bluuebunny/crossref_metadata_2025 huggingface dataset:
In uteropulse injection of isotopic amino acids quantifies protein turnover rates during murine fetal development
Authors: Baeza Josue , Coons Barbara E. , Lin Zongtao , Riley John , Mendoza Mariel , Peranteau William H. , Garcia Benjamin A
Published: May 2023

Protein translational control is highly regulated step in the gene expression program during mammalian development that is critical for ensuring that the fetus develops correctly and that all of the necessary organs and tissues are formed and functional. Defects in protein expression during fetal development can lead to severe developmental abnormalities or premature death. Currently, quantitative techniques to monitor protein synthesis rates in a developing fetus (in utero) are limited. Here, we developed a novelin uterostable isotope labeling approach to quantify tissue-specific protein dynamics of the nascent proteome during mouse fetal development. Fetuses of pregnant C57BL/6J mice were injected with isotopically labeled lysine (Lys8) and arginine (Arg10) via the vitelline vein at various gestational days. After treatment, fetal organs/tissues including brain, liver, lung, and heart were harvested for sample preparation and proteomic analysis. We show that the mean incorporation rate for injected amino acids into all organs was 17.50 ± 0.6%. By analyzing the nascent proteome, unique signatures of each tissue were identified by hierarchical clustering. In addition, the quantified proteome-wide turnover rates (kobs) were calculated between 3.81E-5 and 0.424 hour-1. We observed similar protein turnover profiles for analyzed organs (e.g., liver versus brain), however, their distributions of turnover rates vary significantly. The translational kinetic profiles of developing organs displayed differentially expressed protein pathways and synthesis rates which correlated with known physiological changes during mouse development.
Regulation of metal homeostasis by two F-group bZIP transcription factors bZIP48 and bZIP50 in rice
Authors: Qing Tao , Xie Tian-Ci , Zhu Qiao-Yun , Lu Hai-Ping , Liu Jian-Xiang
Published: May 2023

Zinc (Zn) is an essential microelement for plants as well as for human beings, and it regulates numerous metabolic process and protein activity. Zn deficiency not only impairs plant growth and development, but also affects human health. Rice (Oryza sativaL.) is a staple food for more than half of the world’s population, but how Zn homeostasis in rice is maintained is largely unknown. Here, we demonstrate that two F-group bZIP transcription factors, OsbZIP48 and OsbZIP50, are important for metal homeostasis in rice. Mutation ofOsbZIP48andOsbZIP50impairs plant growth and reduces Zn, Fe, and Cu content in shoots. The N-terminus of either OsbZIP48 or OsbZIP50 contains two cysteine- and histidine-rich (CHR) domains, deletion or mutation of these CHR domains increases nucleus localization of OsbZIP48 and OsbZIP50. Both OsbZIP48 and OsbZIP50 have transcriptional activation activity, and the expression of 1117 genes involved in metal uptake, phenylpropanoid biosynthetic process, cell wall organization, et al., is reduced inOsbZIP48andOsbZIP50double mutant than that in wild-type ZH11 plant under Zn deficiency. Both OsbZIP48 and OsbZIP50 bind to the promoter region of the ZIP family transporter geneOsZIP10in rice, and activate the promoter activity of ZDREcis-element derived from theOsZIP10promoter in effector-reporter assays. Mutation of the CHR domain of OsbZIP48 inOsbZIP50mutant background increases the content of Zn/Fe/Cu in brown rice seeds and leaves. Thus, this study reveals that OsbZIP48 and OsbZIP50 regulate metal homeostasis, especially under Zn deficiency in rice, and provides candidate target genes for biofortification of micronutrients in future.

significance statement

Zinc (Zn) is an essential microelement not only for plants but also for human beings. This paper shows that the N-terminal cysteine- and histidine-rich domain of OsbZIP48/50 is important for their nucleus localization, therefore transcriptional activity, and reveals the downstream genes of OsbZIP48/50 involved in metal homeostasis under Zn deficiency in rice.
Reproductive sexual dimorphisms in two willow species,Salix exiguaNutt.and S. nigraMarshall
Authors: Hu Nan , Hale Haley , Sanderson Brian , Feng Guanqiao , Guo Minghao , Gambhir Diksha , Olson Matt
Published: May 2023

Premise of the Research

The prevalence of sexual dimorphisms, which evolve due to contrasting strategies to maximize reproductive success in males and females, is variable among dioecious plant species. In theSalicaceae, many traits have been assessed across many studies, but direct or indirect associations between these traits and reproductive allocation are often neglected. Given the dynamic evolution of sex determination systems and the strong interest in wood production in the family, we wondered whether sexual dimorphisms related to reproduction may have gone unreported. Here, we assess sexual dimorphism in reproductive traits in two species ofSalix. Recognition of reproductive sexually dimorphic traits will contribute to understanding the evolution of sex determination systems in the Salicaceae.

Methodology

We conducted observational studies in natural populations to assess the presence of sexual dimorphisms in early spring bud density, catkin number, and flower number per catkin across four sampling periods inSalix exigua. We also analyzed flower number and catkin number per flower inSalix nigra.

