bluuebunny/crossref_metadata_2025 huggingface dataset:
Neutrophil-platelet ratio as a predictor of acute kidney injury in severe COVID-19
Authors: Sayan Mihrican , Altinisik Hatice Betul , Sayan Ozan
Published: October 2024

Acute kidney injury (AKI) is one of the most seen complications of coronavirus-2019 (COVID-19) infection. Patients with AKI caused by COVID-19 likely have higher neutrophil counts and lower platelet and lymphocyte levels. Therefore, the predictive value of many inflammation indexes calculated from the total blood count has been investigated to predict the AKI in COVID-19. According to our clinical experience, we thought that neutrophilia and thrombocytopenia may be more common in the development of AKI. For this reason, this study aimed to evaluate the predictive value of the neutrophil-to-platelet ratio (NPR) for AKI in severe COVID-19 patients. This retrospective study included 334 severe COVID-19 patients followed up in the intensive care unit (ICU). Predictive factors for AKI were analyzed. ROC curve analysis was performed to determine the inflammation indexes’ cutoff values for the AKI prediction. Multivariate analyses were performed to determine correlations between the inflammation indexes and AKI. In this study, AKI was determined at the rate of 43% (n:145). Independent risk factors affecting AKI were determined to be age (HR = 1.047, 95% confidence interval [CI]: 1.021–1.072, P < .001), the need for invasive mechanical ventilation (HR = 3.003, 95% CI: 1.645–5.481, P = .001) and the need for vasopressor (HR = 8.111, 95% CI: 3.786–17.375, P < .001). The optimal cutoff values predicting AKI were determined to be 3.9 for the NPR (AUC = 0.679, 95% CI: 0.622–0.737, P < .001) with 71.7% sensitivity and 61.9% specificity, 16.1 for the neutrophil-to-lymphocyte ratio (NLR) (AUC = 0.634, 95% CI: 0.575–0.694, P < .001) with 65.5% sensitivity and 56.1% specificity, and 3872.5 × 109L for the systemic inflammatory index (SII) (AUC = 0.566, 95% CI: 0.504–0.629, P = .038) with 60% sensitivity and 55.6% specificity. In the regression model, only NPR values above the cutoff were related to AKI (HR = 3.817, 95% CI: 1.782–8.177, P = .001). The NPR has more predictive value than the NLPR, NLR, and SII in developing AKI in severe COVID-19 patients in the ICU. NPR is a new helpful index that can help clinicians predict early AKI in critical COVID-19.
Choroid plexus volumes in patients with transient global amnesia: A retrospective study
Authors: Lee Dong Ah , Lee Ho-Joon , Jo Geunyeol , Park Kang Min
Published: October 2024

Increased choroid plexus (ChP) volume is well known to be associated with glymphatic system dysfunction. This study aimed to investigate glymphatic system function in patients with transient global amnesia (TGA) compared to healthy controls through ChP volumes measurements. We retrospectively enrolled patients with TGA from our hospital, as well as healthy controls. This was retrospectively observational study followed STROBE guideline. All participants underwent brain magnetic resonance imaging, including three-dimensional T1-weighted imaging. We analyzed and compared ChP volumes between patients with TGA and healthy controls and investigated the relationship between ChP volumes and clinical characteristics in patients with TGA. We enrolled 44 patients with TGA and 47 healthy controls. Among the 44 patients with TGA, 38 experienced a single TGA event, while 6 had recurrent TGA events. ChP volumes did not significantly differ between patients with TGA and healthy controls (2.140% vs 2.089%, P = .568). However, ChP volumes were higher in patients with a single TGA event compared to those with recurrent events (2.204% vs 1.740%, P < .013). We observed a significant positive correlation between ChP volumes and age in patients with TGA (R = 0.282, P = .007). ChP volumes were not associated with the duration of amnesia in patients with TGA (R = 0.187, P = .274). We find no differences in the glymphatic system function, as demonstrated by ChP volume for the first time. This study also found a significant correlation between ChP volume and age in patients with TGA, indicating that aging influences glymphatic system function.
Dural arteriovenous fistula may be occluded through recanalization of impaired venous sinuses
Authors: Zhao Tong-Yuan , Xu Gang-Qin , Chen Zhong-Can , Xue Jiang-Yu , Cai Dong-Yang , Yang Bo-Wen , Li Tian-Xiao , Gao Bu-Lang
Published: October 2024

To investigate the effect and safety of recanalization of stenosed or occluded venous sinuses for dural arteriovenous fistulas (DAVFs) and possible mechanism of DAVF formation, patients with DAVF accompanied by venous sinus stenosis or occlusion treated with balloon angioplasty and/or stenting were retrospectively enrolled. The clinical data, treatment outcomes and complications were analyzed. In 7 patients enrolled, the DAVF was Cognard IIa grade in 3 (42.9% or 3/7) and IIa + b in 4 (57.1% or 4/7) patients, including complex DAVFs in 2 (28.6% or 2/7). The angioplasty procedure was successful in all (100%) patients, including complete cure in 3 (42.9% or 3/7) patients with the initial Cognard grade IIa, transformation from Cognard grade IIa + b to I in 2 (28.6% or 2/7) patients, and unchanged Cognard grade IIa + b in 2 (28.6% or 2/7) patients. The symptoms were all improved. At 3-month angiographic follow-up, 5 (71.4% or 5/7) cases were cured, whereas 2 cases still had grade I fistulas but no clinical symptoms. Staged embolization in 2 patients resulted in significant symptom improvement. At the last follow-up of a median 4 years, no clinical symptoms were present in 5 (71.4% or 5/7) patients, intermittent headache in 1 (14.3% or 1/7), and death from trauma in 1 (14.3% or 1/7). In conclusion, endovascular recanalization of occluded or stenosed venous sinuses using balloon angioplasty and stenting is able to induce occlusion of DAVFs and is a safe and efficient treatment approach for DAVFs which are possibly caused by significant pressure increase.
A Chinese CADASIL family with a rare heterozygous mutation in exon 2 of NOTCH3: A case report
Authors: Guo Jingrong , Liu Lulu , Yan Minli
Published: October 2024

