bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms Of Meristem Maintenance By Maize Transcriptional Corepressors
Authors: Gregory Jason , Liu Xue , Chen Zongliang , Gallardo Cecilia , Punskovsky Jason , Koslow Gabriel , Galli Mary , Gallavotti Andrea
Published: April 2024

The formation of the plant body proceeds in a sequential post-embryonic manner through the action of meristems. Tightly coordinated meristem regulation is required for development and reproductive success, eventually determining yield in crop species. In maize, the REL2 family of transcriptional corepressors includes four members, REL2, RELK1 (REL2-LIKE1), RELK2, and RELK3. In a screen forrel2enhancers, we identified shorter double mutants with enlarged female inflorescence meristems (IMs) carrying mutations inRELK1. Expression and genetic analysis indicate thatREL2andRELK1cooperatively regulate female IM development by controlling genes involved in redox balance, hormone homeostasis, and differentiation, ultimately tipping the meristem toward an environment favorable to expanded expression of theZmWUSCHEL1gene, a key stem-cell promoting transcription factor. We further demonstrate thatRELKgenes have partially redundant yet diverse functions in the maintenance of various meristem types during development. By exploiting subtle increases in ear IM size inrel2heterozygous plants, we also show that extra rows of kernels are formed across a diverse set of F1 hybrids. Our findings reveal that the REL2 family maintains development from embryonic initiation to reproductive growth and can potentially be harnessed for increasing seed yield in a major crop species.

One sentence summary

REL2-RELKs fine tune hormone and chemical cues to prevent expanded expression of ZmWUSCHEL1 in maize inflorescence meristems, and can potentially be harnessed for increasing seed yield in hybrids.
Reduced Levels of Lagging Strand Polymerases Shape Stem Cell Chromatin
Authors: Snedeker Jonathan , Davis Brendon E. M. , Ranjan Rajesh , Wooten Matthew , Blundon Joshua , Chen Xin
Published: April 2024

Stem cells display asymmetric histone inheritance while non-stem progenitor cells exhibit symmetric patterns in theDrosophilamale germline lineage. Here, we report that components involved in lagging strand synthesis, such as DNA polymerase α and δ (Polα and Polδ), have significantly reduced levels in stem cells compared to progenitor cells. Compromising Polα genetically induces the replication-coupled histone incorporation pattern in progenitor cells to be indistinguishable from that in stem cells, which can be recapitulated using a Polα inhibitor in a concentration-dependent manner. Furthermore, stem cell-derived chromatin fibers display a higher degree of old histone recycling by the leading strand compared to progenitor cell-derived chromatin fibers. However, upon reducing Polα levels in progenitor cells, the chromatin fibers now display asymmetric old histone recycling just like GSC-derived fibers. The oldversusnew histone asymmetry is comparable between stem cells and progenitor cells at both S-phase and M-phase. Together, these results indicate that developmentally programmed expression of key DNA replication components is important to shape stem cell chromatin. Furthermore, manipulating one crucial DNA replication component can induce replication-coupled histone dynamics in non-stem cells in a manner similar to that in stem cells.

One Sentence Summary

Delayed lagging strand synthesis regulates asymmetric histone incorporation.
IL-12/IL23 blockade reveals patterns of asynchronous inflammation in pyoderma gangrenosum
Authors: Yadav Rashi , Vague Morgan , Rettig Malia , Loo Christopher P. , Brown Kasidy , Samiea Abrar , Moreau Joshua M. , Ortega-Loayza Alex G
Published: April 2024

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis causing chronic and recalcitrant painful ulcerations. Pathogenic mechanisms are yet poorly understood limiting therapeutic options, however, IL-12/IL-23 inhibition via ustekinumab has previously been associated with positive outcomes. We aimed to elucidate the dysregulated immune landscape of PG and lesional skin changes associated with IL-12/IL-23 blockade. We applied spatial transcriptomics and comparative computation analysis on lesional biopsies from two patients obtained before and after IL-12/IL-23 blockade with ustekinumab. Our data indicate lesional PG skin exhibits complex patterns of inflammation, including a not previously described major infiltration of B cells and establishment of tertiary lymphoid structures. In both patients, IL-12/IL-23 blockade led to marked clinical improvement but was associated with amelioration of contrasting inflammatory pathways. Notably, plasma cell markers and tertiary structures were recalcitrant to the treatment regime suggesting that B cells might play a role in the refractory nature of PG.
GABA and astrocytic cholesterol determine the lipid environment of GABAAR in cultured cortical neurons
Authors: Yuan Zixuan , Pavel Mahmud Arif , Hansen Scott B.
Published: April 2024

The γ-aminobutyric acid (GABA) type A receptor (GABAAR), a GABA activated pentameric chloride channel, mediates fast inhibitory neurotransmission in the brain. The lipid environment is critical for GABAAR function. How lipids regulate the channel in the cell membrane is not fully understood. Here we employed super resolution imaging of lipids to demonstrate that the agonist GABA induces a rapid and reversible membrane translocation of GABAAR to phosphatidylinositol 4,5-bisphosphate (PIP2) clusters in mouse primary cortical neurons. This translocation relies on nanoscopic separation of PIP2clusters and lipid rafts (cholesterol-dependent ganglioside clusters). In a resting state, the GABAAR associates with lipid rafts and this colocalization is enhanced by uptake of astrocytic secretions. These astrocytic secretions enhance endocytosis and delay desensitization. Our findings suggest intercellular signaling from astrocytes regulates GABAAR location based on lipid uptake in neurons. The findings have implications for treating mood disorders associated with altered neural excitability.
Design principles to tailor Hsp104 therapeutics
Authors: Lin JiaBei , Carman Peter J. , Gambogi Craig W. , Kendsersky Nathan M. , Chuang Edward , Gates Stephanie N. , Yokom Adam L. , Rizo Alexandrea N. , Southworth Daniel R. , Shorter James
Published: April 2024

