cssi/SciSciGPT-SciSciNet huggingface dataset:
For common community phylogenetic analyses, go ahead and use synthesis phylogenies

Should we build our own phylogenetic trees based on gene sequence data, or can we simply use available synthesis phylogenies? This is a fundamental question that any study involving a phylogenetic framework must face at the beginning of the project. Building a phylogeny from gene sequence data (purpose-built phylogeny) requires more effort, expertise, and cost than subsetting an already available phylogeny (synthesis-based phylogeny). However, we still lack a comparison of how these two approaches to building phylogenetic trees influence common community phylogenetic analyses such as comparing community phylogenetic diversity and estimating trait phylogenetic signal. Here, we generated three purpose-built phylogenies and their corresponding synthesis-based trees (two from Phylomatic and one from the Open Tree of Life, OTL). We simulated 1,000 communities and 12,000 continuous traits along each purpose-built phylogeny. We then compared the effects of different trees on estimates of phylogenetic diversity (alpha and beta) and phylogenetic signal (Pagel's λ and Blomberg's K). Synthesis-based phylogenies generally yielded higher estimates of phylogenetic diversity when compared to purpose-built phylogenies. However, resulting measures of phylogenetic diversity from both types of phylogenies were highly correlated (Spearman's ρ > 0.8 in most cases). Mean pairwise distance (both alpha and beta) is the index that is most robust to the differences in tree construction that we tested. Measures of phylogenetic diversity based on the OTL showed the highest correlation with measures based on the purpose-built phylogenies. Trait phylogenetic signal estimated with synthesis-based phylogenies, especially from the OTL, was also highly correlated with estimates of Blomberg's K or close to Pagel's λ from purpose-built phylogenies when traits were simulated under Brownian motion. For commonly employed community phylogenetic analyses, our results justify taking advantage of recently developed and continuously improving synthesis trees, especially the Open Tree of Life.
Density-dependent selection and the limits of relative fitness

Abstract Selection is commonly described by assigning constant relative fitness values to genotypes. Yet population density is often regulated by crowding. Relative fitness may then depend on density, and selection can change density when it acts on a density-regulating trait. When strong density-dependent selection acts on a density-regulating trait, selection is no longer describable by density-independent relative fitnesses, even in demographically stable populations. These conditions are met in most previous models of density-dependent selection (e.g. “ K -selection” in the logistic and Lotka–Volterra models), suggesting that density-independent relative fitnesses must be replaced with more ecologically explicit absolute fitnesses unless selection is weak. Here we show that density-independent relative fitnesses can also accurately describe strong density-dependent selection under some conditions. We develop a novel model of density-regulated population growth with three ecologically intuitive traits: fecundity, mortality, and competitive ability. Our model, unlike the logistic or Lotka–Volterra, incorporates a density-dependent juvenile “reproductive excess”, which largely decouples density-dependent selection from the regulation of density. We find that density-independent relative fitnesses accurately describe strong selection acting on any one trait, even fecundity, which is both density-regulating and subject to density-dependent selection. Pleiotropic interactions between these traits recover the familiar K -selection behavior. In such cases, or when the population is maintained far from demographic equilibrium, our model offers a possible alternative to relative fitness.
Ammonia-promoted fragmentation of 2-alkyl- and 2,4-dialkyl-3-iodo-1- oxocyclohexan-2,4-carbolactones.

2-Alkyl- and 2,4-dialkyl-3-iodo-1-oxocyclohexan-2,4-carbolactones undergo ammonia-promoted fragmentation reactions to provide butenolides, γ-butyrolactone, and/or β,γ-epoxycyclohexanones. Product distribution is governed by the relative size of the substituents at C-2 and C-4 of the cyclohexanones. Butenolide amide, the major product from the fragmentation, is further converted into their respective piperidinone and pyrrolidine derivatives.
Protein Gradients on the Nucleoid Position the Carbon-fixing Organelles of Cyanobacteria

Carboxysomes are protein-based bacterial organelles encapsulating key enzymes of the Calvin-Benson-Bassham cycle. Previous work has implicated a ParA-like protein (hereafter McdA) as important for spatially organizing carboxysomes along the longitudinal axis of the model cyanobacterium Synechococcus elongatus PCC 7942. Yet, how self-organization of McdA emerges and contributes to carboxysome positioning is unknown. Here, we identify a small protein, termed McdB that localizes to carboxysomes and drives emergent oscillatory patterning of McdA on the nucleoid. Our results demonstrate that McdB directly stimulates McdA ATPase activity and its release from DNA, driving carboxysome-dependent depletion of McdA locally on the nucleoid and promoting directed motion of carboxysomes towards increased concentrations of McdA. We propose that McdA and McdB are a previously unknown class of self-organizing proteins that utilize a Brownian-ratchet mechanism to position carboxysomes in cyanobacteria, rather than a cytoskeletal system. These results have broader implications for understanding spatial organization of protein mega-complexes and organelles in bacteria.
Leakage-Resilient Public-Key Cryptography in the Bounded-Retrieval Model.