Rationale:

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease caused by the neurogenic locus notch homolog protein 3 (NOTCH3) gene mutation. In recent years, most of the newly reported mutations of CADASIL patients mainly occur in exon 3 to 24, while the cases related to exon 2 mutation are rare, and clinical research data are relatively insufficient. In this study, we have reported a case of a rare heterozygous mutation c.128G>A (p.Cys43Tyr) in exon 2 of NOTCH3 in a 41-year-old Chinese man in the light of relevant literatures.

Patient concerns:

A 41-year-old man who suffered slurred speech for 5 days and right lower limb weakness for 4 days was admitted to our hospital.

Diagnoses:

Magnetic resonance imaging of the head revealed diffuse white matter lesions involving the outer capsular area and bilateral temporal poles. The rare heterozygous mutation c.128G>A (p.Cys43Tyr) in exon 2 of NOTCH3 was identified through molecular genetic testing. The proband was diagnosed as having CADASIL. Meanwhile, the same mutation was detected in 2 other family members III5 and IV9.

Interventions:

Atorvastatin calcium tablet (20 mg qd) and aspirin enteric-coated tablet (100 mg qd).

Outcomes:

The patient was hospitalized for 3 weeks and discharged after his symptoms improved.

Lessons:

The heterozygous Cys43Tyr mutation in exon 2 of NOTCH3 is rare. Thus, our case report complements the rare mutation of exon 2 and offers additional clinical data for CADASIL patients.
Comparative diagnostic utility of Rockall and Glasgow-Blatchford scores in non-variceal upper gastrointestinal bleeding: a systematic review and meta-analysis
Authors: Kozai Landon , Tan Arvin , Nebrejas Kevin , Nishimura Yoshito
Published: October 2024

Introduction

The Rockall score and Glasgow-Blatchford score (GBS) are two scoring systems validated in the evaluation of upper gastrointestinal bleeding (UGIB). However, no meta-analysis exists to summarize the current data and clarify the use of Rockall score and GBS focusing on non-variceal UGIB. We aimed to evaluate and compare the utility of the Rockall score and GBS in predicting clinical outcomes in non-variceal UGIB.

Methods

We conducted a systematic review and meta-analysis, searching the MEDLINE and EMBASE databases for all peer-reviewed articles using the terms including ‘Glasgow-Blatchford’, ‘Rockall’, and ‘gastrointestinal bleed’ from their inception to 22 March 2023. Outcomes included mortality, rebleeding, need for blood transfusion, and need for surgical intervention.

Results

Seven studies with 755 participants with non-variceal bleeding were included in the analysis. Pooled analysis demonstrated no difference in the area under the receiver operating characteristic (AUROC) between GBS and Rockall score to predict mortality [weighted mean difference (WMD) = 0.01, 95% CI: −0.06 to 0.08] or rebleeding (WMD = 0.04, 95% CI: −0.03 to 0.11). GBS had a higher AUROC to predict the outcomes compared to Rockall score for the needs for transfusion (WMD = 0.09, 95% CI: 0.01–0.16) and surgical intervention (WMD = 0.21, 95% CI: 0.14–0.29).

Conclusion

The GBS could be superior to the Rockall score in predicting the needs for transfusion and surgical intervention in non-variceal UGIB. However, both scores demonstrate low performance for predicting mortality or rebleeding.
Comparative Assessment of Outcomes
Authors: Ahmed Aleena , Fatima Maurish , Khan Muhammad Hammad , Faisal Muhammad Hashim , Sehar Ayesha , Khan Muhammad Jahanzaib , Aziz Hassan
Published: October 2024

Objective:

This systematic review and meta-analysis aimed to compare outcomes between abdominal drain placement and no drain placement post-pancreatectomy

Background:

Left pancreatectomy (LP) is a surgical procedure commonly employed for various pancreatic conditions, often associated with postoperative complications like post-operative pancreatic fistula (POPF). While routine abdominal drainage following LP has been standard practice, recent evidence suggests potential benefits of omitting this approach.

Methods:

A comprehensive search was conducted on PubMed, Cochrane, and Embase from inception up to 15 March 2024, yielding nine studies comprising 15,817 patients. Data were extracted from randomized and non-randomized studies reporting primary and secondary outcomes. The analysis was performed in Revman. Risk ratios were calculated with 95% confidence intervals, and a P-value of <0.05 was considered statistically significant.

Results:

A total of 13,081 patients underwent drain placement after left pancreatectomy, and 2,736 patients were included in the no-drain group. Out of the total, 45.1% (n=7140) patients were male, with 45.9% (n=6012) males in the drain group and 41.2% (n=1128) males in the no-drain group. Major morbidity, defined as Clavien-Dindo grade ≥III complications, was significantly lower in the no-drain group (relative risk [RR]: 0.77, 95% confidence interval [CI]: 0.64–0.93, P=0.006). Similarly, lower rates of postoperative pancreatic fistula (POPF) (RR: 0.51, 95% CI: 0.38–0.67, P<0.00001), readmission (RR: 0.75, 95% CI: 0.59–0.96, P=0.02), and surgical site infections (RR: 0.82, 95% CI: 0.70–0.95, P=0.009) were observed in the no-drain group. Additionally, a shorter length of hospital stay was noted in this group (mean difference MD: –1.65, 95% CI: –2.50 to –0.81, P=0.0001).

