Miracle-dz/UniFAR-FTUs huggingface dataset:
NOX4 links metabolic regulation in pancreatic cancer to endoplasmic reticulum redox vulnerability and dependence on PRDX4

Reductive power in the cytosol of pancreatic cancer cells drives a dependency on the endoplasmic reticulum protein PRDX4. There is an urgent need to identify vulnerabilities in pancreatic ductal adenocarcinoma (PDAC). PDAC cells acquire metabolic changes that augment NADPH production and cytosolic redox homeostasis. Here, we show that high NADPH levels drive activity of NADPH oxidase 4 (NOX4) expressed in the endoplasmic reticulum (ER) membrane. NOX4 produces H2O2 metabolized by peroxiredoxin 4 (PRDX4) in the ER lumen. Using functional genomics and subsequent in vitro and in vivo validations, we find that PDAC cell lines with high NADPH levels are dependent on PRDX4 for their growth and survival. PRDX4 addiction is associated with increased reactive oxygen species, a DNA-PKcs–governed DNA damage response and radiosensitivity, which can be rescued by depletion of NOX4 or NADPH. Hence, this study has identified NOX4 as a protein that paradoxically converts the reducing power of the cytosol to an ER-specific oxidative stress vulnerability in PDAC that may be therapeutically exploited by targeting PRDX4.
Genetic Analysis of Methyl Anthranilate, Mesifurane, Linalool and Other Flavor Compounds in Cultivated Strawberry (Fragaria ×ananassa)

The cultivated strawberry (Fragaria ×ananassa) is an economically important fruit crop that is intensively bred for improved sensory qualities. The diversity of fruit flavors and aromas in strawberry result mainly from the interactions of sugars, acids, and volatile organic compounds (VOCs) that are derived from diverse biochemical pathways influenced by the expression of many genes. This study integrates multi-omics analyses to identify QTL and candidate genes for multiple aroma compounds in a complex strawberry breeding population. Novel fruit volatile QTL were discovered for methyl anthranilate, methyl 2-hexenoate, methyl 2-methylbutyrate, mesifurane, and a shared QTL on Chr 3 was found for nine monoterpene and sesquiterpene compounds, including linalool, 3-carene, β-phellandrene, α-limonene, linalool oxide, nerolidol, α-caryophellene, α-farnesene, and β-farnesene. Fruit transcriptomes from a subset of sixty-four individuals were used to support candidate gene identification. For methyl esters including the grape-like methyl anthranilate, a novel ANTHANILIC ACID METHYL TRANSFERASE–like gene was identified. Two mesifurane QTL correspond with the known biosynthesis gene O-METHYL TRANSFERASE 1 and a novel FURANEOL GLUCOSYLTRANSFERASE. The shared terpene QTL contains multiple fruit-expressed terpenoid pathway-related genes including NEROLIDOL SYNTHASE 1 (FanNES1). The abundance of linalool and other monoterpenes is partially governed by a co-segregating expression-QTL (eQTL) for FanNES1 transcript variation, and there is additional evidence for quantitative effects from other terpenoid-pathway genes in this narrow genomic region. These QTL present new opportunities in breeding for improved flavor in commercial strawberry.
The Marine Gastropod Crepidula fornicata Remains Resilient to Ocean Acidification Across Two Life History Stages