Pivotal Results

We observed no sexual dimorphism in pre-season buds per branch inS. exiguabut did find that males produced more flowers per catkin and more catkins per branch than females in bothS. exiguaandS. nigra.

Conclusions

Higher flower numbers in males compared to females is consistent with expectations from intra-sexual selection among males. The presence of reproductive sexual dimorphisms inSalixsuggests that sexual selection may affect the evolution of mating strategies inSalixspecies, and the evolution of the sex determination system within this genus.
Neurophysiological trajectories in Alzheimer's disease progression
Authors: Kudo Kiwamu , Ranasinghe Kamalini G , Morise Hirofumi , Syed Faatimah , Sekihara Kensuke , Rankin Katherine P. , Miller Bruce L , Kramer Joel , Rabinovici Gil , Vossel Keith , Kirsch Heidi E , Nagarajan Srikantan
Published: May 2023

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β and misfolded tau proteins causing synaptic dysfunction, and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline are unknown. Here, we deployed robust event-based sequencing models (EBMs) to investigate the trajectories of long-range and local neural synchrony across AD stages, estimated from resting-state magnetoencephalography. The increases in neural synchrony in the delta-theta band and the decreases in the alpha and beta bands showed progressive changes throughout the stages of the EBM. Decreases in alpha and beta band synchrony preceded both neurodegeneration and cognitive decline, indicating that frequency-specific neuronal synchrony abnormalities are early manifestations of AD pathophysiology. The long-range synchrony effects were greater than the local synchrony, indicating a greater sensitivity of connectivity metrics involving multiple regions of the brain. These results demonstrate the evolution of functional neuronal deficit along the sequence of AD progression.
BertNDA: A Model Based on Graph-Bert and Multi-scale Information Fusion for ncRNA-disease Association Prediction
Authors: Ning Zhiwei , Wu Jinyang , Ding Yidong , Wang Ying , Peng Qinke , Fu Laiyi
Published: May 2023

Non-coding RNAs (ncRNAs) are a class of RNA molecules that lack the ability to encode proteins in human cells, yet play crucial roles in various biological process. Understanding these relationships and how different ncRNAs interact with each other to affect diseases can vastly contribute to their diagnosis, prevention, and treatment. However, predicting tertiary interactions between ncRNA-disease associations by utilizing structural information across multiple scales remains a challenging task. It should be noted that research on predicting tertiary interaction between trinary ncRNA-disease associations is scarce, highlighting the need for further studies in this area. In this work, we propose a predictive framework, called BertNDA, which aims to predict association between miRNA, lncRNA and disease. The framework employs Laplace transform of graph structure and WL (Weisfeiler-Lehman) absolute role coding to extract global information. Local information is identified by the connectionless subgraph which aggregates neighbor feature. Moreover, an EMLP (Element-wise MLP) structure is designed to fuse the multi-scale feature representation of nodes. Furtherly, feature representation is encoded by using a Transformer-encoder structure, the prediction-layer outputs the final correlation between miRNA, lncRNA and diseases. The 5-fold cross-validation result furtherly demonstrates that BertNDA outperforms the state-of-the-art method in predicting assignment. Furthermore, an online prediction platform that embeds our prediction model is designed for users to experience. Overall, our model provides an efficient, accurate, and comprehensive tool for predicting ncRNA-disease associations. The code of our method is available in:https://github.com/zhiweining/BertNDA-main.
ApoER2-Dab1 disruption as the origin of pTau-related neurodegeneration in sporadic Alzheimer’s disease
Authors: Ramsden Christopher E. , Zamora Daisy , Horowitz Mark S. , Jahanipour Jahandar , Keyes Gregory S. , Li Xiufeng , Murray Helen C. , Curtis Maurice A. , Faull Richard M. , Sedlock Andrea , Maric Dragan
Published: May 2023

BACKGROUND

Sporadic Alzheimer’s disease (sAD) is not a global brain disease. Specific regions, layers and neurons degenerate early while others remain untouched even in advanced disease. The prevailing model used to explain this selective neurodegeneration—prion-like Tau spread—has key limitations and is not easily integrated with other defining sAD features. Instead, we propose that in humans Tau hyperphosphorylation occurs locally via disruption in ApoER2-Dab1 signaling and thus the presence of ApoER2 in neuronal membranes confers vulnerability to degeneration. Further, we propose that disruption of the Reelin/ApoE/ApoJ-ApoER2-Dab1 P85α-LIMK1-Tau-PSD95 (RAAAD-P-LTP) pathway induces deficits in memory and cognition by impeding neuronal lipoprotein internalization and destabilizing actin, microtubules, and synapses. This new model is based in part on our recent finding that ApoER2-Dab1 disruption is evident in entorhinal-hippocampal terminal zones in sAD. Here, we hypothesized that neurons that degenerate in the earliest stages of sAD (1) strongly express ApoER2 and (2) show evidence of ApoER2-Dab1 disruption through co-accumulation of multiple RAAAD-P-LTP components.

