bluuebunny/crossref_metadata_2025 huggingface dataset:
Personalized digital behavior interventions increase short term physical activity: a randomized control crossover trial substudy of the MyHeart Counts Cardiovascular Health study
Authors: Javed Ali , Kim Daniel Seung , Hershman Steven G , Shcherbina Anna , Johnson Anders , Tolas Alexander , O’Sullivan Jack W , McConnell Michael V , Lazzeroni Laura , King Abby C , Christle Jeffrey W , Oppezzo Marily , Mattsson C. Mikael , Harrington Robert A , Wheeler Matthew T , Ashley Euan A
Published: April 2023

Background

Physical activity is strongly protective against the development of chronic diseases associated with aging. We previously demonstrated that digital interventions delivered through a smartphone app can increase short-term physical activity. Our randomized crossover trial has continued to digitally enroll participants, allowing increasing statistical power for greater precision in subsequent analyses.

Methods

We offered enrollment to adults aged ≥18 years with access to an iPhone and the MyHeart Counts app. After completion of a 1-week baseline period, e-consented participants were randomly allocated to four 7-day interventions. Interventions consisted of: 1) daily personalized e-coaching based on the individual’s baseline activity patterns, 2) daily prompts to complete 10,000 steps, 3) hourly prompts to stand following inactivity, and 4) daily instructions to read guidelines from the American Heart Association website. The trial was completed in a free-living setting, where neither the participants or investigators were blinded to the intervention. The primary outcome was change in mean daily step count from baseline for each of the four interventions, assessed in a modified intention-to-treat analysis. This trial is registered withClinicalTrials.gov,NCT03090321.

Findings

Between January 1, 2017 and April 1, 2022, 4500 participants consented to enroll in the trial, of whom 2458 completed 7-days of baseline monitoring (mean daily steps 4232±73) and at least one day of one of the four interventions. The greater statistical power afforded by continued passive enrollment revealed that e-coaching prompts, tailored to an individual, increased step count significantly more than other interventions (402±71 steps,P=7.1×10−8).

Interpretation

Digital studies can continuously recruit participants in a cost-effective manner, allowing for new insights provided by increased statistical power and refinement of prior signals. Here, we show that digital interventions tailored to an individual are effective in increasing short-term physical activity in a free-living cohort. These data suggest that participants are more likely to react positively and increase their physical activity when prompts are personalized.

Funding

Stanford Data Science Initiative and Catalyst Program, Apple, Google
Direct Estimate of the Specificity Constant: A Possibility or a Fluke? Pre-steady-state Substrate Concentrations and Enabling Mathematical Equations
Authors: Udema Ikechukwu Iloh
Published: April 2023

Background

A high-ranking scientist has recently proposed the need for direct estimation of the specificity constant rather than by calculation after a separate determination of maximum velocity and the Michaelis-Menten constant (KM).

Objectives

The objectives of this study are to derive novel equations for the zero-arbitrary determination of pre-steady-state (PSS) concentration of the substrate suitable for PSS assays, direct estimation of specificity constant (SC) under a PSS scenario, saturating concentration [ST] of the substrate, and instantaneous initial rate (otherwise called the “burst phase-like” rate), including its corresponding [ST]0, and to quantitatively evaluate the derived equations so as to give credence to their robustness and applicability.

Methods

The study was experimental and theoretical. It is supported by the Bernfeld method of enzyme assay.

Result

The SC values from the two newest methods for the three different concentrations of the enzyme range between 2,197.546 and 11,101.74 L/g min in one of the methods and 2,185.649 and 13,860.014 L/g min in the other method. The sub-KMvalues of the SC for the three different concentrations of the enzyme range between 1304.368 and 7943 L/g min. The burst phase-like initial rate,v0, and corresponding [ST]0, respectively, range between 14.26 and 55.448 micro-mol./min and 0.171 and 3.752 g/L.

Conclusion

The derivation of the equations for the direct calculations of SC in conditions that validate the reverse and standard quasi-steady-state approximations was a possibility; the SC values are higher at lower concentrations of the enzyme. The concept of SC is very different from catalytic efficiency. The total absence of any calculation is impossible.

Abstract Figure

Graphical abstract figure for the direct estimate of the specificity constant

For the purpose of this study, the legends, SUB (S), ENZ (E), and PRD represents substrate, enzyme and product respectively. Lower number density (red) of the enzyme molecules in Figure 1 showing > number density of the product (light green) for the same concentration of the substrate (darker blue) than in Figure 2 implies that the catalytic efficiency in Figure 1 is > the illustration in Figure 2.
Optimizing rabies vaccination of dogs in India
Authors: Cuddington Kim , McAuliffe William H.B.
Published: April 2023

