cssi/SciSciGPT-SciSciNet huggingface dataset:
Physical Uplink Control Channel Design for 5G New Radio

The next generation wireless communication system, 5G, or New Radio (NR) will provide access to information and sharing of data anywhere, anytime by various users and applications with diverse multi-dimensional requirements. Physical Uplink Control Channel (PUCCH), which is mainly utilized to convey Uplink Control Information (UCI), is a fundamental building component to enable NR system. Compared to Long Term Evolution (LTE), more flexible PUCCH structure is specified in NR, aiming to support diverse applications and use cases. This paper describes the design principles of various NR PUCCH formats and the underlying physical structures. Further, extensive simulation results are presented to explain the considerations behind the NR PUCCH design.
DO MOVIE PRODUCTION INCENTIVES GENERATE ECONOMIC DEVELOPMENT

Movie production incentives (MPIs) are a popular economic development strategy employed by U.S. states. Film subsidies are intended to encourage external investment into a nascent industry that spills over onto complementary industries to generate economic growth through a multiplier. Despite their widespread use, the positive impact of MPIs on state economies has not been documented, and several states have halted their MPI programs due to high costs and questionable efficacy. This study exploits the staggered implementation, suspension, and elimination of film incentive programs across states to estimate the macroeconomic impact of MPIs. Instrumental variable estimates that permit causal inference do not support the hypothesized positive impacts of film incentives on state economies. (JEL H25, H71, L82, R11, R38, Z11, Z18)
A Continuous-Time View of Early Stopping for Least Squares Regression

We study the statistical properties of the iterates generated by gradient descent, applied to the fundamental problem of least squares regression. We take a continuous-time view, i.e., consider infinitesimal step sizes in gradient descent, in which case the iterates form a trajectory called gradient flow. Our primary focus is to compare the risk of gradient flow to that of ridge regression. Under the calibration $t=1/\lambda$---where $t$ is the time parameter in gradient flow, and $\lambda$ the tuning parameter in ridge regression---we prove that the risk of gradient flow is no less than 1.69 times that of ridge, along the entire path (for all $t \geq 0$). This holds in finite samples with very weak assumptions on the data model (in particular, with no assumptions on the features $X$). We prove that the same relative risk bound holds for prediction risk, in an average sense over the underlying signal $\beta_0$. Finally, we examine limiting risk expressions (under standard Marchenko-Pastur asymptotics), and give supporting numerical experiments.
Pricing dynamics of natural gas futures

Abstract Growth in the natural gas market is pronounced since the shale gas boom. Natural gas has become increasingly important in international trade, especially after the recent financialization in commodity markets. Motivated by the high volatility and time-varying nature in natural gas futures prices, understanding the pricing dynamics of natural gas is essential for risk management. In this paper, we adopt a class of computationally efficient discrete-time pricing models and construct futures dynamics by differentiating three subsamples which represent time-varying market conditions. We find strong evidence of positive jumps in the natural gas market and higher jump intensity in a more volatile period. The dynamic jump intensity model has a better model fit both in-sample and out-of-sample, suggesting time-varying jumps are necessary for pricing natural gas derivatives.
Ancestral and offspring nutrition interact to affect life-history traits in Drosophila melanogaster

Ancestral environmental conditions can impact descendant phenotypes through a variety of epigenetic mechanisms. Previous studies on transgenerational effects in Drosophila melanogaster suggest that parental nutrition may affect the body size, developmental duration and egg size of the next generation. However, it is unknown whether these effects on phenotype remain stable across generations, or if specific generations have general responses to ancestral diet. In the current study, we examined the effect on multiple life-history phenotypes of changing diet quality across three generations. Our analysis revealed unforeseen patterns in how phenotypes respond to dietary restriction. Our generalized linear model showed that when considering only two generations, offspring phenotypes were primarily affected by their own diet, and to a lesser extent by the diet of their parents or the interaction between the two generations. Surprisingly, however, when considering three generations, offspring phenotypes were primarily impacted by their grandparents' diet and their own diet. Interactions among different generations' diets affected development time, egg volume and pupal mass more than ovariole number or wing length. Furthermore, pairwise comparisons of diet groups from the same generation revealed commonalities in strong responses to rich versus poor diet: ovariole number, pupal mass and wing length responded more strongly to poor diet than to rich diet, while development time responded strongly to both rich and poor diets. To improve investigations into the mechanisms and consequences of transgenerational, epigenetic inheritance, future studies should closely examine how phenotypes change across a higher number of generations, and consider responses to broader variability in diet treatments.
Polycyclic aromatic hydrocarbons as a potential source of carcinogenicity of mate

Drinking mate, an infusion of the herb ilex paraguariensis, is very common in several South American countries, and has been associated with an increased risk of esophageal cancer. This increased risk may be attributed to drinking mate very hot, or to mate's potentially carcinogenic contaminants, such as polycyclic aromatic hydrocarbons (PAHs). Mate leaves are often dried via smoking, and therefore commercial samples may have high amounts of PAHs. We found 10 original articles that had measured PAHs in commercial dry samples, and nearly all found very high mass fractions. Most studies found benzo[a]pyrene mass fractions to be over 25 ng/g, and some found levels up to 600 ng/g. However, carcinogenic PAHs are often hydrophobic, and may not readily transfer into infusions. Seven articles studied transfer rates, and these rates varied from 1 to 50%, depending on the methods employed. Further careful studies of transfer rates in situations that mimic real life drinking of mate are recommended. Also, further studies of biological indicators of PAH exposure, particularly in randomized experiments, and analyzing DNA from tumor samples of mate drinkers are recommended.
Rapid and accurate interpretation of clinical exomes using Phenoxome: a computational phenotype-driven approach