The hexameric AAA+ disaggregase, Hsp104, collaborates with Hsp70 and Hsp40 via its autoregulatory middle domain (MD) to solubilize aggregated protein conformers. However, how ATP- or ADP-specific MD configurations regulate Hsp104 hexamers remains poorly understood. Here, we define an ATP-specific network of interprotomer contacts between nucleotide-binding domain 1 (NBD1) and MD helix L1, which tunes Hsp70 collaboration. Manipulating this network can: (a) reduce Hsp70 collaboration without enhancing activity; (b) generate Hsp104 hypomorphs that collaborate selectively with class B Hsp40s; (c) produce Hsp70-independent potentiated variants; or (d) create species barriers between Hsp104 and Hsp70. Conversely, ADP-specific intraprotomer contacts between MD helix L2 and NBD1 restrict activity, and their perturbation frequently potentiates Hsp104. Importantly, adjusting the NBD1:MD helix L1 rheostat via rational design enables finely tuned collaboration with Hsp70 to safely potentiate Hsp104, minimize off- target toxicity, and counteract FUS proteinopathy in human cells. Thus, we establish important design principles to tailor Hsp104 therapeutics.

Graphical Abstract
Assembly, comparative analysis, and utilization of a single haplotype reference genome for soybean
Authors: Espina Mary Jane C. , Lovell John T. , Jenkins Jerry , Shu Shengqiang , Sreedasyam Avinash , Jordan Brandon D. , Webber Jenell , Boston LoriBeth , Brůna Tomáš , Talag Jayson , Goodstein David , Grimwood Jane , Stacey Gary , Cannon Steven B. , Lorenz Aaron J. , Schmutz Jeremy , Stupar Robert M.
Published: April 2024

Cultivar ‘Williams 82’ has served as the reference genome for the soybean research community since 2008, but is known to have areas of genomic heterogeneity among different sub-lines. This work provides an updated assembly (version Wm82.a6) derived from a specific sub-line known as ‘Wm82-ISU-01’ (seeds available under USDA accession PI 704477). The genome was assembled using Pacific BioSciences HiFi reads and integrated into chromosomes using HiC. The 20 soybean chromosomes assembled into a genome of 1.01Gb, consisting of 36 contigs. The genome annotation identified 48,387 gene models, named in accordance with previous assembly versions Wm82.a2 and Wm82.a4. Comparisons of Wm82.a6 with other near-gapless assemblies of ‘Williams 82’ reveal large regions of genomic heterogeneity, including regions of differential introgression from the genotype ‘Kingwa’ within approximately 30 Mb and 25 Mb segments on chromosomes 03 and 07, respectively. Additionally, our analysis revealed a previously unknown large (∼20 Mb) heterogeneous region in the pericentromeric region of chromosome 12, where Wm82.a6 matches the ‘Williams’ haplotype while the other two near-gapless assemblies do not match the haplotype of either parent of ‘Williams 82’. In addition to the Wm82.a6 assembly, we also assembled the genome of soybean line ‘Fiskeby III’, a rich resource for abiotic stress resistance genes. A genome comparison of Wm82.a6 with ‘Fiskeby III’ revealed the nucleotide and structural polymorphisms between the two genomes within a QTL region for iron deficiency chlorosis resistance. The Wm82.a6 and ‘Fiskeby III’ genomes described here will enhance comparative and functional genomics capacities and applications in the soybean community.
GraSP Gene Targets to Hierarchically Infer Sub-Classes with CuttleNet
Authors: Budoff Samuel A. , Poleg-Polsky Alon
Published: April 2024

This paper introduces a machine learning approach, GraSP, for retinal cell classification that addresses key challenges in spatial biology, alongside a novel neural network architecture, CuttleNet, tailored for class and subclass inference with incomplete datasets. We propose an innovative, unbiased gene selection method that utilizes simple neural networks for each target cell subclass, such thatGradientSelectedPredictors (GraSP) corresponding to gene importance are found for each. This approach significantly outperforms traditional machine learning techniques and expert-selected gene targets, reducing the necessary genes for classification from over 18k to 300 within the murine retina. Such reduction is crucial for advancing spatial biology, particularly in mapping retinal cell subclasses. Furthermore, our hierarchical architecture inspired by the organization of the cephalopod nervous system, CuttleNet, adeptly handles the pervasive issue of missing data in disjointed single-cell RNA sequencing datasets. CuttleNet operates by first classifying cell classes using consistently measured genes, then dynamically routing to subclass-specific subnetworks that leverage all available data for subclass classification. CuttleNet establishes a new standard in handling systematically missing data, offering substantial improvements over existing models in our targeted application.
Large Language Models for Pathway Curation: A Preliminary Investigation
Authors: Karkera Nikitha , Karkera Nikshita , Kumar Mahanash , Ghosh Samik , Palaniappan Sucheendra K.
Published: April 2024

The pathway curation task involves analyzing scientific literature to identify and represent cellular processes as pathways. This process, often time-consuming and labor-intensive, requires significant curation efforts amidst the rapidly growing biomedical literature. Natural Language Processing (NLP) offers a promising method to automatically extract these interactions from scientific texts. Despite immense progress, there remains room for improvement in these systems. The emergence of Large Language Models (LLMs) provides a promising solution for this challenge. Our study conducts a preliminary investigation into leveraging LLMs for the pathway curation task. This paper first presents a review of the current state-of-the-art algorithms for the pathway curation task. Our objective is to check the feasibility and formulate strategies of using these LLMs to improve the accuracy of pathway curation task. Our experiments demonstrate that our GPT-3.5 based fine-tuned models outperforms existing state-of-the-art methods. Specifically, our model achieved a 10 basis point improvement in over-all recall and F1 score compared to the best existing algorithms. These findings highlight the potential of LLMs in pathway curation tasks, warranting further research and substantial efforts in this direction.