Rising atmospheric CO2 reduces seawater pH causing ocean acidification (OA). Understanding how resilient marine organisms respond to OA may help predict how community dynamics will shift as CO2 continues rising. The common slipper shell snail Crepidula fornicata is a resilient marine gastropod native to eastern North America, which has been a successful invader along the western European coastline and elsewhere. To examine its potential resilience to OA, we conducted two controlled laboratory experiments. First, we examined several phenotypes and genome-wide gene expression of C. fornicata in response to pH treatments (7.5, 7.6, 8.0) throughout the larval stage and then tested how conditions experienced as larvae influenced juvenile stages (i.e. carryover effects). Second, we examined genome-wide gene expression patterns of C. fornicata larvae in response to acute (4, 10, 24 and 48 hours) pH treatment (7.5, 8.0). Both C. fornicata larvae and juveniles exhibited resilience to OA and gene expression responses highlight the role of transcriptome plasticity in OA resilience. Larvae did not exhibit reduced growth under OA until they were at least 4 days old. These phenotypic effects were preceded by broad transcriptomic changes, which likely serve as an acclimation mechanism for combating reduced pH conditions frequently experienced in littoral zones. Delayed metamorphosis was observed for larvae reared at reduced pH. Although juvenile size reflected larval rearing pH conditions, no carryover effects in juvenile growth rates were observed. Transcriptomic analyses suggest increased metabolism under OA, which may indicate compensation in reduced pH environments. Time course transcriptomic analyses suggest energetic burdens experienced under OA eventually dissipate, allowing C. fornicata to reduce metabolic demands and acclimate to reduced pH. This study highlights the importance of assessing the effects of OA across life history stages and demonstrates how transcriptomic plasticity can allow highly resilient organisms, like C. fornicata, acclimate to reduced pH environments.
Review of Five-Level Front-End Converters for Renewable-Energy Applications

With the objective of minimizing environment and energy issues, distributed renewable-energy sources have reached remarkable advancements along the last decades, with special emphasis on wind and solar photovoltaic installations, which are deemed as the future of power generation in modern power systems. The integration of renewable-energy sources into the power system requires the use of advanced power electronic converters, representing a challenge within the paradigm of smart grids, e.g., to improve efficiency, to obtain high power density, to guarantee fault tolerance, to reduce the control complexity, and to mitigate power-quality problems. This paper presents a specific review about front-end converters for renewable-energy applications (more specifically the power inverter that interfaces the renewable-energy source with the power grid). It is important to note that the objective of this paper is not to cover all types of front-end converters; the focus is only on single-phase multilevel structures limited to five voltage levels, based on a voltage-source arrangement and allowing current or voltage feedback control. The established review is presented considering the following main classifications: (a) number of passive and active power semiconductors; (b) fault tolerance features; (c) control complexity; (d) requirements of specific passive components as capacitor or inductors; and (e) number of independent or split dc-link voltages. Throughout the paper, several specific five-level front-end topologies are presented and comparisons are made between them, highlighting the pros and cons of each one of them as a candidate for the interface of renewable-energy sources with the power grid.
Systemic benefits of Gc inhibition to preserve insulin sensitivity

Type 2 diabetes is caused by an imbalanced supply and demand of insulin. Insulin resistance and impaired β-cell function contribute to the onset of hyperglycemia. No single treatment modality can affect both aspects of diabetes pathophysiology. Thus, current treatments focus either on increasing insulin secretion (incretin mimetics, sulfonylureas) or insulin sensitivity (metformin and TZD), or reducing hyperglycemia (insulin, sglt2i). Previously, we reported that ablation of Gc, encoding a secreted protein with a primary role in vitamin D transport, improves pancreatic β-cell function in models of diet-induced insulin resistance. Here, we show that Gc ablation has systemic insulin-sensitizing effects to prevent weight gain, hyperglycemia, glucose intolerance, and lower NEFA and triglyceride in mice fed a high-fat diet. Hyperinsulinemic-euglycemic clamps show that Gc ablation protects insulin’s ability to reduce hepatic glucose production, and increases glucose uptake in skeletal muscle and adipose tissue. Moreover, acute Gc inhibition by way of adeno-associated virus encoding a short hairpin RNA to promote Gc mRNA degradation, prevents glucose intolerance caused by high fat feeding. The data suggest that Gc inhibition can provide an approach to increase insulin production in β-cells, and insulin action in peripheral tissues. RESEARCH IN CONTEXT ▪ The goal was to find a therapeutic target that can improve insulin sensitivity and β-cell function simultaneously. ▪ Gc ablation preserves β-cell insulin secretion ex vivo and in vivo. ▪ Deletion of Gc prevents weight gain, reduces fat mass, lowers fasting glycemia, improves glucose tolerance, reduces hepatic glucose production after feeding, and increased glucose uptake in muscle and adipose. ▪ Acute Gc inhibition improves glucose tolerance, which suggests that targeting Gc could provide an alternative way to treat type 2 diabetes.
The Enhanced Pharmacological Effects of Modified Traditional Chinese Medicine in Attenuation of Atherosclerosis Is Driven by Modulation of Gut Microbiota