Conclusions:

Omitting routine drainage after left pancreatectomy is associated with reduced complications and shorter hospital stays, supporting its potential benefits in improving postoperative outcomes.
Novel hot spring Nitrososphaera support vertical inheritance of ammonia oxidation & carbon fixation in Thaumarchaeota
Authors: Slosser T , Wenick M , Markert E , Trembath-Reichert E , Ward L M
Published: October 2024

Aerobic ammonia oxidation is crucial to the nitrogen cycle and is only known to be performed by a small number of bacterial lineages (Ammonia Oxidizing Bacteria, or AOB) and a single clade of archaea belonging to the Nitrososphaera class of Thaumarchaeota (Ammonia Oxidizing Archaea, or AOA). Most cultivated AOA originate from marine or soil environments, but this may capture only a limited subset of the full diversity of this clade. Here, we describe several genomes of AOA from metagenomic sequencing of a hot spring microbial mat, representing several poorly characterized basal lineages that may be important for understanding the early evolution of archaeal ammonia oxidation. These genomes include a novel genus most closely related to Nitrosphaera as well as novel species belonging to the genera Nitrosotenuis, Nitrososphaera, and Nitrosotalea. Furthermore, the distributions and phylogenetic relationships of key metabolic genes support a history of vertical inheritance of ammonia oxidation and carbon fixation from the last common ancestor of crown group AOA.
Genomics unveils country-to-country transmission between animal hospitals of a multidrug-resistant and sequence type 2 Acinetobacter baumannii clone
Authors: André Amédée , Plantade Julie , Durieux Isabelle , Durieu Pauline , Godeux Anne-Sophie , Decellieres Maxence , Pouzot-Nevoret Céline , Venner Samuel , Charpentier Xavier , Laaberki Maria-Halima
Published: October 2024

Acinetobacter baumannii is a globally distributed opportunistic pathogen in human health settings, including in intensive care units (ICUs). We investigated the contamination of a French small animal ICU with A. baumannii. We discovered repeated animal contamination by A. baumannii, and phylogenetic analysis traced contamination back to a potential foreign animal origin. Genomic analysis combined with antibiotic susceptibility testing revealed heteroresistance to penicillin and aminoglycoside mediated by insertion sequence dynamics and also suggest a potential cross-resistance to human-restricted piperacillin–tazobactam combination. The A. baumannii isolates of the animal ICU belong to the International Clone 2 commonly found in human health settings. Our results suggest a high adaptation of this lineage to healthcare settings and provide questions on the requirements for genetic determinants enabling adaptation to host and abiotic conditions.
Bacterial sensing via Neuronal Receptor Initiates Gut Mitochondrial Surveillance for Host Adaptation
Authors: Liu Huimin , Chen Panpan , Yang Xubo , Hao FanRui , Tian Guojing , Shan Zhao , Qi Bin
Published: October 2024

Animals exist within a microbial world and are constantly challenged by pathogen infections. Microbe-mediated protection for against infection is the survival strategy for host. However, elucidating specific microbial molecules and understanding how they interact with the host’s intracellular surveillance system for protection is difficult but highly desirable. Here, by establishing “pathogen-like-bacteria” screening system, we identifiedE. colimutants, including ΔymcB, that act as “pathogen-like-bacteria” to defend animals againstPseudomonas aeruginosaPA14 infection by activating UPRmt. Additionally, through genetic screening, we identified neuronal transmembrane protein, MDSS-1, that is crucial for sensing ΔymcBand activating intestinal UPRmt. Moreover, we demonstrated that MDSS-1 functions as a receptor in ASE neurons, responsible for detecting ΔymcB. It then communicates microbial signals through neuropeptides, GPCR, Wnt signaling and endopeptidase inhibitors to trigger intestinal UPRmt, that defends the host animals against infections. Furthermore, Constitutionally activation of MDSS-1 in ASE neurons is sufficient to trigger intestinal UPRmtin animals, resulting in protection against infection. Our study uncovers an intriguing mechanism involving intracellular mitochondrial surveillance, where neuron-intestine crosstalk originates from ASE neurons to detect bacteria and combat pathogens. This study identifies a bacteria-sensing mechanism in neurons that regulates intestinal mitochondrial surveillance pathway for host adaptation.

Highlights

Establishment of “pathogen-like-bacteria” screening system inC. elegans

ΔymcBpromotes animal defend against infections via triggering UPRmt

Neuronal MDSS-1, a single transmembrane protein, detects “pathogen-like-bacteria”

Activated-MDSS-1 induces distant UPRmtvia inter-tissue communication factors
Insights into the Molecular Mechanism of Pulmonary Vein Stenosis in Pediatric Patients
Authors: Kalustian Alyssa B , Ji Pengfei , Wadhwa Lalita , Caldarone Christopher A. , Bansal Manish , Qureshi Athar M. , Heinle Jeffrey S. , Birla Ravi K.
Published: October 2024

Background

Pediatric pulmonary vein stenosis (PVS) is associated with substantial morbidity and mortality for the subset of patients with recurrent or progressive disease. The molecular mechanisms underlying the development and trajectory of PVS remain unclear. This study characterizes the transcriptome of clinical and phenotypic subtypes of PVS.