Dog vaccination is the key to controlling rabies in human populations. However, in countries like India, with large free-roaming dog populations, vaccination strategies that rely only on parenteral vaccines are unlikely to be either feasible or successful. Oral rabies vaccines could be used to reach these dogs. We use costs estimates for an Indian city and linear optimization to find the most cost-effective vaccination strategies. We show that an oral bait handout method for dogs that are never confined can reduce the per dog costs costs of vaccination, and increase vaccine coverage. This finding holds even when baits cost up to 10x the price of parenteral vaccines, if there is a large dog population or proportion of dogs that are never confined. We suggest that oral rabies vaccine baits will be part of the most cost-effective strategies to eradicate human deaths from dog-mediated rabies by 2030.
Sex Differences in BNST Signaling and BNST CRF in Fear Processing: Implications for Unpredictable Threat in Sustained Fear
Authors: Hon Olivia J. , Neira Sofia , Flanigan Meghan E. , Roland Alison V. , Caira Christina M. , Sides Tori , D’Ambrosio Shannon , Lee Sophia , Simpson Yolanda , Buccini Michelle , Machinski Samantha , Yu Waylin , Boyt Kristen M. , Kash Thomas L.
Published: April 2023

Fear responses to perceived danger are critical for survival, as they prompt the individual to respond to threats and avoid harm. However, excessive fear can impede normal biological processes and become harmful. This study investigates the neural mechanisms underlying two distinct forms of fear—phasic and sustained—in male and female mice, with a focus on the bed nucleus of the stria terminalis (BNST) and corticotropin-releasing factor (CRF) signaling. Phasic fear is characterized by immediate responses to clear threats, while sustained fear is driven by ambiguous or uncertain cues and persists longer. Using rodent models, we found that sustained fear, modeled by partial fear conditioning, induced greater arousal and BNST activity in males, especially during ambiguous threat cues. In contrast, females exhibited reduced BNST and BNSTCRFactivity, highlighting significant sex differences in fear learning and expression. Additionally, CRF is crucial for appropriate fear response in females, as CRF knockdown led to increased fear responses, but had no effect in males. These sex-specific differences could help inform the development of targeted treatments for anxiety and trauma-related disorders, which disproportionately affect women.
Synaptic dysfunction and dysregulation of extracellular matrix-related genes in dopaminergic neurons derived from Parkinson’s disease sporadic patients and withGBA1mutations
Authors: Rosh Idan , Tripathi Utkarsh , Hussein Yara , Rike Wote Amelo , Manole Andreea , Cordeiro Diogo , Houlden Henry , Winkler Jurgen , Gage Fred , Stern Shani
Published: April 2023

Parkinson’s disease (PD) is a neurodegenerative disease with both genetic and sporadic origins. In this study, we investigated the electrophysiological properties, synaptic activity, and gene expression differences in dopaminergic (DA) neurons derived from induced pluripotent stem cells (iPSCs) of healthy controls, sporadic PD (sPD) patients, and PD patients with GBA1 mutations. Our results demonstrate reduced sodium currents and synaptic activity in DA neurons derived from PD patients with GBA1 mutations, suggesting a potential contribution to PD pathophysiology. We also observed distinct electrophysiological alterations in sPD DA neurons that were dependent on the age of disease onset. RNA sequencing analysis revealed unique dysregulated pathways in early and late-onset sPD neurons, further supporting the notion that molecular mechanisms driving PD may be different between PD patients. In agreement with our previous reports, ECM and focal adhesion genes were the top dysregulated pathways in DA neurons from sPD patients and from patients with GBA1 mutations. Overall, this study gives further confirmation that the convergent functional phenotypes of DA neurons derived from PD patients are synaptic abnormalities and at the transcriptome level, ECM and focal adhesion pathways are highly involved in PD pathology across multiple PD-associated mutations as well as sPD.
MORE IS DIFFERENT: DRUG PROPERTY ANALYSIS ON CELLULAR HIGH-CONTENT IMAGES USING DEEP LEARNING
Authors: Gao Xiangrui , Guo Xueyu , Zhang Fan , Yao Mengcheng , Wang Xiaoxiao , Chen Dong , Wang Xiaodong , Lai Lipeng
Published: April 2023

High-content analysis (HCA) holds enormous potential for drug discovery and research, but widely used methods can be cumbersome and yield inaccurate results. Noise and high similarity in cell images impede the accuracy of deep learning-based image analysis. To address these issues, we introduce More Is Different (MID), a novel HCA method that combines cellular experiments, image processing, and deep learning modeling. MID effectively combines the convolutional neural network and Transformer to encode high-content images, effectively filtering out noisy signals and characterizing cell phenotypes with high precision. In comparative tests on drug-induced cardiotoxicity and mitochondrial toxicity classification, as well as compound classification, MID outperformed both DeepProfiler and CellProfiler, which are two highly recognized methods in HCA. We believe that our results demonstrate the utility and versatility of MID and anticipate its widespread adoption in HCA for advancing drug development and disease research.
Single-Copy Orthologs (SCOs) improve species discrimination: A case study in subgusJensoa(Cymbidium)
Authors: He Zheng-Shan , Li De-Zhu , Yang Jun-Bo
Published: April 2023

