bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic interaction betweenGL15andFDL1modulates juvenile cuticle deposition and leaf permeability in maize
Authors: Castorina Giulia , Domergue Frédéric , Consonni Gabriella 
Published: October 2024

AbstractThe plant cuticle is a hydrophobic layer that serves as the primary barrier between plant surfaces and the external environment, limiting water loss and protecting against various stresses. This study investigates the genetic interaction between the maizeZmFDL1andZmGL15genes and their role in modulating juvenile cuticle deposition and leaf permeability. The research was undertaken to understand how these genes influence cuticle composition and structure, which are crucial for plant protection against environmental stresses such as drought. We analysed the chemical composition of cutin and waxes, as well as cuticle-dependent leaf permeability. Our findings reveal that ZmFDL1 and ZmGL15 individually and synergically regulate the deposition of cuticular components, with significant impacts on leaf permeability. Thegl15-Smutant exhibited an adult-like cuticle with higher cutin and lower wax contents, leading to reduced leaf permeability and improved water retention under drought conditions. These results highlight the importance of cutin in forming an effective water barrier and suggest that modulating cuticle composition with enhanced cutin content could be a strategy for improving drought tolerance in crops. This study provides new insights into the genetic regulation of cuticle biosynthesis and its relevance for plant adaptation to water scarcity.HighlightZmFDL1 and ZmGL15 interact to modulate cuticle composition and reduce leaf water loss.ZmFDL1andZmGL15genes regulate juvenile cuticle deposition in maize.Thegl15-Smutant shows an adult-like cuticle with higher cutin and lower wax contents.Thegl15-Smutation is epistatic tofdl1-1, partially rescuing the defectivefdl1cuticle phenotype.The cuticle composition ingl15-Smutants leads to reduced leaf permeability and improved water retention under drought conditions.Cuticular layer with enhanced cutin content could improve drought tolerance in crops.
Scale invariance of mechanical properties in the developing mammalian retina
Authors: Shelton Elijah Robinson , Frischmann Michael , Brinkop Achim Theo , James Rebecca Marie , Serwane Friedhelm 
Published: October 2024

AbstractNeuronal tissues, like the retina, form through physical forces which induce remodeling over a range of time and length scales. How these mechanical stresses accumulate and relax during retinogenesis is unknown due to the difficulty in applying stressin situfrom seconds to hours in living neuronal tissue. In non-neuronal tissue and 2D cell culture, previous studies have revealed that material properties exhibit scale-free behavior. Whether this translates to developing neuronal tissues has remained an open question.Here we demonstrate the existence of scale-free rheology in 3D neuronal tissue. We probed time-dependent tissue mechanics in anin vitromodel of the developing retina using magnetic droplets in mouse stem cell-derived retina organoids. We recorded strain responses to an applied stress across four orders of magnitude in time, up to one hour. Dynamic creep compliance and tensile moduli followed a power law with an exponent consistent with a material just above the glass transition. Our findings demonstrate that neuronal tissue remodels in a scale-free manner, prompting the question of whether scale-invariant mechanical properties are a general motif of neurodevelopment.
The effective multiplicity of infection for HCMV depends on activity of the cellular 20S proteasome
Authors: Cataldo Katie M. , Roche Kathryn L. , Monti Christopher E. , Dash Ranjan K. , Murphy Eain A. , Terhune Scott S. 
Published: October 2024