Methods

Bulk RNA sequencing analysis was performed on human pulmonary vein tissue samples obtained from surgical interventions for pediatric patients with PVS. Transcriptomic profiles were compared for primary versus post-repair PVS as well as aggressive versus non-aggressive clinical phenotypes. Principal component analysis was performed, the differential gene expression quantified, and pathway analysis conducted based on gene ontology, KEGG and Reactome.

Results

When comparing AggPPVS vs NonAggPPVS, differences were noted in the genes associated in extracellular matrix regulation and PIEZO1, a mechanosensitive receptor present in endothelial cells. In addition, there were notable changes in cardiac muscle contractility, calcium handling, respiratory and energy metabolism. These results point to a potential mechanism for aggressive PPVS phenotype, due to an overexpression of PIEOZ1 in response to elevated shear stress, subsequent activation of intracellular signaling pathways and leading to reduced contractility and intracellular calcium transients with cardiomyocytes.

Conclusions

The result of this study suggests that aggressive PPVS phenotype is caused by an increase in PIEZO1 expression and subsequent changes in extracellular matrix production, heart muscle contractility and changes in calcium transients within cardiomyocytes. These results provide a potential target for therapeutic invention for primary PPVS by inhibiting the activity of PIEZO1. This could potentially reduce morbidity in this patient population.
Granulocyte colony-stimulating factor protects against arthritogenic alphavirus pathogenesis in a type I IFN-dependent manner
Authors: Hameed Muddassar , Hossain Md Shakhawat , Daamen Andrea R. , Lipsky Peter E. , Weger-Lucarelli James
Published: October 2024

Arthritogenic alphaviruses cause disease characterized by fever, rash, and incapacitating joint pain. Alphavirus infection stimulates robust inflammatory responses in infected hosts, leading to the upregulation of several cytokines, including granulocyte colony-stimulating factor (G-CSF). G-CSF is secreted by endothelial cells, fibroblasts, macrophages, and monocytes and binds to colony stimulating factor 3 receptor (CSF3R, also known as G-CSFR) on the surface of myeloid cells. G-CSFR signaling initiates proliferation, differentiation, and maturation of myeloid cells, especially neutrophils. Importantly, G-CSF has been found at high levels in both the acute and chronic phases of chikungunya disease; however, the role of G-CSF in arthritogenic alphavirus disease remains unexplored. Here, we sought to test the effect of G-CSF on chikungunya virus (CHIKV) and Mayaro virus (MAYV) infection using G-CSFR-deficient mice (G-CSFR−/−). We observed sustained weight loss in G-CSFR−/−mice following viand MAYV infection compared to wild-type mice. Furthermore, G-CSFR−/−mice had a significantly higher percentage of inflammatory monocytes and reduction in neutrophils throughout infection. The difference in weight loss in G-CSFR−/−mice induced by alphavirus infection was corrected by blocking type I IFN signaling. In summary, these studies show that type I IFN signaling contributes to G-CSFR mediated control of arthritogenic alphavirus disease.
CandyCollect: An Open-Microfluidic Device for the Direct Capture and Enumeration of Salivary-Extracellular Vesicles
Authors: Pierce Corinne , Suryoraharjo Kezia , Robertson Ingrid H. , Su Xiaojing , Hatchett Daniel B. , Shin Albert , Adams Karen N. , Berthier Erwin , Thongpang Sanitta , Ogata Alana , Theberge Ashleigh B. , Sohn Lydia L.
Published: October 2024

Extracellular Vesicles (EVs) are membrane-derived vesicles shed by cells into the extracellular space that play key roles in intercellular communication and other biological processes. As membrane-bound cargos of nucleic acids and other proteins that are abundantly found in virtually every biofluid including blood, urine, and saliva, EVs are widely regarded as promising biomarkers for disease detection. While it is an increasingly promising biofluid from which to isolate EVs, saliva poses challenges due its complexity and heterogeneity—cells, debris, and other proteins can inhibit the isolation of EVs by traditional platforms. Here, we employ the CandyCollect, a lollipop-inspired sampling device with open microfluidic channels, as a non-invasive and patient-friendly alternative for the capture of salivary EVs. The CandyCollect simplifies sample preparation by effectively pre-concentrating EVs on the device surface before EVs are eluted off of the CandyCollect, labeled with cholesterol-tagged oligonucleotides, and subsequently detected by qPCR with primers specific for the tagged oligos to enumerate the relative number of EVs. We demonstrate that downstream EV cargo analysis can be performed using Simoa. Overall, the CandyCollect ushers a new method to capture, enumerate, and analyze salivary EVs.
Lack of evidence for the contribution of cone photoreceptors to human melatonin suppression and alerting response to light at night
Authors: Fazlali Fatemeh , Lazar Rafael , Yahya Faady , Epple Christian , Spitschan Manuel , Stefani Oliver , Cajochen Christian
Published: October 2024