Standard barcodes and ultra-barcodes face challenges in delimitation and discrimination of closely related species with deep coalescence, hybrid speciation, gene flow or low sequence-variation. Single copy orthologs (SCOs) have been recommended as standardized nuclear markers in metazoan DNA taxonomy. Here, we assessed the performance of SCOs in identifying recently diverged species in subgenusJensoa(Cymbidium) which has been poorly settled by ultra-barcode. More than 90% of target 9094 reference SCOs inferred from three genomes ofCymbidiumwere successfully retrieved for all 11 representative species in subg.Jensoaby ALiBaSeq from as low as 5× depth whole genome shotgun sequences. Species tree reconstructed from multiple refined SCO matrices under multispecies coalescent model successfully discriminated all species and discerned wrongly identified or labeled species. Plentiful and refined SCOs matrices obtained by implementing our pipeline facilitate not only phylogenetic study, but also high-resolution species diagnosing. Biparentally inherited SCOs as multi-locus marker not only advances the force of DNA barcoding, but also facilitates an eventual transition to species-tree-based barcoding strategies.
3D environment promotes persistent changes in lamin B1 distribution, the biomechanical signature of the nucleus, and adaptative survival and migratory functions
Authors: González-Novo Raquel , Zamora-Carreras Héctor , Lope-Planelles Ana de , López-Menéndez Horacio , Roda-Navarro Pedro , Monroy Francisco , Wang Lin , Toseland Christopher P. , Redondo Muñoz Javier
Published: April 2023

The interplay between cells and their surrounding microenvironment drives multiple cellular functions, including migration, proliferation, and cell fate transitions. The nucleus is a mechanosensitive organelle that adapts external mechanical and biochemical signals provided by the environment into nuclear changes with functional consequences for cell biology. However, the morphological and functional changes of the nucleus induced by 3D extracellular signals remain unclear. Here, we demonstrated that cells derived from 3D conditions conserve changes from cell confinement and show an aberrant nuclear morphology and localization of lamin B1, even in the absence of cellular confinement. We found that actin polymerization and protein kinase C (PKC) activity mediate the abnormal distribution of lamin B1 in 3D conditions-derived cells. These cells present altered chromatin compaction, gene transcription and cellular functions such as cell viability and migration. By combining biomechanical techniques and single-nucleus analysis, we have determined that the nucleus from 3D conditions-derived cells shows a different mechanical behavior and biophysical signature than the nucleus from control cells. Together, our work substantiates novel insights into how the extracellular environment alters the cell biology by promoting permanent changes in the chromatin, morphology, lamin B1 distribution, and the mechanical response of the nucleus.
The soil-borne white root rot pathogenRosellinia necatrixexpresses antimicrobial proteins during host colonization
Authors: Chavarro-Carrero Edgar A. , Snelders Nick C. , Torres David E. , Kraege Anton , López-Moral Ana , Petti Gabriella C. , Punt Wilko , Wieneke Jan , García-Velasco Rómulo , López-Herrera Carlos J. , Seidl Michael F. , Thomma Bart P.H.J.
Published: April 2023

Rosellinia necatrixis a prevalent soil-borne plant-pathogenic fungus that is the causal agent of white root rot disease in a broad range of host plants. The limited availability of genomic resources forR. necatrixhas complicated a thorough understanding of its infection biology. Here, we sequenced nineR. necatrixstrains with Oxford Nanopore sequencing technology, and with DNA proximity ligation we generated a gapless assembly of one of the genomes into ten chromosomes. Whereas many filamentous pathogens display a so-called two-speed genome with more dynamic and more conserved compartments, theR. necatrixgenome does not display such genome compartmentalization. It has recently been proposed that fungal plant pathogens may employ effectors with antimicrobial activity to manipulate the host microbiota to promote infection. In the predicted secretome ofR. necatrix, 26 putative antimicrobial effector proteins were identified, nine of which are expressed during plant colonization. Two of the candidates were tested, both of which were found to possess selective antimicrobial activity. Intriguingly, some of the inhibited bacteria are antagonists ofR. necatrixgrowthin vitroand can alleviateR. necatrixinfection on cotton plants. Collectively, our data show thatR. necatrixencodes antimicrobials that are expressed during host colonization and that may contribute to modulation of host-associated microbiota to stimulate disease development.
A novel and highly specific Forssman antigen-binding protein from sheep polyomavirus
Authors: Rustmeier Nils H. , Silva Lisete M. , Di Maio Antonio , Müller Joshua C. , Herrmann Alexander , Feizi Ten , Liu Yan , Stehle Thilo
Published: April 2023