We study the design of cryptographic primitives resilient to key-leakage attacks, where an attacker can repeatedly and adaptively learn information about the secret key, subject only to the constraint that the overall amount of such information is bounded by some parameter `. We construct a variety of leakage-resilient public-key systems including the first known identification schemes (ID), signature schemes and authenticated key agreement protocols (AKA). Our main result is an efficient three-round leakage-resilient AKA in the Random-Oracle model. This protocol ensures that session keys are private and authentic even if (1) the adversary leaks a large fraction of the long-term secret keys of both users prior to the protocol execution and (2) the adversary completely learns the long-term secret keys after the protocol execution. In particular, our AKA protocol provides qualitatively stronger privacy guarantees than leakage-resilient public-encryption schemes (constructed in prior and concurrent works), since such schemes necessarily become insecure if the adversary can perform leakage attacks after seing a ciphertext. Moreover, our schemes can be flexibly extended to the Bounded-Retrieval Model, allowing us to tolerate very large absolute amount of adversarial leakage ` (potentially many gigabytes of information), only by increasing the size of the secret key and without any other loss of efficiency in communication or computation. Concretely, given any leakage parameter `, security parameter λ, and any desired fraction 0 < δ ≤ 1, our schemes have the following properties:  Secret key size is `(1 + δ) +O(λ). In particular, the attacker can learn an approximately (1− δ) fraction of the secret key.  Public key size is O(λ), and independent of `.  Communication complexity is O(λ/δ), and independent of `.  All computation reads at most O(λ/δ) locations of the secret key, independently of `. Lastly, we show that our schemes allow for repeated “invisible updates” of the secret key, allowing us to tolerate up to ` bits of leakage in between any two updates, and an unlimited amount of leakage overall. These updates require that the parties can securely store a short “master update key” (e.g. on a separate secure device protected against leakage), which is only used for updates and not during protocol execution. The updates are invisible in the sense that a party can update its secret key at any point in time, without modifying the public key or notifying the other users. ∗Computer Science Dept. NYU. Email: jalwen@cs.nyu.edu. †Computer Science Dept. NYU. Email: dodis@cs.nyu.edu. ‡Computer Science Dept. NYU. Email: wichs@cs.nyu.edu.
Loading-unloading contact law for micro-crystalline cellulose particles under large deformations

Abstract A semi-empirical mechanistic contact law for micro-crystalline cellulose (Avicel PH-200) particles is proposed and characterized experimentally using force-displacement curves obtained from diametrical compression of single particles. The concepts of a shape factor and a master contact law are introduced first for elastic ellipsoidal particles, and subsequently generalized to plastic irregular particles. The proposed loading-unloading contact law is a function of three characteristic diameters (lengths of the principal axes of an approximated ellipsoid), a geometric parameter associated with the loading condition, three plastic and one elastic material properties. The force-displacement curves obtained using a micro-compression tester exhibit an apparent strain-hardening at distinctly different strain values, which is captured by the shape factor function and its geometric parameter. The three plastic material properties are log-normal distributions estimated from the loading experimental curves, while the elastic property is estimated from the unloading experimental curves. The study shows a very good agreement between predictions of the calibrated loading-unloading contact law and the experimental values.
Synthesis of polycyclic guanidines by cyclocondensation reactions of N-amidinyliminium ions.

A new method for the synthesis of polycyclic guanidines is described. The N-amidinyliminium ion generated from α-(phenylthio)amidine precursor 16 by reaction with Cu(OTf)2 undergoes cyclocondensation with 1,3-dienes, styrenes, and β-dicarbonyl compounds to give 1-iminohexahydropyrrolo[1,2-c]pyrimidines having side chains at C3 and C7. In all cases, major products have a cis relationship of the C7 side chain and angular C4a hydrogen, whereas C3 side chains are incorporated with lower stereoselectivity (dr = 2−5:1) in cyclocondensations with dienes and styrenes to give stereoisomer 39 as the major product. In contrast to most cycloadditions of alkenes with N-acyliminium ions, cyclocondensations of alkenes with N-amidinyliminium ions proceed by a stepwise pathway. Cyclocondensation of the cognate ureido aminal 31 with styrene provides the rare 2-imino-5,6-dihydro-4H-1,3-oxazine derivative 32, rather than a pyrimidine as the major product. The high stereoselectivity observed in condensations of 16 with benzyl...
RstA Is a Major Regulator of Clostridioides difficile Toxin Production and Motility.