Light exposure at night can suppress melatonin production and increase alertness, primarily through the action of melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs). This study investigated whether cone photoreceptors also influence melatonin suppression and subjective alertness using non-visual metameric light emitted from a display. Forty-eight participants with normal trichromatic vision were exposed to three lighting conditions: a baseline (9 lxmEDI), constant background (149 lxmEDI), and cone-modulated flickering light targeting different cone combinations and post-receptoral channels (149 lxmEDI) for 2 hours after their habitual bedtime. Salivary melatonin levels and subjective alertness were measured throughout a 9-h protocol. Bayesian analysis showed that cone-modulated flickering light did not significantly affect melatonin suppression or alertness, providing evidence against the hypothesis that cone photoreceptors contribute to these non-visual effects of light. In conclusion, our results suggest cone photoreceptors do not play a measurable role in light’s effects on melatonin suppression and subjective alertness at night.
Comparative single-cell analyses reveal evolutionary repurposing of a conserved gene program in bat wing development
Authors: Schindler Magdalena , Feregrino Christian , Aldrovandi Silvia , Lo Bai-Wei , Monaco Anna A. , Ringel Alessa R. , Morales Ariadna , Zehnder Tobias , Behncke Rose Yinghan , Glaser Juliane , Barclay Alexander , Andrey Guillaume , Kragesteen Bjørt K. , Hägerling René , Haas Stefan , Vingron Martin , Ulitsky Igor , Marti-Renom Marc , Hechavarria Julio , Fasel Nicolas , Hiller Michael , Lupiáñez Darío , Mundlos Stefan , Real Francisca M.
Published: October 2024

Bats are the only mammals capable of self-powered flight, an evolutionary innovation based on the transformation of forelimbs into wings. The bat wing is characterized by an extreme elongation of the second to fifth digits and a wing membrane calledchiropatagiumconnecting them. Here we investigated the developmental and cellular origin of this structure by comparing bat and mouse limbs using omics tools and single-cell analyses. Despite the substantial morphological differences between the species, we observed an overall conservation of cell populations and gene expression patterns including interdigital apoptosis. Single-cell analyses of micro-dissected embryonic chiropatagium identified a specific fibroblast population, independent of apoptosis-associated interdigital cells, as the origin of this tissue. These distal cells express a conserved gene program including the transcription factorsMEIS2andTBX3, which are commonly known to specify and pattern the early proximal limb. Transgenic ectopic expression ofMEIS2andTBX3in mouse distal limb cells resulted in the activation of genes expressed during wing development and phenotypic changes related to wing morphology, such as the fusion of digits. Our results elucidate fundamental molecular mechanisms of bat wing development and illustrate how drastic morphological changes can be achieved through repurposing of existing developmental programs during evolution.
Inhibition of the transcription factor PU.1 suppresses tumor growth in mice by promoting the recruitment of cytotoxic lymphocytes through the CXCL9-CXCR3 axis
Authors: Sleapnicov Nichita , Ha Soon-Duck , Zhong Shanshan Jenny , Duchscher Jackie , Ezra Sally , Li Shawn Shun-Cheng , Kim Sung O.
Published: October 2024

Tumor-associated macrophages (TAMs) are among the most abundant immune cells associated with tumors, which often exhibit immune regulatory phenotypes that promote tumor growth and confer resistance to anti-tumor immune therapies. Despite extensive efforts in developing immunotherapeutic strategies aimed at controlling the recruitment or reprogramming of TAMs, success has been limited due to strategic caveats, underscoring the need for a novel approach targeting the TAMs. PU.1, a lineage-dependent transcription factor, is highly expressed throughout the lifespan of macrophages. We have found that inhibition of PU.1 by the small molecule DB2313 suppresses melanoma tumor growth in mice through enhanced tumor recruitment of CD4+ T helper cells and cytotoxic T/NK cells mediated by TAMs. Whole transcriptome and targeted gene expression analyses revealed that DB2313 upregulates CXCL9 expression in bone marrow-derived macrophages (BMDMs) and TAMs. The anti-tumor effects of DB2313 were abolished by depleting macrophages with clodronate or inhibiting the CXCL9-CXCR3 chemokine axis using neutralizing antibodies against CXCL9 or CXCR3. Collectively, these results suggest that pharmacological inhibition of PU.1 suppresses tumor growth by promoting tumor infiltrating lymphocytes through the CXCL9-CXCR3 chemokine axis. Our study establishes a framework for developing TAM-modulating immunotherapies by targeting the transcriptional factor PU.1.
Exploring the Pharmacological Potential of Kaurenoic Acid Produced via Synthetic Biology
Authors: Pimentel Lígia L. , Teixeira Francisca S. , Soares Ana M. S. , Costa Paula T. , Fontes Ana Luiza , Vidigal Susana S. M. P. , Pintado Manuela E. , Rodríguez-Alcalá Luis M.
Published: October 2024

Background

Kaurenoic acid (KA) is a bioactive diterpenoid commonly found in traditional medicinal plants such as Copaifera species, widely used in Amazonian ethnomedicine for its anti-inflammatory and antimicrobial properties. However, the sustainable supply of KA is limited due to environmental pressures and its complex extraction process from natural sources. Synthetic biology presents an innovative solution for producing KA, potentially reducing environmental impact while maintaining its traditional medicinal value.

Aim of the study

This work discusses the potential bioactive properties of kaurenoic acid (KA) obtained through synthetic biology. While ethnopharmacological studies have highlighted the anti-inflammatory and antimicrobial effects of plant extracts containing KA, limited research has focused on the pure compound due to its cost and limited availability.

Materials and methods

The study employed quantitative structure-activity relationship (QSAR) modeling and in vitro assays to investigate the anti-inflammatory and antimicrobial activities of S-KA and KNa. Physicochemical characterization, including Fourier transform infrared spectroscopy (FTIR-ATR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD), was conducted to compare structural properties and purity with G-KA. Additionally, solubility studies were performed across various solvents to assess the potential for different bioapplications.