Clinical exome sequencing (CES) has become the preferred diagnostic platform for complex pediatric disorders with suspected monogenic etiologies. Despite rapid advancements, the major challenge still resides in identifying the casual variants among the thousands of variants detected during CES testing, and thus establishing a molecular diagnosis. To improve the clinical exome diagnostic efficiency, we developed Phenoxome, a robust phenotype-driven model that adopts a network-based approach to facilitate automated variant prioritization. Phenoxome dissects the phenotypic manifestation of a patient in concert with their genomic profile to filter and then prioritize variants that are likely to affect the function of the gene (potentially pathogenic variants). To validate our method, we have compiled a clinical cohort of 105 positive patient samples that represent a wide range of genetic heterogeneity. Phenoxome identifies the causative variants within the top 5, 10, or 25 candidates in more than 50%, 71%, or 88% of these exomes, respectively. Furthermore, we show that our method is optimized for clinical testing by outperforming the current state-of-art method. We have demonstrated the performance of Phenoxome using a clinical cohort and showed that it enables rapid and accurate interpretation of clinical exomes. Phenoxome is available at https://phenoxome.chop.edu/ .
Satellite scatterometer estimation of urban built-up volume: Validation with airborne lidar data

Abstract Accurately mapping urban infrastructure and extent is a high priority for resource management and service allocation as well as for addressing environmental, socioeconomic, and geopolitical concerns. Most available data products only document surficial (two-dimensional) land use and land cover (LULC), yet a substantial component of urban growth occurs in the vertical dimension. Light detection and ranging (lidar) data offer the potential for monitoring three-dimensional (3D) change, but the extreme lack of systematic lidar coverage worldwide inflicts considerable gaps in both spatial and temporal coverage. Satellite scatterometer (radar) data may serve as an alternative data source for characterizing urban growth and development in both the horizontal and vertical directions. The accuracy of these radar-based datasets for estimating building volumes remains to be validated quantitatively. For nine U.S. cities, we test whether scatterometer data can be used to estimate 3D urban built-up volume. We found strong, linear correlations between the lidar-derived and radar-derived building volume estimates for all cities with r2 values as high as 0.98 when using spatial trend analysis. Given the high expense that limits lidar data acquisition to small areas at sporadic points in time, satellite scatterometer data provide a breakthrough method for monitoring both vertical growth and horizontal expansion of cities across the world with a continuous decadal time scale.
Black hole entropy, the black hole information paradox, and time travel paradoxes from a new perspective

ABSTRACTRelatively simple but apparently novel ways are proposed for viewing three related subjects: black hole entropy, the black hole information paradox, and time travel paradoxes. (1) Gibbons a...
Naive Learning with Uninformed Agents

The DeGroot model has emerged as a credible alternative to the standard Bayesian model for studying learning on networks, offering a natural way to model naive learning in a complex setting. One unattractive aspect of this model is the assumption that the process starts with every node in the network having a signal. We study a natural extension of the DeGroot model that can deal with sparse initial signals. We show that an agent's social influence in this generalized DeGroot model is essentially proportional to the degree-weighted share of uninformed nodes who will hear about an event for the first time via this agent. This characterization result then allows us to relate network geometry to information aggregation. We show information aggregation preserves "wisdom" in the sense that initial signals are weighed approximately equally in a model of network formation that captures the sparsity, clustering, and small-world properties of real-world networks. We also identify an example of a network structure where essentially only the signal of a single agent is aggregated, which helps us pinpoint a condition on the network structure necessary for almost full aggregation. Simulating the modeled learning process on a set of real-world networks, we find that there is on average 22.4 percent information loss in these networks. We also explore how correlation in the location of seeds can exacerbate aggregation failure. Simulations with real-world network data show that with clustered seeding, information loss climbs to 34.4 percent.
Novel device to detect enterotomies in real time during laparoscopy: first in human trial during Roux-en-y gastric bypass

Undetected bowel perforations occur in 0.3–1% of laparoscopic surgical procedures with an associated mortality rate of 5.3%. The purpose of the study was to evaluate the clinical feasibility of a novel medical device to accurately detect bowel gas, specifically hydrogen (H2) and methane (CH4), from a sample of gas from the abdominal cavity during laparoscopic surgery when a known bowel wall perforation has occurred. Setting: University (Academic) Hospital. A prospective single arm study was composed of 8 patients undergoing a standard laparoscopic roux-en-y gastric bypass. At seven time points during the operation intra-abdominal gas was pulled from the abdominal cavity and analyzed using the novel device for H2 and CH4. The time points included after insufflation (T1), after first jejunotomy (T2), after closure of jejunotomy (T3), after recycle of carbon dioxide gas (T4), after gastrostomy (T5), after jejunotomy (T6), at procedure end (T7). Eight patients were enrolled in the study; in 7 (87.5%) patients data from all 7 time points were obtained. After the first opening of the small bowel (T2) mean hydrogen levels were significantly increased compared to baseline hydrogen levels (T1, T4, T7) (p < 0.001). At all time points, there was no significant detection of methane. There were no intra-operative or post-operative complications during the study. Hydrogen gas is released into the intra-abdominal cavity when bowel is opened and can be detected in real time using a novel device during laparoscopic surgery. The presence or absence of hydrogen directly correlates to whether the bowel is open (perforated) or intact. This device could be used in the future to detect unintended bowel perforations during laparoscopic surgery, prior to the conclusion of the operation. This technology could also potentially lead to novel mechanism for detecting postoperative leaks using gas detection technology.
Competitive environment and innovation intensity