ABSTRACTHuman cytomegalovirus (HCMV) is a betaherpesvirus capable of infecting numerous cell types and persisting throughout an infected individual’s life. Disease usually occurs in individuals with compromised or underdeveloped immune systems. Several antivirals exist but have limitations relating to toxicity and resistance. HCMV replication involves upregulation of host proteasomal activities which play important roles in the temporal stages of replication. Here, we defined the impact on replication kinetics of the proteasome inhibitor, bortezomib. We demonstrate that bortezomib significantly reduces levels of viral genomes and infectious virions produced from a population of cells. Inhibition reduced expression of viral proteins that are influenced by genome synthesis. When added prior to 24 hpi, we observe decreases in PCNA and Cdk1 while increases in p21 whose regulations contribute to efficient replication. This response synergized with an antiviral, maribavir. Since some replication occurred, we tested the hypothesis that a subset of infected cells might break through inhibition. Initially, we simulated bortezomib activities using a mechanistic computational model of late-lytic replication. Upon reducing MOIin-silico, we observed near identical simulated results compared to experimental data. Next, we analyzed replication using live-cell imaging. This revealed treated cultures do contain a population of cells with fully developed late-stage cytoplasmic assembly compartments but at significantly lower numbers. We refer to this as the effective MOI. Overall, our studies support a hypothesis in which 20S proteasome inhibition disrupts HCMV replication by reducing the MOI to an effective MOI, defined by a fraction of infected cells capable of progressing to fulminant infection.IMPORTANCEHCMV infection and reactivation continues to contribute to morbidity and mortality around the world. Antiviral compounds are available but have limitations. Here, we have defined the impact of the proteasome inhibitor bortezomib on HCMV replication. Proteasomal activities play a critical role in temporal changes required for replication. We demonstrate that disrupting these activities inhibits viral replication while likely supporting increased antiviral activity of the anti-HCMV agent, maribavir. Using a combination of live cell imaging and computational tools, we discover that a subset of infected cells progresses to fulminant infection which we define as the effective MOI, and this subset would otherwise be missed when analyzing the average of the population.
Blood pressure variability compromises vascular function in middle-aged mice
Authors: Mendiola Perenkita J. , O’Herron Philip , Xie Kun , Brands Michael W. , Bush Weston , Patterson Rachel E. , Di Stefano Valeria , Filosa Jessica A. 
Published: October 2024

ABSTRACTBlood pressure variability (BPV) has emerged as a novel risk factor for cognitive decline and dementia, independent of alterations in average blood pressure (BP). However, the underlying consequences of large BP fluctuations on the neurovascular complex are unknown. We developed a novel mouse model of BPV in middle-aged mice based on intermittent Angiotensin II infusions. Using radio telemetry, we demonstrated that the 24-hr BP averages of these mice were similar to controls, indicating BPV without hypertension. Chronic (20-25 days) BPV led to a blunted bradycardic response and cognitive deficits. Two-photon imaging of parenchymal arterioles showed enhanced pressure-evoked constrictions (myogenic response) in BPV mice. Sensory stimulus-evoked dilations (neurovascular coupling) were greater at higher BP levels in control mice, but this pressure-dependence was lost in BPV mice. Our findings support the notion that large BP variations impair vascular function at the neurovascular complex and contribute to cognitive decline.
The relationship between health literacy and adherence to physical activity guidelines: a scoping review
Authors: Lawrence Alex , Wardle Jon , Yoxall Jacqui Susan 
Published: October 2024

AbstractObjectiveTo examine the relationship between health literacy and adherence to physical activity guidelines.MethodsIn line with the Joanna Briggs Institute framework, we conducted a scoping review of the literature.ResultsOut of 2,098 articles identified, 19 met the inclusion criteria. The studies utilised various health literacy measurement tools, with the European Health Literacy Survey being used the most. Fifteen studies examined the association between total health literacy scores and achieving >150 minutes of moderate-to-vigorous physical activity weekly. Nine studies reported a positive association, while others found no significant association. In particular, studies using self-reported physical activity more frequently found an association, whereas no association was found when using objective physical activity measures.ConclusionsThe findings of this review were inconclusive. The lack of standard health literacy instruments and reporting presents a barrier to the field of knowledge progressing. Moreover, longitudinal relationships between health literacy, mediators and physical activity need to be investigated.
Structural basis for a dual-function type II-B CRISPR-Cas9
Authors: Hibshman Grace N. , Taylor David W. 
Published: October 2024