METHODS

We appliedin situhybridization and immunohistochemistry to characterize ApoER2 expression and accumulation of RAAAD-P-LTP components in five regions that are prone to early pTau pathology in 64 rapidly autopsied cases spanning the clinicopathological spectrum of sAD.

RESULTS

We found that: (1) selectively vulnerable neuron populations strongly express ApoER2; (2) numerous RAAAD P-LTP pathway components accumulate in neuritic plaques and abnormal neurons; and (3) RAAAD-P-LTP components were higher in MCI and sAD cases and correlated with histological progression and cognitive deficits. Multiplex-IHC revealed that Dab1, pP85αTyr607, pLIMK1Thr508, pTau and pPSD95Thr19accumulated together within dystrophic dendrites and soma of ApoER2-expressing neurons in the vicinity of ApoE/ApoJ enriched extracellular plaques. These observations provide evidence for molecular derangements that can be traced back to ApoER2-Dab1 disruption, in each of the sampled regions, layers, and neuron populations that are prone to early pTau pathology.

CONCLUSION

Findings support the RAAAD-P-LTP hypothesis, a unifying model that implicates dendritic ApoER2-Dab1 disruption as the major driver of both pTau accumulation and neurodegeneration in sAD. This model provides a new conceptual framework to explain why specific neurons degenerate and identifies RAAAD-P-LTP pathway components as potential mechanism-based biomarkers and therapeutic targets for sAD.
Fatigue during acute systemic inflammation is associated with reduced mental effort expenditure while task accuracy is preserved
Authors: Lambregts B.I.H.M. , Vassena E. , Jansen A. , Stremmelaar D.E. , Pickkers P. , Kox M. , Aarts E. , van der Schaaf M.E.
Published: May 2023

Background

Earlier work within the physical domain showed that acute inflammation changes motivational prioritization and effort allocation rather than physical abilities. It is currently unclear whether a similar motivational framework accounts for the mental fatigue and cognitive symptoms of acute sickness. Accordingly, this study aimed to assess the relationship between fatigue, cytokines and mental effort-based decision making during acute systemic inflammation.

Methods

Eighty-five participants (41 males; 18-30 years (M=23.0, SD=2.4)) performed a mental effort-based decision-making task before, 2 hours after, and 5 hours after intravenous administration of 1 ng/kg bacterial lipopolysaccharide (LPS) to induce systemic inflammation. Plasma concentrations of cytokines (interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)) and fatigue levels were assessed at similar timepoints. In the task, participants decided whether they wanted to perform (i.e., ‘accepted’) arithmetic calculations of varying difficulty (3 levels: easy, medium, hard) in order to obtain rewards (3 levels: 5, 6 or 7 points). Acceptance rates were analyzed using a binomial generalized estimated equation (GEE) approach with effort, reward and time as independent variables. Arithmetic performance was measured per effort level prior to the decisions and included as a covariate. Associations between acceptance rates, fatigue (self-reported) and cytokine concentrations levels were analyzed using partial correlation analyses.

Results

Plasma cytokine concentrations and fatigue were increased at 2 hours post-LPS compared to baseline and 5 hours post-LPS administration. Acceptance rates decreased for medium, but not for easy or hard effort levels at 2 hours post-LPS versus baseline and 5 hours post-LPS administration, irrespective of reward level. This reduction in acceptance rates occurred despite improved accuracy on the arithmetic calculations itself. Reduced acceptance rates for medium effort were associated with increased fatigue, but not with increased cytokines.

Conclusion

Fatigue during acute systemic inflammation is associated with alterations in mental effort allocation, similarly as observed previously for physical effort-based choice. Specifically, willingness to exert mental effort depended on effort and not reward information, while task accuracy was preserved. These results extend the motivational account of inflammation to the mental domain and suggest that inflammation may not necessarily affect domain-specific mental abilities, but rather affects domain-general effort-allocation processes.
Deconstructing the contributions of heterogeneity to combination treatment of hormone sensitive breast cancer
Authors: Linn Samantha , Moore-Ott Jenna A. , Shuttleworth Robyn , Zhang Wenjing , Craig Morgan , Jenner Adrianne L.
Published: May 2023

Combination therapies are fundamental to cancer treatments, including in breast cancer the most common invasive malignancy in women. Breast cancer treatment is determined based on molecular subtypes, and since 2016, combination palbociclib and fulvestrant has been used to treat hormone receptor-positive breast cancer. However, the impact of heterogeneity of the tumour landscape and tumour composition dynamics on scheduling decisions remains poorly understood. To elucidate the contributions of variability at multiple scales to treatment outcomes in hormone receptor-positive breast cancer, we developed a simple mathematical model of two unique estrogen receptor positive (ER+) breast cancer cell types and their response to combination treatment with palbociclib and fulvestrant. We used this model to understand how the initial fraction of either cell type may impact the fraction remaining after treatment and examined how heterogeneity in pharmacokinetics and pharmacodynamics result in a large distribution of outcomes. Our results suggest that the pharmacokinetics and pharmacodynamics of fulvestrant were the major drivers of final tumour size and composition. We then leveraged our model to guide therapeutic scheduling of combination palbociclib and fulvestrant, demonstrating the use of mathematical modelling to improve our understanding of cancer biology and treatments.
Inference of annealed protein fitness landscapes with AnnealDCA
Authors: Sesta Luca , Pagnani Andrea , Fernandez-de-Cossio-Diaz Jorge , Uguzzoni Guido
Published: May 2023