Abstract We find a U-shaped relation between industry concentration and innovation. The relation is driven by neck-and-neck industries where firms operate with similar productivity. When industry concentration is low, innovation intensity decreases as concentration increases. However, when industry concentration is high, increased concentration causes industry firms to increase innovation intensity to escape competition. The U-shaped relation is more pronounced in industries where firms compete in strategic substitutes. Using tariff rate reductions as an exogenous shock to the competitive environment, firms in neck-and-neck industries and industries where firms compete in strategic substitutes respond to foreign competitive threats by increasing innovation intensity.
Decision making for others involving risk: A review and meta-analysis

Abstract Are choices for others riskier than choices people make for themselves? This question has been asked by economists, psychologists, and other researchers in the social sciences – which has generated a diversity of research accounts and results. For example, a number of studies have found strong instances of a risky shift in choices for others, while other studies have found no such effect or have found that choices for others instead generate a cautious shift. In a meta-analysis of 128 effects from 71 published and unpublished papers (totaling 14,443 observations), we found a significant though small effect size (d = 0.105) in favor of a risky shift when people choose for others. Moreover, we found considerable variance between studies (Q = 1106.25), suggesting that the net effect is susceptible to moderating factors or study characteristics, which we identify and discuss as well (viz. choice recipient, decision frame, decision reciprocity, theoretical perspective, study design). Thus, we document not only whether decisions for others are riskier, but when (and when such decisions are less risky). We further discuss what is distinctly unique about decision making for others – how such choices are not just different in degree from personal choices but different in kind.
Dynamic Learning with Frequent New Product Launches: A Sequential Multinomial Logit Bandit Problem

Motivated by the phenomenon that companies introduce new products to keep abreast with customers' rapidly changing tastes, we consider a novel online learning setting where a profit-maximizing seller needs to learn customers' preferences through offering recommendations, which may contain existing products and new products that are launched in the middle of a selling period. We propose a sequential multinomial logit (SMNL) model to characterize customers' behavior when product recommendations are presented in tiers. For the offline version with known customers' preferences, we propose a polynomial-time algorithm and characterize the properties of the optimal tiered product recommendation. For the online problem, we propose a learning algorithm and quantify its regret bound. Moreover, we extend the setting to incorporate a constraint which ensures every new product is learned to a given accuracy. Our results demonstrate the tier structure can be used to mitigate the risks associated with learning new products.
A high throughput substrate binding assay reveals hexachlorophene as an inhibitor of the ER-resident HSP70 chaperone GRP78.

Abstract Glucose-regulated protein 78 (GRP78) is the ER resident 70 kDa heat shock protein 70 (HSP70) and has been hypothesized to be a therapeutic target for various forms of cancer due to its role in mitigating proteotoxic stress in the ER, its elevated expression in some cancers, and the correlation between high levels for GRP78 and a poor prognosis. Herein we report the development and use of a high throughput fluorescence polarization-based peptide binding assay as an initial step toward the discovery and development of GRP78 inhibitors. This assay was used in a pilot screen to discover the anti-infective agent, hexachlorophene, as an inhibitor of GRP78. Through biochemical characterization we show that hexachlorophene is a competitive inhibitor of the GRP78-peptide interaction. Biological investigations showed that this molecule induces the unfolded protein response, induces autophagy, and leads to apoptosis in a colon carcinoma cell model, which is known to be sensitive to GRP78 inhibition.
Catalytic, asymmetric synthesis and diastereoselective aldol reactions of dipropionate equivalents.

The dimer of methylketene can be conveniently prepared in one step and high enantiomeric excess from propionyl chloride, using a catalytic amount of a silylated cinchona alkaloid as a source of chirality. Opening of the dimer with a lithiated sulfonamide affords a β-ketosulfonimide, which undergoes Sn(II)-mediated aldol reactions to diastereoselectively afford the anti,syn-aldol adduct. Alternatively, reduction of the dimer to the β-hydroxy ketone, followed by acylation, affords a β-acyloxyl ketone that undergoes diastereoselective, dialkylboron chloride-mediated aldol reactions to produce the anti,anti-aldol adduct.
A two-step probing method to compare lysine accessibility across macromolecular complex conformations