Results

Purity assessments revealed 99.06% for S-KA versus 98.83% for a commercial standard. In silico calculations indicated that KA is hydrophobic. Solubility tests prompted the synthesis of a sodium salt derivative (KNa), increasing water solubility. Experimental evaluations demonstrated that S-KA and KNa exhibited similar (IL-6, IL-8) anti-inflammatory activity compared to betamethasone, and growth inhibition was observed against Staphylococcus aureus and Staphylococcus epidermidis.

Conclusion

These findings highlight that kaurenoic acid from fermentation offers a sustainable alternative to naturally sourced KA with comparable bioactivity. The sodium salt derivative (KNa) enhances water solubility, expanding its potential for pharmacological applications. This study highlights the relevance of synthetic biology in preserving traditional medicinal knowledge while promoting environmental sustainability.
The evolution of root hydraulic traits in wheat over 100 years of breeding
Authors: Baca Cabrera Juan C. , Vanderborght Jan , Boursiac Yann , Behrend Dominik , Gaiser Thomas , Nguyen Thuy Huu , Lobet Guillaume
Published: October 2024

Wheat (Triticum aestivumL.) plays a vital role in global food security, and understanding its root traits is essential for improving water uptake under varying environmental conditions. This study investigates how breeding over a century has influenced root morphological and hydraulic properties in six German winter wheat cultivars released between 1895 and 2002. Field and hydroponic experiments were used to measure root diameter, root number, branching density, and whole root system hydraulic conductance (Krs). Results showed a significant decline in root axes number andKrsover time, while root diameter remained stable across cultivars. Additionally, dynamic functional-structural modeling using the whole-plant model CPlantBox was employed to simulate the development ofKrswith root system growth, revealing that older cultivars consistently had higher hydraulic conductance than modern ones. The combined approach of field phenotyping and modeling provided a comprehensive view of the changes in root traits with breeding. These findings suggest that breeding may have unintentionally favored cultivars with smaller root systems and more conservative water uptake strategies, under the high-input, high-density conditions of modern agriculture. The lessons from this study may inform future breeding efforts aimed at optimizing wheat root systems, helping to develop cultivars with water uptake better tailored to locally changing environmental conditions.
Latitudinal clines in climate and sleep patterns shape disease outcomes inDrosophila melanogasterinfected byMetarhizium anisopliae
Authors: Nan Mintong , Wang Jonathan B. , Siokis Michail , St. Leger Raymond J.
Published: October 2024

Major latitudinal clines have been observed inDrosophila melanogaster, a human commensal that originated in tropical Africa and has spread world-wide to colonize temperate habitats. However, despite the significant impact of pathogens on species distribution, the influence of geographical factors on disease susceptibility remains poorly understood. This study investigated the effects of latitudinal clines and biomes on disease resistance using the common fly pathogenMetarhizium anisopliaeand 43 globalDrosophila melanogasterpopulations. The results showed that disease resistance was correlated with latitudinal gradients of sleep duration, temperature and humidity. While fungal diversity at tropical latitudes may drive enhanced defenses, the most disease-resistant males were also the most susceptible to desiccation, indicating potential trade-offs between abiotic stress resistance, necessary for survival in temperate habitats, and disease resistance. The study also found that sex, mating status, and sleep interacted with abiotic stresses to impact disease resistance, with longer-sleeping males and virgin flies surviving infections longer, and extra daytime sleep post-infection being protective, especially in the most resistant fly lines. These findings promote the idea that sleep and defense against disease are intertwined traits related to organismal fitness and subject to joint clinal evolution.

Abstract Figure
CLCFM3: An advanced photogrammetry algorithm for high-precision plant 3D modeling
Authors: Hayashi Atsushi , Kochi Nobuo , Kodama Kunihiro , Isobe Sachiko , Tanabata Takanari
Published: October 2024

This research aims to develop a novel technique to acquire a large amount of high-density, high-precision 3D point cloud data for plant phenotyping using photogrammetry technology. The complexity of plant structures, characterized by overlapping thin parts such as leaves and stems, makes it difficult to reconstruct accurate 3D point clouds. One challenge in this regard is occlusion, where points in the 3D point cloud cannot be obtained due to overlapping parts, preventing accurate point capture. Another is the generation of erroneous points in non-existent locations due to image-matching errors along object outlines. To overcome these challenges, we propose a 3D point cloud reconstruction method, CLCFM3 (Closed-Loop Coarse-to-Fine method with Multi-Masked Matching). This method repeatedly executes a process that generates point clouds locally to suppress occlusion (multi-matching) and a process that removes noise points using a mask image (masked matching). Furthermore, we propose the Closed-Loop Coarse-to-Fine Method (CLCFM) to improve the accuracy of structure from motion, which is essential for implementing the proposed point cloud reconstruction method. CLCFM solves loop-closure by performing coarse-to-fine camera position estimation. By facilitating the acquisition of high-density, high-precision 3D data on a large number of plant bodies, as is necessary for research activities, this approach is expected to enable comparative analysis of visible phenotypes in the growth process of a wide range of plant species based on 3D information.
Integrated Molecular Profiling of Rhabdomyosarcoma Subtypes by Targeted RNAseq
Authors: Avenarius Matthew R , Patton Ashley , Mohamed Nehad , Pan Xiaokang , Jones Dan
Published: October 2024

All subtypes of rhabdomyosarcoma (RMS) show skeletal muscle differentiation but each has different oncogenic mechanisms including recurrentPAX3andPAX7gene fusions (alveolar), a hotspot mutation inMYOD1(spindle/sclerosing) and mutations in other oncogenes and tumor suppressors (embryonal, pleomorphic). This range of genomic findings typically requires several different DNA and RNA-based diagnostic assays. Here, we utilize a clinically validated, targeted RNA next-generation sequencing (RNAseq) panel to simultaneously detectMYOD1transcript levels for lineage assignment,PAX3andPAX7translocations and mutations inMYOD1and other RMS-related genes for definitive subtyping in a single assay. RNA-based detection ofMYOD1p.L122R and other mutations were orthogonally validated with digital droplet (dd)PCR or DNA-based NGS. Expanding the utility of clinical-grade RNAseq data beyond the detection of gene fusions is a cost-effective and time-efficient approach for more comprehensive screening of RMS.

