bluuebunny/crossref_metadata_2025_split huggingface dataset:
Architectural traits underlie growth form diversity and polycarpic versus monocarpic life histories inCerberiopsis(Apocynaceae)
Authors: Salmon Camille , Isnard Sandrine , Caraglio Yves , Heuret Patrick 
Published: June 2023

AbstractPlant architecture strongly influences plant growth habits, as it determines the arrangement, function and fate of meristems. How architecture could be involved in the monocarpic life history, i.e. dying after flowering, remains poorly investigated. Monocarpy is evident in some species since they are annual or because their single stem flowers apically. However, monocarpy in long-lived branched trees is rare and remains poorly understood. We aim to highlight the architectural features involved in the monocarpic strategy of Cerberiopsis candelabra, a rainforest tree endemic to New Caledonia. We conducted a comparative analysis of the genus, which comprises three species with different growth habits. Twenty plants of each species were studied at different ontogenic stages. We compared their developmental sequence and analysed their processes of growth, branching, flowering and reiteration. We identified a combination of traits that distinguish the species, and we found a syndrome of two architectural features that support the monocarpic strategy in C. candelabra: the synchronous flowering of all terminal meristems and the absence of delayed branching. Flowering in C. candelabra preferentially occurs when the complete architectural sequence is developed, but the plant never shows signs of senescence, suggesting that environmental stresses, such as wind disturbance, could be the main trigger for flowering. The architecture of C. candelabra is suggested to be the most derived in the genus.
Optimizing the Design of Clinical Trials to Evaluate the Efficacy of Function-Promoting Therapies
Authors: Bhasin Shalender , Cawthon Peggy M , Correa-de-Araujo Rosaly , Storer Thomas W , Volpi Elena , Newman Anne B , Dioh Waly , Tourette Cendrine , Evans William J , Fielding Roger A 
Published: June 2023

Abstract

Background
Several candidate molecules that may have application in treating physical limitations associated with aging and chronic diseases are in development. Challenges in the framing of indications, eligibility criteria, and endpoints and the lack of regulatory guidance have hindered the development of function-promoting therapies.

Methods
Experts from academia, pharmaceutical industry, National Institutes of Health (NIH), and Food and Drug Administration (FDA) discussed optimization of trial design including the framing of indications, eligibility criteria, and endpoints.

Results
Mobility disability associated with aging and chronic diseases is an attractive indication because it is recognized by geriatricians as a common condition associated with adverse outcomes, and it can be ascertained reliably. Other conditions associated with functional limitation in older adults include hospitalization for acute illnesses, cancer cachexia, and fall injuries. Efforts are underway to harmonize definitions of sarcopenia and frailty. Eligibility criteria should reconcile the goals of selecting participants with the condition and ensuring generalizability and ease of recruitment. An accurate measure of muscle mass (eg, D3 creatine dilution) could be a good biomarker in early-phase trials. Performance-based and patient-reported measures of physical function are needed to demonstrate whether treatment improves how a person lives, functions, or feels. Multicomponent functional training that integrates training in balance, stability, strength, and functional tasks with cognitive and behavioral strategies may be needed to translate drug-induced muscle mass gains into functional improvements.

Conclusions
Collaborations among academic investigators, NIH, FDA, pharmaceutical industry, patients, and professional societies are needed to conduct well-designed trials of function-promoting pharmacological agents with and without multicomponent functional training.
Drugs Targeting Mechanisms of Aging to Delay Age-Related Disease and Promote Healthspan: Proceedings of a National Institute on Aging Workshop
Authors: Espinoza Sara E , Khosla Sundeep , Baur Joseph A , de Cabo Rafael , Musi Nicolas 
Published: June 2023