Structural models of large and dynamic molecular complexes are appearing in increasing numbers, in large part because of recent technical advances in cryo-electron microscopy. However, the inherent complexity of such biological assemblies comprising dozens of moving parts often limits the resolution of structural models and leaves the puzzle as to how each functional configuration transitions to the next. Orthogonal biochemical information is crucial to understanding the molecular interactions that drive those rearrangements. We present a two-step method for chemical probing detected by tandem mass-spectrometry to globally assess the reactivity of lysine residues within purified macromolecular complexes. Because lysine side chains often balance the negative charge of RNA in ribonucleoprotein complexes, the method is especially useful for detecting changes in protein-RNA interactions. By probing the E. coli 30S ribosome subunit, we established that the reactivity pattern of lysine residues quantitatively reflects structure models derived from X-ray crystallography. We also used the strategy to assess differences in three conformations of purified human spliceosomes in the context of recent cryo-electron microscopy models. Our results demonstrate that the probing method yields powerful biochemical information that helps contextualize architectural rearrangements of intermediate resolution structures of macromolecular complexes, often solved in multiple conformations.
Construction of a sterically congested carbon framework via 5-hexenyllithium cyclization : synthesis of (±)-cuparene

Abstract The naturally occurring sesquiterpene (±)-cuparene [1,1,2-trimethyl-2-(4-methylphenyl)cyclopentane], which contains two contiguous quaternary centers, is produced in good yield by 5-exo-trig cyclization of the 5-hexenyllithium ( 2 ) generated from 6-iodo-3,3-dimethyl-2-(4-methylphenyl)-1-hexene ( 3 ) by low temperature lithium - iodine exchange. In contrast, radical mediated cyclization of 3 proceeds via the 6-endotrig mode to give 1,1-dimethyl-2-(4-methylphenyl)cyclohexane.
Stereospecific Synthesis and Biological Evaluation of Farnesyl Diphosphate Isomers

A unified, stereospecific synthetic route to the three geometric isomers of (E,E)-farnesyl diphosphate (E,E-FPP) (1, 2, and 3) has been developed. The key feature of this synthesis is the ability to control the stereochemistry of triflation of the β-ketoester 10 to give either 11 or 14. Preliminary evaluation of these compounds with protein-farnesyl transferase indicates that 1 and 2 are surprisingly effective substrates; however, Z,Z-FPP (3) is a poor substrate and a sub-micromolar inhibitor.
A Nomenclature and Structural Representation System for Ladder and Spiro Polymers

A “ring-by-ring” nomenclature and structural representation system for ladder and spiro polymers is presented. This novel system differs markedly from the International Union of Pure and Applied Chemistry (IUPAC) and Chemical Abstracts Service (CAS) systems, which require ring fracture, naming of complete ring assemblies, and occasional use of nomenclature to determine final orientation of structural repeating units (SRUs). The advantages of the system presented are as follows: SRU identification and orientation are completely independent of nomenclature; no rings are fractured; and each individual ring is named separately (except in one rare and precisely defined situation) and thus names of complete ring assemblies are not required.
Synthesis and photochemical properties of aluminum, gallium, silicon, and tin naphthalocyanines

The synthesis and characterization of 30 Al, Ga, Si, and Sn naphthalocyanines relevant to the search for improved photodynamic therapy agents are reported. The compounds that have been studied are AlNcCl, AlNcOH, AlNcOSi-(n-C 6 H 13 ) 3 ...
Metatranscriptomics Supports the Mechanism for Biocathode Electroautotrophy by " Candidatus Tenderia electrophaga"

ABSTRACT Biocathodes provide a stable electron source to drive reduction reactions in electrotrophic microbial electrochemical systems. Electroautotrophic biocathode communities may be more robust than monocultures in environmentally relevant settings, but some members are not easily cultivated outside the electrode environment. We previously used metagenomics and metaproteomics to propose a pathway for coupling extracellular electron transfer (EET) to carbon fixation in “ Candidatus Tenderia electrophaga,” an uncultivated but dominant member of an electroautotrophic biocathode community. Here we validate and refine this proposed pathway using metatranscriptomics of replicate aerobic biocathodes poised at the growth potential level of 310 mV and the suboptimal 470 mV (versus the standard hydrogen electrode). At both potentials, transcripts were more abundant from “ Ca. Tenderia electrophaga” than from any other constituent, and its relative activity was positively correlated with current. Several genes encoding key components of the proposed “ Ca. Tenderia electrophaga” EET pathway were more highly expressed at 470 mV, consistent with a need for cells to acquire more electrons to obtain the same amount of energy as at 310 mV. These included cyc2 , encoding a homolog of a protein known to be involved in iron oxidation. Mean expression of all CO 2 fixation-related genes is 0.27 log 2 -fold higher at 310 mV, indicating that reduced energy availability at 470 mV decreased CO 2 fixation. Our results substantiate the claim that “ Ca. Tenderia electrophaga” is the key electroautotroph, which will help guide further development of this community for microbial electrosynthesis. IMPORTANCE Bacteria that directly use electrodes as metabolic electron donors (biocathodes) have been proposed for applications ranging from microbial electrosynthesis to advanced bioelectronics for cellular communication with machines. However, just as we understand very little about oxidation of analogous natural insoluble electron donors, such as iron oxide, the organisms and extracellular electron transfer (EET) pathways underlying the electrode-cell direct electron transfer processes are almost completely unknown. Biocathodes are a stable biofilm cultivation platform to interrogate both the rate and mechanism of EET using electrochemistry and to study the electroautotrophic organisms that catalyze these reactions. Here we provide new evidence supporting the hypothesis that the uncultured bacterium “ Candidatus Tenderia electrophaga” directly couples extracellular electron transfer to CO 2 fixation. Our results provide insight into developing biocathode technology, such as microbial electrosynthesis, as well as advancing our understanding of chemolithoautotrophy.
EFFICIENT ONE-POT SYNTHESIS OF JM3100