Accumulating evidence indicated that gut microbiota-targeted therapy is a promising strategy to treat Cardiovascular Disease (CVD). Traditional Chinese Medicine (TCM) has been used in CVD treatments for over 2,000 years which is believed to result from the modulation of gut microbiota, yet the underlying mechanism remains elusive. According to the theoretical system of TCM, we developed an innovative formula of TCM named “TongMai ZhuYu (TMZY)” on top of one classic Chinese herbal formula [“XueFu ZhuYu (XFZY)”], which can more effectively alleviate CVD in the clinical practice. Here, we first systematically assessed the pharmacological effects of TMZY, XFZY, and atorvastatin on atherosclerosis (AS) induced by high-fat diet (HFD) in rats. TMZY typically outperformed others in alleviating AS rats by characterization of pathological morphology, immunohistochemistry, inflammatory cytokines. Remarkably, combining this modified TCM formula (TMZY) with atorvastatin can further help the alleviation of AS in rats by suppressing immune and inflammatory responses. Furthermore, to test whether TMZY alleviated AS symptoms by altering gut microbial compositions (dysbiosis), we employed 16S amplicon sequencing to investigate gut microbiota changes in the AS mice induced by high choline diet (HCD) using both TMZY and XFZY under antibiotic-treated and untreated conditions. TCM formulas induced consistent and remarkable changes in the phenotypes and microbiota in the HCD mice. TMZY modulated more changes in the gut microbiota to improve diseased phenotypes than XFZY. Notably, the TMZY-intervention effect on CVD in mice attenuated after the suppression of gut microbial activity by antibiotics. Collectively, we demonstrated that TCM herbals could effectively modulate the gut microbiota as a mechanism for altering the pathogenesis of cardiovascular disorders in mice/rats.
Phylogeographic analysis of shrubby beardtongues reveals range expansions during the Last Glacial Maximum and implicates the Klamath Mountains as a hotspot for hybridization

Quaternary glacial cycles often altered species’ geographic distributions, which in turn altered the geographic structure of a species’ genetic diversity. In many cases, glacial expansion forced species in temperate climates to contract their ranges and reside in small pockets of suitable habitat (refugia), where they were likely to interact closely with other species, setting the stage for potential gene exchange. These introgression events, in turn, would have degraded species boundaries, making the inference of phylogenetic relationships challenging. Using high-throughput sequence data, we employ a combination of species distribution models, models of demographic history, and hybridization tests to assess the effect of glaciation on the geographic distributions, phylogenetic relationships, and patterns of gene flow of five species of Penstemon subgenus Dasanthera, long-lived shrubby angiosperms distributed throughout the Pacific Northwest of North America. Surprisingly, we find that rather than reducing their ranges to small refugia, most Penstemon subgenus Dasanthera species experienced increases in suitable habitat during the Last Glacial Maximum. We also find substantial evidence for gene exchange between species, with the bulk of introgression events occurring in or near the Klamath Mountains of southwestern Oregon and northwestern California. Subsequently, our phylogenetic inference reveals blurred taxonomic boundaries in the Klamath Mountains, where introgression is most prevalent. Our results question the classical paradigm of temperate species’ responses to glaciation, and highlight the importance of contextualizing phylogenetic inference with the demographic histories of the species of interest.
TMEM41B is a pan-flavivirus host factor

Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication cycle. Our mechanistic studies on TMEM41B revealed that all members of the Flaviviridae family that we tested require TMEM41B. We tested 12 additional virus families and found that SARS-CoV-2 of the Coronaviridae also required TMEM41B for infection. Remarkably, single nucleotide polymorphisms (SNPs) present at nearly twenty percent in East Asian populations reduce flavivirus infection. Based on our mechanistic studies we hypothesize that TMEM41B is recruited to flavivirus RNA replication complexes to facilitate membrane curvature, which creates a protected environment for viral genome replication. HIGHLIGHTS TMEM41B and VMP1 are required for both autophagy and flavivirus infection, however, autophagy is not required for flavivirus infection. TMEM41B associates with viral proteins and likely facilitates membrane remodeling to establish viral RNA replication complexes. TMEM41B single nucleotide polymorphisms (SNPs) present at nearly twenty percent in East Asian populations reduce flavivirus infection. TMEM41B-deficient cells display an exaggerated innate immune response upon high multiplicity flavivirus infection.
Uncertainty is maintained and used in working memory

What are the contents of working memory? In both behavioral and neural computational models, the working memory representation of a stimulus is typically described by a single number, namely a point estimate of that stimulus. Here, we asked if people also maintain the uncertainty associated with a memory, and if people use this uncertainty in subsequent decisions. We collected data in a two-condition orientation change detection task; while both conditions measured whether people used memory uncertainty, only one required maintaining it. For each condition, we compared an optimal Bayesian observer model, in which the observer uses an accurate representation of uncertainty in their decision, to one in which the observer does not. We find that this “Use Uncertainty” model fits better for all participants in both conditions. In the first condition, this result suggests that people use uncertainty optimally in a working memory task when that uncertainty information is available at the time of decision, confirming earlier results. Critically, the results of the second condition suggest that this uncertainty information was maintained in working memory. We test model variants and find that our conclusions do not depend on our assumptions about the observer’s encoding process, inference process, or decision rule. Our results provide evidence that people have uncertainty that reflects their memory precision at an item-specific level, maintain this information over a working memory delay, and use it implicitly in a way consistent with an optimal observer. These results challenge existing computational models of working memory to update their frameworks to represent uncertainty.
Increased light availability enhances tolerance against ocean acidification stress in Halimeda opuntia

Although the adverse impacts of ocean acidification (OA) on marine calcifiers have been investigated substantially, the anti-stress abilities regulated by increased light availability are unclear. Herein, the interactive effects of three light levels combined with two pCO2 concentrations on the physiological acclimation of the calcifying macroalga Halimeda opuntia were investigated using a pCO2–light coupling experiment. The results indicate that OA exhibits an adverse role in influencing algal growth, calcification, photosynthesis and other physiological performances in H. opuntia. The relative growth rate in elevated pCO2 significantly declined by 13.14%–41.29%, while net calcification rates decreased by nearly three-fold under OA. Notably, increased light availability could enhance stress resistance by the accumulation of soluble organic molecules, especially soluble carbohydrate, soluble protein and free amino acids, and in combination with metabolic enzyme-driven activities alleviated OA stress. Carotenoid content in low light conditions accumulated remarkably and rapid light curves for relative electron transport rate was significantly enhanced by increasing light intensities, indicating that this new organization of the photosynthetic machinery in H. opuntia accommodated light variations and elevated pCO2 conditions. Taken together, the results describe stress resistance by the enhancement of metabolic performance in marine calcifiers to mitigate OA stress. One sentence summary Increased light availability enhances stress resistance in Halimeda opuntia by the accumulation of soluble organic molecules and enzyme-driven activities to alleviate ocean acidification stress. Credit authorship contribution statement Fangfang Yang and Lijuan Long conceived and designed the experiments. Zhangliang Wei performed the experiments and wrote the paper. Yuanzi Huo analyzed the data, while Chao Long and Yating Zhang contributed materials and analysis tools. Lijuan Long agrees to serve as the author responsible for contact and communication. Highlights Elevated pCO2 adversely affects the physiological performance of Halimeda. Moderately high light increases soluble organic molecules and enzymatic-driven activities. Increased light availability enables H. opuntia to alleviate the negative effects of ocean acidification.
The coevolution of mammae number and litter size

