bluuebunny/crossref_metadata_2025 huggingface dataset:
Subtherapeutic Meropenem Antibiotic Exposure in Children With Septic Shock Assessed by Noncompartmental Pharmacokinetic Analysis in a Prospective Dataset
Authors: Bradley John S. , Harvey Helen , Stout Dayna , Momper Jeremiah , Capparelli Edmund , Avedissian Sean N. , Barbato Courtney , Mak Robert H. , Jones Tom P. , Jones Douglas , Le Jennifer
Published: February 2025

Objectives:

To define meropenem plasma concentrations and pharmacodynamic exposure metrics in children with septic shock during the first 3 days of PICU hospitalization.

Design:

Pharmacokinetic sampling was undertaken in 19 subjects receiving standard meropenem dosing (20 mg/kg/dose, 8 hr) recruited from March 2019 to March 2022. Sampling occurred once each day following meropenem given 24 hours apart, during the first 3 PICU days. Data analysis was completed in 2023 and noncompartmental analysis was performed to assess pharmacodynamic exposure targets for sepsis. Clearance and volume of distribution at 20 mg/kg/dose were used to simulate mean exposures at 40 and 60 mg/kg/dose.

Setting:

PICU in a tertiary care center.

Subjects:

Patients 4 weeks old or older with hypotension requiring fluid resuscitation and vasopressor therapy, receiving meropenem as empiric therapy for sepsis.

Interventions:

None.

Measurements and Main Results:

Augmented renal clearance (ARC) was documented in eight of 19 subjects, previously associated with subtherapeutic plasma concentrations, while three of 19 had acute kidney injury and decreased renal clearance. When assessed by pharmacodynamic exposure targets for sepsis (plasma meropenem concentrations above the minimum inhibitory concentration [MIC] of Pseudomonas aeruginosa for 70% or 100% of the dosing interval), ten of 19 and nine of 19 children, respectively, had subtherapeutic plasma meropenem exposures during PICU day 1, even for pathogens with an MIC considered “susceptible” by U.S. Food and Drug Administration criteria. Therapeutic meropenem pharmacodynamic exposures were associated with a positive 24-hour fluid balance on PICU day 1 and a negative 24-hour fluid balance by day 3, although profound variability was noted in fluid administered and renal output.

Conclusions:

Given the variability in meropenem systemic exposure in pediatric septic shock, therapeutic drug monitoring, or monitoring for ARC, is suggested during the first days of hospitalization to allow daily assessments of dosing needs to achieve pharmacodynamic exposure targets for sepsis.
Comparing Harm Reduction Vending Machines and In-Person Overdose Prevention Services in Practice: A Case Study From Rhode Island
Authors: Shaw Leah C. , Brown Erin A. , Creegan Emma , Bertrand Thomas E. , Ogundare Sarah , Park Carolyn J. , Berk Justin , Chan Philip A. , Marshall Brandon D. L.
Published: February 2025

Objective:

Improved harm reduction approaches are needed to address the ongoing opioid epidemic in the United States. The study aimed to evaluate the statewide implementation of harm reduction vending machines (HRVMs) and existing in-person harm reduction services.

Design:

We analyzed 2 years of data from in-person harm reduction encounters and an HRVM pilot program between January 1, 2022, and December 31, 2023.

Setting:

Rhode Island.

Participants:

This analysis compared unique persons served, total encounters, types of products dispensed, and time and day of transaction (weekday vs weekend) for in-person services provided by state-funded community organizations and the HRVMs in operation during the pilot program.

Main Outcome Measures:

At each encounter, the date, location, sociodemographic information, and product(s) dispensed were recorded, among other information for both in-person and HRVM services.

Results:

Over 15 000 people accessed in-person and HRVM services during the 2-year study period (N = 15 267 in-person; N = 485 HRVM or both). Overall, 38% were female, and 64% were white and non-Hispanic. People who frequented the HRVMs tended to be an average of 5 years younger (P< .001). Twenty-eight percent of HRVM encounters happened over the weekend, while only 2% of in-person encounters occurred during this time. Notably, 29% of HRVM encounters occurred overnight or during the early morning hours. Safer injection kits, safer smoking kits, and naloxone kits were the 3 most common products dispensed during in-person encounters, with 68% of encounters also supplying basic needs like water, snacks, and clothing. Safer injection kits represented 89% of products dispensed by the HRVMs.

Conclusions:

HRVMs are a feasible method of distributing harm reduction supplies as a complement to in-person services. HRVMs could complement other services already offered in many communities. Around-the-clock access is a key component of effective HRVMs.
A Framework for Managing Moral Challenges Related to Health Policy for the Surgeon
Authors: Mannava Sindhu V , Shakhsheer Baddr A , Statter Mindy , Perrone Erin E , Brandt Mary L , Stehr Wolfgang , Knod J Leslie , Buchmiller Terry L , Henry Marion C , Berdan Elizabeth A , Hu Yue-Yung , Gow Kenneth W , Baerg Joanne
Published: February 2025