Abstract A facile synthesis of JM3100 was reported. This strategy could also be successfully applied in the cyclen series.
Tetramethylguanidinium azide as a new reagent for the stereoselective synthesis of glycosyl azides

Abstract Tetramethylguanidinium azide was used in the quantitative conversion of glycosyl halides 1 – 6 to the corresponding glycosyl azides 7 – 12. The stereoselective reactions occurred with complete inversion at the anomeric centers.
Radical [n + 1] Annulations with Sulfur Dioxide

A new methodology for [n + 1] radical annulation using sulfur dioxide as a geminal radical acceptor/donor is presented. This methodology provides a novel route to the formation of five-, six-, and seven-membered cyclic sulfones utilizing a radical chain mechanism under very mild conditions.
Theoretical Studies on Structures of Neptunyl Carbonates: NpO2(CO3)m(H2O)nq (m = 1−3, n = 0−3) in Aqueous Solution

Extensive ab inito computations have been carried out to study the equilibrium structure, infrared spectra, and bonding characteristics of a variety of hydrated NpO2(CO3)mq complexes by considering the solvent as a polarizable dielectric continuum as well as the corresponding anhydrate complexes in the gas phase. The computed structural parameters and vibrational results at the MP2 level in aqueous solution are in good agreement with Clark et al.'s experiments and provide realistic pictures of the neptunyl complexes in an aqueous environment. Our computed hydration energies reveal that the complex with water molecules directly bound to it yields the best results. Our analysis of the nature of the bonding of neptunyl complexes provides insight into the nature of 6d and 5f bonding in actinide complexes.
Starve cancer cells of glutamine: Break the spell or make a hungry monster?

Distinct from normal differentiated tissues, cancer cells reprogram nutrient uptake and utilization to accommodate their elevated demands for biosynthesis and energy production. A hallmark of these types of reprogramming is the increased utilization of, and dependency on glutamine, a nonessential amino acid, for cancer cell growth and survival. It is well-accepted that glutamine is a versatile biosynthetic substrate in cancer cells beyond its role as a proteinogenic amino acid. In addition, accumulating evidence suggests that glutamine metabolism is regulated by many factors, including tumor origin, oncogene/tumor suppressor status, epigenetic alternations and tumor microenvironment. However, despite the emerging understanding of why cancer cells depend on glutamine for growth and survival, the contribution of glutamine metabolism to tumor progression under physiological conditions is still under investigation, partially because the level of glutamine in the tumor environment is often found low. Since targeting glutamine acquisition and utilization has been proposed to be a new therapeutic strategy in cancer, it is central to understand how tumor cells respond and adapt to glutamine starvation for optimized therapeutic intervention. In this review, we first summarize the diverse usage of glutamine to support cancer cell growth and survival, and then focus our discussion on the influence of other nutrients on cancer cell adaptation to glutamine starvation as well as its implication in cancer therapy.
First inverse electron-demand Diels-Alder methodology of 3-chloroindoles and methyl coumalate to carbazoles.

The first successful inverse electron-demand Diels–Alder has been demonstrated with the 2-pyrone methyl coumalate in conjunction with substituted indoles. Utilizing 1-alkyl-3-chloroindoles as the e...
Challenge data set for macromolecular multi-microcrystallography

A synthetic data set demonstrating a particularly challenging case of indexing ambiguity in the context of radiation damage was generated. This set shall serve as a standard benchmark and reference point for the ongoing development of new methods and new approaches to robust structure solution when single-crystal methods are insufficient. Of the 100 short wedges of data, only the first 36 are currently necessary to solve the structure by `cheating', or using the correct reference structure as a guide. The total wall-clock time and number of crystals required to solve the structure without cheating is proposed as a metric for the efficacy and efficiency of a given multi-crystal automation pipeline.
A Convenient Synthesis of Some 1,4-Disubstituted 7-Oxabicyclo[2.2.1]heptanes

Abstract An efficient synthesis of a 1,4-disubstituted 7-oxabicyclo[2.2.1]heptane intermediate and its subsequent conversion to a potential PAF antagonist is described.
Anterior cingulate is a source of valence-specific information about value and uncertainty.