AbstractCas9 fromStreptococcus pyogenes(SpCas9) revolutionized genome editing by enabling programmable DNA cleavage guided by an RNA. However, SpCas9 tolerates mismatches in the DNA-RNA duplex, which can lead to deleterious off-target editing. Here, we reveal that Cas9 fromFrancisella novicida(FnCas9) possesses a unique structural feature—the REC3 clamp—that underlies its intrinsic high-fidelity DNA targeting. Through kinetic and structural analyses, we show that the REC3 clamp forms critical contacts with the PAM-distal region of the R-loop, thereby imposing a novel checkpoint during enzyme activation. Notably,F. novicidaencodes a non-canonical small CRISPR-associated RNA (scaRNA) that enables FnCas9 to repress an endogenous bacterial lipoprotein gene, subverting host immune detection. Structures of FnCas9 with scaRNA illustrate how partial R-loop complementarity hinders REC3 clamp docking and prevents cleavage in favor of transcriptional repression. The REC3 clamp is conserved in type II-B CRISPR-Cas9 systems, pointing to a potential path for engineering precise genome editors or developing novel antibacterial strategies. These findings reveal the dual mechanisms of high specificity and virulence by FnCas9, with broad implications for biotechnology and therapeutic development.Graphical Abstract
HuR-dependent expression of RyR2 contributes to calcium-mediated thermogenesis in brown adipocytes
Authors: Guarnieri Adrienne R. , Anthony Sarah R. , Acharya Pooja , Wen Bo Yao , Lanzillotta Lindsey , Gavin Rylie , Tranter Michael 
Published: October 2024

AbstractSeveral uncoupling protein 1 (UCP1)-independent thermogenic pathways have been described in thermogenic adipose tissue, including calcium-mediated thermogenesis in beige adipocytes via sarco/endoplasmic reticulum ATPase (SERCA). We have previously shown that adipocyte-specific deletion of the RNA binding protein human antigen R (HuR) results in thermogenic dysfunction independent of UCP1 expression. RNA sequencing revealed the downregulation of several genes involved in calcium ion transport upon HuR deletion. The goal of this work was to define the HuR-dependent mechanisms of calcium driven thermogenesis in brown adipocytes.We generated (BAT)-specific HuR-deletion (BAT-HuR-/-) mice and show that their body weight, glucose tolerance, brown and white adipose tissue weights, and total lipid droplet size were not significantly different compared to wild-type. Similar to our initial findings in Adipo-HuR-/-mice, mice with BAT-specific HuR deletion are cold intolerant following acute thermal challenge at 4°C, demonstrating specificity of acute HuR-dependent thermogenesis to BAT. We also found decreased expression of ryanodine receptor 2 (RyR2), but no changes in RyR2, SERCA1, SERCA2, or UCP1 expression, in BAT from BAT-HuR-/-mice. Next, we used Fluo-4 calcium indicator dye to show that genetic deletion or pharmacological inhibition of HuR blunts the increase in cytosolic calcium concentration in SVF-derived primary brown adipocytes. Moreover, we saw a similar blunting in β-adrenergic-mediated heat generation, as assessed by ERtherm AC fluorescence, in SVF-derived brown adipocytes following HuR inhibition or deletion. Mechanistically, we show that HuR directly binds and reduces the decay rate of RyR2 mRNA in brown adipocytes, and stabilization of RyR2 via S107 rescues β-adrenergic-mediated cytosolic calcium increase and heat generation in HuR deficient brown adipocytes.In conclusion, our results suggest that HuR-dependent control of RyR2 expression plays a significant role in the thermogenic function of brown adipose tissue through modulation of SR calcium cycling.
ALS-associated RNA binding proteins converge onUNC13Atranscription through regulation of REST
Authors: Watanabe Yasuaki , Suzuki Naoki , Nakagawa Tadashi , Hosogane Masaki , Akiyama Tetsuya , Warita Hitoshi , Aoki Masashi , Nakayama Keiko 
Published: October 2024

AbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Although multiple pathophysiological mechanisms have been identified, a unified molecular basis for ALS has remained elusive. The ALS-associated RNA binding protein (RBP) TDP-43 has previously been shown to stabilizeUNC13AmRNA by preventing cryptic exon inclusion. We here show that three ALS-associated RBPs—MATR3, FUS, and hnRNPA1—regulateUNC13Aexpression by targeting the silencing transcription factor REST. These three RBPs bind to and downregulateRESTmRNA and thereby promoteUNC13Atranscription. REST overexpression was detected not only in response to the loss of each of these three RBPs in cultured cells but also in motor neurons of individuals with familial or sporadic ALS. The functional convergence of four RBPs on the regulation ofUNC13A, a gene essential for synaptic transmission, highlights a pivotal contribution of these proteins to maitainance of synaptic integrity. Our findings thus provide key insight into ALS pathogenesis and a basis for the development of new therapeutic agents.
Extreme precipitation, exacerbated by anthropogenic climate change, drove Peru’s record-breaking 2023 dengue outbreak
Authors: Harris Mallory J. , Trok Jared T. , Martel Kevin S. , Borbor Cordova Mercy J. , Diffenbaugh Noah S. , Munayco César V. , Lescano Andrés G. , Mordecai Erin A. 
Published: October 2024