Polyomaviruses are small, non-enveloped double-stranded DNA viruses of humans and other mammals, birds, and fish. Infections are usually asymptomatic and result in latency, however, some polyomaviruses can induce severe diseases, including cancer, in immunocompromised individuals. Established cellular receptors for polyomavirus infection are sialylated glycolipids (such as gangliosides), membrane proteins, and glycosaminoglycans. Polyomaviruses are usually highly host specific but the exact principles that govern host tropism remain unknown in many cases. Here, glycan array screening shows that the major capsid protein VP1 of sheep polyomavirus (ShPyV) binds to the Forssman glycolipid, an antigen of many vertebrates and a potential tumor marker in humans. Following closer investigation, we can report for the first time that a neutral, non-sialylated glycolipid acts as a polyomavirus receptor. Concurrently, we present the first report of a viral protein that specifically engages the Forssman antigen. We demonstrate that ShPyV VP1 binds to Forssman-positive erythrocytes but not those of human A, B and O blood groups, which is a clear distinction from features thus far described for Forssman lectins. X-ray crystallography and structural analysis of the VP1-Forssman glycan complex define the terminal Forssman disaccharide as the determinant of this protein-receptor interaction. These results strongly suggest that the sheep polyomavirus can use Forssman antigen for infectious cell entry. Furthermore, the ability of ShPyV VP1 to distinguish Forssman-positive from -negative cells may prove useful for monitoring the Forssman-‘status’ of normal, preneoplastic and neoplastic cells and tissues and establishing the antigen level as a biomarker.

Author summary

Elucidation of host cell receptor specificities of viral infection is crucial to understand the pathobiology of associated diseases and develop treatments. However, for many polyomaviruses the receptor engagement as the initial event in infection is poorly understood. In only a few cases polyomavirus tropism has been pinned down to a single type of glycan receptor. While many polyomaviruses utilize sialyl glycans to attach to host cells, the role of non-sialylated glycans as receptors is so far underestimated. Here, we show for the first time that a glycan of neutral charge, in this case the carbohydrate portion of the Forssman antigen, acts as a ligand for a polyomavirus capsid protein and may thus contribute to host tropism and infective cell entry. These results represent a significant addition to knowledge on polyomavirus-glycan interactions and complement general principles of carbohydrate engagement by viruses. Furthermore, as a specific binding protein of Forssman antigen, VP1 may help to determine levels of this antigen in healthy and malignant tissues in humans.
Impact of Zinc Pre-exposure on de novo Antibiotic Resistance Development
Authors: Suprenant Mark P. , Ching Carly , Sutradhar Indorica , Gross Neila , Anderson Jessica E. , El Sherif Nourhan , Zaman Muhammad H.
Published: April 2023

Antimicrobial resistance (AMR) is a global health crisis that is currently predicted to worsen. While the impact of improper antibiotics is an established driver, much less is known on the impacts of metal supplements. Here, we specifically probe the impact of zinc (Zn) on AMR. In conflict settings where diarrhea disease cases are high, Zn is both given as a supplement for treatment of these diseases prior to use of antibiotics such as ciprofloxacin and is associated with weapons of war. In this study, we find that the order with whichE. coliis exposed to zinc impacts resistance development, with increasing pre-exposure time leading to accelerated ciprofloxacin resistance, while combined exposure of zinc with ciprofloxacin delays ciprofloxacin resistance. We did not find evidence that zinc pre-exposure leads to genetic changes or change in antibiotic tolerance, though it does increase both the lag phase and doubling time ofE. coli, suggesting the mechanism may be due to changes in gene expression. While the zinc phenotype behavior is not permeant and would no longer be observed if ciprofloxacin exposure did not occur right after zinc pre-exposure, the elevated MIC phenotype resulting from the zinc pre-exposure was more stable than the zinc phenotype. These results are important as they highlight the need to reexamine the clinical role of zinc in treating diarrheal diseases and assess if changes in resistance development observed in vitro are also observed in vivo.

Importance

Antimicrobial resistance (AMR) is a global problem. According to a 2014 Review on Antimicrobial Resistance, it is projected to result in several million deaths by 2050 (Review on Antimicrobial Resistance, Tackling a Crisis for the Health and Wealth of Nations, 2014). While the improper usage of antibiotic treatments is an accepted driver of AMR, little work has focused on how non-antibiotic medication, such as supplements, might impact this when combined with antibiotics. One supplement of interest is the heavy metal zinc which is used in conjunction with ciprofloxacin to treat diarrheal diseases in children. We find that the order and duration of zinc exposure has significant impact on resistance development. More specifically, although the combined presence of zinc and ciprofloxacin delays the onset of resistance, when used successively as they often are in practice, zinc pre-exposure followed by ciprofloxacin exposure results in faster resistance development.
Hyperexcitability in the olfactory bulb and impaired fine odor discrimination in theFmr1KO mouse model of fragile X syndrome
Authors: Kuruppath Praveen , Xue Lin , Pouille Frederic , Jones Shelly T. , Schoppa Nathan E.
Published: April 2023

Fragile X syndrome (FXS) is the single most common monogenetic cause of autism spectrum disorders in humans. FXS is caused by loss of expression of the Fragile X mental retardation protein (FMRP), an mRNA-binding protein encoded on the X chromosome involved in suppressing protein translation. Sensory processing deficits have been a major focus of studies of FXS in both humans and rodent models of FXS, but olfactory deficits remain poorly understood. Here we conducted experiments in wild-type andFmr1KO (Fmr1-/y) mice (males) that lack expression of the gene encoding FMRP to assess olfactory circuit and behavioral abnormalities. In patch-clamp recordings conducted in slices of the olfactory bulb, output mitral cells (MCs) inFmr1KO mice displayed greatly enhanced excitation, as evidenced by a much higher rate of occurrence of spontaneous network-level events known as long-lasting depolarizations (LLDs). The higher probability of LLDs did not appear to reflect changes in inhibitory connections onto MCs but rather enhanced spontaneous excitation of external tufted cells (eTCs) that provide feedforward excitation onto MCs within glomeruli. In addition, in a go/no-go operant discrimination paradigm, we found thatFmr1KO mice displayed impaired discrimination of odors in difficult tasks that involved odor mixtures but not altered discrimination of monomolecular odors. We suggest that the higher excitability of MCs inFmr1KO mice may impair fine odor discrimination by broadening odor tuning curves of MCs and/or altering synchronized oscillations through changes in transient inhibition.