Surgeons of all specialties are impacted by health policies, primarily written and executed by non-medical parties. The sequelae of policy change may limit the patient-physician relationship across numerous surgical disciplines, including general and acute care surgery, obstetrics and gynecologic surgery, pediatric and fetal surgery, and others. The discordance between a surgeon’s imperative to provide excellent patient care and legislative limitations that hinder patient care can impact surgeon wellness, career longevity, and attrition as well as reduce access and outcomes for patients, across specialties. Limited literature addresses this presage to physician wellness and patient outcomes. Combatting moral distress requires a framework which considers a multifactorial approach including open communication and respect among colleagues, free discussion of challenges related to health policy, resources for coaching and therapeutic counseling, and organizational actions promoting surgeon wellness. In this paper, we present strategies, curated and executed by our subspecialty advocacy group, for navigating moral challenges secondary to health policy. This framework may be implemented across specialties to promote discussion of controversial or difficult topics in the professional setting and help prevent distress and attrition.
Right Heart Remodeling in End-Stage Pulmonary Arterial Hypertension and the Impact of Treatment Intensity
Authors: Gong Su-Gang , Zhang Qi-Hang , Zhang Jia-Yi , Zhang Qian , Rui-Zhang  , Qiu Hong-Ling , Luo Ci-Jun , Li Hui-Ting , Wu Wen-Hui , Yuan Ping , He Jing , Xu Jian , Liu Jin-Ming , Zhao Qin-Hua , Wang Lan
Published: February 2025

Background

Research on the limits of compensatory right heart remodeling and the effects of pulmonary artery hypertension (PAH) targeted therapies on these mechanisms is limited.

Method

Chest x-ray and echocardiographic data were collected from 143 deceased patients with PAH confirmed by right heart catheterization at their end-stage disease. Right heart remodeling was compared across different PAH treatment strategies.

Results

This study of 143 deceased PAH patients (49 ± 17 years, 74.1% female) characterized right heart remodeling at the time of death. Mean cardiothoracic ratio (CTR), right atrial area (RAA) and mid-cavity RV linear dimension (RVD) measured by echocardiography were 0.61±0.09, 27 cm² (median 27, IQR 21–38), and 4.97±0.97 cm, respectively, with extremes of 0.88, 102 cm², and 7.50 cm. Intensive therapy resulted in larger CTR (0.63±0.08 vs. 0.60±0.09, p=0.016), RAA (30 [24–40] vs. 25 [19–34] cm², p=0.020), and RVD (5.30±0.97 vs. 4.65±0.85 cm, p<0.001) compared with monotherapy. After adjusting for confounders, intensive therapy independently predicted increases in CTR (0.03, 95% CI 0.00-0.05, p=0.054), RAA (6.63 cm², 95% CI 1.46-11.80, p=0.013), and RVD (0.66 cm, 95% CI 0.34-0.98, p<0.001).

Conclusion

These findings suggest that more aggressive PAH treatment is associated with greater right heart remodeling, highlighting the complex relationship between therapeutic intervention and disease progression in PAH patients.
Post-Zika anti-NS1 serum IgA drives increased neutrophil functions in severe dengue disease
Authors: Cardona-Ospina Jaime A. , Roy Vicky , Marcano-Jiménez Dorca E. , Bos Sandra , Duarte Elias , Zambrana José V. , Bal Agamjot , Dias Antonio Gregorio , Zhiteneva Julia , Huffaker Julia , Montenegro Carlos , Kuan Guillermina , Ramos-Benitez Marcos J. , Balmaseda Angel , Alter Galit , Harris Eva
Published: February 2025

Primary immunity against Zika virus (ZIKV) increases the risk of a subsequent severe dengue virus 2 (DENV2) infection, presenting a significant challenge for developing safe and effective ZIKV vaccines. However, the mechanisms driving this phenomenon remain unclear. We show that post-ZIKV infection IgA antibodies in serum targeting the DENV2 nonstructural protein 1 (NS1) drive neutrophil activation and correlate with increased risk of a subsequent severe DENV2 infection in a pediatric cohort study. Increased neutrophil degranulation correlated with IgA binding to DENV2 NS1 and preceded vascular leakage in paired acute-phase samples from the same individuals and in dengue patients after prior ZIKV infection in an orthogonal hospital-based study. Thus, serum anti-NS1 IgA enhances neutrophil activation in severe dengue, with implications for prognostics, therapeutics, and vaccines.
Inhibition of acute lung inflammation by a neuroimmune circuit induced by vagal nerve stimulation
Authors: Murray Kaitlin , Cremin Michael , Tay Emmy , Sanchez Kristina , Schreiber Sierra , Brust-Mascher Ingrid , Leigh Wesley , Ashfaq Jannat , Gareau Melanie G. , Reardon Colin
Published: February 2025

Vagus nerve stimulation (VNS) has been shown to limit immune cell activity across several pathologies ranging from sepsis to auto-immune diseases. While stimulation of vagal efferent neurons has been previously demonstrated to reduce maladaptive host responses during endotoxemia, only selective stimulation of vagal afferent neurons was able to inhibit TLR7-induced macrophage activation and neutrophil recruitment in the lung. These anti-inflammatory actions are facilitated by systemic increases in epinephrine, as VNS significantly increased epinephrine in the serum and bronchoalveolar lavage fluid, and inhibition of epinephrine production eliminated the protection afforded by VNS. Selective afferent VNS induced activation in the nucleus tractus solitarius and the rostral ventrolateral medulla. Inhibition of neuronal activity in this brain region that controls peripheral sympathetic nervous system activity rendered VNS ineffective. Activation of the β2-adrenergic receptor (β2AR) is critical for innate immune cell suppression, as the anti-inflammatory effects of VNS were eliminated in β2AR-knock out mice, and with pharmacological inhibition of the β2AR. Analysis of the immune cells responding to R848 critically identified that plasmacytoid dendritic cells were refractive to inhibition by VNS, and this corresponded to lack of β2AR expression. These findings demonstrate a novel neuro-immune circuit elicited by VNS that can control acute lung inflammation.