Anterior cingulate cortex (ACC) is thought to control a wide range of reward, punishment, and uncertainty-related behaviors. However, how it does so is unclear. Here, in a Pavlovian procedure in which monkeys displayed a diverse repertoire of reward-related, punishment-related, and uncertainty-related behaviors, we show that many ACC-neurons represent expected value and uncertainty in a valence-specific manner, signaling value or uncertainty predictions about either rewards or punishments. Other ACC-neurons signal prediction information about rewards and punishments by displaying excitation to both (rather than excitation to one and inhibition to the other). This diversity in valence representations may support the role of ACC in many behavioral states that are either enhanced by reward and punishment (e.g., vigilance) or specific to either reward or punishment (e.g., approach and avoidance). Also, this first demonstration of punishment-uncertainty signals in the brain suggests that ACC could be a target for the treatment of uncertainty-related disorders of mood.
Fast assembling of neuron fragments in serial 3D sections

Reconstructing neurons from 3D image-stacks of serial sections of thick brain tissue is very time-consuming and often becomes a bottleneck in high-throughput brain mapping projects. We developed NeuronStitcher, a software suite for stitching non-overlapping neuron fragments reconstructed in serial 3D image sections. With its efficient algorithm and user-friendly interface, NeuronStitcher has been used successfully to reconstruct very large and complex human and mouse neurons.
Synthesis, structure, and bonding of orthorhombic R5Au2Te2 (R = Lu, Ho, Dy, Y). Electronic structure of the binary parent valence compound Eu5As4.

Four examples of R5Au2Te2 (vec = 29 e–; R = Lu, Ho, Dy, Y) have been synthesized by high-temperature solid-state techniques, isotypic examples of Tm5Sb2Si2 (vec = 33 e–) and binary Eu5As4 (vec = 30...
Synthesis of 5‐trifluoromethyl‐5,8‐dideazafolic acid and 5‐trifluoromethyl‐5,8‐dideazaisofolic acid

The target folate analogue 5-trifluoromethyl-5,8-dideazafolic acid has been elaborated in a seven-step reaction sequence beginning with 2-fluoro-6-trifluoromethylbenzonitrile. The bridge-reversed isomer 5-trifluoromethyl-5,8-dideazaisofolic acid was prepared in six steps using the common intermediate 2,6-diamino-3,4-dihydro-4-oxo-5-trifluoromethylquinazoline. The key intermediate 2-amino-3,4-dihydro-4-oxo-5-trifluoromethyl-quinazoline was prepared using two distinct synthetic routes and the resulting products were found to be identical.
Reactions of trifluoroamine oxide: a new method for selective fluorination of 1,3-diketones and β-ketoesters

Fluorination of 1,3-diketones and β-ketoesters with trifluoroamine oxide in the presence of tetrabutylammonium hydroxide (TBAH) provides a one step route to mono- and difluoro-products selectively fluorinated at the α-position in good yields.
Diffusion MRI Indices and Their Relation to Cognitive Impairment in Brain Aging: The Updated Multi-protocol Approach in ADNI3

Brain imaging with diffusion-weighted MRI (dMRI) is sensitive to microstructural white matter (WM) changes associated with brain aging and neurodegeneration. In its third phase, the Alzheimer's Disease Neuroimaging Initiative (ADNI3) is collecting data across multiple sites and scanners using different dMRI acquisition protocols, to better understand disease effects. It is vital to understand when data can be pooled across scanners, and how the choice of dMRI protocol affects the sensitivity of extracted measures to differences in clinical impairment. Here, we analyzed ADNI3 data from 317 participants (mean age: 75.4 ± 7.9 years; 143 men/174 women), who were each scanned at one of 47 sites with one of six dMRI protocols using scanners from three different manufacturers. We computed four standard diffusion tensor imaging (DTI) indices including fractional anisotropy (FADTI) and mean, radial, and axial diffusivity, and one FA index based on the tensor distribution function (FATDF), in 24 bilaterally averaged WM regions of interest. We found that protocol differences significantly affected dMRI indices, in particular FADTI. We ranked the diffusion indices for their strength of association with four clinical assessments. In addition to diagnosis, we evaluated cognitive impairment as indexed by three commonly used screening tools for detecting dementia and AD: the AD Assessment Scale (ADAS-cog), the Mini-Mental State Examination (MMSE), and the Clinical Dementia Rating scale sum-of-boxes (CDR-sob). Using a nested random-effects regression model to account for protocol and site, we found that across all dMRI indices and clinical measures, the hippocampal-cingulum and fornix (crus)/stria terminalis regions most consistently showed strong associations with clinical impairment. Overall, the greatest effect sizes were detected in the hippocampal-cingulum (CGH) and uncinate fasciculus (UNC) for associations between axial or mean diffusivity and CDR-sob. FATDF detected robust widespread associations with clinical measures, while FADTI was the weakest of the five indices for detecting associations. Ultimately, we were able to successfully pool dMRI data from multiple acquisition protocols from ADNI3 and detect consistent and robust associations with clinical impairment and age.
Enantioselective Total Syntheses of Allopumiliotoxins 267A, 323B‘, and 339A. Application of Iodide-Promoted Iminium Ion−Alkyne Cyclizations for Forming Allopumiliotoxin A Alkaloids

A concise, stereocontrolled strategy for the total synthesis of allopumiliotoxin A alkaloids is described. A much improved second generation total synthesis of enantiopure (+)-allopumiliotoxin 267A (3) was accomplished in 10 steps and 11% overall yield from the commercially available oxazolidinone precursor of alcohol 32 and 17 steps and 4% overall yield from N-[(benzyloxy)carbonyl]-l-proline. The first synthesis of (+)-allopumiliotoxin 323B‘ (4) rigorously confirms the complete stereostructure of 4 and establishes that the major C(15) epimer isolated from dendrobatid frogs has the 15S configuration. The total synthesis of 4 was realized in 5 steps and 17% overall yield from alkyne 39 and aldehyde 20; the synthesis proceeded in 13 steps and 6% overall yield from (S)-2-methyl-1-penten-3-ol and 17 steps and 3.5% overall yield from N-[(benzyloxy)carbonyl]-l-proline, the precursors, respectively, of alkyne 39 and pyrrolidine aldehyde 20. The first total synthesis of allopumiliotoxin 339A (5) also confirmed th...
History of antibiotic adaptation influences microbial evolutionary dynamics during subsequent treatment.