Impact statement

Comprehensive and rapid molecular diagnostics is a key driver in the selection and initiation of targeted therapies.
The dinucleotide structure of NAD enables specific reduction on mineral surfaces
Authors: Henriques Pereira Delfina P. , Xie Xiulan , Beyazay Tuğçe , Paczia Nicole , Subrati Zainab , Belz Jürgen , Volz Kerstin , Tüysüz Harun , Preiner Martina
Published: October 2024

Nucleotide-derived cofactors could function as a missing link between the informational and the metabolic part at life’s emergence. One well-known example is nicotinamide dinucleotide (NAD), one of the evolutionarily most conserved redox cofactors found in metabolism. Here, we propose that the role of these cofactors could even extend to missing links between geo- and biochemistry. We show NAD+can be reduced under close-to nature conditions with nickel-iron-alloys found in water-rock-interaction settings rich in hydrogen (serpentinizing systems) and that nicotinamide mononucleotide (NMN), a precursor molecule to NAD, has different properties regarding reduction specificity and sensitivity than NAD. The additional adenosine monophosphate (AMP) “tail” of the dinucleotide, a shared trait between many organic cofactors, seems to play a crucial mechanistic role in preventing overreduction of the nicotinamide-bearing nucleotide. This specificity is also connected to the used transition metals. While the combination of nickel and iron promotes the reduction of NAD+to 1,4-NADH most efficiently, in the case of NMN, the presence of nickel leads to the accumulation of overreduction products. Testing the reducing abilities of both NADH and NMNH under abiotic conditions showed that both molecules act as equally effective, soluble hydride donors in non-enzymatic, proto-metabolic stages of life’s emergence.
Limitations of ad hoc genotyping in detecting ash dieback tolerance in Fraxinus excelsior
Authors: Szukala Aglaia , Unger Gregor , Trujillo-Moya Carlos , Geburek Thomas , Kirisits Thomas , Schueler Silvio , Konrad Heino
Published: October 2024

Ash dieback (ADB), caused by the invasive alien fungal pathogen Hymenoscyphus fraxineus, is an emerging disease that poses major threats to the survival of common ash (Fraxinus excelsior) in Europe. Here, we report on a field trial aiming at the identification of ADB tolerant genotypes while encompassing the genetic diversity of common ash in Austria. Over 35,000 progenies from more than 600 putative tolerant mother trees were assessed for ADB symptoms over a period of three years. One tolerant and one susceptible progeny from a subset of the mother tree range (570 trees) were genotyped using the 4TREE array, a genotyping tool developed specifically to screen common ash provenances for their tolerance to ash dieback. We aimed to (1) better characterize the genetic structure of common ash in Austria, (2) identify hybrids between common ash and F. angustifolia (narrow-leaved ash), (3) detect genetic loci associated with tolerance to ADB, and (4) identify genetic variation associated with abiotic factors such as temperature and precipitation influencing the severity of ADB. We identify ash individuals from Eastern Austria matching putative hybrids with F. angustifolia showing varying degrees of F. angustifolia ancestry in structure analyses. The non-hybrid gene pool is characterized by shallow genetic structure following a west to east geographic pattern. In contrast to our expectations, genotype-damage association analyses overall fail to detect SNPs associated with tolerance to ADB. Our findings underscore that the polygenic architecture governing tolerance and the rapid decay of genomic linkage disequilibrium (LD) (within approximately 10 kb) significantly limit the ability to identify association outliers using the 4TREE SNP array. This highlights the constrained utility of chip genotyping approaches for this specific purpose. In contrast, the array proves successful in detecting hybrids between common ash and narrow-leaved ash, as well as outlier SNPs associated with abiotic predictors (such as annual precipitation and temperature) known to influence the severity of ADB damage.
Methylparaben dampens virulence and transmissibility of theDrosophilapathogenPseudomonas entomophila
Authors: Henry Youn , Canal-Domènech Berta , La Mendola Christine , Kawecki Tadeusz J.
Published: October 2024

In the last 20 years,Pseudomonas entomophila(Pe) has emerged as a model to explore insect immunity to bacterial intestinal pathogens. Laboratory studies evidenced multiple detrimental effects of Pe onDrosophila melanogaster. However, these effects require that the bacteria are ingested in extremely high concentrations of 1010– 1011CFU per mL (OD60020 – 200), questioning the relevance of this pathogen in nature. Here, we tested whether the need for such high doses may be due to protective effects of the food preservative methylparaben (Nipagin), a standard ingredient of artificialDrosophiladiets. While significant mortality in flies fed diet containing standard methylparaben concentration required doses of >1010CFU per mL, when methylparaben was absent we could observe mortality using 500,000× lower doses. Consistent with these results, we demonstrated strong bactericidal properties of methylparaben on Pein vitro. In the absence of methylparaben even the smallest inocula (105CFU per mL) led to high bacterial loads (106CFU per fly) after several days, indicating the ability of Pe to grow and overcome the flies’ defenses. We also demonstrate that in the absence of methylparaben, infected flies could easily transmit the pathogen to other adults and to offspring, resulting in high mortality and thus highlighting the potential of Pe as a pathogen ofDrosophilain nature. Our study also underscores that careful consideration should be given to food additives used in standard diets in laboratory research on host-pathogen interaction.