Abstract
The geroscience hypothesis posits that by targeting key hallmarks of aging we may simultaneously prevent or delay several age-related diseases and thereby increase healthspan, or life span spent free of significant disease and disability. Studies are underway to examine several possible pharmacological interventions for this purpose. As part of a National Institute on Aging workshop on the development of function-promoting therapies, scientific content experts provided literature reviews and state-of-the-field assessments for the studies of senolytics, nicotinamide adenine dinucleotide (NAD+) boosters, and metformin. Cellular senescence increases with age, and preclinical studies demonstrate that the use of senolytic drugs improves healthspan in rodents. Human studies using senolytics are in progress. NAD+ and its phosphorylated form, NADP+, play vital roles in metabolism and cellular signaling. Increasing NAD+ by supplementation with precursors including nicotinamide riboside and nicotinamide mononucleotide appears to extend healthspan in model organisms, but human studies are limited and results are mixed. Metformin is a biguanide widely used for glucose lowering, which is believed to have pleiotropic effects targeting several hallmarks of aging. Preclinical studies suggest it improves life span and healthspan, and observational studies suggest benefits for the prevention of several age-related diseases. Clinical trials are underway to examine metformin for healthspan and frailty prevention. Preclinical and emerging clinical studies suggest there is potential to improve healthspan through the use of pharmacologic agents reviewed. However, much further research is needed to demonstrate benefits and general safety for wider use, the appropriate target populations, and longer-term outcomes.
Weight Gain and Metabolic Changes in Patients With First-Episode Psychosis or Early-Phase Schizophrenia Treated With Olanzapine: A Meta-Analysis
Authors: Correll Christoph U , Højlund Mikkel , Graham Christine , Todtenkopf Mark S , McDonnell David , Simmons Adam 
Published: June 2023

Abstract

Background
Patients with first-episode psychosis or early-phase schizophrenia are susceptible to olanzapine-associated weight gain and cardiometabolic dysregulation. This meta-analysis characterized weight and metabolic effects observed during olanzapine treatment in randomized clinical trials in this vulnerable patient population.

Methods
PubMed, EMBASE, and Dialog were searched for randomized controlled trials (RCTs) reporting weight or cardiometabolic outcomes associated with olanzapine treatment in first-episode psychosis or early-phase schizophrenia. Random-effects meta-analysis and meta-regression were conducted using R v4.0.5.

Results
Of 1203 records identified, 26 RCTs informed the analyses. The meta-analytic mean (95% CI) weight gain was 7.53 (6.42–8.63) kg in studies (n = 19) that reported weight gain with olanzapine treatment. Stratified by duration, the mean (95% CI) weight gain was significantly higher in studies &gt;13 weeks in duration than in those lasting ≤13 weeks: 11.35 (10.05–12.65) vs 5.51 (4.73–6.28) kg, respectively. Despite between-study variability, increases from baseline in most glycemic and lipid parameters were generally small in studies of both ≤13 and &gt;13 weeks. There were no correlations, however, between weight gain and metabolic parameter changes when stratified by study duration.

Conclusions
In RCTs enrolling patients with first-episode psychosis or early-phase schizophrenia, olanzapine was consistently associated with weight gain that was greater in studies lasting &gt;13 weeks compared with those of ≤13 weeks. Metabolic changes observed across studies suggest that RCTs may underestimate metabolic sequelae vs real-world treatment observations. Patients with first-episode psychosis or early-phase schizophrenia are vulnerable to olanzapine-associated weight gain; strategies minimizing olanzapine-associated weight gain should be carefully considered.
Polynomial Relations Among Kappa Classes on the Moduli Space of Curves
Authors: Kazarian Maxim , Norbury Paul 
Published: June 2023

Abstract
We construct an infinite collection of universal—independent of $(g,n)$—polynomials in the Miller–Morita–Mumford classes $\kappa _m\in H^{2m}( \overline{\mathcal{M}}_{g,n},{\mathbb{Q}})$, defined over the moduli space of genus $g$ stable curves with $n$ labeled points. We conjecture vanishing of these polynomials in a range depending on $g$ and $n$.
Negative Moments of L–Functions With Small Shifts Over Function Fields
Authors: Florea Alexandra 
Published: June 2023