Antibiotic regimens often include the sequential changing of drugs to limit the development and evolution of resistance of bacterial pathogens. It remains unclear how history of adaptation to one antibiotic can influence the resistance profiles when bacteria subsequently adapt to a different antibiotic. Here, we experimentally evolved Pseudomonas aeruginosa to six 2-drug sequences. We observed drug order–specific effects, whereby adaptation to the first drug can limit the rate of subsequent adaptation to the second drug, adaptation to the second drug can restore susceptibility to the first drug, or final resistance levels depend on the order of the 2-drug sequence. These findings demonstrate how resistance not only depends on the current drug regimen but also the history of past regimens. These order-specific effects may allow for rational forecasting of the evolutionary dynamics of bacteria given knowledge of past adaptations and provide support for the need to consider the history of past drug exposure when designing strategies to mitigate resistance and combat bacterial infections.
High ambient temperature facilitates the acquisition of 3,4-methylenedioxymethamphetamine (MDMA) self-administration.

Rationale MDMA alters body temperature in rats with a direction that depends on the ambient temperature (TA). The thermoregulatory effects of MDMA and TA may affect intravenous self-administration (IVSA) of MDMA but limited prior reports conflict.
Preparation of benzo[c][2,7]naphthyridines

A divergent synthesis of substituted benzo[c][2,7]naphthyridines 5a-h is described, which features an intramolecular pyridyne cyclization step as the key reaction. The pyridyne precursors are conveniently prepared from the pyridinium hydrochloride 2 and the requisite anilines. Cyclization of the non-symmetric substrates 3e and 3f did not proceed with significant regioselectivity.
Fragment-Based Design of NbRuB as a New Metal-Rich Boride Superconductor

The title compound is synthesized by arc-melting of the elements and characterized by powder and single crystal XRD, electrical resistivity and magnetic susceptibility measurements, and by TB-LMTO-ASA calculations.
Intramolecular aromatic nucleophilic substitution of the benzimidazole-activated nitro group.

A wide range of 2-(2-nitrophenyl)-1H-benzimidazoles undergo high-yielding intramolecular SNAr of nitrite with N-pendant alkoxides under mild conditions (DMF, rt). When this operationally simple process is carried out at elevated temperatures in the presence of excess NaH, the initially formed SNAr products are converted to the corresponding N-vinyl-substituted 2-(2-hydroxyphenyl)-1H-benzimidazoles via base-catalyzed isomerization.
A green one-pot multicomponent synthesis of 4H-pyrans and polysubstituted aniline derivatives of biological, pharmacological, and optical applications using silica nanoparticles as reusable catalyst

A one-pot practical, efficient, and environmentally benign multicomponent synthesis of 4H-pyrans and polysubstituted aniline derivatives of biological, pharmacological, and optical applications has been developed using a very mild, neutral, and reusable silica nanoparticles as catalyst. The 4H-pyran derivatives were synthesized by a three component reaction of an aldehyde, malononitrile, and 5,5-dimethyl-1,3-cyclohexanedione or ethyl acetoacetate at room temperature or refluxing in ethanol. Alternatively, polysubstituted anilines were synthesized via a four component reaction of an aldehyde, a ketone, and two equivalents of malononitrile in ethanol.
Triflic anhydride mediated cyclization of 5-hydroxy-substituted pyrrolidinones for the preparation of α-trifluoromethylsulfonamido furans

The reaction of α-angelica lactone with alkylamines under aqueous conditions afforded 5-hydroxy-5-methylpyrrolidinones in high yield. When the reaction was carried out under anhydrous conditions, the only products obtained were the corresponding 4-oxopentanoic acid amides. Treatment of either class of compound with triflic anhydride (Tf2O) in pyridine resulted in the formation of various substituted sulfonamidofurans. The suggested mechanism involves initial formation of an iminium ion which is subsequently transformed into a transient imino triflate. Cyclization of the highly electrophilic imine onto the oxygen atom of the adjacent carbonyl group generates an imino dihydrofuran intermediate. This species reacts further with another equivalent of Tf2O to give the observed product. The nature of the Lewis acid used was found to affect the outcome of the cyclization reaction. In certain cases, the sulfonamide furan was utilized as a cycloaddition substrate for the synthesis of indolines and related heterocy...
Measures of possible allostatic load in comorbid cocaine and alcohol use disorder: Brain white matter integrity, telomere length, and anti-saccade performance.

