstrate the utility of sCIP-TMT for chemoproteomic target hunting, identifying 789 total liganded cysteines. Distinguished by its compatibility with established enrichment and quantification protocols, we expect sCIP-TMT will readily translate to a wide range of chemoproteomic applications

Photoaffinity labelling strategies for mapping the small molecule–protein interactome

Nearly all FDA approved drugs and bioactive small molecules exert their effects by binding to and modulating proteins. Consequently, understanding how small molecules interact with proteins at an molecular level is a central challenge of modern chemical biology and drug development. Complementary to structure-guided approaches, chemoproteomics has emerged as a method capable of high-throughput identification of proteins covalently bound by small molecules. To profile noncovalent interactions, established chemoproteomic workflows typically incorporate photoreactive moieties into small molecule probes, which enable trapping of small molecule-protein interactions (SMPIs). This strategy, termed photoaffinity labelling (PAL), has been utilized to profile an array of small molecule interactions, including for drugs, lipids, metabolites, and cofactors. Herein we describe the discovery of photocrosslinking chemistries, including a comparison of the strengths and limitations of implementation of each chemotype in chemoproteomic workflows. In addition, we highlight key examples where photoaffinity labelling has enabled target deconvolution and interaction site mapping

Synthesis of Highly Congested Tertiary Alcohols via the [3,3] Radical Deconstruction of Breslow Intermediates

Pericyclic processes such as [3,3]-sigmatropic rearrangements leading to the rapid generation of molecular complexity constitute highly valuable tools in organic synthesis. Herein, we report the formation of particularly hindered tertiary alcohols via rearrangement of Breslow intermediates formed in situ from readily available N-allyl thiazolium salts and benzaldehyde derivatives. Experimental mechanistic studies performed suggest that the reaction proceeds via a close radical pair which recombine in a regio- and diastereoselective manner, formally leading to [3,3]-rearranged products

Oxodealkenylative Cleavage of Alkene C(sp3 )-C(sp2 ) Bonds: A Practical Method for Introducing Carbonyls into Chiral Pool Materials.

Reported herein is a one-pot protocol for the oxodealkenylative introduction of carbonyl functionalities into terpenes and terpene-derived compounds. This transformation proceeds by Criegee ozonolysis of an alkene, reductive cleavage of the resulting α-alkoxy hydroperoxide, trapping of the generated alkyl radical with 2,2,6,6-tetramethylpiperidin-1-yl (TEMPO), and subsequent oxidative fragmentation with MMPP. Using readily available starting materials from chiral pool, a variety of carbonyl-containing products have been accessed rapidly in good yields