Abstract
We consider negative moments of quadratic Dirichlet $L$–functions over function fields. Summing over monic square-free polynomials of degree $2g+1$ in $\mathbb{F}_{q}[x]$, we obtain an asymptotic formula for the $k^{\textrm{th}}$ shifted negative moment of $L(1/2+\beta ,\chi _{D})$, in certain ranges of $\beta $ (e.g., when roughly $\beta \gg \log g/g $ and $k&lt;1$). We also obtain non-trivial upper bounds for the $k^{\textrm{th}}$ shifted negative moment when $\log (1/\beta ) \ll \log g$. Previously, almost sharp upper bounds were obtained in [ 3] in the range $\beta \gg g^{-\frac{1}{2k}+\epsilon }$.
Integrating genomic prediction and genotype specific parameter estimation in ecophysiological models: overview and perspectives
Authors: Poudel Pratishtha , Naidenov Bryan , Chen Charles , Alderman Phillip D , Welch Stephen M 
Published: June 2023

Abstract
The Genome-to-Phenome (G2P) problem is one of the highest-priority challenges in applied biology. Ecophysiological crop models (ECM) and genomic prediction (GP) models are quantitative algorithms, which, when given information on a genotype and environment, can produce an accurate estimate of a phenotype of interest. In this article, we discuss how the GP algorithms can be used to estimate genotype-specific parameters (GSPs) in ECMs to develop robust prediction methods. In this approach, the numerical constants (GSPs) that ECMs use to distinguish and characterize crop cultivars/varieties are treated as quantitative traits to be predicted by genomic prediction models from underlying genetic information. In this article we provide information on which GP methods appear favorable for predicting different types of GSPs, such as vernalization sensitivity or potential radiation use efficiency. For each example GSP, we assess a number of GP methods in terms of their suitability using a set of three criteria grounded in genetic architecture, computational requirements, and the use of prior information. In general, we conclude that the most useful algorithms were dependent on both the nature of the particular GSP and the GP methods considered.
Should Canada adopt managed access agreements in Canada for expensive drugs?
Authors: McPhail Melanie , Bubela Tania 
Published: June 2023

Abstract
Drugs are increasingly authorized based on less mature evidence, leaving payors faced with significant clinical and cost-effectiveness uncertainties. As a result, payors must often choose between reimbursing a drug that may not turn out to be cost-effective (or may even be unsafe) or delaying the reimbursement of a drug that is cost-effective and offers clinical benefit to patients. Novel reimbursement decision models and frameworks, such as managed access agreements (MAAs), may address this decision challenge. Here, we provide a comprehensive overview of the legal limitations, considerations, and implications for adopting MAAs in Canadian jurisdictions. We begin with an overview of current drug reimbursement processes in Canada, terminology and definitions of the different types of MAAs, and select international experiences with MAAs. We discuss the legal barriers to MAA governance frameworks, design and implementation considerations, and legal and policy implications of MAAs. Finally, we provide recommendations to guide policy development for implementing MAAs in Canada, based on existing literature, international experience, and our legal analysis. We conclude that legal and policy barriers likely prevent the adoption of a pan-Canadian MAA governance framework. More feasible is a quasi-federal or provincial approach, building on existing infrastructure.
An unusual case of gallstone ileus within the cecum and ascending colon: a case report
Authors: Rana Asama , Hooda Zamaan , Kulkarni Sayali , Choi Karmina 
Published: June 2023

Abstract
Gallstone ileus is a rare cause of intestinal obstruction. Due to long-standing inflammation of the gallbladder, fistulization can occur within nearby structures, most commonly to the duodenum or hepatic flexure of the colon. Through these fistulas, a stone can migrate and result in a small bowel obstruction or a large bowel obstruction. This case exemplifies the diagnosis and treatment of gallstone ileus, along with potential complications due to stone migration. Early recognition and treatment of gallstone ileus is important, as stone migration can lead to increased mortality with delayed diagnosis.
Temperature–chemistry coupling in the evolution of gas giant atmospheres driven by stellar flares
Authors: Nicholls Harrison , Hébrard Eric , Venot Olivia , Drummond Benjamin , Evans Elise 
Published: June 2023