We have identified a novel neuro-immune circuit activated by afferent vagus nerve stimulation to reduce acute lung inflammation. This effect was dependent on vagal-induced adrenal gland-derived epinephrine release that initiates anti-inflammatory β2-adrenergic receptor signaling in innate immune cells within the lung.
High throughput isolation of male gametophyte cells ofSolanum lycopersicumvar. Micro-Tom by fluorescence-activated cell sorting
Authors: Flores-Tornero María , Sapeta Helena , Lobato-Gómez Maria , Teixeira Beatriz , Monteiro Marta , Granell Antonio , Becker Jörg D.
Published: February 2025

Efficient isolation of male gametes has enabled unprecedented advances in omics research, crucial for elucidating the molecular mechanisms governing male gametogenesis and fertilization. In this study, we developed a method for isolating generative and sperm cells from the economically important cropSolanum lycopersicum.

A double fluorescent marker line was generated in the tomato variety Micro-Tom, employing mTurquoise and mScarlet-I fluorescent proteins under the control of promoters exhibiting preferential activity in generative and sperm cells, respectively. Then we developed a protocol that combines male gamete release from pollen of this line and SYTOX Red live/dead cell stain to obtain viable cells by Fluorescence-activated cell sorting. This allows the isolation of generative cells from mature pollen grains, and of sperm cells from pollen tubes after semi-in vivogrowth, both in high quantity and purity. Additionally, an unexpected mScarlet-I signal in the vegetative nucleus, that persists until the sperm cells are formed, allows the sorting of vegetative nuclei.

We anticipate that our novel double-marker line will accelerate research into tomato male gametogenesis, thereby enhancing efforts to improve the resilience of fertilization processes to climate change.
Host-microbe mutualism drives urea carbon salvage and acetogenesis during hibernation
Authors: Regan Matthew D. , Chiang Edna , Grahn Michael , Tonelli Marco , Assadi-Porter Fariba M. , Suen Garret , Carey Hannah V.
Published: February 2025

Hibernation is a wintertime survival strategy employed by certain mammals that, through torpor use, reduces overall energy expenditure and permits long-term fasting. Although fasting resolves the challenge of winter food scarcity, it also removes dietary carbon, a critical biomolecular building block. Here, we demonstrate a process of urea carbon salvage (UCS) in the 13-lined ground squirrel, whereby urea carbon is reclaimed through gut microbial ureolysis and used in reductive acetogenesis, producing acetate—a short-chain fatty acid (SCFA) of major value to the host and its microbial community. We find that urea carbon incorporation into acetate is more efficient during hibernation than the summer active season, and that while both host and gut microbes oxidize acetate for energy throughout the year, the host’s ability to absorb and oxidize acetate is highest during hibernation. Metagenomic data of the gut microbiome indicate retention during hibernation of genes involved in the degradation of gut mucin, an abundant endogenous nutrient. The hydrogen disposal associated with reductive acetogenesis from urea carbon provides a luminal environment that sustains fermentation of mucin oligosaccharides, thereby generating SCFAs and other metabolites usable by both the host and its gut microbes. Our findings introduce UCS as a novel mechanism that enables hibernating squirrels and their gut microbes to exploit two key endogenous nutrient sources – urea and mucins – in the resource-limited hibernation season.
Significant variations in tolerance to clothianidin and pirimiphos-methyl inAnopheles gambiaeandAnopheles funestuspopulations during a dramatic malaria resurgence despite sustained indoor residual spraying in Uganda
Authors: Oruni Ambrose , Arinaitwe Emmanuel , Adiga James , Otto Geoffrey , Kyagamba Patrick , Okoth Joseph , Ayo Daniel , Asiimwe Jackson Rwatooro , Zedi Maato , Rek John , Walker Kyle J , Braithwaite Ashlee , Kayondo Jonathan , Conrad Melissa D , Bousema Teun , Paine Mark J I , Ismail Hanafy M , Krezanoski Paul , Wondji Charles S. , Kamya Moses R. , Dorsey Grant , Donnelly Martin J.
Published: February 2025