ABSTRACT Clostridioides difficile infection (CDI) is a toxin-mediated diarrheal disease. Several factors have been identified that influence the production of the two major C. difficile toxins, TcdA and TcdB, but prior published evidence suggested that additional unknown factors were involved in toxin regulation. Previously, we identified a C. difficile regulator, RstA, that promotes sporulation and represses motility and toxin production. We observed that the predicted DNA-binding domain of RstA was required for RstA-dependent repression of toxin genes, motility genes, and rstA transcription. In this study, we further investigated the regulation of toxin and motility gene expression by RstA. DNA pulldown assays confirmed that RstA directly binds the rstA promoter via the predicted DNA-binding domain. Through mutational analysis of the rstA promoter, we identified several nucleotides that are important for RstA-dependent transcriptional regulation. Further, we observed that RstA directly binds and regulates the promoters of the toxin genes tcdA and tcdB, as well as the promoters for the sigD and tcdR genes, which encode regulators of toxin gene expression. Complementation analyses with the Clostridium perfringens RstA ortholog and a multispecies chimeric RstA protein revealed that the C. difficile C-terminal domain is required for RstA DNA-binding activity, suggesting that species-specific signaling controls RstA function. Our data demonstrate that RstA is a transcriptional repressor that autoregulates its own expression and directly inhibits transcription of the two toxin genes and two positive toxin regulators, thereby acting at multiple regulatory points to control toxin production. IMPORTANCEClostridioides difficile is an anaerobic, gastrointestinal pathogen of humans and other mammals. C. difficile produces two major toxins, TcdA and TcdB, which cause the symptoms of the disease, and forms dormant endospores to survive the aerobic environment outside the host. A recently discovered regulatory factor, RstA, inhibits toxin production and positively influences spore formation. Herein, we determine that RstA directly binds its own promoter DNA to repress its own gene transcription. In addition, our data demonstrate that RstA directly represses toxin gene expression and gene expression of two toxin gene activators, TcdR and SigD, creating a complex regulatory network to tightly control toxin production. This study provides a novel regulatory link between C. difficile sporulation and toxin production. Further, our data suggest that C. difficile toxin production is regulated through a direct, species-specific sensing mechanism.
An Accessible Continuous-Culture Turbidostat for Pooled Analysis of Complex Libraries

We present an accessible, robust continuous-culture turbidostat system that greatly facilitates the generation and phenotypic analysis of highly complex libraries in yeast and bacteria. Our system has many applications in genomics and systems biology; here, we demonstrate three of these uses. We first measure how the growth rate of budding yeast responds to limiting nitrogen at steady state and in a dynamically varying environment. We also demonstrate the direct selection of a diverse, genome-scale protein fusion library in liquid culture. Finally, we perform a comprehensive mutational analysis of the essential gene RPL28 in budding yeast, mapping sequence constraints on its wild-type function and delineating the binding site of the drug cycloheximide through resistance mutations. Our system can be constructed and operated with no specialized skills or equipment and applied to study genome-wide mutant pools and diverse libraries of sequence variants under well-defined growth conditions.
K10M4Sn4S17 (M = Mn, Fe, Co, Zn): soluble quaternary sulfides with the discrete [M4Sn4S17]10- supertetrahedral clusters.

Four cubic compounds are reported that contain the supertetrahedral cluster [M4Sn4S17]10- where M = Mn, Fe, Co, Zn. The cluster features a central quadruply bridging sulfide ion (μ4-S) that holds t...
A new method for the functionalization of [60] fullerene: an unusual 1,3-dipolar cycloaddition pathway leading to a C60 housane derivative.

A variant of the Huisgen 1,3-dipolar cycloaddition reaction provides a new and convenient functionalization of fullerenes. This method complements the widely used Prato and Bingel−Hirsch reactions. The derived, highly functionalized cyclopentenone and cyclopentenamine fullerene compounds upon hydrolysis are suitable for further functionalization and may serve well in the synthesis of new C60 derivatives possessing uncommon and interesting properties.
Markov models of the apo-MDM2 lid region reveal diffuse yet two-state binding dynamics and receptor poses for computational docking

MDM2 is a negative regulator of p53 activity and an important target for cancer therapeutics. The N-terminal lid region of MDM2 modulates interactions with p53 via competition for its binding cleft, exchanging slowly between docked and undocked conformations in the absence of p53. To better understand these dynamics, we constructed Markov State Models (MSMs) from large collections of unbiased simulation trajectories of apo-MDM2, and find strong evidence for diffuse, yet two-state folding and binding of the N-terminal region to the p53 receptor site. The MSM also identifies holo-like receptor conformations highly suitable for computational docking, despite initiating trajectories from closed-cleft receptor structures unsuitable for docking. Fixed-anchor docking studies using a test set of high-affinity small molecules and peptides show simulated receptor ensembles achieve docking successes comparable to cross-docking studies using crystal structures of receptors bound by alternative ligands. For p53, the best-scoring receptor structures have the N-terminal region lid region bound in a helical conformation mimicking the bound structure of p53, suggesting lid region association induces receptor conformations suitable for binding. These results suggest that MD + MSM approaches can sample binding-competent receptor conformations suitable for computational peptidomimetic design, and that inclusion of disordered regions may be essential to capturing the correct receptor dynamics.
Pentavalent and tetravalent uranium selenides, Tl3Cu4USe6 and Tl2Ag2USe4: syntheses, characterization, and structural comparison to other layered actinide chalcogenide compounds.