Keypoints/Objectives

Study evaluates the feasibility of using Large Language Models (LLMs) for pathway curation in scientific literature.

Using GPT-3.5 based fine tuned models for pathway curation, we compare its performance with existing methods, focusing on precision, recall and F1 score metrics.

Emphasize the promise and need for further research on using LLMs for pathway curation.
Endothelial SHP-1 regulates diabetes-induced abnormal collateral vessel formation and endothelial cell senescence
Authors: Nadeau Alexandre , Ouellet Marike , Béland Raphaël , Mercier Clément , Robillard Stéphanie , Lizotte Farah , Despatis Marc-Antoine , Benzinger C. Florian , Geraldes Pedro
Published: April 2024

Objective

Ischemia due to narrowing of the femoral artery and distal vessels is a major cause of peripheral arterial disease and morbidity affecting patients with diabetes. Diabetes-induced premature senescence of endothelial cells (EC) has been proposed as a mechanism leading to impaired ischemia-driven angiogenesis. Importantly, our previous work has shown that hyperglycemia reduced vascular endothelial growth factor (VEGF) activity in ischemic muscle of diabetic mice, which was associated with increased expression of the protein tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1 (SHP-1). Here, we evaluate the impact of SHP-1 deletion on EC function and senescence.

Approach and Results

Ligation of the femoral artery was performed in nondiabetic (NDM) and 3 months diabetic (DM) mice with EC-specific deletion of SHP-1 and blood flow reperfusion was measured for 4 weeks. Blood flow reperfusion and limb function during voluntary wheel running were reduced by 43% and 82%, respectively in DM mice as compared to NDM mice. EC-specific deletion of SHP-1 in DM mice restored blood flow reperfusion by 60%, limb function by 86%, while capillary density was similar to NDM mice. Moreover, ablation of SHP-1 in EC prevented diabetes-induced expression of the senescence markers p53 and p21 and counteracted Nrf2 downregulation. In cultured EC, overexpression of dominant negative of SHP-1 prevented HG-induced inhibition of proliferation, migration, tubule formation and VEGFR2/Akt phosphorylation following VEGF stimulation. In addition, the expression of senescence markers and suppression of Nrf2 in EC exposed to HG levels were reversed by overexpression of dominant negative SHP-1.

Conclusion

SHP-1 in ECs is a central effector of diabetes-induced senescence that blocks VEGF action, and induces aberrant collateral vessel formation and blood flow reperfusion. Reduced SHP-1 expression counteracts these pathologic features suggesting the notion that it represents a promising therapeutic target.

HIGHLIGHTS

Endothelial specific deletion of SHP-1 (Scr homology 2-containing phosphatase-1) improves blood flow reperfusion, limb motricity and vessel density in the diabetic ischemic limb.

Diabetes-induced SHP-1 protein expression inhibits VEGF proangiogenic actions and promotes endothelial senescence.

Endothelial specific deletion of SHP-1 restores VEGF proangiogenic actions and prevents senescence in ischemic muscle and artery of diabetic mice and patients.
PRIMITI: a computational approach for accurate prediction of miRNA-target mRNA interaction
Authors: Uthayopas Korawich , de Sá Alex G. C. , Alavi Azadeh , Pires Douglas E. V. , Ascher David B.
Published: April 2024

Current medical research has been demonstrating the roles of miRNAs in a variety of cellular mechanisms, lending credence to the association between miRNA dysregulation and multiple diseases. Understanding the mechanisms of miRNA is critical for developing effective diagnostic and therapeutic strategies. miRNA-mRNA interactions emerge as the most important mechanism to be understood despite their experimental validation constraints. Accordingly, several computational models have been developed to predict miRNA-mRNA interactions, albeit presenting limited predictive capabilities, poor characterisation of miRNA-mRNA interactions and low usability. To address these drawbacks, we developed PRIMITI, a PRedictive model for the Identification of novel MIRNA-Target mRNA Interactions. PRIMITI is a novel machine learning model that utilises CLIP-seq and expression data to characterise functional target sites in 3’-untranslated regions (3’-UTRs) and predict miRNA-target mRNA repression activity. The model was trained using a reliable negative sample selection approach and the robust extreme gradient boosting (XGBoost) model, which was coupled with newly introduced features, including sequence and genetic variation information. PRIMITI achieved an area under the receiver operating characteristic (ROC) curve (AUC) up to 0.96 for a prediction of functional miRNA-target site binding and 0.96 for a prediction of miRNA-target mRNA repression activity on cross-validation and an independent blind test. Additionally, the model outperformed state-of-the-art methods in recovering miRNA-target repressions in an unseen microarray dataset and in a collection of validated miRNA-mRNA interactions, highlighting its utility for preliminary screening. PRIMITI is available on a reliable, scalable and user-friendly web server athttps://biosig.lab.uq.edu.au/primiti.
Investigating Musculoskeletal Pain Among Pregnant Women in Dhaka Division: A Cross-Sectional Study
Authors: Uddin Jalal , Shumi Shahida Sultana
Published: April 2024

Objectives

This study aimed to investigate musculoskeletal pain among pregnant women in Dhaka Division, Bangladesh, considering demographic factors, pain and pregnancy-related experiences.