ABSTRACT
The effect of enhanced UV irradiation associated with stellar flares on the atmospheric composition and temperature of gas giant exoplanets was investigated. This was done using a 1D radiative-convective-chemical model with self-consistent feedback between the temperature and the non-equilibrium chemistry. It was found that flare-driven changes to chemical composition and temperature give rise to prolonged trends in evolution across a broad range of pressure levels and species. Allowing feedback between chemistry and temperature plays an important role in establishing the quiescent structure of these atmospheres, and determines their evolution due to flares. It was found that cooler planets are more susceptible to flares than warmer ones, seeing larger changes in composition and temperature, and that temperature–chemistry feedback modifies their evolution. Long-term exposure to flares changes the transmission spectra of gas giant atmospheres; these changes differed when the temperature structure was allowed to evolve self-consistently with the chemistry. Changes in spectral features due to the effects of flares on these atmospheres can be associated with changes in composition. The effects of flares on the atmospheres of sufficiently cool planets will impact observations made with JWST. It is necessary to use self-consistent models of temperature and chemistry in order to accurately capture the effects of flares on features in the transmission spectra of cooler gas giants, but this depends heavily on the radiation environment of the planet.
Three low-mass companions around aged stars discovered by TESS
Authors: Lin Zitao , Gan Tianjun , Wang Sharon X , Shporer Avi , Rabus Markus , Zhou George , Psaridi Angelica , Bouchy François , Bieryla Allyson , Latham David W , Mao Shude , Stassun Keivan G , Hellier Coel , Howell Steve B , Ziegler Carl , Caldwell Douglas A , Clark Catherine A , Collins Karen A , Curtis Jason L , Faherty Jacqueline K , Gnilka Crystal L , Grunblatt Samuel K , Jenkins Jon M , Johnson Marshall C , Law Nicholas , Lendl Monika , Littlefield Colin , Lund Michael B , Lund Mikkel N , Mann Andrew W , McDermott Scott , Mishra Lokesh , Mounzer Dany , Paegert Martin , Pritchard Tyler , Ricker George R , Seager Sara , Srdoc Gregor , Sun Qinghui , Tang Jiaxin , Udry Stéphane , Vanderspek Roland , Watanabe David , Winn Joshua N , Yu Jie 
Published: June 2023

ABSTRACT
We report the discovery of three transiting low-mass companions to aged stars: a brown dwarf (TOI-2336b) and two objects near the hydrogen burning mass limit (TOI-1608b and TOI-2521b). These three systems were first identified using data from the Transiting Exoplanet Survey Satellite (TESS). TOI-2336b has a radius of 1.05 ± 0.04 RJ, a mass of 69.9 ± 2.3 MJ and an orbital period of 7.71 d. TOI-1608b has a radius of 1.21 ± 0.06 RJ, a mass of 90.7 ± 3.7 MJ and an orbital period of 2.47 d. TOI-2521b has a radius of 1.01 ± 0.04 RJ, a mass of 77.5 ± 3.3 MJ, and an orbital period of 5.56 d. We found all these low-mass companions are inflated. We fitted a relation between radius, mass, and incident flux using the sample of known transiting brown dwarfs and low-mass M dwarfs. We found a positive correlation between the flux and the radius for brown dwarfs and for low-mass stars that is weaker than the correlation observed for giant planets. We also found that TOI-1608 and TOI-2521 are very likely to be spin-orbit synchronized, leading to the unusually rapid rotation of the primary stars considering their evolutionary stages. Our estimates indicate that both systems have much shorter spin-orbit synchronization time-scales compared to their ages. These systems provide valuable insights into the evolution of stellar systems with brown dwarf and low-mass stellar companions influenced by tidal effects.
Secular dynamics of stellar spin driven by planets inside Kozai–Lidov resonance
Authors: Lei Hanlun , Gong Yan-Xiang 
Published: June 2023