AbstractAnthropogenic forcing is increasing the likelihood and severity of certain extreme weather events, which may catalyze outbreaks of climate-sensitive infectious diseases. Extreme precipitation events can promote the spread of mosquito-borne illnesses by creating vector habitat, destroying infrastructure, and impeding vector control. Here, we focus on Cyclone Yaku, which caused heavy rainfall in northwestern Peru from March 7th - 20th, 2023 and was followed by the worst dengue outbreak in Peru’s history. We apply generalized synthetic control methods to account for baseline climate variation and unobserved confounders when estimating the causal effect of Cyclone Yaku on dengue cases across the 56 districts with the greatest precipitation anomalies. We estimate that 67 (95% CI: 30 - 87) % of cases in cyclone-affected districts were attributable to Cyclone Yaku. The cyclone significantly increased cases for over six months, causing 38,209 (95% CI: 17,454 - 49,928) out of 57,246 cases. The largest increases in dengue incidence due to Cyclone Yaku occurred in districts with a large share of low-quality roofs and walls in residences, greater flood risk, and warmer temperatures above 24°C. Analyzing an ensemble of climate model simulations, we found that extremely intense March precipitation in northwestern Peru is 42% more likely in the current era compared to a preindustrial baseline due to climate forcing. In sum, extreme precipitation like that associated with Cyclone Yaku has become more likely with climate change, and Cyclone Yaku caused the majority of dengue cases across the cyclone-affected districts.Significance StatementAnthropogenic climate change is increasing the risk of extreme events that can lead to infectious disease epidemics, but few studies have directly measured this health cost of climate change. We do so by focusing on Cyclone Yaku, which affected northwestern Peru in March 2023, and was immediately followed by a dengue epidemic. Cyclone Yaku caused 67% of cases reported over six months in the affected region. Industrial-era climate forcing has increased the likelihood of extreme March precipitation like that associated with Cyclone Yaku by 42%. Assessing the linkages between climate change, extreme weather, and outbreaks of dengue and other infectious diseases is crucial for understanding the impact that climate change has already had and preparing for future health risks.
Gene Regulatory Network Based Biomarker Transition from Normalcy to Malignancy: A study of Lung Cancer Using Differential Gene Expression Data
Authors: Mandal Supriya , Biswas Surama 
Published: October 2024

AbstractLung cancer is a global threat, and understanding its pathology through gene regulatory network (GRN)-based biomarkers could offer significant insights. In this study, GRN-based biomarkers have been constructed to demonstrate the topology shift of GRN from a normal condition to a lung cancer condition. This study employed three distinct processes to identify significant genes from differential gene expression data related to lung cancer: 1) simple variance-based screening, 2) a recent gene selection algorithm incorporating simulated annealing and a biologically inspired objective function, and 3) a volcano plot comparing log2 fold changes against -log10 P values. These comprehensive methods identified 21 common genes as significant genes, including KRT5, SFTPC, KRT16, and AKR1B10, which have strong associations with lung cancer pathology according to previous literature. To gain deeper insights into the underlying biological mechanisms, co-expression-modelled GRNs have been constructed for both normal and lung cancer conditions based on these significant genes. These networks provide a detailed visual and mathematical representation of gene interactions within the cellular environment, illustrating how these interactions differ between healthy and diseased states. The shift in network biomarker topologies from normal to diseased conditions have been closely analysed using centrality measures, which quantify the importance of genes based on their connectivity and position within the network. Notably, the pronounced change in the degree of centrality for genes such as GJB6 between normal and diseased states suggests their pivotal roles in the transition to lung cancer. Rigorous statistical and machine learning methods validated the significance of the selected genes and their interconnections, ensuring the robustness of the findings.
Mycobacterium tuberculosis-specific cytokine responses of infants born to mothers with active tuberculosis in Uganda
Authors: Sitenda Diana , Ssekamatte Phillip , Nakavuma Rose , Kyazze Andrew Peter , Bongomin Felix , Baluku Joseph , Nabatanzi Rose , Kibirige Davis , Cose Stephen , Andia-Biraro Irene , Nakimuli Annettee 
Published: October 2024