Materials and Methods

Data were collected from 300 pregnant women attending outpatient clinical check-ups at two hospitals in Dhaka Division, Bangladesh. A standardized questionnaire covering demographic information, pregnancy-related inquiries, and pain assessment using the Numeric Pain Rating Scale (NPRS) was administered. Data were analyzed using SPSS version 25 software.

Results

The majority of participants were aged 20-25 years, resided in rural areas, and had completed primary education. Most participants were housewives. A significant proportion reported experiencing musculoskeletal pain, predominantly in the second trimester. Associations were found between musculoskeletal pain and both age (p=0.025) and trimester of pregnancy (p=0.008).

Conclusions

The findings emphasized significant associations between maternal age and musculoskeletal pain, highlighting the importance of considering age-related factors in maternal care. Additionally, a high prevalence of musculoskeletal pain during the second trimester was observed.
Diabetes as risk factor to severity of dengue in naïve patients
Authors: dos Santos Bárbara F. , Gandolfi Flora A. , Milhim Bruno H. G. A. , Dourado Fernanda S. , Silva Gislaine C. D. , Zini Nathalia , Rezende Gratão Victor Hugo , Mariani Matheus Pascoal , Abbas Tamires Nasie , Garcia Pedro H. C. , Rocha Rodrigo S. , Vasilakis Nikos , Nogueira Maurício L. , Estofolete Cássia F.
Published: April 2024

Background

Dengue cases can progress to severe ant life-threating forms particularly in subsequent heterologous infections. However, recent studies had explored additional risk factors, including underlying health conditions, even in individuals without prior exposure to dengue, notably, in patients with endothelial dysfunction and chronic inflammation. This study examines the link between diabetes and the development of severe dengue disease in dengue-naive patients during the 2019 dengue outbreak in São Jose do Rio Preto, Brazil.

Methodology

We enrolled 529 laboratory-confirmed dengue cases, identified through DENV RT-PCR or NS1 antigen assays in a hospital cohort of acute febrile illness. Subsequently, we investigated the presence of anti-dengue and anti-Zika IgG antibodies. Samples testing positive for Zika were excluded from the analyses. Two groups were analyzed: naïve (DV-), and dengue history (DV+).

Results

Initially, presence of diabetes and kidney disease, as well as being dengue-naive, were associated with a higher frequency of severe and potentially severe clinical outcomes. Multivariate analysis identified diabetes as a risk factor, while the presence of anti-dengue antibodies was considered protective. Analysis of dengue naïve samples, highlighted diabetes as an independent risk factor to severe forms of dengue disease. In DV+ patients, no condition was highlighted as a risk factor by univariate analysis or multivariate analysis.

Conclusions

We investigated and confirmed diabetes as a risk factor for severe dengue disease in individuals without prior dengue or Zika exposure. Our conclusions raise significant concerns given diabetes’ ever increasing global prevalence and its potential impact on patients with or previous dengue exposure.

The simultaneous escalation of diabetes and dengue worldwide is striking. Notably, diabetes presents as a significant risk factor for severe dengue. This accentuates the necessity of diabetes control in dengue prevention, considering its widespread prevalence and influence on disease severity.
Triggering and modulation of a complex behavior by a single peptidergic command neuron inDrosophila
Authors: Fernandez-Acosta Magdalena , Zanini Rebeca , Heredia Fabiana , Volonté Yanel , Menezes Juliane , Prüger Katja , Ibarra Julieta , Arana Maite , Perez María Sol , Veenstra Jan A , Wegener Christian , Gontijo Alisson , Garelli Andrés
Published: April 2024

At the end of their growth phase,Drosophilalarvae remodel their bodies, firmly glue themselves to a substrate, and harden their cuticle in preparation for metamorphosis. This process is termed pupariation and it is triggered by a surge in the steroid hormone ecdysone. Substrate attachment is achieved by a recently-described pupariation subprogram called glue expulsion and spreading behavior (GSB). An epidermis-to-CNS Dilp8-Lgr3 relaxin signaling event that occurs downstream of ecdysone after pupariation initiation is critical for unlocking progression of the pupariation motor program towards GSB, but the factors and circuits acting downstream of Lgr3 signaling remain unknown. Here, we screened for such factors using cell type-specific RNA interference (RNAi) and behavioral monitoring. We identify Myoinhibiting peptide (Mip) and its highly conserved neuronal receptor, Sex peptide receptor (SPR), as a critical neuropeptidergic signaling pathway required to trigger and modulate multiple action components of GSB. In addition, we find that Mip is specifically required in a pair of descending neurons, whose optogenetic activation at a specific competence window triggers GSB-like behavior and whose neurogenetic silencing completely abrogates GSB without overtly affecting other pupariation components. This strongly suggests that these descending Mip neurons are developmentally-regulated GSB command neurons. Dissection of the GSB action components via muscle calcium-level monitoring coupled with cell-type specific RNAi indicates that Mip acts on multiple SPR-positive neuronal populations, which collectively define and pattern the sequence and timing of GSB actions. Hence, we have identified a pair of descending command neurons that utilize both synaptic transmission and neuropeptidergic signaling to trigger and modulate a complex innate behavior inDrosophila. Our results advance our molecular and cellular understanding of pupariation control, reveal the complexity of glue expulsion and spreading behavior control, provide insight into conserved aspects of Mip-SPR signaling in animals, and contribute to the understanding of how multi-step innate behaviors are coordinated in time and with other developmental processes through command neurons and neuropeptidergic signaling.
High-throughput crystallographic fragment screening of Zika virus NS3 Helicase
Authors: Godoy Andre S , Mesquita Nathalya C. M. R. , Noske Gabriela Dias , Gawriljuk Victor Oliveira , Lithgo Ryan M , Balcomb Blake H , Aschenbrenner Jasmin Cara , Tomlinson Charles W.E. , Winokan Max , Scheen Jenke , Marples Peter George , Chandran Anu V. , Ni Xiaomin , Thompson Warren , Fairhead Michael , Fearon Daren , Koekemoer Lizbé , Xavier Mary-Ann Elvina , Walsh Martin , Oliva Glaucius , von Delft Frank
Published: April 2024