The design of proteins with specific tasks is a major challenge in molecular biology with important diagnostic and therapeutic applications. High-throughput screening methods have been developed to systematically evaluate protein activity, but only a small fraction of possible protein variants can be tested using these techniques. Computational models that explore the sequence spacein-silicoto identify the fittest molecules for a given function are needed to overcome this limitation. In this article, we propose AnnealDCA, a machine-learning framework to learn the protein fitness landscape from sequencing data derived from a broad range of experiments that use selection and sequencing to quantify protein activity. We demonstrate the effectiveness of our method by applying it to antibody Rep-Seq data of immunized mice and screening experiments, assessing the quality of the fitness landscape reconstructions. Our method can be applied to most experimental cases where a population of protein variants undergoes various rounds of selection and sequencing, without relying on the computation of variant enrichment ratios, and thus can be used even in cases of disjoint sequence samples.
Neuromodulation via muscarinic acetylcholine pathway can facilitate distinct, complementary, and sequential roles for NREM and REM states during sleep-dependent memory consolidation
Authors: Satchell Michael , Fry Blaine , Noureddine Zahraa , Simmons Alexis , Ognjanovski Nicolette N. , Aton Sara J. , Zochowski Michal R.
Published: May 2023

Across vertebrate species, sleep consists of repeating cycles of NREM followed by REM. However, the respective functions of NREM, REM, and their stereotypic cycling pattern are not well understood. Using a simplified biophysical network model, we show that NREM and REM sleep can play differential and critical roles in memory consolidation primarily regulated, based on state-specific changes in cholinergic signaling. Within this network, decreasing and increasing muscarinic acetylcholine (ACh) signaling during bouts of NREM and REM, respectively, differentially alters neuronal excitability and excitatory/inhibitory balance. During NREM, deactivation of inhibitory neurons leads to network-wide disinhibition and bursts of synchronized activity led by firing in engram neurons. These features strengthen connections from the original engram neurons to less-active network neurons. In contrast, during REM, an increase in network inhibition suppresses firing in all but the most-active excitatory neurons, leading to competitive strengthening/pruning of the memory trace. We tested the predictions of the model againstin vivorecordings from mouse hippocampus during active sleep-dependent memory storage. Consistent with modeling results, we find that functional connectivity between CA1 neurons changes differentially at transition from NREM to REM sleep during learning. Returning to the model, we find that an iterative sequence of state-specific activations during NREM/REM cycling is essential for memory storage in the network, serving a critical role during simultaneous consolidation of multiple memories. Together these results provide a testable mechanistic hypothesis for the respective roles of NREM and REM sleep, and their universal relative timing, in memory consolidation.

Significance statement

Using a simplified computational model andin vivorecordings from mouse hippocampus, we show that NREM and REM sleep can play differential roles in memory consolidation. The specific neurophysiological features of the two sleep states allow for expansion of memory traces (during NREM) and prevention of overlap between different memory traces (during REM). These features are likely essential in the context of storing more than one new memory simultaneously within a brain network.
SPLIT HAND/FOOT VARIANTS FAIL TO RESCUE PRDM1A MUTANT CRANIOFACIAL DEFECTS
Authors: Truong Brittany T. , Shull Lomeli C. , Lencer Ezra , Artinger Kristin B.
Published: May 2023

Background

Split Hand/Foot Malformation (SHFM) is a congenital limb disorder presenting with limb anomalies, such as missing, hypoplastic, or fused digits, and often craniofacial defects, including a cleft lip/palate, microdontia, micrognathia, or maxillary hypoplasia. We previously identified three novel variants in the transcription factor,PRDM1, that are associated with SHFM phenotypes. One individual also presented with a high arch palate. Studies in vertebrates indicate that PRDM1 is important for development of the skull; however, prior to our study, human variants inPRDM1had not been associated with craniofacial anomalies.

Methods

Using transient mRNA overexpression assays inprdm1a-/-mutant zebrafish, we tested whether thePRDM1SHFM variants were functional and could lead to a rescue of the craniofacial defects observed inprdm1a-/-mutants. We also mined a CUT&RUN and RNA-seq dataset to examine Prdm1a binding and the effect of Prdm1a loss on craniofacial genes.

Results

prdm1a-/-mutants exhibit craniofacial defects including a hypoplastic neurocranium, a loss of posterior ceratobranchial arches, a shorter palatoquadrate, and an inverted ceratohyal. Injection of wildtypehPRDM1inprdm1a-/-mutants partially rescues these structures. However, injection of each of the three SHFM variants fails to rescue the skeletal defects. Loss ofprdm1aleads to a decreased expression of important craniofacial genes, such asdlx5a/dlx6a, hand2, sox9b, col2a1a, andhoxbgenes.