Significance Statement

Fragile X syndrome (FXS) in humans is associated with a range of debilitating deficits including aberrant sensory processing. One sensory system that has received comparatively little attention in studies in animal models of FXS is olfaction. Here, we report the first comprehensive physiological analysis of circuit defects in the olfactory bulb in the commonly-usedFmr1knockout (KO) mouse model of FXS. Our studies indicate thatFmr1KO alters the local excitation/inhibition balance in the bulb – similar to whatFmr1KO does in other brain circuits – but through a novel mechanism that involves enhanced feedforward excitatory drive. Furthermore,Fmr1KO mice display behavioral impairments in fine odor discrimination, an effect that may be explained by enhanced neural excitability.
Rewiring of RNA methylation by the oncometabolite fumarate in renal cell carcinoma
Authors: Fitzsimmons Christina M. , Mandler Mariana D. , Lunger Judith C. , Chan Dalen , Maligireddy Siddhardha S. , Schmiechen Alexandra C. , Gamage Supuni Thalalla , Link Courtney , Jenkins Lisa M. , Crooks Daniel R. , Meier Jordan L. , Linehan W. Marston , Batista Pedro J.
Published: April 2023

Metabolic reprogramming is a hallmark of cancer that facilitates changes in many adaptive biological processes. Mutations in the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) lead to fumarate accumulation and cause hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC is a rare, inherited disease characterized by the development of non-cancerous smooth muscle tumors of the uterus and skin, and an increased risk of a highly metastatic and aggressive form of kidney cancer. Fumarate has been shown to inhibit 2-oxyglutarate-dependent dioxygenases (2OGDDs) involved in the hydroxylation of HIF1α, as well as in DNA and histone demethylation. However, the link between fumarate accumulation and changes in RNA post-transcriptional modifications has not been defined. Here, we determine the consequences of fumarate accumulation on the activity of different members of the 2OGDD family targeting RNA modifications. By evaluating multiple RNA modifications in patient-derived HLRCC cell lines, we show that mutation of FH selectively alters the activity of demethylases acting upon N6-methyladenosine (m6A), while the demethylase acting upon N1-methyladenosine (m1A) and 5-formylcytosine (f5C) in mitochondrial RNA are unaffected. The observation that metabolites modulate specific subsets of RNA-modifying enzymes offers new insights into the intersection between metabolism and the epitranscriptome.
Body size affects specialization and modularity in the global resin foraging meta-network of stingless bees
Authors: Nakamura Daniel Yudi Miyahara , Koffler Sheina , Francoy Tiago Mauricio
Published: April 2023

Bees are in global decline and specialized species might be the most vulnerable to extinctions. Bee conservation can be studied using interaction networks, whose relative importance of nodes might correlate with morphological traits. Specifically, body size could affect flying range and thus influence the set of plant-bee interactions. Although several studies have reported botanical sources of resins in stingless bees, resin foraging networks were rarely assembled. Here we aim to describe the global resin-foraging meta-network of stingless bees, identify the most specialized species, and test how body size influences modularity and specialization. We found a modular and nested structure, in which some modules exhibit significant differences in body size and specialization.Melipona beecheiiis the most specialized stingless bee in collecting resins. Body size is positively correlated with specialization, in which larger bees are more specialized to collect resins from a subset of plants, possibly because larger bees with broader flying ranges avoid competition by collecting less disputed resources. Our results demonstrate how resin collection can be analyzed in a meta-network framework to test ecological hypotheses and identify specialized species as candidate priorities for the conservation of stingless bees.
Geochemical constraints on bacteriophage infectivity in terrestrial environments
Authors: Carlson Hans K. , Piya Denish , Moore Madeline L. , Magar Roniya Thapa , Elisabeth Nathalie H. , Deutschbauer Adam M. , Arkin Adam P. , Mutalik Vivek K.
Published: April 2023