AbstractBackgroundImmunizing infants with various vaccines, includingBacillus Calmette–Guérin(BCG), Diphtheria-Pertusis-Tetanus (DPT), and measles, aims to enhance immunity. In instances where vaccine responses have been reported to be compromised, individuals are prone to infection. The BCG vaccine, for example, induces strong type 1 immune responses, particularly interferon-gamma (IFN-γ) expression, that are essential for protection againstMycobacterium tuberculosis(Mtb). However, there is scanty evidence on whether this effect is established or sustained when infants are exposed toMtbeither in utero or after birth. We compared TB-specific cytokine responses for IFN-γ, interleukin (IL)-2 (IL-2), tumour necrosis factor-alpha (TNF-α), IL-17A, and Granulocyte-macrophage colony-stimulating factor (GM-CSF) using supernatants harvested from QFT-Plus Blood Collection Tubes.MethodsThis cross-sectional study compared 22 infants born to mothers with bacteriologically confirmed active tuberculosis (TB), defined as TB exposed or cases, to 20 infants born to mothers without active TB, defined as TB non-exposed or controls. Plasma harvested from the QFT-plus tubes (TB1 and TB2) was used to perform a 5-plex Luminex assay using the LX 100/200 Luminex machine and measured in pg/mL. Data was analysed using R (v.4.4.1). The Mann-Whitney U test was used to determine statistical significance at a p-value less than 0.05 and a 95% confidence interval. Data was expressed as median and interquartile ranges (IQR).ResultsTB-exposed infants showed IFNγ responses were slightly higher among TB-exposed infants compared to non-exposed (Medians (IQR): 15.49 (14.58-16.49) versus 14.96 (14.60-16.60), p=0.68, respectively. There was a strong expression of total IL-17A among TB-exposed compared to non-exposed 11.91 (10.89-13.50) versus 10.69 (10.17-11.64), p=0.035. We observed no differences in IL-2, TNF, and GM-CSF responses.ConclusionTB exposure among infants slightly alters theirMtb-specific cytokine responses, especially IL-17A cytokine responses. This suggests possible ongoingMtbinfection among TB-exposed infants. Follow-up studies of such infants are necessary to assess their risk of future TB infection and disease and the potential need for TB chemoprophylaxis.
Electroencephalography Markers of Perinatal Depression and Anxiety in a Diverse Longitudinal Cohort: A Preliminary Study
Authors: Attre Maigh , Alvernaz Suzanne , Wenzel Elizabeth , Pettineo Abigail , Parikh Sarah , Conway Catherine , Kroeger Molly , Ajilore Olu , Maki Pauline , Leow Alex , Bernabé Beatriz Peñalver 
Published: October 2024

ABSTRACTPerinatal mental health disorders, such as depression and anxiety, are highly prevalent and can have severe consequences on maternal morbidity and mortality, and on infant neurodevelopment. Yet, the biological mechanisms of these disorders are underexplored, especially in Black, Indigenous, and People of Color (BIPOC) populations. Here, we aim to investigate functional brain alterations across the perinatal period using portable electroencephalography (pEEG) in a diverse cohort of pregnant individuals reporting symptoms of depression or anxiety. Participants (61 subjects, 45% Non-Hispanic Black and 32% Hispanic) were followed longitudinally from early pregnancy through postpartum. Brain electrical activity was quantified with pEEG (61 subjects, 209 pEEG recordings) and mental health was assessed using the PHQ-9 and GAD-7 at multiple time points throughout the perinatal period. Using linear models and linear mixed models, our preliminary findings suggest significant changes in brain wave activity, such as alpha and delta waves, are associated with depression and anxiety severity during the perinatal period. The study addresses critical gaps in understanding perinatal mental health in racially, ethnically, and socioeconomically diverse populations, with the goal of developing sensitive clinically feasible diagnostic tools to mitigate health disparities.