The compounds Tl3Cu4USe6 and Tl2Ag2USe4 were synthesized by the reaction of the elements in excess TlCl at 1123 K. Both compounds crystallize in new structure types, in space groups P21/c and C2/m, respectively, of the monoclinic system. Each compound contains layers of USe6 octahedra and MSe4 (M = Cu, Ag) tetrahedra, separated by Tl+ cations. The packing of the octahedra and the tetrahedra within the layers is compared to the packing arrangements found in other layered actinide chalcogenides. Tl3Cu4USe6 displays peaks in its magnetic susceptibility at 5 and 70 K. It exhibits modified Curie–Weiss paramagnetic behavior with an effective magnetic moment of 1.58(1) μB in the temperature range 72–300 K, whereas Tl2Ag2USe4 exhibits modified Curie–Weiss paramagnetic behavior with μeff = 3.4(1) μB in the temperature range 100–300 K. X-ray absorption near-edge structure (XANES) results from scanning transmission X-ray spectromicroscopy confirm that Tl3Cu4USe6 has Se bonding characteristic of discrete Se2– units, ...
Stereocontrolled intramolecular iron-mediated tandem [6+2]-ene-type diene/dienol ether double cyclization reactions

Abstract A stereocontrolled intramolecular iron-mediated diene/diene tandem double cyclocoupling reaction has been explored using vinyl ethers as the olefin partners. Diastereomerically pure spirotricyclic products with functionalized (alkoxymethyl) side chains can be formed efficiently under photothermal conditions. With a methoxy substituent on the iron-complexed cyclohexadiene core, demetallation and acidic hydrolysis of the cyclocoupling product afforded a cyclohexenone ring.
Effects of water decontamination methods and bedding material on the gut microbiota

Rodent models are invaluable to understanding health and disease in many areas of biomedical research. Unfortunately, many models suffer from lack of phenotype reproducibility. Our laboratory has shown that differences in gut microbiota (GM) can modulate phenotypes of models of colon cancer and inflammatory bowel disease. We and others have also shown that a number of factors associated with rodent research, including vendor, cage system, and bedding can alter GM. The objective of this study was to expand these studies to examine the effect of additional bedding materials and methods of water decontamination on GM diversity and composition. To this end, Crl:CD1 (ICR) mice were housed on corn cob or compressed paper chip bedding and provided water that was decontaminated by four different methods: autoclaving with reverse osmosis, autoclaving with hydrochloric acid, autoclaving with sulfuric acid, and autoclaving alone. Feces was collected at day 0, and at day 28 (endpoint), fecal and cecal samples were collected. DNA was extracted from samples, amplified by PCR using conserved bacterial primer sets and subjected to next generation sequencing. Sequence data were analyzed using Qiime and groups were compared using principal coordinate analysis (PCoA) and permutational multivariate analysis of variance (PERMANOVA). Two factor PERMANOVA of cecal GM data revealed significant changes when comparing bedding and water decontamination methods, while no significant effects were noted in the fecal GM data. Subsequent PERMANOVA and PCoA of cecal data revealed that several combinations of bedding and water decontamination methods resulted in differing GM, highlighting the complexity by which environmental factors interact to modulate GM.
Detritylation with ytterbium triflate

Abstract Ytterbium triflate catalyzes the hydrolysis of tritylamines and trityloxy compounds to the corresponding amines and alcohols under mild conditions in high yields. The reactions are conducted in tetrahydrofuran in the presence of 1 equivalent of water.
Peroxide-Mediated Wacker Oxidations for Organic Synthesis.

The Wacker oxidation is a powerful synthetic transformation, which converts a terminal olefin to a methyl ketone via palladium catalysis, traditionally employing molecular oxygen as the terminal oxidant and a copper cocatalyst.1–3 Good functional group tolerance, ease of reaction, and the orthogonal reactivity of the substrate and product have led to the widespread application of this transformation in the industrial preparation of commodity chemicals, such as acetaldehyde, and in target directed synthesis.4 The most common system used is that initially reported by Clement and further advanced by Tsuji, employing a mixed DMF and water solvent system.2,3 In the Tsuji-Wacker oxidation, water is the source of the oxygen atom which is incorporated into the product, and molecular oxygen is the terminal oxidant (Figure 1). Figure 1 Oxidase type catalysis of the Wacker oxidation. An alternative approach to the same transformation, which is less commonly employed for synthetic applications, utilizes an electrophilic metalloperoxide species, formed by metal activation of molecular oxygen or exogenous hydro- or alkylperoxides. These peroxymetallo reagents and/or catalysts are proposed to coordinate an olefin. Subsequently, the olefin inserts in a peroxymetallation step (Scheme 1).5 Early work in this field follows closely with similar metal-catalyzed peroxide-mediated epoxidation reactions.6,7 An advantage of this mechanistic manifold for affecting the transformation of terminal alkenes to methyl ketones seems to lie in the “preloaded” catalyst and the selective syn-metallation step. This is contrary to the Tsuji-Wacker oxypalladation step, which may occur in an anti fashion, but can be particularly dependent on the reaction conditions.8–16 Overall, some of the peroxymetallation reactions display good synthetic potential as they predominantly lead to single oxidation products via catalyst control, whereas the Tsuji-Wacker reaction is subject to substrate control (vide infra). Scheme 1 Activation of molecular oxygen leads to intermediates similar to those proposed when exogenous hydro- or alkylperoxides are used. More recently, peroxide-mediated, ligand-modulated, palladium-catalyzed systems have been reported. These systems, which utilize commercially-available peroxides, allow for the efficient and selective oxidation of substrates, which would otherwise give mixtures of products when oxidized using Tsuji-Wacker conditions. The Wacker oxidation has been extensively reviewed,4,17–20 including instances which produce aldehydes;21 however, peroxide-mediated Wacker-type oxidations have not recently been reviewed and is the focus of the discussion herein.
Synthesis, structure determination, and infrared spectroscopy of (NpO2)2(SO4)(H2O)4: Prevalence of cation–cation interactions and cationic nets in neptunyl sulfate compounds