Conclusion

These data suggest that the three SHFM variants are not functional and may have led to the craniofacial defects observed in the humans. Finally, they demonstrate how Prdm1a can directly bind and regulate craniofacial gene expression.
Accelerated Nitrogen Cycling on Seagrass Leaves in a High-CO2World
Authors: Berlinghof Johanna , Montilla Luis M. , Peiffer Friederike , Quero Grazia M. , Marzocchi Ugo , Meador Travis B. , Margiotta Francesca , Abagnale Maria , Wild Christian , Cardini Ulisse
Published: May 2023

Seagrass meadows form highly productive and diverse ecosystems in coastal areas worldwide, where they are increasingly exposed to ocean acidification (OA). Efficient nitrogen (N) cycling and uptake are essential to maintain plant productivity, but the effects of OA on N transformations in these systems are poorly understood. Here we show that complete N cycling occurs on leaves of the Mediterranean seagrassPosidonia oceanica, with OA affecting both N gain and loss while the prokaryotic community structure remains largely unaffected. Daily leaf-associated N2fixation contributed to 35% of the plant’s N demand under ambient pH, whereas it contributed to 45% under OA. Nitrification potential was only detected under OA, and N-loss via N2production increased, although the balance remained decisively in favor of enhanced N gain. Our work highlights the role of the N-cycling microbiome in seagrass adaptation to OA, with key N transformations accelerating towards increased N gain.
Single-cell analysis of innate spinal cord regeneration identifies intersecting modes of neuronal repair
Authors: Saraswathy Vishnu Muraleedharan , Zhou Lili , Mokalled Mayssa H.
Published: May 2023

Adult zebrafish have an innate ability to recover from severe spinal cord injury. Here, we report a comprehensive single nuclear RNA sequencing atlas that spans 6 weeks of regeneration. We identify cooperative roles for adult neurogenesis and neuronal plasticity during spinal cord repair. Neurogenesis of glutamatergic and GABAergic neurons restores the excitatory/inhibitory balance after injury. In addition, a transient population of injury-responsive neurons (iNeurons) show elevated plasticity between 1 and 3 weeks post-injury. We found iNeurons are injury-surviving neurons that acquire a neuroblast-like gene expression signature after injury. CRISPR/Cas9 mutagenesis showed iNeurons are required for functional recovery and employ vesicular trafficking as an essential mechanism that underlies neuronal plasticity. This study provides a comprehensive resource of the cells and mechanisms that direct spinal cord regeneration and establishes zebrafish as a model of plasticity-driven neural repair.
Scaling the Discrete-time Wright Fisher model to biobank-scale datasets
Authors: Spence Jeffrey P. , Zeng Tony , Mostafavi Hakhamanesh , Pritchard Jonathan K.
Published: May 2023

The Discrete-Time Wright Fisher (DTWF) model and its large population diffusion limit are central to population genetics. These models describe the forward-in-time evolution of the frequency of an allele in a population and can include the fundamental forces of genetic drift, mutation, and selection. Computing like-lihoods under the diffusion process is feasible, but the diffusion approximation breaks down for large sample sizes or in the presence of strong selection. Unfortunately, existing methods for computing likelihoods under the DTWF model do not scale to current exome sequencing sample sizes in the hundreds of thousands. Here we present an algorithm that approximates the DTWF model with provably bounded error and runs in time linear in the size of the population. Our approach relies on two key observations about Binomial distributions. The first is that Binomial distributions are approximately sparse. The second is that Binomial distributions with similar success probabilities are extremely close as distributions, allowing us to approximate the DTWF Markov transition matrix as a very low rank matrix. Together, these observations enable matrix-vector multiplication in linear (as opposed to the usual quadratic) time. We prove similar properties for Hypergeometric distributions, enabling fast computation of likelihoods for subsamples of the population. We show theoretically and in practice that this approximation is highly accurate and can scale to population sizes in the billions, paving the way for rigorous biobank-scale population genetic inference. Finally, we use our results to estimate how increasing sample sizes will improve the estimation of selection coefficients acting on loss-of-function variants. We find that increasing sample sizes beyond existing large exome sequencing cohorts will provide essentially no additional information except for genes with the most extreme fitness effects.
Mycolactone A vs. B: Does localization or association explain isomer-specific toxicity?
Authors: Nguyen John D. M. , da Hora Gabriel C. A. , Swanson Jessica M. J.
Published: May 2023