A dramatic malaria resurgence occurred in areas of Uganda between 2020 and 2022 coincident with the switch to clothianidin-based formulations for indoor residual spraying. During the resurgence,Anopheles funestusnumbers increased but when an alternative insecticide, pirimiphos methyl, was reintroduced in 2023, both malaria cases andAn. funestusmosquito density fell. In this study, we investigated possible causes of the resurgence by assessing; 1) whether sufficient quantities of insecticide were sprayed; 2) the residual insecticide bioefficacy against wild mosquitoes and; 3) the insecticide susceptibility of vector populations using standard test tube assays and wall cone assays. In 2023, after adjusting for extraction efficiency, 70-80% of the houses had optimal residual concentrations of insecticides (clothianidin >0.3g/m2; pirimiphos methyl >0.5g/m2) with significant variations between sampling rounds and wall types. Mud walls had the lowest residual concentration of insecticides, and the lowest observed mortality in wall cone assays, compared to fired bricks with plaster/cement/paint. In the studies of residual bio efficacy, by World Health Organization (WHO) definitions,An. funestusshowed resistance to clothianidin (<80% mortality) up to 11 months and susceptibility to pirimiphos methyl (>90% mortality) when exposed to wall surfaces up to 7 months post-spray. In WHO tube tests, variations were observed in susceptibility to clothianidin inAn. funestuspopulations using dose- and time-response assays (80-98% mortality). In 2022,An. gambiaewas largely susceptible to the clothianidin-based formulation Sumishield (85-90% mortality) although the levels dropped slightly in 2023 (60-85% mortality) mainly in mud and pole houses. In contrast,An. gambiaewas mildly susceptible to the pirimiphos methyl-based formulation Actellic (∼80% mortality) and time response assays showedAn. gambiae populationshad very low knockdown and mortality at lower exposure time compared toAn. funestus. Regression models showed a positive association between residual insecticide concentration (RIC) and mortality in houses sprayed with Sumishield but not Actellic houses.

Despite the possible variations observed in spray operations, the study revealed thatAn.funestusexhibited a higher tolerance to clothianidin-based formulations compared toAn. gambiae, and this might have driven the malaria resurgence observed in Uganda. However, there are signals ofAn. gambiaeresistance to pirimiphos-methyl which will require further investigation and monitoring.
Rewiring protein sequence and structure generative models to enhance protein stability prediction
Authors: Li Ziang , Luo Yunan
Published: February 2025

Predicting changes in protein thermostability due to amino acid substitutions is essential for understanding human diseases and engineering useful proteins for clinical and industrial applications. While recent advances in protein generative models, which learn probability distributions over amino acids conditioned on structural or evolutionary sequence contexts, have shown impressive performance in predicting various protein properties without task-specific training, their strong unsupervised prediction ability does not extend to all protein functions. In particular, their potential to improve protein stability prediction remains underexplored. In this work, we present SPURS, a novel deep learning framework that adapts and integrates two general-purpose protein generative models–a protein language model (ESM) and an inverse folding model (ProteinMPNN)–into an effective stability predictor. SPURS employs a lightweight neural network module to rewire per-residue structure representations learned by ProteinMPNN into the attention layers of ESM, thereby informing and enhancing ESM’s sequence representation learning. This rewiring strategy enables SPURS to harness evolutionary patterns from both sequence and structure data, where the sequence like-lihood distribution learned by ESM is conditioned on structure priors encoded by ProteinMPNN to predict mutation effects. We steer this integrated framework to a stability prediction model through supervised training on a recently released mega-scale thermostability dataset. Evaluations across 12 benchmark datasets showed that SPURS delivers accurate, rapid, scalable, and generalizable stability predictions, consistently outperforming current state-of-the-art methods. Notably, SPURS demonstrates remarkable versatility in protein stability and function analyses: when combined with a protein language model, it accurately identifies protein functional sites in an unsupervised manner. Additionally, it enhances current low-Nprotein fitness prediction models by serving as a stability prior model to improve accuracy. These results highlight SPURS as a powerful tool to advance current protein stability prediction and machine learning-guided protein engineering workflows. The source code of SPURS is available athttps://github.com/luo-group/SPURS.
Learning maximally spanning representations improves protein function annotation
Authors: Luo Jiaqi , Luo Yunan
Published: February 2025

Automated protein function annotation is a fundamental problem in computational biology, crucial for understanding the functional roles of proteins in biological processes, with broad implications in medicine and biotechnology. A persistent challenge in this problem is the imbalanced, long-tail distribution of available function annotations: a small set of well-studied function classes account for most annotated proteins, while many other classes have few annotated proteins, often due to investigative bias, experimental limitations, or intrinsic biases in protein evolution. As a result, existing machine learning models for protein function prediction tend to only optimize the prediction accuracy for well-studied function classes overrepresented in the training data, leading to poor accuracy for understudied functions. In this work, we develop MSRep, a novel deep learning-based protein function annotation framework designed to address this imbalance issue and improve annotation accuracy. MSRep is inspired by an intriguing phenomenon, called neural collapse (NC), commonly observed in high-accuracy deep neural networks used for classification tasks, where hidden representations in the final layer collapse to class-specific mean embeddings, while maintaining maximal inter-class separation. Given that NC consistently emerges across diverse architectures and tasks for high-accuracy models, we hypothesize that inducing NC structure in models trained on imbalanced data can enhance both prediction accuracy and generalizability. To achieve this, MSRep refines a pre-trained protein language model to produce NC-like representations by optimizing an NC-inspired loss function, which ensures that minority functions are equally represented in the embedding space as majority functions, in contrast to conventional classification methods whose embedding spaces are dominated by overrepresented classes. In evaluations across four protein function annotation tasks on the prediction of Enzyme Commission numbers, Gene3D codes, Pfam families, and Gene Ontology terms, MSRep demonstrates superior predictive performance for both well- and underrepresented classes, outperforming several state-of-the-art annotation tools. We anticipate that MSRep will enhance the annotation of understudied functions and novel, uncharacterized proteins, advancing future protein function studies and accelerating the discovery of new functional proteins. The source code of MSRep is available athttps://github.com/luo-group/MSRep.
Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrictLegionellainfection
Authors: Vázquez Marrero Víctor R. , Doerner Jessica , Wodzanowski Kimberly A. , Zhang Jenna , Lu Allyson , Boyer Frankie D. , Vargas Isabel , Hossain Suzana , Kammann Karly B. , Dresler Madison V. , Shin Sunny
Published: February 2025