ABSTRACT
In many exoplanetary systems with ‘hot Jupiters’, it is observed that the spin axes of host stars are highly misaligned to planetary orbital axes. In this study, a possible channel is investigated for producing such a misalignment under a hierarchical three-body system, where the evolution of stellar spin is subjected to the gravitational torque induced from the planet inside Kozai–Lidov (KL) resonance. In particular, two special configurations are explored in detail. The first one corresponds to the configuration with planets at KL fixed points, and the second one corresponds to the configurations with planets moving on KL librating cycles. When the planet is located at the KL fixed point, the corresponding Hamiltonian model is of one degree of freedom and there are three branches of libration centres for stellar spin. When the planet is moving on KL cycles, the technique of Poincaré section is taken to reveal global structures of stellar spin in phase space. To understand the complex structures, perturbative treatments are adopted to study rotational dynamics. It shows that analytical structures in phase portraits under the resonant model can agree well with numerical structures arising in Poincaré sections, showing that the complicated dynamics of stellar spin are governed by the primary resonance under the unperturbed Hamiltonian model in combination with the 2:1 (high-order and/or secondary) spin–orbit resonances.
Safety of multiple administrations of spermicidal LL-37 antimicrobial peptide into the mouse female reproductive tract
Authors: Lee Seung Gee , Kiattiburut Wongsakorn , Burke Schinkel Stephanie C , Angel Jonathan , Tanphaichitr Nongnuj 
Published: June 2023

Abstract
We have previously demonstrated spermicidal activity of LL-37 antimicrobial peptide on mouse/human sperm and its contraceptive effects in female mice. With its microbicidal action against Neisseria gonorrhoeae, LL-37 warrants development into a multipurpose prevention technology (MPT) agent for administering into the female reproductive tract (FRT). However, it is important to verify that multiple administrations of LL-37 do not lead to damage of FRT tissues and/or irreversible loss of fecundity. Herein, we transcervically injected LL-37 (36 µM–10× spermicidal dose) into female mice in estrus in three consecutive estrous cycles. A set of mice were sacrificed for histological assessment of the vagina/cervix/uterus 24 h after the last injection, while the second set were artificially inseminated with sperm from fertile males 1 week afterwards, and then monitored for pregnancy. Mice injected with PBS in parallel were regarded as negative controls, whereas those injected with vaginal contraceptive foam (VCF, available over the counter), containing 12.5% nonoxynol-9, served as positive controls for vaginal epithelium disruption. We demonstrated that the vagina/cervix/uterus remained normal in both LL-37-injected and PBS-injected mice, which also showed 100% resumption of fecundity. In contrast, VCF-injected mice showed histological abnormalities in the vagina/cervix/uterus and only 50% of them resumed fecundity. Similarly, LL-37 multiply administered intravaginally caused no damage to FRT tissues. While our results indicate the safety of multiple treatments of LL-37 in the mouse model, similar studies have to be conducted in non-human primates and then humans. Regardless, our study provides an experimental model for studying in vivo safety of other vaginal MPT/spermicide candidates.
RIG-I recognizes metabolite-capped RNAs as signaling ligands
Authors: Schweibenz Brandon D , Solotchi Mihai , Hanpude Pranita , Devarkar Swapnil C , Patel Smita S 
Published: June 2023

Abstract
The innate immune receptor RIG-I recognizes 5′-triphosphate double-stranded RNAs (5′ PPP dsRNA) as pathogenic RNAs. Such RNA-ends are present in viral genomes and replication intermediates, and they activate the RIG-I signaling pathway to produce a potent interferon response essential for viral clearance. Endogenous mRNAs cap the 5′ PPP-end with m7G and methylate the 2′-O-ribose to evade RIG-I, preventing aberrant immune responses deleterious to the cell. Recent studies have identified RNAs in cells capped with metabolites such as NAD+, FAD and dephosphoCoA. Whether RIG-I recognizes these metabolite-capped RNAs has not been investigated. Here, we describe a strategy to make metabolite-capped RNAs free from 5′ PPP dsRNA contamination, using in vitro transcription initiated with metabolites. Mechanistic studies show that metabolite-capped RNAs have a high affinity for RIG-I, stimulating the ATPase activity at comparable levels to 5′ PPP dsRNA. Cellular signaling assays show that the metabolite-capped RNAs potently stimulate the innate antiviral immune response. This demonstrates that RIG-I can tolerate diphosphate-linked, capped RNAs with bulky groups at the 5′ RNA end. This novel class of RNAs that stimulate RIG-I signaling may have cellular roles in activating the interferon response and may be exploited with proper functionalities for RIG-I-related RNA therapeutics.