Mycolactone is an exotoxin produced byMycobacterium ulceransthat causes the neglected tropical skin disease Buruli ulcer. This toxin inhibits the Sec61 translocon in the endoplasmic reticulum (ER), preventing the host cell from producing many secretory and transmembrane proteins, resulting in cytotoxic and immunomodulatory effects. Interestingly, only one of the two dominant isoforms of mycolactone is cytotoxic. Here, we investigate the origin of this specificity by performing extensive molecular dynamics (MD) simulations with enhanced free energy sampling to query the association trends of the two isoforms with both the Sec61 translocon and the ER membrane, which serves as a toxin reservoir prior to association. Our results suggest that mycolactone B (the cytotoxic isoform) has a stronger association with the ER membrane than mycolactone A due to more favorable interactions with membrane lipids and water molecules. This could increase the reservoir of toxin proximal to the Sec61 translocon. Isomer B also interacts more closely with the lumenal and lateral gates of the translocon, the dynamics of which are essential for protein translocation. These interactions induce a more closed conformation, which has been suggested to block signal peptide insertion and subsequent protein translocation. Collectively, these findings suggest that isomer B’s unique cytotoxicity is a consequence of both increased localization to the ER membrane and channel-locking association with the Sec61 translocon, facets that could be targeted in the development of Buruli Ulcer diagnostics and Sec61-targeted therapeutics.
Cardiomyocyte-specific deletion of PTP1B protects against HFD-induced cardiomyopathy through direct regulation of cardiac metabolic signaling
Authors: Sun Yan , Chanrasekhar Vasanth , Kessinger Chase W. , Tang Peiyang , Gao Yunan , Kamli-Salino Sarah , Nelson Katherine , Delibegovic Mirela , Abel E. Dale , Kontaridis Maria I.
Published: May 2023

Background

Heart failure is the number one cause of death worldwide and mortality is directly correlated with the high incidence of obesity and diabetes. Indeed, the epidemic phenomenon of obesity was projected to reach 50% in the US by the year 2030. However, the mechanisms linking metabolic dysfunction with heart disease are not clear. Protein Tyrosine Phosphatase 1B (PTP1B), a negative regulator of insulin signaling, is considered to be an emerging therapeutic target against the development of obesity, insulin resistance, and diabetes. Increased PTP1B levels and activity have been observed in brain, muscle and adipose tissues isolated from obese and/or diabetic animals, as well as in human obese human patients. Its role, however, and the mechanisms by which it modulates metabolic processes in the heart remain unknown.

Method and Results

We generated cardiomyocyte (CM)-specific PTP1B knock-out (PTP1Bfl/fl::ꭤMHCCre/+) mice to investigate the cardiomyocyte-specific role of PTP1B in response to high fat diet (HFD)-induced cardiac dysfunction. While we did not observe any physiological or functional cardiac differences at baseline, in response to HFD, we found that PTP1Bfl/fl::ꭤMHCCre/+mice were protected against development of cardiac hypertrophy, mitochondrial dysfunction, and diminished cardiac steatosis. Metabolomics data revealed that hearts with CM-specific deletion of PTP1B had increased fatty acid oxidation and NAD+metabolism, but reduced glucose metabolism; we further validated these findings by real-time qPCR analysis. Mechanistically, we identified a novel PTP1B PKM2-AMPK axis in the heart, which acts as a molecular switch to promote fatty acid oxidation. In this regard, we identified that hearts from PTP1Bfl/fl::ꭤMHCCre/+mice had upregulated levels of nicotinamide adenine dinucleotide (NAD+) and NAD phosphate (NADPH), leading to higher levels of nicotinamide phosphoribosyl transferase (NAMPT), the rate-limiting step of the NAD+salvage pathway and an enzyme associated with obesity and diabetes.

Conclusions

Together, these results suggest that CM-specific deletion of PTP1B mediates a substrate switch from glucose to fatty acid metabolism, protecting hearts against development of HFD-induced cardiac hypertrophy and dysfunction through mechanisms involving a novel PTP1B/PKM2/AMPK axis that is critical for the regulation of NAMPT and NAD+biosynthesis.
Protocol for Generation of a Patient-Reported Outcome Measure of Quality of Life in Heart Valve Disease: The VALVQ
Authors: Pons Ariel , Whalley Gillian , Jenkinson Crispin , Morley David , Coffey Sean
Published: May 2023

Background

There is an increasing prevalence of people worldwide with heart valve diseases (HVD), especially rheumatic heart disease, aortic stenosis, and mitral regurgitation, as well as people with a previous valve repair or replacement. Treatment decisions for HVD can be complex, making quality of life an important factor, but no questionnaire to measure quality of life across the lifespan of HVD exists. In this article, we describe the protocol for the development of such a questionnaire.

Methods and Results

The project will occur over four phases. First, people with HVD, family members and clinical experts will be interviewed to generate a list of questions (‘items’) that comprehensively describe participants’ quality of life. In the second phase, this will be formatted into a questionnaire that is pilot tested for functionality. In the third phase, items will be selected according to item distributions, factor analysis and rotation, and item response theory using the Graded Response Model to generate a final questionnaire containing only the best-performing items, which will then be tested for validity.

Validity assessments will be repeated after final questionnaire administration in a new sample in the fourth phase.