Mammals are unique in provisioning their offspring with milk, lactiferous nourishment produced in glandular organs called mammae. Mammae number is hypothesized to coevolve with litter size, acting as a constraint on offspring survival. However, predicted canonical relations between mammae number and litter size (i.e., the ‘one-half’ and ‘identity’ rules) are untested across Mammalia. Here we analyze data for 2,301 species and show how these characters coevolve. In Mammalia, mammae number approximates the maximum reported litter size of a species, and mammae number explains more variation in litter size than other species-level traits (mass, gestation length, diet, and seasonality of contemporary geographic distribution). Clades show differences in these patterns, indicating that certain life history strategies might break the ‘rules’ of mammary evolution. Mammae number is an underappreciated constraint on fecundity that has influenced the radiation of mammals.
Exploration of Susceptible Genes with Clustered Regularly Interspaced Short Palindromic Repeats–Tissue-Specific Knockout (CRISPR-TSKO) to Enhance Host Resistance

Abstract Susceptible (S) genes are those plant genes that facilitate pathogen infection and disease. The loss of function of these genes primarily interrupts the growth and development of invading pathogens and thus makes plants resistant. The S-gene-targeted resistance may produce durable immunity in plants. Because, S gene-based resistance is derived from the inactivation of a host factor required for the survival of a pathogen in the host. To bypass the S gene-based resistance, a parasitic pathogen must evolve and develop the same or similar functions provided naturally by its host factors, which is far more difficult or even may be impossible. However, it is critical to identify and target the appropriate S gene(s) aiming to gain resistant capacity against a particular disease, because S genes may be pathogen-specific in many cases. The clustered regularly interspaced short palindromic repeats (CRISPR) technology has shown great potential in manipulating S genes in plants. The CRISPR-TSKO (CRISPR-based tissue-specific knock-out) tool kit can provide an understanding of the exact function of an individual gene in a tissue and developmental stage-specific manner while also producing a heritable mutant allele. In this review, candidate S genes have been summarized for CRISPR-TSKO mediated tissue-specific gene knockdown to enhance host resistance.
The China Miracle in a technological and socio-political framework—The role of institutions

ABSTRACT China’s economy has grown at an average annual rate of around 9.5% in the past four decades, which is often hailed as the China Miracle. This paper proposes a new theoretical model to analyse the causes of China’s phenomenal growth in a technological and socio-political framework. In our new framework, the contemporary technology (T) determines what an economy can achieve; the objective (O) of the society has a fundamental impact on its economic growth; the performance (P) in implementing the social objective largely determines the growth rate of the economy; and the stability (S) of the society determines the sustainability of the economic growth. China’s institutions have played key roles in the TOPS framework to initiate and sustain China’s rapid growth in the past four decades. Socio-political changes caused by economic growth might affect the capacity of these institutions to promote economic growth in future.
Adherent Intestinal Cells From Atlantic Salmon Show Phagocytic Ability and Express Macrophage-Specific Genes

Our knowledge of the intestinal immune system of fish is rather limited compared to mammals. Very little is known about the immune cells including the phagocytic cells in fish intestine. Hence, employing imaging flow cytometry and RNA sequencing, we studied adherent cells isolated from healthy Atlantic salmon. Phagocytic activity and selected gene expression of adherent cells from the distal intestine (adherent intestinal cells, or AIC) were compared with those from head kidney (adherent kidney cells, or AKC). Phagocytic activity of the two cell types was assessed based on the uptake of Escherichia coli BioParticlesTM. AIC showed phagocytic ability but the phagocytes were of different morphology compared to AKC. Transcriptomic analysis revealed that AIC expressed genes associated with macrophages, T cells, and endothelial cells. Heatmap analysis of selected genes indicated that the adherent cells from the two organs had apparently higher expression of macrophage-related genes. We believe that the adherent intestinal cells have phagocytic characteristics and high expression of genes commonly associated with macrophages. We envisage the possibilities for future studies on enriched populations of adherent intestinal cells.