Lytic phages can be potent and selective inhibitors of microbial growth and can have profound impacts on microbiome composition and function. However, there is uncertainty about the biogeochemical conditions under which phage predation can proceed and modulate microbial ecosystem function, particularly in terrestrial systems. Ionic strength is known to be critical for infection of bacteria by many phages, but there is limited quantitative data on ion thresholds for phage infection that can be compared with environmental ion concentrations. Similarly, while carbon composition varies in terrestrial environments, we know little of which carbon sources favor or disfavor phage infection and how these higher order interactions impact microbiome function. Here, we measured the half-maximal effective concentrations (EC50) of 80 different inorganic ions for the infection ofE. coliwith two canonical dsDNA and ssRNA phages, T4 and MS2, respectively. We found that many alkaline earth metals and alkali metals enabled successful lytic infection but that the ionic strength thresholds varied for different ions between phages. Additionally, using a freshwater nitrate reducing microbiome, we found that the ability of lytic phage to influence nitrate reduction end-products was dependent on the carbon source as well as the ion concentration. For all phage:host pairs we tested, the ion EC50s for phage infection we measured exceed the ion concentrations found in many terrestrial freshwater systems. Thus, our findings support a model where the influence of phages on terrestrial microbial functional ecology is greatest in hot spots and hot moments such as metazoan guts, drought influenced soils, or biofilms where ion concentration is locally or transiently elevated and carbon source composition is of a sufficiently low complexity to enrich for a dominant phage susceptible population.

Significance

Viral-prokaryote dynamics greatly influence microbial ecology and the earth’s biogeochemical cycles. Thus, identifying the key environmental controls on phage predation is critical for predictive microbial ecology. Here we conduct laboratory experiments that implicate ionic strength and carbon composition as major controls on phage interactions with bacterial hosts in terrestrial microbiomes. We propose a model in which terrestrial phage predation is most favored in drought impacted soils and in higher ionic strength environments such as metazoan guts or between adjacent cells in biofilms.
A Predictive Coding Model of the N400
Authors: Eddine Samer Nour , Brothers Trevor , Wang Lin , Spratling Michael , Kuperberg Gina R.
Published: April 2023

The N400 event-related component has been widely used to investigate the neural mechanisms underlying real-time language comprehension. However, despite decades of research, there is still no unifying theory that can explain both its temporal dynamics and functional properties. In this work, we show that predictive coding – a biologically plausible algorithm for approximating Bayesian inference – offers a promising framework for characterizing the N400. Using an implemented predictive coding computational model, we demonstrate how the N400 can be formalized as the lexico-semantic prediction error produced as the brain infers meaning from linguistic form of incoming words. We show that the magnitude of lexico-semantic prediction error mirrors the functional sensitivity of the N400 to various lexical variables, priming, contextual effects, as well as their higher-order interactions. We further show that the dynamics of the predictive coding algorithm provide a natural explanation for the temporal dynamics of the N400, and a biologically plausible link to neural activity. Together, these findings directly situate the N400 within the broader context of predictive coding research, and suggest that the brain may use the same computational mechanism for inference across linguistic and non-linguistic domains.
Tree diversity increases productivity through enhancing structural complexity across mycorrhizal types
Authors: Ray Tama , Delory Benjamin M. , Bruelheide Helge , Eisenhauer Nico , Ferlian Olga , Quosh Julius , Oheimb Goddert von , Fichtner Andreas
Published: April 2023

Tree species diversity plays a central role for forest productivity, but factors driving positive biodiversity-productivity relationships remain poorly understood. In a biodiversity experiment manipulating tree diversity and mycorrhizal associations, we examined the roles of above- and belowground processes in modulating wood productivity in young temperate tree communities, as well as potential underlying mechanisms. We found that tree species richness increased forest productivity indirectly by enhancing structural complexity within communities. After six years, structurally complex communities were twice as productive as structurally simple stands. This pattern was consistent across stands with different mycorrhizal associations. Our results also demonstrate that taxonomic diversity and functional variation in shade tolerance, but not phenotypic plasticity, are key drivers of structural complexity in mixtures, which in turn lead to overyielding. Consideration of stand structural complexity appears to be a crucial element in predicting carbon sequestration in the early successional stages of mixed-species forests.
Crystal structure and Hirshfeld surface analysis of 1,6-diamino-2-oxo-4-(thiophen-2-yl)-1,2-dihydropyridine-3,5-dicarbonitrile
Authors: Naghiyev Farid N. , Khrustalev Victor N. , Akkurt Mehmet , Khalilov Ali N. , Bhattarai Ajaya , Kerimli Fuad Sh. , Mamedov İbrahim G.
Published: April 2023

The asymmetric unit of the title compound, C11H7N5OS, contains two independent molecules (1 and 2). The thiophene ring in molecule 2 is rotationally disordered (flip disorder) by ca 180° (around the single C—C bond, to which it is attached) over two sites with the site-occupation factors of 0.9 and 0.1. These two orientations of the thiophene ring in molecule 2 are not equivalent. In the crystal, molecules are linked by intermolecular N—H...O and N—H...N hydrogen bonds into ribbons parallel to (022) along the a axis. Within the (022) planes, these ribbons are connected by van der Waals interactions and between the (022) planes by N—H...O hydrogen bonds. In molecule 1, Hirshfeld surface analysis showed that the most important contributions to the crystal packing are from N...H/H...N (27.1%), H...H (17.6%), C...H/H...C (13.6%) and O...H/H...O (9.3%) interactions, while in molecule 2, H...H (25.4%) interactions are the most significant contributors to the crystal packing.
9-(Pyrrolidinium-1-yl)-9-boranuidabicyclo[3.3.1]nonane
Authors: Herbig Marcus , Böhme Uwe
Published: April 2023