Abstract The compound (NpO2)2(SO4)(H2O)4 was synthesized by evaporation of a Np5+ sulfate solution. The crystal structure was determined using single crystal X-ray diffraction and refined to an R1=0.0310. (NpO2)2(SO4)(H2O)4 crystallizes in triclinic space group P-1, a=8.1102(7) A, b=8.7506(7) A, c=16.234(1) A, α=90.242(2)°, β=92.855(2)°, γ=113.067(2)°, V=1058.3(2) A3, and Z=2. The structure contains neptunyl pentagonal bipyramids that share vertices through cation–cation interactions to form a sheet or cationic net. The sheet is decorated on each side by vertex sharing with sulfate tetrahedra, and adjacent sheets are linked together through hydrogen bonding. A graphical representation of (NpO2)2(SO4)(H2O)4 was constructed to facilitate the structural comparison to similar Np5+ compounds. The prevalence of the cationic nets in neptunyl sulfate compounds related to the overall stability of the structure is also discussed.
Synthesis of Bicyclic Enediynes from Bis[phenyl[(trifluoromethanesulfonyl)oxy]iodo]acetylene: A Tandem Diels-Alder/Palladium(II)- and Copper(I)-Cocatalyzed Cross-Coupling Approach.

The reaction of bicycloalkenylbis(phenyliodonium) triflates 1a or b (available via the Diels−Alder reaction of bis[phenyl[(trifluoromethanesulfonyl)oxy]iodo]acetylene with cyclopentadiene or furan,...
P-directed borylation of phenols.

Internal borylation occurs upon activation of aryl di-isopropylphosphinite boranes with HNTf2 to give heterocyclic intermediates that can be reductively quenched to afford 6 or treated with KHF2 to give the phenolic potassium aryl trifluoroborate salts 10. The latter salts are useful for Pd-catalyzed coupling with aryl iodides under Molander conditions, provided that precautions are taken to remove the KNTf2 byproduct from the preceding KHF2 step.
Highly efficient synthesis of 1,1-difluoro-2-substituted-1,3-dienes and dienynes from gem-difluorohomoallenyl bromide via palladium-catalyzed cross-coupling reactions.

A stable gem-difluoroallenylindium 1 is readily transformed to a potentially bifunctional electrophile 2, which can then undergo a transition-metal-promoted isomerization−cross-coupling cascade to yield diene 3 and dienyne 4 in very high yields.
Ni3Cr2P2Q9 (Q = S, Se): New Quaternary Transition Metal Chalcogenides with a Unique Layered Structure

The new transition metal chalcogenides Ni3Cr2P2S9 and Ni3Cr2P2Se9 have been discovered and characterized. Single-crystal X-ray diffraction studies of the selenide reveal a new layered structure type (space group P63/m, a = 6.244(4) A, c = 18.479(19) A, Z = 2, R1 = 0.0235). Powder X-ray diffraction and electron microprobe analysis suggest that the sulfide is isostructural to the selenide and that a solid solution forms between them. The layers are composed of transition metal centered octahedra with chalcogenides at the vertices which are joined in pairs by face sharing along the c-direction. These units share edges to form honeycomb layers in the ab-plane with linear P−Ni−P units in the holes of the honeycomb nets. Transport properties measurements from 80−300 K on single crystals with compositions Ni3Cr2P2S9-xSex (x = 0, 3, 6) revealed activated behavior in electrical resistivity (Ea = 0.02−0.03 eV, ρ300K = 50−220 mΩ·cm) and positive values of the Seebeck coefficient (S300K = 80−225 μV/K), showing that t...
Selection-Like Biases Emerge in Population Models with Recurrent Jackpot Events

Evolutionary dynamics driven out of equilibrium by growth, expansion, or adaptation often generate a characteristically skewed distribution of descendant numbers: the earliest, the most advanced, or the fittest ancestors have exceptionally large number of descendants, which Luria and Delbruck called "jackpot" events. Here, I show that recurrent jackpot events generate a deterministic median bias favoring majority alleles, which is akin to positive frequency-dependent selection (proportional to the log ratio of the frequencies of mutant and wild-type alleles). This fictitious selection force results from the fact that majority alleles tend to sample deeper into the tail of the descendant distribution. The flip side of this sampling effect is the rare occurrence of large frequency hikes in favor of minority alleles, which ensures that the allele frequency dynamics remains neutral in expectation, unless genuine selection is present. The resulting picture of a selection-like bias compensated by rare big jumps allows for an intuitive understanding of allele frequency trajectories and enables the exact calculation of transition densities for a range of important scenarios, including population-size variations and different forms of natural selection. As a general signature of evolution by rare events, fictitious selection hampers the establishment of new beneficial mutations, counteracts balancing selection, and confounds methods to infer selection from data over limited timescales.
End-to-End Differentiable Learning of Protein Structure.