The innate immune system relies on pattern recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs) and guard proteins to monitor pathogen disruption of host cell processes. How different immune cell types engage PRR- and guard protein-dependent defenses in response to infection is poorly understood. Here, we show that macrophages and dendritic cells (DCs) respond in distinct ways to bacterial virulence activities. In macrophages, the bacterial pathogenLegionella pneumophiladeploys its Dot/Icm type IV secretion system (T4SS) to deliver effector proteins that facilitate its robust intracellular replication. In contrast, T4SS activity triggers rapid DC death that potently restrictsLegionellareplication within this cell type. Intriguingly, we found that infected DCs exhibit considerable heterogeneity at the single cell level. Initially, a subset of DCs activate caspase-11 and NLRP3 inflammasome-dependent pyroptosis and release IL-1βearly during infection. At later timepoints, a separate DC population undergoes apoptosis driven by T4SS effectors that block host protein synthesis, thereby depleting the levels of the pro-survival proteins Mcl-1 and cFLIP. Together, pyroptosis and effector-triggered apoptosis robustly restrictLegionellareplication in DCs. Collectively, our work suggests a model where Mcl-1 and cFLIP guard host translation in DCs, and that macrophages and DCs distinctly employ innate immune sensors and guard proteins to mount divergent responses toLegionellainfection.
Differences in cell-associated and cell-free microbial DNA in blood
Authors: Bowie Kate R. , Fischer Jared , Karstens Lisa
Published: February 2025

In the absence of infection, blood has previously been understood to be free of microbes. However, with advances in sequencing technology this notion has been challenged, prompting new investigations into microbial DNA within the blood of both healthy and diseased individuals. To comprehensively survey microbial DNA in blood, we separated blood into fractions (plasma, red blood cells, and buffy coat) and assessed if the microbial-DNA is cell-free by the addition of DNase to a subset of each fraction. We measured 16S rRNA gene copy number with digital droplet PCR and identified the taxonomic origin of the microbial DNA with synthetic full-length 16S rRNA gene sequencing. As a use case, we examine microbial DNA from the blood of 5 men without prostate cancer (PC), 5 men with low-grade PC, and 5 men with high-grade PC. Our study demonstrates that the majority of microbial DNA is cell-free, indicating that it is not representative of proliferating microbes. Our analyses also revealed buffy coat had the lowest number of 16S rRNA gene copies yet highest number of genera of the fractions (median 23.3 copies/µL and 10 genera) and thus may be a useful fraction to study moving forward. Additionally, microbial DNA in blood may have utility as a biomarker, as we detected disease-associated compositional differences in the plasma and buffy coat fractions. This study lays the groundwork for rigorously studying microbial DNA in blood, however larger studies are needed to confirm our disease-association findings.

Importance

The concept of a “blood microbiome” has sparked debate in recent years, with questions about whether microbes truly exist in circulation. This study provides a crucial evaluation of the fractions of blood and their capacity to harbor microbial DNA, offering important context for prior and future research. By using DNase to differentiate between cell-associated and cell-free microbial DNA, we show that while microbial DNA is present in blood, it is sparse and heterogenous. These findings highlight the need for rigorous study design that carefully considers both positive and negative controls, as well as the specific blood fractions being examined.
Astrocytic contribution to auditory hypersensitivity in a mouse model of fragile X syndrome
Authors: Bergdolt Lara , Anding Alexandria , Alshaqi Ola , Arbabi Zahra , Douchey Michael , Eldridge Ember , Hoffman Katherine , Reid Ashley , Sapkota Kiran , Padmashri Ragunathan , Monaghan Daniel , Taraschenko Olga , Dunaevsky Anna
Published: February 2025