The title compound, C12H24BN, is an adduct formed from 9-borabicyclo[3.3.1]nonane (9-BBN) and pyrrolidine. It crystallizes in the triclinic space group P\overline{1} with three molecules in the asymmetric unit, one of which has disorder of the pyrrolidine ring. The B—N bond lengths are between 1.631 (2) and 1.641 (2) Å. The boron and nitrogen atoms are bound to one hydrogen atom each. These hydrogen atoms are in antiperiplanar orientation. Both six-membered rings of the 9-BBN unit are in a chair conformation in all three molecules. Differences between the three crystallographic independent molecules are found in the five-membered rings of the pyrrolidine unit. These adopt different twisted and envelope conformations.
Strategic change in the health sector: a literature review and future challenges
Authors: Pereira Sérgio A.F. , Ferreira João J. , Rammal Hussain Gulzar , Peris-Ortiz Marta
Published: April 2023

Purpose

The health sector is increasingly dynamic and complex, in which (strategic) change has become a constant in the sector's adaptation to different challenges. This study aims to meet the need to understand which trends in the literature on strategic change in the health sector and which elements comprise it.

Design/methodology/approach

To advance research in this area, the authors systematically review 285 articles collected from the Scopus database. The authors conducted a bibliometric analysis using the VOSviewer software by applying the bibliographic matching method to understand how these articles were grouped and thus characterise the literature trends.

Findings

Through a systematic literature review (SLR), this study analyses the various lenses of literature on strategic change in the context of the health sector, classifying and conceptually mapping existing research into four thematic groups: key factors in strategic change, theories and models underlying strategic change, decentralisation in strategic change and the challenges to strategic change in this millennium.

Research limitations/implications

The trends in the literature on strategic change in the health sector explore strategic change from different perspectives. Key features in strategic change suffered reciprocal influence from the theories/models of strategic change and decentralisation of health care so that the health sector could define strategies to respond to the challenges it faced.

Originality/value

The health sector has been in great prominence worldwide, specifically due to the recent events that have occurred on a planetary scale. Therefore, a systematic review is essential to help understand the strategic changes that have occurred in the health sector and their impact. The authors did not find any SLR that focuses on global strategic changes in the health sector, so this study will fill this gap, systematising the main topics on strategic change in the health sector. The authors also suggest an integrative research framework and a future research agenda.
Sin versus green investment: A retrospective study on investor choice during pre- and through COVID regime
Authors: Bhatnagar Chandra Shekhar , Bhatnagar Dyal , Kumari Vineeta , Bhullar Pritpal Singh
Published: April 2023

Purpose

Increasing focus on socially responsible investments (SRIs) and green projects in recent times, coupled with the arrival of COVID pandemic, are the main drivers of this study. The authors conduct a post-factum analysis of investor choice between sin and green investments before and through the COVID outbreak.

Design/methodology/approach

A passive investor is introduced who seeks maximum risk-adjusted return and/or investment variance. When presented an opportunity to add sin and/or green investments to her initial one-asset market-only investment position, she views and handles this issue as a portfolio problem (MPT). She estimates value-at-risk (VaR) and conditional-value-at-risk (CVaR) for portfolios to account for downside risk.

Findings

Green investments offer better overall risk-return optimization in spite of major inter-period differences in return-risk dynamics and substantial downside risk. Portfolios optimized for minimum variance perform just as well as the ones optimized for minimum downside risk. Return and risk have settled at higher levels since the onset of COVID, resulting in shifting the efficient frontier towards north-east in the return-risk space.

Originality/value

The study contributes to the literature in two ways: One, it examines investor choice between sin and green investments during a global health emergency and views this choice against the one made during normal times. Two, instead of using the principles of modern portfolio theory (MPT) explicitly for diversification, the study uses them to identify investor preference for one over the other investment type. This has not been widely done thus far.
Meadow transformations alter above‐ and below‐ground ecological networks and ecosystem multifunctionality
Authors: Gao Erliang , Ma Hui , Yang Ting , Kaiser‐Bunbury Christopher N. , Zhao Zhigang
Published: April 2023

Human‐mediated environmental change transforms ecosystems worldwide. Understanding the detailed impact of these unprecedented changes on biodiversity and ecosystem functioning, however, is challenging. Meadow ecosystems on the Tibetan Plateau transform as a result of climate change and anthropogenic disturbances. Evaluating the consequences of these meadow transformations on above‐ and below‐ground community structure, ecological network and ecosystem functioning is critical for predicting the impact on biodiversity and developing mitigation strategies.

Here, we used a natural experiment across replicated sites to assess the responses of ecological networks of soil microbial communities and plant‐pollinator communities to meadow transformations and investigate the impacts of these changes on ecosystem multifunctionality.

As a result of swampy meadow desiccation, species richness and ecological network complexity at multiple trophic levels increased, pollination networks became more robust while soil microbial networks became more vulnerable to species loss. Pollination function appeared to benefit from increased diversity in resources and the formation of dry soil, but important below‐ground functions decreased. When alpine meadows degraded further because of extensive grazing pressure, above‐ground diversity and network complexity tended to decline. Soil microbial richness and composition remained unchanged but associations among soil microbes homogenized, and ecosystem productivity and pollination function decreased.