Summary Predicting protein structure from sequence is a central challenge of biochemistry. Co-evolution methods show promise, but an explicit sequence-to-structure map remains elusive. Advances in deep learning that replace complex, human-designed pipelines with differentiable models optimized end to end suggest the potential benefits of similarly reformulating structure prediction. Here, we introduce an end-to-end differentiable model for protein structure learning. The model couples local and global protein structure via geometric units that optimize global geometry without violating local covalent chemistry. We test our model using two challenging tasks: predicting novel folds without co-evolutionary data and predicting known folds without structural templates. In the first task, the model achieves state-of-the-art accuracy, and in the second, it comes within 1–2 A; competing methods using co-evolution and experimental templates have been refined over many years, and it is likely that the differentiable approach has substantial room for further improvement, with applications ranging from drug discovery to protein design.
Incremental and Decremental Maintenance of Planar Width

We present an algorithm for maintaining the width of a planar point set dynamically, as points are inserted or deleted. Our algorithm takes time O(kn?) per update, where k is the amount of change the update causes in the convex hull, n is the number of points in the set, and ?0 is any arbitrarily small constant. For incremental or decremental update sequences, the amortized time per update is O(n?).
Free Radical Studies and Solutions to the Synthesis of (+)-Cyclophellitol‡

d-Xylose serves as a starting material for approaches to the synthesis of the glucosidase inhibitors, (+)-cyclophellitol (1) and (+)-epi-cyclophellitol (2). An investigation of the cyclization of diastereomeric oxiranyl radicals to achieve this goal was moderately successful with the diastereomer that would have led to epi-cyclophellitol undergoing cyclization. An alternative route to cyclophellitol from d-xylose employed Grubbs' ring closure metathesis and radical transformations to complete the synthesis.
Synthesis and evaluation of a novel dirhodium tetraprolinate catalyst containing bridging prolinate ligands

Abstract The D2 symmetric dirhodium prolinate complex 2 is an effective catalyst for asymmetric vinylcarbenoid cyclopropanations
A Farewell to Falsity Shifting Standards in Medicare Fraud Enforcement

For the better part of a decade, Americans have had a front-row seat to a fervent and turbulent debate over the future of their health care system. The passage of the Patient Protection and Affordable Care Act of 2010 (ACA), the most comprehensive health reform effort since the mid-1960s, ushered in a new era in health law and policy, granting millions of Americans access to health care. After multiple legal challenges and congressional efforts that ultimately failed to slay the law, the ACA had become entrenched by the end of the Obama administration, even though pieces of the law had failed to work exactly as planned. Now, with the surprising election of President Donald Trump, reenergized Republicans are targeting the law once more, and it suddenly appears more vulnerable than ever. Dynamic uncertainty again permeates the national debate. Although most powerful protections of the ACA may evaporate--no small event, to be sure--the value-based era which it unleashed seems here to stay. Indeed, this era--focused on efficiency, standardization, and quality within American medicine--has just begun to bear fruit. Illustrated prominently by recent changes to Medicare that alter how the program pays its doctors for services they provide to its beneficiaries, America is moving away from the old strictures of fee-for-service medicine. At the same time, traditional legal tools, and particularly the federal government’s most prominent anti-fraud tool, the civil federal False Claims Act (FCA), seem to be facing new limits. This has been recently evident in medical necessity-based fraud cases, and particularly highly publicized fights that have targeted the burgeoning industry of hospice care. This Article tracks this development, ultimately arguing that the move to "reimbursement-based regulation" may be a positive step in finally reining in the worst excesses of American health care. But it also cautions against the deceptive simplicity of allowing medical heterogeneity and clinical complexity to prevent application of America’s most powerful anti-fraud tools to its medical industry. Just because reimbursement policy has shifted to shoulder some of the regulatory burden of overtreatment does not mean that health care fraud--like fee-for-service medicine--should be confined to the past. In the end--and regardless of whatever legislation the national debate surrounding American health care produces--American medicine must adequately address its susceptibility to overtreatment, its incentives toward financial excess and waste, and its inability to push providers and entities into adopting more efficient practices. Medicare is finally moving quickly to bring about effective changes, and the program is seeking clarity in the midst of a period of tremendous uncertainty for American health care.
Extensive Epitranscriptomic Methylation of A and C Residues on Murine Leukemia Virus Transcripts Enhances Viral Gene Expression.