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and a leading cause of autism spectrum disorder (ASD). FXS is caused by mutations in the fragile X messenger ribonucleoprotein gene 1 (FMR1), which result in complete or partial loss of expression of its protein product, fragile X messenger ribonucleoprotein (FMRP). Neuronal impairments in the absence of FMRP have been extensively characterized. However, much less is known about the impact that loss of FMRP has on the physiology and function of astrocytes and the implications for behavior. A common behavior exhibited by both FXS and ASD patients is hypersensitivity to sensory stimuli, but how astrocytes contribute to hypersensitivity in the context of FXS remains unknown. Using mice with astrocyte-specific reduction of Fmr1 (Fmr1 conditional KO (cKO)) and mice with astrocyte-specific expression of Fmr1 (Fmr1 cON), we demonstrated that reduction of astrocytic FMRP is sufficient but not necessary to confer susceptibility to audiogenic seizures, an indication of auditory hypersensitivity. In addition, reduction of astrocytic FMRP impacts neuronal activity, resulting in spontaneous seizures. In contrast, we assessed tactile hypersensitivity using a whisker stimulation paradigm but did not detect significant differences in Fmr1 cKO mice. Our results reveal that astrocytes lacking FMRP contribute to auditory hypersensitivity and spontaneous seizures.
Association between fractional exhaled nitric oxide (FeNO) and peripheral eosinophils in patients with asthma: a retrospective cohort study
Authors: Habis Yahya Z. , Sakkat Abdullah , Alaidaroos Shahad H. , AlGhamdi Reema D. , Almuwalad Nada H. , Aljuhani Joud M. , Alharbi Atheer A.
Published: February 2025

Background

Fractional exhaled nitric oxide (FeNO) and peripheral eosinophils are important biomarkers of Type 2 inflammation in asthma. FeNO reflects airway inflammation, while eosinophil counts indicate systemic eosinophilic activity. Their combined utility in asthma management warrants further investigation.

Objective

This study aimed to assess and compare FeNO levels and peripheral eosinophils in asthmatic patients, examining their relationship with disease characteristics and bronchodilator responsiveness (BDR).

Methods

A retrospective analysis of 101 adult asthmatic patients at King Abdulaziz University, Jeddah, was conducted. Patient data on FeNO, eosinophil counts, spirometry, and comorbidities were collected and analyzed using correlation and receiver operating characteristic (ROC) curve analysis.

Results

The mean FeNO level was 68.9±61.3 ppb, and the mean eosinophil count was 310.5±344.2 cells/μL. FeNO levels were significantly higher in patients with eosinophil counts ≥300 cells/μL (p=0.012) and correlated positively with BDR (r=0.38, p=0.001) but not with eosinophil counts (r=0.16, p=0.11) or asthma control test (ACT) scores. Eosinophil counts were significantly associated with moderate airway obstruction (p=0.041). FeNO showed a borderline ability to differentiate allergic rhinitis (p=0.059) but limited performance in identifying other comorbidities, such as chronic rhinosinusitis (p=0.17), GERD (p=0.87), and eczema/atopic dermatitis (p=0.11 and p=0.24, respectively).

Conclusion

FeNO and peripheral eosinophil counts are valuable complementary biomarkers for assessing type 2 inflammation in asthma and guiding treatment. However, their variability across clinical contexts underscores the need for integration with other assessments. These findings support a multidimensional approach to asthma management and call for further research to refine their clinical applications.
Body movement perception is shaped by both generic and actor-specific models of human bodies
Authors: Vandenberghe Antoine , Vannuscorps Gilles
Published: February 2025

Body movement perception is shaped by knowledge of the human body biomechanics. Apparent motion elicited by rapidly alternating pictures follows the shortest path between two body postures only if it is biomechanically plausible. And although we tend to perceive the location of a moving body part as slightly shifted forward along its trajectory, this perceptual extrapolation is absent (or reduced) if the movement would have been unlikely to continue along the same trajectory because of the body biomechanical constraints. The received view is that perception is shaped by a model of the observer’s own body. Here, we report three lines of evidence suggesting otherwise. First, we report the typical influence of knowledge of the upper limb biomechanics on apparent movement perception and perceptual extrapolation in two individuals born completely without (upper and lower) limbs (Experiments 1 and 2). Second, we report that we failed to find evidence that observers’ own biomechanics influence perceptual extrapolation of body movements (Experiment 3). Third, we show that participants’ perception is influenced by their knowledge of actor-specific biomechanics (Experiments 4- 8). We conclude that body movement perception is shaped by visually acquired models of both generic and actor-specific body biomechanics.

Public significance statement

Although information about others’ body movements reaches our visual system with a considerable delay, we can interact with them in real-time. Although we often blink, we perceive uninterrupted body movements. To solve the problems posed by informational lag and intermittence, the visual system appears to rely on knowledge of the human body biomechanics to extrapolate the most likely future (or unseen) position of observed limb movements. For the last 20 years, the received view has been that perceptual “filling-in” and extrapolation of others’ body movements are underpinned by a model of the observer’s own body, acquired through motor experience and proprioceptive feedback. Here, we report three lines of evidence indicating that body movement perception is rather shaped by visually acquired models of both generic and actor-specific body biomechanics. These findings provide new insight into how the human visual system extrapolates future body positions.
SUMO2 Promotes Histone Pre-mRNA Processing by Stabilizing Histone Locus Body Interactions and Facilitating U7 snRNP Assembly
Authors: He Shuying , Lyu Pin , Skinner Marnie W. , Desotell Anthony , Foley Brendan , McCaig C.M. , Wang Wei , Qian Jiang , Tong Liang , Marzluff William F. , Matunis Michael J.
Published: February 2025