Our study provides empirical evidence that human‐mediated meadow transformations influence above‐ and below‐ground ecological networks and ecosystem functioning simultaneously. The findings highlight that ecosystem transformations can have contrasting effects on above‐ and below‐ground diversity and ecological networks, as well as ecosystem functions. Such contrasting responses call for targeted and nuanced management strategies to conserve biodiversity and ecosystem functioning in the Tibetan Plateau.

Read the freePlain Language Summaryfor this article on the Journal blog.
A p21‐GFP zebrafish model of senescence for rapid testing of senolytics in vivo
Authors: Morsli Samir , Henriques Catarina M. , Ellis Pamela S. , Mortiboys Heather , Baxendale Sarah , Loynes Catherine A. , Renshaw Stephen A. , Bellantuono Ilaria
Published: April 2023

Senescence drives the onset and severity of multiple ageing‐associated diseases and frailty. As a result, there has been an increased interest in mechanistic studies and in the search for compounds targeting senescent cells, known as senolytics. Mammalian models are commonly used to test senolytics and generate functional and toxicity data at the level of organs and systems, yet this is expensive and time consuming. Zebrafish share high homology in genes associated with human ageing and disease. They can be genetically modified relatively easily. In larvae, most organs develop within 5 days of fertilisation and are transparent, which allows tracking of fluorescent cells in vivo in real time, testing drug off‐target toxicity and assessment of cellular and phenotypic changes. Here, we have generated a transgenic zebrafish line that expresses green fluorescent protein (GFP) under the promoter of a key senescence marker, p21. We show an increase in p21:GFP+cells in larvae following exposure to ionising radiation and with natural ageing. p21:GFP+cells display other markers of senescence, including senescence‐associated β‐galactosidase and IL6. The observed increase in senescent cells following irradiation is associated with a reduction in the thickness of muscle fibres and mobility, two important ageing phenotypes. We also show that quercetin and dasatinib, two senolytics currently in clinical trials, reduce the number of p21:GFP+cells, in a rapid 5‐day assay. This model provides an important tool to study senescence in a living organism, allowing the rapid selection of senolytics before moving to more expensive and time‐consuming mammalian systems.
Lakota basketball and racism: Performance, performativity, and engaged acrimony
Authors: Klein Alan
Published: April 2023

Sporting contests between communities actively engaged in societal struggle comprise an event I call “engaged acrimony.” In these sporting contests, ideas of sport as promoting harmony get tested and often give way to demonstrations of vitriol that mirror actual relations. In this article, I discuss Lakota basketball teams from Pine Ridge Indian Reservation as they played against neighboring white teams, examining how their responses to racism were safely expressed within and around sporting events. I analyze two of the best‐known instances of engaged acrimony using Turner's sense of performance and Butler's theory of performativity. In doing so, I offer an understanding of how Native communities can fashion an empowering response to racism.
Stability for 6 months and accuracy of a specific enteral caffeine base preparation for a multisite clinical trial
Authors: Erickson Grant , McAnulty Michael , Powers Chelsea , Luong Thu‐Lan , Dobson Nicole R. , Hunt Carl E.
Published: April 2023

The ‘Intermittent Hypoxia and Caffeine in Infants Born Preterm (ICAF)’ study (NCT03321734) uses an extemporaneously compounded enteral caffeine base solution for its study drug. The primary aim of this report is to determine the stability of this specific enteral caffeine base preparation stored for up to 6 months and assess optimal storage temperature. To analyse stability, caffeine solutions were prepared and stored at 4°C and 25°C (room temperature). The caffeine concentrations were analysed over time using high‐performance liquid chromatography (HPLC). To confirm the accuracy of compounded caffeine concentrations, study drug samples from three research pharmacies were analysed. Stability results showed that caffeine concentrations are within 5% of the expected concentration when stored for up to 6 months at room temperature. Our results also show that accurate caffeine concentrations were achieved by multiple research pharmacies.
Management of luspatercept therapy in patients with transfusion‐dependent β‐thalassaemia
Authors: Sheth Sujit , Taher Ali T. , Coates Thomas D. , Kattamis Antonis , Cappellini Maria Domenica
Published: April 2023

Patients with transfusion‐dependent β‐thalassaemia require lifelong, regular red blood cell transfusions for survival; however, frequent blood transfusions are associated with an increased risk of iron overload, transfusion‐transmitted disease and alloimmunization, as well as reduced quality of life. Luspatercept, an erythroid maturation agent that promotes late‐stage erythroid maturation independently of erythropoietin, has demonstrated efficacy in reducing transfusion burden in patients with transfusion‐dependent β‐thalassaemia. In this review, we discuss treatment initiation, ongoing evaluation, dose adjustment and management of adverse events in transfusion‐dependent patients with β‐thalassaemia receiving luspatercept, and we provide guidance on how to determine whether patients are deriving clinical benefit.