Chronic cocaine and alcohol use impart significant stress on biological and cognitive systems, resulting in changes consistent with an allostatic load model of neurocognitive impairment. The present study measured potential markers of allostatic load in individuals with comorbid cocaine/alcohol use disorders (CUD/AUD) and control subjects. Measures of brain white matter (WM), telomere length, and impulsivity/attentional bias were obtained. WM (CUD/AUD only) was indexed by diffusion tensor imaging metrics, including radial diffusivity (RD) and fractional anisotropy (FA). Telomere length was indexed by the telomere to single copy gene (T/S) ratio. Impulsivity and attentional bias to drug cues were measured via eye-tracking, and were also modeled using the Hierarchical Diffusion Drift Model (HDDM). Average whole-brain RD and FA were associated with years of cocaine use (R2 = 0.56 and 0.51, both p control = p > 0.99). Telomere length was shorter in CUD/AUD, but the difference was not statistically significant. Within the CUD/AUD group, exploratory regression using an elastic-net model determined that more years of cocaine use, older age, larger HDDM drift rate differences and shorter telomere length were all predictive of WM as measured by RD (model R2 = 0.79). Collectively, the results provide modest support linking CUD/AUD to putative markers of allostatic load.
Genome-wide colocalization of RNA–DNA interactions and fusion RNA pairs

Fusion transcripts are used as biomarkers in companion diagnoses. Although more than 15,000 fusion RNAs have been identified from diverse cancer types, few common features have been reported. Here, we compared 16,410 fusion transcripts detected in cancer (from a published cohort of 9,966 tumor samples of 33 cancer types) with genome-wide RNA-DNA interactions mapped in two normal, noncancerous cell types [using iMARGI, an enhanced version of the mapping of RNA-genome interactions (MARGI) assay]. Among the top 10 most significant RNA-DNA interactions in normal cells, 5 colocalized with the gene pairs that formed fusion RNAs in cancer. Furthermore, throughout the genome, the frequency of a gene pair to exhibit RNA-DNA interactions is positively correlated with the probability of this gene pair to present documented fusion transcripts in cancer. To test whether RNA-DNA interactions in normal cells are predictive of fusion RNAs, we analyzed these in a validation cohort of 96 lung cancer samples using RNA sequencing (RNA-seq). Thirty-seven of 42 fusion transcripts in the validation cohort were found to exhibit RNA-DNA interactions in normal cells. Finally, by combining RNA-seq, single-molecule RNA FISH, and DNA FISH, we detected a cancer sample with EML4-ALK fusion RNA without forming the EML4-ALK fusion gene. Collectively, these data suggest an RNA-poise model, where spatial proximity of RNA and DNA could poise for the creation of fusion transcripts.
Carbamoylsilanes from the in situ metalation–silylation of a formamide

Abstract In situ treatment (−78°C) of N-methoxymethyl–N-methylformamide and chlorotrimethylsilane with LDA affords synthetically useful yields of the carbamoylsilane. The latter undergoes silyl group exchange at 145°C in the presence of a chlorosilane and CsF.
Highly selective rhodium-catalyzed conjugate addition reactions of 4-oxobutenamides.

A variety of 4-oxobutenamides 1 were subjected to rhodium-catalyzed conjugate addition with arylboronic acids providing high regio- and enantioselectivity (97:3 to >99:1, >96% ee) and moderate to e...
Minor isozymes tailor yeast metabolism to carbon availability

Isozymes are enzymes that differ in sequence but catalyze the same chemical reactions. Despite their apparent redundancy, isozymes are often retained over evolutionary time, suggesting that they contribute to fitness. We developed an unsupervised computational method for identifying environmental conditions under which isozymes are likely to make fitness contributions. This method analyzes published gene expression data to find specific experimental perturbations that induce differential isozyme expression. In yeast, we found that isozymes are strongly enriched in the pathways of central carbon metabolism and that many isozyme pairs show anticorrelated expression during the respirofermentative shift. Building on these observations, we assigned function to two minor central carbon isozymes, aconitase 2 (ACO2) and pyruvate kinase 2 (PYK2). ACO2 is expressed during fermentation and proves advantageous when glucose is limiting. PYK2 is expressed during respiration and proves advantageous for growth on three-carbon substrates. PYK2's deletion can be rescued by expressing the major pyruvate kinase only if that enzyme carries mutations mirroring PYK2's allosteric regulation. Thus, central carbon isozymes help to optimize allosteric metabolic regulation under a broad range of potential nutrient conditions while requiring only a small number of transcriptional states. IMPORTANCE Gene duplication is one of the main evolutionary paths to new protein function. Typically, duplicated genes either accumulate mutations and degrade into pseudogenes or are retained and diverge in function. Some duplicated genes, however, show long-term persistence without apparently acquiring new function. An important class of isozymes consists of those that catalyze the same reaction in the same compartment, where knockout of one isozyme causes no known functional defect. Here we present an approach to assigning specific functional roles to seemingly redundant isozymes. First, gene expression data are analyzed computationally to identify conditions under which isozyme expression diverges. Then, knockouts are compared under those conditions. This approach revealed that the expression of many yeast isozymes diverges in response to carbon availability and that carbon source manipulations can induce fitness phenotypes for seemingly redundant isozymes. A driver of these fitness phenotypes is differential allosteric enzyme regulation, indicating isozyme divergence to achieve more-optimal control of metabolism.