Conclusion

The article gives a template for development of a patient report outcome measure (PROM) in the health sciences. It is expected that the final questionnaire, called the VALVQ, will allow clinical trials to more sensitively assess quality of life changes across the spectrum and lifespan in HVD.
Carcinogenesis is associated with sex-biased tissue environments and imbalances between estrogen receptor alpha and thyroid hormone receptors
Authors: Zhang Feng , Deng Minghua
Published: May 2023

There is extensive evidence of sex differences in the susceptibility and prognosis of non-reproductive cancers. In addition to external factors, biological sex bias (e.g., sex chromosomes, hormones, and immune function) is suspected to function as a selective pressure that influences the evolutionary process of carcinogenesis. However, there remains a lack of clarity concerning the extent of the effect of sex bias on carcinogenesis, as well as the underlying mechanism. In this study, we show that tissue sex bias, correlated to gonadotropin-releasing hormone, varies among tissues and is associated with two distinct age-specific patterns of cancer incidence: parallel and nonparallel. Additionally, we reveal that imbalances in estrogen receptor alpha and thyroid hormone receptors are associated with levels of hypoxia-inducible factors, which have three phases (hypoxia, hyperoxia, and “chaotic-oxia”) that exist in most cancers and are linked to specific cancer subtypes, including cancers with microsatellites, the CpG island methylator phenotype, or hypermethylation. Our results suggest that sex-biased tissue environments and hormonal imbalances may influence the incidence pattern and direction of carcinogenesis, emphasizing the importance of maintaining hormonal homeostasis for cancer prevention and providing insights toward improving therapies for cancer types with hormonal imbalances.

Plain English summary

Sex bias has been long observed in cancer susceptibility and prognosis. Hormone difference between the two sexes was believed to play a role. However, the mechanism is still largely unknown. Our study has shown that the activity of one hormone secreted from pituitary, namely gonadotropin-releasing hormone, are correlated to sex-biased tissue environment, which was speculated to influence incidence patterns of carcinogenesis. Furthermore, hormonal imbalance, particularly imbalance in receptors of estrogen and thyroid hormone, which is associated with specific cancer subtypes, was speculated to influence the direction of carcinogenesis.

Highlights

There are two distinct patterns of cancer age-specific incidence curve between the two sexes: parallel and nonparallel.

The parallel and nonparallel patterns are associated with sex bias in tissue environments which is correlated with sex-biased activity of gonadotropin-releasing hormone.

Three sex-biased mutated genes:PTEN,PGM5andLARP4B, have tissue-specific hotspot mutations which are associated with microsatellite instability (MSI), and the proportion of MSI exhibit sex bias in stomach cancer.

Three hypoxia induce factors (HIFs) phases: hypoxia, hyperoxia, and “chaotic-oxia”, exist in most cancers and are linked to specific cancer subtypes, including cancers with MSI, the CpG island methylator phenotype, and hypermethylation.

The phases of HIFs are associated with imbalances between estrogen receptor alpha and thyroid hormone receptors.
Convergent mutations in phage virion assembly proteins enable evasion of Type I CBASS immunity
Authors: Richmond-Buccola Desmond , Hobbs Samuel J. , Garcia Jasmine M. , Toyoda Hunter , Gao Jingjing , Shao Sichen , Lee Amy S. Y. , Kranzusch Philip J.
Published: May 2023

CBASS is an anti-phage defense system that protects bacteria from phage infection and is evolutionarily related to human cGAS-STING immunity. cGAS-STING signaling is initiated by viral DNA but the stage of phage replication which activates bacterial CBASS remains unclear. Here we define the specificity of Type I CBASS immunity using a comprehensive analysis of 975 operon-phage pairings and show that Type I CBASS operons composed of distinct CD-NTases, and Cap effectors exhibit striking patterns of defense against dsDNA phages across five diverse viral families. We demonstrate that escaper phages evade CBASS immunity by acquiring mutations in structural genes encoding the prohead protease, capsid, and tail fiber proteins. Acquired CBASS resistance is highly operon-specific and typically does not affect overall fitness. However, we observe that some resistance mutations drastically alter phage infection kinetics. Our results define late-stage virus assembly as a critical determinant of CBASS immune activation and evasion by phages.
Upgraded D22 SEC–SANS setup dedicated to the biology community
Authors: Martel Anne , Cocho Cristina , Caporaletti Francesca , Jacques Mark , El Aazzouzi Abdelali , Lapeyre Franck , Porcar Lionel
Published: May 2023

Described here is the current status of the upgraded in situ size-exclusion chromatography (SEC) system implemented with the D22 small-angle neutron scattering (SANS) instrument at the Institut Laue–Langevin. Since its initial proof of principle in 2016, this SEC–SANS arrangement has been continuously requested by the user community, leading to the design of an upgraded version. A detailed description of the setup and its control is provided, and a few examples of protein structural investigations are presented, which will highlight the various possibilities and limitations of the setup to optimize experimental success.
Achieving popularity to attract more patients via free knowledge sharing in the online health community
Authors: Ouyang Peng , Liu Jiaming , Zhang Xiaofei
Published: May 2023

Purpose

Free knowledge sharing in the online health community has been widely documented. However, whether free knowledge sharing can help physicians accumulate popularity and further the accumulated popularity can help physicians attract patients remain unclear. To unveil these gaps, this study aims to examine how physicians' popularity are affected by their free knowledge sharing, how the relationship between free knowledge sharing and popularity is moderated by professional capital, and how the popularity finally impacts patients' attraction.