Histone mRNAs are the only non-polyadenylated mRNAs in eukaryotic cells and require specialized processing in the histone locus body (HLB), a nuclear body where essential processing factors, including the U7 snRNP, are concentrated. Recent studies have revealed that misregulation of histone pre-mRNA processing can lead to polyadenylation of histone mRNAs and disruption of histone protein homeostasis. Despite links to human disease, the factors contributing to polyadenylation of histone mRNAs and the mechanisms underlying HLB assembly and U7 snRNP biogenesis remain unclear. Here, we report novel functions of the small ubiquitin-related modifier 2 (SUMO2) in promoting histone pre-mRNA processing. Using a SUMO2 knockout osteosarcoma cell line, we identified a defect in 3’ end cleavage and a global increase in histone mRNA polyadenylation. Subsequent analysis of HLBs revealed increased dynamics and reduced levels of the U7 snRNP complex. By over-expressing U7 snRNP-specific components, Lsm11 and U7 snRNA, we rescued U7 snRNP levels and processing defects in SUMO2 knockout cells. Through analysis of Lsm11, we identified a SUMO-interacting motif in its N-terminus required for efficient formation of U7 snRNP. Collectively, we demonstrate that SUMO2 promotes histone pre-mRNA 3’ end processing by stabilizing HLB interactions and facilitating U7 snRNP assembly.
Microarray, validation and gene-enrichment approach for assessing differentially expressed circulating miRNAs in obese and lean heart failure patients
Authors: dos Santos Soares Douglas , Lopes Amanda , Recamonde-Mendoza Mariana , Bueno Rodrigo Haas , Calloni Raquel , Clausell Nadine , Tobar Leitão Santiago Alonso , Biolo Andreia
Published: February 2025

Background

Obesity is a risk factor associated with cardiovascular diseases that may lead to heart failure (HF). However, in HF, overweight and obese patients have longer survival than underweight patients, a phenomenon known as the obesity paradox. MiRNAs play a fundamental role in gene regulation and transcription factors involved in obesity and HF. The main objective of this study was to identify and validate differentially expressed circulating miRNAs in HF-obese and HF-lean patients.

Materials and Methods

This case-control study was carried out in two parts; the discovery and validation phase. In the discovery phase, plasma samples from 20 HF patients and from 10 healthy controls for microarray analysis were selected. The miRNAs were extracted and then analyzed on the miRNA 4.0 Affymetrix GeneChip array following the manufacturer’s instructions. Raw data were normalized using Robust Microarray Average (RMA), batch effects were adjusted with Surrogate Variable Analysis (SVA), and differential expression analysis was performed with the Limma R package. Differentially expressed miRNAs were ranked based on effect size, p-value, and biological plausibility, and selected for validation. In the validation phase, plasma miRNAs from 80 patients and controls were extracted and miRNAs -451a, - 22-3p, and -548ac were validated by quantitative reverse transcription-PCR. Then, they were subjected to target analysis using miRTarBase release 8.0 and TarBase v8.0. We performed functional enrichment analysis of miRNA targets using pathway annotation from the KEGG Pathway Database using the ClueGO software.

Results

MiRNAs -451a, -22-3p, and -548ac were up-regulated in HF-lean and HF-obese groups compared to control, showing an association of these miRNAs with HF. Enrichment analysis showed an association of validated miRNAs withAKT1,MAPK1,GRB2, andIGF1Rgenes. These genes are associated with different biological processes, such as apoptosis, carbohydrate metabolism, neurogenesis, sugar transport, translation regulation, transport, cell cycle, actin cytoskeleton reorganization, cardiac neural crest cell development involved in heart development, and aging.

Conclusion

miR-451a, miR-22-3p, and miR-548ac are up-regulated in HF, independent of obesity, and are associated with metabolic, morphological, and functional outcomes. These results might help in the selection of targets for studies aiming to underscore the mechanisms of HF.
VIRUS-MVP: A framework for comprehensive surveillance of viral mutations and their functional impacts
Authors: Anwar Muhammad Zohaib , Gill Ivan S. , Iseminger Madeline , Sehar Anoosha , Griffiths Emma J. , Dooley Damion , Duan Jun , Vora Khushi , Van Domselaar Gary , Brinkman Fiona S.L. , Gordon Paul M.K. , Hsiao William W.L.
Published: February 2025

As viruses evolve, they accumulate genetic mutations that can influence disease severity, transmissibility, and the effectiveness of vaccines and therapeutics. Real-time tracking of viral mutations and their functional impacts is essential to understand these changes and assess their implications for public health responses. VIRUS-MVP is an interactive, portable platform designed for the comprehensive surveillance of viral mutations. Initially developed for SARS-CoV-2, it now fully supports mpox and is expanding to include influenza and RSV. The platform links viral mutations to functional annotations, providing insights into their predicted effects on viral infectivity, immune evasion, and protein functionality. It features an interactive interface for visualizing mutation distributions, a modular and reproducible genomics workflow, and a curated annotation resource that captures known impacts on viral proteins and host interactions. Users can also import custom functional annotations to tailor analyses to specific research needs or emerging pathogens. Developed collaboratively with public health and academic partners, VIRUS-MVP enhances understanding of viral evolution and its public health impact by bridging genomic data with biological insights. The platform is open-source, adaptable, and accessible on GitHub.
A Metabolic Complex Involved in Tomato Specialized Metabolism
Authors: Dwivedi Varun , Okertchiri Ernest , Yokom Adam , Schenck Craig A.
Published: February 2025

