bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Pax transcription factor EGL-38 links EGFR signaling to assembly of a cell-type specific apical extracellular matrix in theCaenorhabditis elegansvulva
Authors: Schmidt Helen F. , Darwin Chelsea B. , Sundaram Meera V. 
Published: September 2024

AbstractThe surface of epithelial tissues is covered by an apical extracellular matrix (aECM). The aECMs of different tissues have distinct compositions to serve distinct functions, yet how a particular cell type assembles the proper aECM is not well understood. We used the cell-type specific matrix of theC. elegansvulva to investigate the connection between cell identity and matrix assembly. The vulva is an epithelial tube composed of seven cell types descending from EGFR/Ras-dependent (1°) and Notch-dependent (2°) lineages. Vulva aECM contains multiple Zona Pellucida domain (ZP) proteins, which are a common component of aECMs across life. ZP proteins LET-653 and CUTL-18 assemble on 1° cell surfaces, while NOAH-1 assembles on a subset of 2° surfaces. All three ZP genes are broadly transcribed, indicating that cell-type specific ZP assembly must be determined by features of the destination cell surface. The paired box (Pax) transcription factor EGL-38 promotes assembly of 1° matrix and prevents inappropriate assembly of 2° matrix, suggesting that EGL-38 promotes expression of one or more ZP matrix organizers. Our results connect the known signaling pathways and various downstream effectors to EGL-38/Pax expression and the ZP matrix component of vulva cell fate execution. We propose that dedicated transcriptional networks may contribute to cell-appropriate assembly of aECM in many epithelial organs.HighlightsC. elegansvulva apical extracellular matrix is cell-type specificBroadly transcribed Zona Pellucida domain proteins assemble in specific matricesThe Pax2/5/8 homolog EGL-38 promotes assembly of the 1° vulva cell matrixEGL-38 expression and 1° cell matrix assembly depend on EGFR signaling
Lifestyle Profiling Using Wearables and Prediction of Glucose Metabolism in Individuals with Normoglycemia or Prediabetes
Authors: Park Heyjun , Metwally Ahmed A. , Delfarah Alireza , Wu Yue , Perelman Dalia , Rodgar Majid , Mayer Caleb , Celli Alessandra , McLaughlin Tracey , Mignot Emmanuel , Snyder Michael 
Published: September 2024

AbstractThis study examined the relationship between lifestyles (diet, sleep, and physical activity) and glucose responses at a personal level. 36 healthy adults in the Bay Area were monitored for their lifestyles and glucose levels using wearables and continuous glucose monitoring (NCT03919877). Gold-standard metabolic tests were conducted to phenotype metabolic characteristics. Through the lifestyle data (2,307 meals, 1,809 nights, and 2,447 days) and 231,206 CGM readings from metabolically-phenotyped individuals with normoglycemia or prediabetes, we found: 1) eating timing was associated with hyperglycemia, muscle insulin resistance (IR), and incretin dysfunction, whereas nutrient intakes were not; 2) timing of increased activity in muscle IS and IR participants was associated with differential benefits of glucose control; 3) Integrated ML models using lifestyle factors predicted distinct metabolic characteristics (muscle, adipose IR or incretin dysfunction). Our data indicate the differential impact of lifestyles on glucose regulation among individuals with different metabolic phenotypes, highlighting the value of personalized lifestyle modifications.
Neuroligin fragments as blood-based biomarkers for early detection of Alzheimer’s disease
Authors: Forestieri Fernandes Milton Guilherme , Pinard Maxime , Sokullu Esen , Gagnon Jean-François , Calon Frédéric , Coulombe Benoit ,   the Consortium for the early identification of Alzheimer’s disease-Quebec (CIMA-Q), Brouillette Jonathan 
Published: September 2024

ABSTRACTINTRODUCTIONBiomarkers for early detection of Alzheimer’s disease (AD) are essential for improving treatments. Fragments of the synaptic protein neuroligins (NLGNs) are released into the blood due to synaptic degeneration, which occurs in the early stages of AD.METHODSWe used MS2-targeted mass spectrometry on blood samples from the CIMA-Q cohort to assess the potential of NLGN fragments as blood-based biomarkers for amnestic mild cognitive impairment (aMCI), a prodromal stage of AD.RESULTSWe found higher blood levels of certain NLGN fragments in both aMCI and AD patients compared to healthy subjects. Within these same samples, the levels of Tau phosphorylated at various epitopes were higher in AD subjects but not in aMCI individuals.DISCUSSIONSynaptic proteins such as NLGNs could serve as effective biomarkers for detecting the disease in its prodromal stage. This early detection could accelerate diagnosis and therapeutic intervention before neurodegeneration leads to irreversible brain damage.
Dissecting causal relationships between cortical morphology and neuropsychiatric disorders: a bidirectional Mendelian randomization study
Authors: Lin Bochao Danae , Li Yunzhi , Goula Anastasia A. , Chang Xiao , Grasby Katrina L. , Medland Sarah , Andreassen Ole A. , Rutten Bart P. F. , Guloksuz Sinan , van der Meer Dennis , Luykx Jurjen J. 
Published: September 2024