ABSTRACT While it has been known for several years that viral RNAs are subject to the addition of several distinct covalent modifications to individual nucleotides, collectively referred to as epitranscriptomic modifications, the effect of these editing events on viral gene expression has been controversial. Here, we report the purification of murine leukemia virus (MLV) genomic RNA to homogeneity and show that this viral RNA contains levels of N6-methyladenosine (m6A), 5-methylcytosine (m5C), and 2′O-methylated (Nm) ribonucleotides that are an order of magnitude higher than detected on bulk cellular mRNAs. Mapping of m6A and m5C residues on MLV transcripts identified multiple discrete editing sites and allowed the construction of MLV variants bearing silent mutations that removed a subset of these sites. Analysis of the replication potential of these mutants revealed a modest but significant attenuation in viral replication in 3T3 cells in culture. Consistent with a positive role for m6A and m5C in viral replication, we also demonstrate that overexpression of the key m6A reader protein YTHDF2 enhances MLV replication, while downregulation of the m5C writer NSUN2 inhibits MLV replication. IMPORTANCE The data presented in the present study demonstrate that MLV RNAs bear an exceptionally high level of the epitranscriptomic modifications m6A, m5C, and Nm, suggesting that these each facilitate some aspect of the viral replication cycle. Consistent with this hypothesis, we demonstrate that mutational removal of a subset of these m6A or m5C modifications from MLV transcripts inhibits MLV replication in cis, and a similar result was also observed upon manipulation of the level of expression of key cellular epitranscriptomic cofactors in trans. Together, these results argue that the addition of several different epitranscriptomic modifications to viral transcripts stimulates viral gene expression and suggest that MLV has therefore evolved to maximize the level of these modifications that are added to viral RNAs.
Facile synthesis of d-amino acids from an l-serine-derived aziridine

Abstract Using the concept that l -serine can be converted into a desymmetrized γ-diol derivative, five d -amino acids were synthesized from a common aziridine intermediate by a general, high-yielding three-step process. The key 2- t -butyldimethylsiloxymethyl N- t -butoxycarbonyl aziridine intermediate was synthesized in four steps and 65% overall yield.
FURTHER EVALUATION OF 5-ALKYL-5-DEAZA ANTIFOLATES. 5-PROPYL- AND 5-BUTYL-5-DEAZA ANALOGUES OF AMINOPTERIN AND METHOTREXATE

5-Propyl-5-deaza and 5-butyl-5-deaza analogues of classical antifolates were synthesized by extensions of a previously reported general route which proceeds through 2,4-diamino-5-alkylpyrido[2,3-d]pyrimidine-6-carbonitrile intermediates followed by reductive condensation with diethyl N-4-(aminobenzoyl)-L-glutarnate to give diethyl esters of 5-alkyl-5-deazaaminopterin types. N10-Methyl derivatives, i.e., derivatives of 5-alkyl-5-deazamethotrexate, were also prepared by reductive methylation of the N10-H compounds. 5-Ethyl-5-deazamethotrexate was prepared using an alternative route through 6-(bromomethyl)-2,4-diamino-5-ethylpyrido[2,3-d]pyrimidine. These antifolates were evaluated for inhibition of dihydrofolate reductase (DHFR) from L1210 cells, their effect on L1210 and S180 tumor cell growth in culture, and carrier-mediated transport through L1210 cell membranes. Inhibitory effect on DHFR was lowered relative to methotrexate in 5-propyl-5-deazaaminopterin and 5-propyl-5-deazamethotrexate by 2- to 3-fold (Ki = 9.3 and 11.7 pM, respectively, vs. 4.3 pM for methotrexate) and by 17- to 18-fold in 5-butyl-5-deaza-aminopterin and 5-butyl-5-deazamethotrexate (Ki = 74 and 78 pM, respectively). Molecular modeling using graphics derived from human DHFR show the propyl and butyl compounds interacting with the enzyme in conformations that account for these slight decreases in binding.
Stereoselective route to mitosanes via tricarbonyl η6 arene chromium complexes

Abstract Stereoselective reduction followed by metalation of a η6 arene chromium tricarbonyl complex allows rapid access to substituted mitosanes, whose skeleton mimics the mitomycin family of antitumour agents.
The Stress-Chip: A microfluidic platform for stress analysis in Caenorhabditis elegans

An organism's ability to mount a physiological response to external stressors is fundamental to its interaction with the environment. Experimental exploration of these interactions benefits greatly from the ability to maintain tight control of the environment, even under conditions in which it would be normal for the subject to flee the stressor. Here we present a nematode research platform that pairs automated image acquisition and analysis with a custom microfluidic device. This platform enables tight environmental control in low-density, single-worm arenas, which preclude animal escape while still allowing a broad range of behavioral activities. The platform is easily scalable, with two 50 arena arrays per chip and an imaging capacity of 600 animals per scanning device. Validating the device using dietary, osmotic, and oxidative stress indicates that it should be of broad use as a research platform, including eventual adaptation for additional stressors, anthelmintic-drug screening, and toxicology studies.
Insect Egg Size and Shape Evolve With Ecology but Not Developmental Rate

Over the course of evolution, organism size has diversified markedly. Changes in size are thought to have occurred because of developmental, morphological and/or ecological pressures. To perform phylogenetic tests of the potential effects of these pressures, here we generated a dataset of more than ten thousand descriptions of insect eggs, and combined these with genetic and life-history datasets. We show that, across eight orders of magnitude of variation in egg volume, the relationship between size and shape itself evolves, such that previously predicted global patterns of scaling do not adequately explain the diversity in egg shapes. We show that egg size is not correlated with developmental rate and that, for many insects, egg size is not correlated with adult body size. Instead, we find that the evolution of parasitoidism and aquatic oviposition help to explain the diversification in the size and shape of insect eggs. Our study suggests that where eggs are laid, rather than universal allometric constants, underlies the evolution of insect egg size and shape. Analyses of insect eggs as well as genetic and life-history traits of insects show that where eggs are laid, rather than universal allometric constants, developmental rate or adult body size, underlies size and shape evolution.
CuSbSe2 photovoltaic devices with 3% efficiency