Specialized metabolites mediate diverse plant-environment interactions. Although, recent work has begun to enzymatically characterize entire plant specialized metabolic pathways, little is known about how different pathway components organize and interact within the cell. Here we use acylsugars – a class of specialized metabolites found across the Solanaceae family – as a model to explore cellular localization and metabolic complex formation of pathway enzymes. These compounds consist of a sugar core decorated with acyl groups, which are connected through ester linkages. InSolanum lycopersicum(tomato) four acylsugar acyltransferases (SlASAT1-4) sequentially add acyl chains to specific hydroxyl positions on a sucrose core leading to accumulation of tri and tetraacylated sucroses in the trichomes. To elucidate the spatial organization and interactions of tomato ASATs, we expressed SlASAT1-4 proteins fused with YFP inN. benthamianaand Arabidopsis protoplasts. Our findings revealed a distributed ASAT pathway with SlASAT1 and SlASAT3 localized to the mitochondria, SlASAT2 localized to the cytoplasm and nucleus, and SlASAT4 localized to the endoplasmic reticulum. To explore potential pairwise protein-protein interactions in acylsugar biosynthesis, we used various techniques, including co-immunoprecipitation, split luciferase assays, and bimolecular fluorescence complementation. These complementary approaches based on different interaction principles all demonstrated interactions among the different SlASAT pairs. Following transient expression of SlASAT1-4 inN. benthamiana, we were able to pull down a complex consisting of SlASAT1-4, which was confirmed through proteomics. Size exclusion chromatography of the SlASAT pulldown suggests a heteromultimeric complex consisting of SlASATs and perhaps other proteins involved in this interaction network. This study sheds light on the metabolic coordination for acylsugar biosynthesis through formation of an interaction network of four sequential steps coordinating efficient production of plant chemical defenses.
Transcriptomic and proteomic effects of gene deletion are not evolutionarily conserved
Authors: Li Yang , Zhang Jianzhi George
Published: February 2025

Although the textbook definition of gene function is the effect for which the gene was selected and/or by which it is maintained, gene function is commonly inferred from the phenotypic effects of deleting the gene. Because some of the deletion effects are byproducts of other effects, they may not reflect the gene's selected-effect function. To evaluate the degree to which the phenotypic effects of gene deletion inform gene function, we compare the transcriptomic and proteomic effects of systematic gene deletions in budding yeast (Saccharomyces cerevisiae) with those effects in fission yeast (Schizosaccharomyces pombe). Despite evidence for functional conservation of orthologous genes, their deletions result in no more sharing of transcriptomic or proteomic effects than that from deleting non-orthologous genes. Because the wild-type mRNA and protein levels of orthologous genes are significantly correlated between the two yeasts and because transcriptomic effects of deleting the same gene strongly overlap between studies in the sameS. cerevisiaestrain by different laboratories, our observation cannot be explained by rapid evolution or large measurement error of gene expression. Analysis of transcriptomic and proteomic effects of gene deletions in multipleS. cerevisiaestrains by the same laboratory reveals a high sensitivity of these effects to the genetic background, explaining why these effects are not evolutionarily conserved. Together, our results suggest that most transcriptomic and proteomic effects of gene deletion do not inform selected-effect function. This finding has important implications for assessing and/or understanding gene function, pleiotropy, and biological complexity.
Toward sustainable development: an assessment of the performance of green construction sites using fuzzy synthetic evaluation
Authors: Thach Thao Nguyen , Nguyen Minh Van , Khanh Ha Duy , Phan Chien Thanh , Ahn Yonghan
Published: February 2025

Purpose

Unlike the design or planning phases, the construction phase necessitates the coordination of multiple project stakeholders, real-time problem-solving and effectively managing physical resources under fluctuating site conditions. However, recent green rating systems are not yet designed to accommodate the unique nature of this stage. Thus, this study aims to develop an empirical measurement model to evaluate the performance of green construction sites (GCS), focusing on the Vietnamese construction industry.

Design/methodology/approach

Initially, a list of assessment criteria was identified by reviewing previous studies and semi-structured interviews. After that, a questionnaire survey was used to collect practitioners’ views regarding GCS performance. The 155 valid responses were analyzed employing the fuzzy synthetic evaluation (FSE) method.

Findings

The findings showed that the performance of GCS in Vietnam is at a moderate level, with a GCS index of 5.48. Indeed, the human-related factor was the most significant performance group for GCS in Vietnam. Construction site, energy, innovation and material-related factors were among the average performance factors. Moreover, water and waste-related factors were among the lowest performance factors.

Originality/value

This study highlights the importance of human-related factors, such as worker safety and environmental training, in achieving effective GCS performance. It is recommended that governments should enforce stricter guidelines on using low-embodied carbon materials, sustainable sourcing and effective waste management to improve GCS performance. Neighboring countries can also use valuable insights from this study to enhance their GCS performance.