The Zika virus (ZIKV), discovered in Africa in 1947, swiftly spread across continents, causing significant concern due to its recent association with microcephaly in newborns and Guillain-Barré syndrome in adults. Despite a decrease in prevalence, the potential for a resurgence remains, necessitating urgent therapeutic interventions. Like other flaviviruses, ZIKV presents promising drug targets within its replication machinery, notably the NS3 helicase (NS3Hel) protein, which plays critical roles in viral replication. However, a lack of structural information impedes the development of specific inhibitors targeting NS3Hel. Here we applied high-throughput crystallographic fragment screening on ZIKV NS3Hel, which yielded structures that reveal 3D binding poses of 46 fragments at multiple sites of the protein, including 11 unique fragments in the RNA-cleft site. These fragment structures provide templates for direct design of hit compounds and should thus assist the development of novel direct-acting antivirals against ZIKV and related flaviviruses, thus opening a promising avenue for combating future outbreaks.
MT-125 Inhibits Non-Muscle Myosin IIA and IIB, Synergizes with Oncogenic Kinase Inhibitors, and Prolongs Survival in Glioblastoma
Authors: Kenchappa Rajappa , Radnai Laszlo , Young Erica J. , Zarco Natanael , Lin Li , Dovas Athanassios , Meyer Christian T. , Haddock Ashley , Hall Alice , Canoll Peter , Cameron Michael D. , Nagaiah Naveen KH , Rumbaugh Gavin , Griffin Patrick R. , Kamenecka Theodore M. , Miller Courtney A. , Rosenfeld Steven S.
Published: April 2024

We have identified a NMIIA and IIB-specific small molecule inhibitor, MT-125, and have studied its effects in GBM. MT-125 has high brain penetrance and retention and an excellent safety profile; blocks GBM invasion and cytokinesis, consistent with the known roles of NMII; and prolongs survival as a single agent in murine GBM models. MT-125 increases signaling along both the PDGFR- and MAPK-driven pathways through a mechanism that involves the upregulation of reactive oxygen species, and it synergizes with FDA-approved PDGFR and mTOR inhibitorsin vitro. Combining MT-125 with sunitinib, a PDGFR inhibitor, or paxalisib, a combined PI3 Kinase/mTOR inhibitor significantly improves survival in orthotopic GBM models over either drug alone, and in the case of sunitinib, markedly prolongs survival in ∼40% of mice. Our results provide a powerful rationale for developing NMII targeting strategies to treat cancer and demonstrate that MT-125 has strong clinical potential for the treatment of GBM.

Highlights

MT-125 is a highly specific small molecule inhibitor of non-muscle myosin IIA and IIB, is well-tolerated, and achieves therapeutic concentrations in the brain with systemic dosing.

Treating preclinical models of glioblastoma with MT-125 produces durable improvements in survival.

MT-125 stimulates PDGFR- and MAPK-driven signaling in glioblastoma and increases dependency on these pathways.

Combining MT-125 with an FDA-approved PDGFR inhibitor in a mouse GBM model synergizes to improve median survival over either drug alone, and produces tumor free, prolonged survival in over 40% of mice.
TheWnt/β-catenin/TCF/Sp5/Zic4gene network that regulates head organizer activity inHydrais differentially regulated in epidermis and gastrodermis
Authors: Iglesias Ollé Laura , Perruchoud Chrystelle , Sanchez Paul Gerald Layague , Vogg Matthias Christian , Galliot Brigitte
Published: April 2024

InHydra, head formation depends on Wnt/β-catenin signaling, which positively regulatesSp5andZic4, with Sp5 limitingWnt3/β-cateninexpression and Zic4 triggering tentacle formation. Using transgenic lines in which theHySp5promoter drives eGFP expression in the epidermis or gastrodermis, we show that in intact animals, epidermalHySp5:GFP is expressed strongly apically and weakly along the body column, while gastrodermalHySp5:GFP is also maximally expressed apically but absent from the oral region, and remains high along the upper body column. During apical regeneration, gastrodermalHySp5:GFP appears early and diffusely, epidermalHySp5:GFP later. Upon alsterpaullone treatment, apicalHySp5:GFPexpression is shifted to the body column where epidermalHySp5:GFP transiently forms ectopic circular figures. Afterβ-catenin(RNAi), only epidermalHySp5:GFP is down-regulated, while pseudo-bud structures expressing gastrodermalHySp5:GFP develop.Sp5(RNAi) highlights the negative autoregulation ofSp5in epidermis, involving direct binding of Sp5 to its own promoter as observed in human HEK293T cells. In these cells, HyZic4, which can interact with huTCF1, regulatesWnt3negatively andSp5positively. This differential regulation of theWnt/β-catenin/TCF/Sp5/Zic4network in epidermis and gastrodermis highlights distinct architectures and patterning roles in the hypostome, tentacle and body column, as well as distinct regulations in homeostatic and developmental organizers.
Microenvironment Drives Reentrant Condensation of Aβ40
Authors: Sarkar Susmita , Mondal Jagannath
Published: April 2024