Design/methodology/approach

The authors collect a panel dataset from Hepatitis B within an online health community platform with 10,888 observations from April 2020 to August 2020. The authors develop a model that integrates free knowledge sharing, popularity, professional capital, and patients' attraction. The hierarchical regression model is used to for examining the impact of free knowledge sharing on physicians' popularity and further investigating the impact of popularity on patients' attraction.

Findings

The authors find that the quantity of articles acted as the heuristic cue and the quality of articles acted as the systematic cue have positive effect on physicians' popularity, and this effect is strengthened by physicians' professional capital. Furthermore, physicians' popularity positively influences their patients' attraction.

Originality/value

This study reveals the aggregation of physicians' popularity and patients' attraction within online health communities and provides practical implications for managers in online health communities.
The choice of destination country of international franchise networks: the case of Mexican franchisors
Authors: Flores Villanueva Cesario Armando , Gaytán Ramírez María del Carmen , Núñez García Aleida
Published: May 2023

Purpose

This article examines the influence of market opportunity, risk, and distance on the choice of destination country for Mexican franchises.

Design/methodology/approach

The research hypotheses are developed under the theoretical approaches of institutional theory, agency theory, and transaction costs theory and were contrasted on the data obtained from 52 Mexican international franchisors operating in 37 countries as of 2016. This study uses linear regression with ordinary minimums using the STATA 13.1 software.

Findings

The results reveal that a larger market size, a greater level of economic freedom, and a smaller geographic distance are determining factors in the choice of destination country. No statistical significance was found in the variables GDP per capita, level of democracy and cultural distance.

Originality/value

This research contributes to the theoretical and practical field. On the theoretical side, this study integrates institutional theory, agency theory, and transaction cost theory to evaluate the factors of the destination country that influence the internationalization process of the franchise. Another contribution of this study is to apply theories and models of developed economies to the process of internationalization of franchises in an emerging economy. Additionally, this study is based on a model that considers the distance, opportunities and risks that are considered by Mexican franchisors in the selection of the international markets in which they maintain operations. This study contains important practical implications that can serve as relevant information for decision-making in the franchise sector and its internationalization. This data is valuable for new models of Mexican franchises that decide to start their internationalization process.
Connection between corporate diversification, CSR and firm performance in South Asia
Authors: Shira Ruba Khalid
Published: May 2023

Purpose

The manufacturing sector plays an important role in any economy. The sector opts for diversification techniques and CSR initiatives in a competitive business environment for growth, survival and reputation. This study examined the impact of corporate diversification and CSR on the financial performance of South Asian manufacturing firms.

Design/methodology/approach

Data is obtained from the financial statements of 350 listed South Asian manufacturing firms as well as the respective stock exchanges of these countries. The data for research analysis ranges from 2010 to 2020. Diversification is measured using product diversification and geographic diversification. CSR is quantified in terms of social contribution value. Accounting measurements (ROA and ROE) are also used to capture corporate performance. For hypothesis testing, the study also uses fixed effect panel regression, and for assessing the robustness of the findings, the two-step dynamic panel system-GMM regression approach is used.

Findings

Findings of study indicate a positive impact of product and geographic diversification on financial performance measured with ROA. However, geographic diversification is insignificantly linked with ROA and ROE. Further, CSR positively impacts the performance of firms in South Asia with both performance measures.

Originality/value

The study has several policy implications based on the findings, including the need for the manufacturing sector to practice and implement appropriate diversification approaches and CSR initiatives to improve its financial performance and reputation.
Purchase intention of organic foods from the perspective of consumers
Authors: Eberle Luciene , Milan Gabriel Sperandio , Graciola Ana Paula , Borchardt Miriam , Pereira Giancarlo Medeiros
Published: May 2023

Purpose

The present research had the objectives of proposing, testing and validating a theoretical model that includes ecological awareness, healthy consumption, consumer attitude and price awareness as determinants of the purchase intention of organic foods and analyzing the moderating effect of gender, educational level and income of families in the relationship between price awareness and purchase intention.

Design/methodology/approach

A survey research was implemented with 382 Brazilians who consume organic foods from a non-probabilistic sample for convenience. For data analysis, structural equation modeling was used to test the proposed theoretical model and its respective relationships.

Findings

The results showed that ecological awareness, healthy consumption, consumer attitude and price awareness are determinants of the purchase intention of organic foods 79.1% of the variance of purchase intention of organic foods could be explained by such determinants. Another relevant result is that gender and family income has a positive moderating effect on the relationship between price awareness and the intention to purchase organic food.

Originality/value

Environmental problems and their adverse impacts on humans have become an important issue to be analyzed by academics (researchers), governments and organizations, and their managers, especially when organic foods are considered.