Recent technical and commercial successes of existing thin-film solar cell technologies encourage the exploration of next-generation photovoltaic (PV) absorber materials. Of particular scientific interest are compounds that do not exhibit conventional tetrahedral semiconductor bonding, such as CuSbSe2. CuSbSe2 has a 1.1 eV optical absorption onset, a 105 cm−1 absorption coefficient, and a hole concentration of 1017 cm−3. Here, we demonstrate CuSbSe2 PV prototypes with efficiencies >3%, prepared by a self-regulated sputtering process using a conventional substrate device architecture. Bulk recombination, device engineering issues, and a nonideal CuSbSe2/CdS band offset likely limit the promising initial result.
Commutative Algorithms Approximate the LLL-distribution

Following the groundbreaking Moser-Tardos algorithm for the Lovasz Local Lemma (LLL), a series of works have exploited a key ingredient of the original analysis, the witness tree lemma, in order to: derive deterministic, parallel and distributed algorithms for the LLL, to estimate the entropy of the output distribution, to partially avoid bad events, to deal with super-polynomially many bad events, and even to devise new algorithmic frameworks. Meanwhile, a parallel line of work, has established tools for analyzing stochastic local search algorithms motivated by the LLL that do not fall within the Moser-Tardos framework. Unfortunately, the aforementioned results do not transfer to these more general settings. Mainly, this is because the witness tree lemma, provably, no longer holds. Here we prove that for commutative algorithms, a class recently introduced by Kolmogorov and which captures the vast majority of LLL applications, the witness tree lemma does hold. Armed with this fact, we extend the main result of Haeupler, Saha, and Srinivasan to commutative algorithms, establishing that the output of such algorithms well-approximates the LLL-distribution, i.e., the distribution obtained by conditioning on all bad events being avoided, and give several new applications. For example, we show that the recent algorithm of Molloy for list coloring number of sparse, triangle-free graphs can output exponential many list colorings of the input graph.
Recovery Guarantees for One-hidden-layer Neural Networks

In this paper, we consider regression problems with one-hidden-layer neural networks (1NNs). We distill some properties of activation functions that lead to local strong convexity in the neighborhood of the ground-truth parameters for the 1NN squared-loss objective and most popular nonlinear activation functions satisfy the distilled properties, including rectiﬁed linear units (ReLUs), leaky ReLUs, squared ReLUs and sigmoids. For activation functions that are also smooth, we show local linear convergence guarantees of gradient descent under a resampling rule. For homogeneous activations, we show tensor methods are able to initialize the parameters to fall into the local strong convexity region. As a result, tensor initialization followed by gradient descent is guaranteed to recover the ground truth with sample complexity d·log(1/)·poly(k,λ) and computational complexity n·d·poly(k,λ) for smooth homogeneous activations with high probability, where d is the dimension of the input, k (k ≤ d) is the number of hidden nodes, λ is a conditioning property of the ground-truth parameter matrix between the input layer and the hidden layer,  is the targeted precision and n is the number of samples. To the best of our knowledge, this is the ﬁrst work that provides recovery guarantees for 1NNs with both sample complexity and computational complexity linear in the input dimension and logarithmic in the precision.
Optimization Algorithms for Catching Data Manipulators in Power System Estimation Loops

In this paper, we develop a set of algorithms that can detect the identities of malicious data manipulators in distributed optimization loops for estimating oscillation modes in large-power system models. The estimation is posed in terms of a consensus problem among multiple local estimators that jointly solve for the characteristic polynomial of the network model. If any of these local estimates is compromised by a malicious attacker, resulting in an incorrect value of the consensus variable, then the entire estimation loop can be destabilized. We present four iterative algorithms by which this instability can be quickly detected, and the identities of the compromised estimators can be revealed. The algorithms are solely based on the computed values of the estimates, and do not need any information about the model of the power system. Both large and covert attacks are considered. The results are illustrated using simulations of the IEEE 68-bus power system model.
Generating Fine-Grained Open Vocabulary Entity Type Descriptions.

While large-scale knowledge graphs provide vast amounts of structured facts about entities, a short textual description can often be useful to succinctly characterize an entity and its type. Unfortunately, many knowledge graphs entities lack such textual descriptions. In this paper, we introduce a dynamic memory-based network that generates a short open vocabulary description of an entity by jointly leveraging induced fact embeddings as well as the dynamic context of the generated sequence of words. We demonstrate the ability of our architecture to discern relevant information for more accurate generation of type description by pitting the system against several strong baselines.
Paramodular abelian varieties of odd conductor

A precise and testable modularity conjecture for rational abelian surfaces A with trivial endomorphisms, End_Q A = Z, is presented. It is consistent with our examples, our non-existence results and recent work of C. Poor and D. S. Yuen on weight 2 Siegel paramodular forms. We obtain fairly precise information on ell-division fields of semistable abelian varieties A, mainly when A[ell] is reducible, by considering extension problems for groups schemes of small rank. Our general results imply, for instance, that the least prime conductor of an abelian surface is 277.