Within the framework of liquid-liquid phase separation (LLPS), biomolecular condensation orchestrates vital cellular processes and its dysregulation is implicated in severe pathological conditions. Recent studies highlight the role of intrinsically disordered proteins (IDPs) in LLPS, yet the influence of microenvironmental factors has remained a puzzling factor. Here, via computationally simulating the impact of solution conditions on LLPS behavior of neurologically pathogenic IDP Aβ40, we chanced upon a salt-driven reentrant condensation phenomenon, wherein Aβ40 aggregation increases with low salt concentrations (25-50 mM), followed by a decline with further salt increments.. An exploration into the thermodynamic and kinetic signatures of reentrant condensation unveils a nuanced interplay between protein electrostatics and ionic strength as potential drivers. Notably, the charged residues of the N-terminus exhibit a non-monotonic response to salt screening, intricately linked to the recurrence of reentrant behavior in hydrophobic core-induced condensation. Intriguingly, our findings also unveil the reappearance of similar reentrant condensation phenomena under varying temperature conditions. Collectively, our study illuminates the profoundly context-dependent nature of Aβ40’s liquid-liquid phase separation behavior, extending beyond its intrinsic molecular framework, where microenvironmental cues wield significant influence over its aberrant functionality.
Origin of the far-red absorbance in eustigmatophyte algae red-shifted Violaxanthin-ChlorophyllaProtein
Authors: Agostini Alessandro , Bína David , Barcytė Dovilė , Bortolus Marco , Eliáš Marek , Carbonera Donatella , Litvín Radek
Published: April 2024

Photosynthetic organisms harvest light for energy. Some eukaryotic algae have specialized in harvesting far-red light by tuning chlorophyllaabsorption through a mechanism still to be elucidated. Here, we combined optically detected magnetic resonance and pulsed electron paramagnetic resonance measurements on red-adapted light-harvesting complexes, rVCP, isolated from the freshwater eustigmatophyte algaTrachydiscus minutusto identify the location of the pigments responsible for this remarkable adaptation. The pigments have been found to belong to an excitonic cluster of chlorophyllsaat the core of the complex, close to the central carotenoids in L1/L2 sites. A pair of structural features of the Chla403/a603 binding site, namely the histidine-to-asparagine substitution in the magnesium-ligation residue and the small size of the amino acid at thei-4 position, are proposed to be the origin of this trait. Phylogenetic analysis of various eukaryotic red antennae identified several potential LHCs that could share this tuning mechanism.
Novel sulfatase cancer therapeutics negatively impact Bacteroidota of the colonic microbiota in a non-sulfatase dependent manner
Authors: Crawford Conor J. , Gunawan Christian , Chen Zongjia , Byrne Dominic P , Darby Cosette , Luis Ana S , Elli Stefano , Yates Edwin A , Bolam David N , van der Post Sjoerd , Williams Spencer J , Cartmell Alan
Published: April 2024

The S1 family of sulfatases is the sole family of enzymes that desulfate carbohydrates, linking them to inflammatory bowel diseases and various cancers. There is an unmet need for therapeutics against carbohydrate sulfatases, and while effective, orally available inhibitors of S1 steroid sulfatases exist, their efficacy against S1 carbohydrate sulfatases remains largely unexplored. In this study we assess a library of aryl- and carbohydrate sulfamates/sulfonates for their ability to inhibit carbohydrate sulfatases from human colonic bacteria. Surprisingly, these compounds prove ineffective. We show that arylsulfamate inhibitors inhibit the growth of anti-cancer human gut microbiota species independent of sulfatase activity. Leveraging thermal proteome profiling, we identify the non-sulfatase targets responsible for these effects. This work highlights the imperative for developing specific inhibitors targeting carbohydrate sulfatases and unveils the adverse effects of arylsulfamates, a class of drugs designed for hormone cancer treatment, on the human gut microbiota, potentially influencing their therapeutic efficacy.
Structure-Function Relationship in Electrical and Hemodynamic Brain Networks: Insights from EEG and fNIRS during Rest and Task States
Authors: Blanco Rosmary , Preti Maria Giulia , Koba Cemal , Van De Ville Dimitri , Crimi Alessandro
Published: April 2024