Importance

Accurate characterization of pathogen infections requires appropriate experimental methodologies. Infections of insects with Pe are frequently studied using fruit flies as a model organism, with laboratory cultures typically maintained on artificial media containing various food preservatives. In this study, we show that one commonly used preservative, methylparaben, significantly influences the outcome of oral infections with Pe. We found that minimal infection doses, far below the standards of the field, could be still lethal to flies raised on media without methylparaben. This increased virulence was also associated with increased transmission of the pathogen, both from infected adult flies to their offspring and to uninfected adults. Our findings show how subtle variations in experimental conditions can profoundly affect how we perceive pathogenic threats.
Comparative impact of porcine reproductive and respiratory virus and swine influenza A virus infections on respiratory lymph nodes B cells and macrophages
Authors: Hervet C. , Perrin A. , Renson P. , Deblanc C. , Muñoz M. , Meurens F. , Argilaguet J. , Simon G. , Bourry O. , Maisonnasse P. , Bertho N.
Published: October 2024

Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) strongly impacts the pig rearing sector due to its persistence in infected animals. Interestingly, although the PRRSV family exhibits considerable genome variability, with the PRRSV-1 and PRRSV-2 subtypes having been finally classified in two different species (Betaarterivirus suid 1 and 2). Both viruses, as well as their derived-attenuated vaccine strains, persist for months, due in part to their ability to delay the appearance of neutralizing antibodies. Thanks to extensive efforts over the past years, we have developed the capability to perform in-depth analysis of the previously poorly understood porcine inverted lymph node (LN). In this study, by comparing the early stages of LN B cell maturation upon PRRSV-1 infection to those induced upon the acute swine influenza A virus infection, we highlighted PRRSV-specific mechanisms, including the expression of PD-L1 in efferent macrophages, the induction of extrafollicular plasmocytes, and the influx of inflammatory monocytes/macrophages. Studies on PRRSV-2 infections report observations compatible with our results, that thus might be generalized to all PRRSV-strains. Moreover, these mechanisms can be compared with those used by the human immunodeficiency virus (HIV) and the murine chronic lymphocytic choriomeningitis virus (LCMV) to hijack the immune response. These similarities can be harnessed to develop new strategies to improve the development of more efficient anti-PRRSV vaccines.
Directional Immobilisation of SpyTag Bacteriophage on PDMS surfaces for Phage based Microfluidics
Authors: Liyanagedera Sahan B.W. , Williams Joshua , Wheatley Joseph P. , Biketova Alona Yu , Sagona Antonia P. , Feher Tamas , Kulkarn Vishwesh
Published: October 2024

The increasing incidence of bacterial infections caused by antibiotic-resistant pathogens worldwide underlines the need to develop novel diagnostic tools enabling the early initiation of targeted antimicrobial therapy. One promising possibility is to unite the high specificity and sensitivity of phage-based applications with the speed and sensitivity provided by microfluidic devices. As a prerequisite of developing such systems, we aimed at the directional immobilization of phages on the surface of Polydimethylsiloxane (PDMS), a material commonly used for building such devices. Our work utilised the covalent interaction between two proteins: SpyTag, genetically encoded on the capsid of the phage, and BslA-SpyCatcher fusion protein, purified and surface displayed on PDMS. We demonstrate a simple methodology for the directional tail up immobilisation of SpyTagged Phage on to user defined locations on the surface of a PDMS device and subsequent on chip capture and infection of a cognate host. Our technique serves to illustrate a generally applicable solution to develop the next generation of phage based bio-sensors.
Human brain changes after first psilocybin use
Authors: Lyons T , Spriggs M , Kerkelä L , Rosas FE , Roseman L , Mediano PAM , Timmermann C , Oestreich L , Pagni BA , Zeifman RJ , Hampshire A , Trender W , Douglass HM , Girn M , Godfrey K , Kettner H , Sharif F , Espasiano L , Gazzaley A , Wall MB , Erritzoe D , Nutt DJ , Carhart-Harris RL
Published: October 2024

Psychedelics have robust effects on acute brain function and long-term behavior but whether they also cause enduring functional and anatomical brain changes is unknown. In a placebo-controlled, within-subjects, electroencephalography, and magnetic resonance imaging study in 28 healthy, entirely psychedelic-naive participants, anatomical and functional brain changes were detected from one-hour to one-month after a single high-dose (25 mg) of psilocybin. Increases in cognitive flexibility, psychological insight, and well-being were seen at one-month. Diffusion imaging done before and one-month after 25mg psilocybin revealed decreased axial diffusivity bilaterally in prefrontal-subcortical tracts that correlated with decreased brain network modularity over the same time period. Decreased modularity also correlated with improved well-being. Increased cortical signal entropy at 1– and 2-hours post-dosing predicted improved psychological well-being at one-month. Next-day psychological insight mediated the entropy to well-being relationship. All effects were exclusive to 25mg psilocybin; no effects occurred with a 1mg psilocybin ‘placebo’ dose.