Identifying relationships between structural and functional networks is crucial for understanding the large-scale organization of the human brain. The potential contribution of emerging techniques like functional near-infrared spectroscopy to investigate the structure-functional relationship has yet to be explored. In our study, we characterize global and local structure-function coupling using source-reconstructed Electroencephalography (EEG) and Functional near-infrared spectroscopy (fNIRS) signals in both resting state and motor imagery tasks, as this relationship during task periods remains underexplored. Employing the mathematical framework of graph signal processing, we investigate how this relationship varies across electrical and hemodynamic networks and different brain states. Results show that fNIRS structure-function coupling resembles slower-frequency EEG coupling at rest, with variations across brain states and oscillations. Locally, the relationship is heterogeneous, with greater coupling in the sensory cortex and increased decoupling in the association cortex, following the unimodal to transmodal gradient. Discrepancies between EEG and fNIRS are noted, particularly in the frontoparietal network. Cross-band representations of neural activity revealed lower correspondence between electrical and hemodynamic activity in the transmodal cortex, irrespective of brain state while showing specificity for the somatomotor network during a motor imagery task. Overall, these findings initiate a multimodal comprehension of structure-function relationship and brain organization when using affordable functional brain imaging.
Chemical proteomic profiling of protein dopaminylation in colorectal cancer cells
Authors: Zhang Nan , Gao Shuaixin , Peng Haidong , Wu Jinghua , Li Huapeng , Gibson Connor , Wu Sophia , Zhu Jiangjiang , Zheng Qingfei
Published: April 2024

Histone dopaminylation is a newly identified epigenetic mark that plays a role in the regulation of gene transcription, where an isopeptide bond is formed between the fifth amino acid residue of H3 (i.e., glutamine) and dopamine. In our previous studies, we discovered that the dynamics of this post-translational modification (including installation, removal, and replacement) were regulated by a single enzyme, transglutaminase 2 (TGM2), through reversible transamination. Recently, we developed a chemical probe to specifically label and enrich histone dopaminylation via bioorthogonal chemistry. Given this powerful tool, we found that histone H3 glutamine 5 dopaminylation (H3Q5dop) was highly enriched in colorectal tumors, which could be attributed to the high expression level of TGM2 in colon cancer cells. Due to the enzyme promiscuity of TGM2, non-histone proteins have also been identified as targets of dopaminylation on glutamine residues, however, the dopaminylated proteome in cancer cells still remains elusive. Here, we utilized our chemical probe to enrich dopaminylated proteins from colorectal cancer cells in a bioorthogonal manner and performed the chemical proteomics analysis. Therefore, 425 dopaminylated proteins were identified, many of which are involved in nucleic acid metabolism and transcription pathways. More importantly, a number of modification sites of these dopaminylated proteins were identified, attributed to the successful application of our chemical probe. Overall, these findings shed light on the significant association between cellular protein dopaminylation and cancer development, further suggesting that to block the installation of protein dopaminylation may become a promising anti-cancer strategy.

TOC
Acute stress yields a sex-dependent facilitation of signaled active avoidance in rats
Authors: Plas Samantha L. , Oleksiak Cecily R. , Pitre Claire , Melton Chance , Moscarello Justin M. , Maren Stephen
Published: April 2024

Post-traumatic stress disorder (PTSD) is a debilitating disorder characterized by excessive fear, hypervigilance, and avoidance of thoughts, situations or reminders of the trauma. Among these symptoms, relatively little is known about the etiology of pathological avoidance. Here we sought to determine whether acute stress influences avoidant behavior in adult male and female rats. We used a stress procedure (unsignaled footshock) that is known to induce long-term sensitization of fear and potentiate aversive learning. Rats were submitted to the stress procedure and, one week later, underwent two-way signaled active avoidance conditioning (SAA). In this task, rats learn to prevent an aversive outcome (shock) by performing a shuttling response when exposed to a warning signal (tone). We found that acute stress significantly enhanced SAA acquisition rate in females, but not males. Female rats exhibited significantly greater avoidance responding on the first day of training relative to controls, reaching similar levels of performance by the second day. Males that underwent the stress procedure showed similar rates of acquisition to controls but exhibited resistance to extinction. This was manifest as both elevated avoidance and intertrial responding across extinction days relative to non-stressed controls, an effect that was not observed in females. In a second experiment, acute stress sensitized footshock unconditioned responses in males, not females. However, males and females exhibited similar levels of stress-enhanced fear learning (SEFL), which was expressed as sensitized freezing to a shock-paired context. Together, these results reveal that acute stress facilitates SAA performance in both male and female rats, though the nature of this effect is different in the two sexes. We did not observe sex differences in SEFL, suggesting that the stress-induced sex difference in performance was selective for instrumental avoidance. Future work will elucidate the neurobiological mechanisms underlying the differential effect of stress on instrumental avoidance in male and female rats.
Rare germline structural variants increase risk for pediatric solid tumors
Authors: Gillani Riaz , Collins Ryan L. , Crowdis Jett , Garza Amanda , Jones Jill K. , Walker Mark , Sanchis-Juan Alba , Whelan Chris , Pierce-Hoffman Emma , Talkowski Michael , Brand Harrison , Haigis Kevin , LoPiccolo Jaclyn , AlDubayan Saud H. , Gusev Alexander , Crompton Brian D. , Janeway Katie A. , Van Allen Eliezer M.
Published: April 2024

Abstract

Pediatric solid tumors are rare malignancies that represent a leading cause of death by disease among children in developed countries. The early age-of-onset of these tumors suggests that germline genetic factors are involved, yet conventional germline testing for short coding variants in established predisposition genes only identifies pathogenic events in 10-15% of patients. Here, we examined the role of germline structural variants (SVs)—an underexplored form of germline variation—in pediatric extracranial solid tumors using germline genome sequencing of 1,766 affected children, their 943 unaffected relatives, and 6,665 adult controls. We discovered a sex-biased association between very large (>1 megabase) germline chromosomal abnormalities and a four-fold increased risk of solid tumors in male children. The overall impact of germline SVs was greatest in neuroblastoma, where we revealed burdens of ultra-rare SVs that cause loss-of-function of highly expressed, mutationally intolerant, neurodevelopmental genes, as well as noncoding SVs predicted to disrupt three-dimensional chromatin domains in neural crest-derived tissues. Collectively, our results implicate rare germline SVs as a predisposing factor to pediatric solid tumors that may guide future studies and clinical practice.
CryoEM structure of the di-domain core ofMycobacterium tuberculosispolyketide synthase 13, essential for mycobacterial mycolic acid synthesis
Authors: Johnston Hannah E , Batt Sarah M , Brown Alistair K , Savva Christos G , Besra Gurdyal S , Fütterer Klaus
Published: April 2024

Mycobacteria are known for their complex cell wall, which comprises layers of peptidoglycan, polysaccharides and unusual fatty acids known as mycolic acids that form their unique outer membrane. Polyketide synthase 13 (Pks13) ofMycobacterium tuberculosis,the bacterial organism causing tuberculosis (TB), catalyses the last step of mycolic acid synthesis prior to export to and assembly in the cell wall. Due to its essentiality, Pks13 is a target for several novel anti-tubercular inhibitors, but its 3D structure and catalytic reaction mechanism remain to be fully elucidated. Here, we report the molecular structure of the catalytic core domains ofM. tuberculosisPks13 (Mt-Pks13), determined by transmission cryo-electron microscopy (cryoEM) to a resolution of 3.4 Å. We observe a homodimeric assembly comprising the ketoacyl synthase (KS) domain at the centre, mediating dimerization, and the acyltransferase (AT) domains protruding in opposite directions from the central KS domain dimer. In addition to the KS-AT di-domains, the cryoEM map includes features not covered by the di-domain structural model that we predict to contain a dimeric domain with similarity to dehydratases, yet likely lacking catalytic function. Analytical ultracentrifugation data indicate a pH-dependent equilibrium between monomeric and dimeric assembly states, while comparison with the previously determined structures ofM. smegmatisPks13 indicates architectural flexibility. Combining the experimentally determined structure with modelling in AlphaFold2 suggests a structural scaffold with a relatively stable dimeric core, that combines with considerable conformational flexibility to facilitate the successive steps of the Claisen-type condensation reaction catalysed by Pks13.
Heterogeneity of the human immune response to malaria infection and vaccination driven by latent cytomegalovirus infection
Authors: Mukhiya Reena , Fleischmann Wim A. , Loughland Jessica R. , Chan Jo-Anne , de Labastida Rivera Fabian , Andrew Dean , Beeson James G. , McCarthy James S , Barber Bridget E , Lopez J. Alejandro , Engwerda Christian , Thomson-Luque Richard , Boyle Michelle J
Published: April 2024

Human immune responses to infection and vaccination are heterogenous, driven by multiple factors including genetics, environmental exposures and personal infection histories. For malaria caused byPlasmodium falciparumparasites, host factors that impact on humoral immunity are poorly understood. We investigated the role of latent cytomegalovirus (CMV) on the host immune response to malaria using blood stageP. falciparumControlled Human Malaria Infection (CHMI) and in a MSP1 vaccine Phase 1a clinical trial. CMV seropositivity was associated with reduced induction of parasite specific antibodies following malaria infection and vaccination. During infection, reduced antibody induction was associated with modifications to the T -follicular helper (Tfh) cell compartment. CMV seropositivity was associated with a skew towards Tfh1 cell subsets before and after malaria infection, and reduced activation of Tfh2 cells. Protective Tfh2 cell activation was only associated with antibody development in CMV seronegative individuals, and a higher proportion of Tfh1 cells was associated with lower antibody development in CMV seropositive individuals. During MSP1 vaccination, reduced antibody induction in CMV seropositive individuals was associated with CD4 T cell expression of terminal differentiation marker CD57. These findings are particularly relevant for malaria endemic regions where CMV infection is acquired early in life and may modify immunity to malaria gained during infection or vaccination.
DNA methylation in pituitary adenomas: scoping review protocol
Authors: Møller Morten Winkler , Nortvig Mathias Just , Andersen Mikkel Schou , Poulsen Frantz Rom
Published: April 2024

Objective

The general objective of this study is to map the current knowledge in DNA methylation in Pituitary Adenomas, and in particular focus on genetic and epigenetic findings and the translation into a clinical setting.

Introduction

Pituitary tumorigenesis is currently under major investigation. The current research has turned to epigenomic analysis, investigating whether several epigenetic components like DNA methylation and histone modification can be used as markers for tumorigenesis. Several studies report genes involved in relation to hypo/hypermethylated sites. Others describe differential methylated probes/regions (DMR or DMP) and show subclassification traits. Furthermore, most recent studies aim to cluster samples based on full methylome data (unsupervised cluster analysis), while others chose to assess the most different probes (example 2000 probes) and perform the same data-analysis.

Inclusion criteria

In this review, we will include all primary studies on pituitary adenomas analyzed by DNA methylation. No review studies will be included. All papers describing DNA methylation in pituitary adenomas in humans will be included. In addition, all languages will be included. However, both title and abstract needs to be written in English.

Methods

Papers will be identified via systematic search using the bibliographic databases: Medline, Embase, Cochrane Library and Scopus. Two reviewers will screen all papers based on title and abstract. All relevant papers will be included for further assessment by the same two reviewers. Full texts from each selected paper will be read, and if relevant regarding the eligibility criteria, papers will be included in the review. Disputes between these reviewers, the paper/papers will be discussed in the entire research-group.

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Funding

No external funding for this review, funded by in-house resources.