AbstractBrain cortical morphology, indexed by its surface area and thickness, is known to be highly heritable. Previous research has suggested a relationship of cortical morphology with several neuropsychiatric phenotypes. However, the multitude of potential confounders makes it difficult to establish causal relationships. Here, we employ Generalized Summary-data-based Mendelian Randomization and a series of sensitivity analyses to investigate causal links between 70 cortical morphology measures and 199 neuropsychiatric, behavioral, and metabolic phenotypes. We show that total brain cortical surface area (TSA) has significant positive causal effects on 18 phenotypes. The strongest effects include TSA positively influencing cognitive performance, while reverse analyses reveal small effects of cognitive performance on TSA. Global mean cortical thickness (MTH) exhibits significant causal effects on five phenotypes, including schizophrenia. MTH reduces schizophrenia risk and bidirectional causality is found between MTH and smoking initiation. Finally, in regional analyses we detect positive influences of the transverse temporal surface area on cognitive performance and negative influences of transverse temporal thickness on schizophrenia risk. Overall, our results highlight bidirectional associations between TSA, MTH, and neuropsychiatric traits. These insights offer potential avenues for intervention studies aimed at improving brain health.
Dynamic cerebral autoregulation during and 3 months after endovascular treatment in large-vessel occlusion stroke
Authors: Heiberg Adam Vittrup , Lukassen Troels Gil , Truelsen Thomas Clement , Borgwardt Henrik Gutte , Benndorf Goetz , Sølling Christine , Schytz Henrik Winther , Møller Kirsten , Hansen Klaus , Iversen Helle Klingenberg 
Published: September 2024

AbstractAcute ischemic stroke caused by large-vessel occlusion is effectively treated by endovascular treatment (EVT). However, treatment could be further refined by improved understanding of the pathophysiology, including dynamic cerebral autoregulation (dCA). Near-infrared spectroscopy (NIRS) requires virtually no setup time and enables dCA investigation during EVT by measuring dynamic concentration in cortical oxygenated hemoglobin (OxyHb). We aimed to investigate dCA during EVT, before and after recanalization, and at follow-up (FU) after 24 hours and 90 days. We applied interhemispheric transfer function analysis (TFA) of low-frequency (LF) oscillations (0.07-0.2 Hz) in OxyHb that yields the dCA measures, gain and phase shift. We found higher LF gain in patients with favorable outcome. While dCA was stable for most patients during EVT, LF phase shift increased immediately after recanalization for patients with milder symptom severity and at 24-hour FU for patients with more severe symptoms. Adjusted for age, infarct size before EVT, and recanalization success, average LF gain predicted independent functional outcome, symptom severity and mortality at 90-day FU. In conclusion, interhemispheric TFA based on NIRS provides insights into dCA during EVT that could potentially be applied in the development of individualized treatment. The method relies on intact contralateral dCA which needs further investigation.Clinical Trial RegistrationClinicalTrial.gov:NCT03738644.Https://clinicaltrials.gov/study/NCT03738644.
The isoniazid analog IQG-607 is not a direct substrate for theMycobacterium tuberculosiscatalase-peroxidase KatG
Authors: Barsé Laísa Quadros , Roth Candida Deves , da Silva Dadda Adilio , Rambo Raoní Scheibler , Dalberto Pedro Ferrari , Pissinate Kenia , Nunes José Eduardo Sacconi , Etchart Renata Jardim , Machado Pablo , Basso Luiz Augusto , Bizarro Cristiano Valim 
Published: September 2024

AbstractTuberculosis (TB) is an infectious disease caused mainly byMycobacterium tuberculosis(Mtb) and is responsible for millions of deaths. New Mtb strains resistant to TB drugs are emerging and spreading. The first-line TB drug, isoniazid (INH), must be activated inside mycobacterial cells by the catalase-peroxidase enzyme KatG to exert its antimicrobial activity, and mutations on thekatGgene are a significant cause of INH resistance in clinics. The metal-containing compound IQG-607 is an INH analog developed to inhibit the target of INH, the FASII enzyme enoyl-ACP-reductase (InhA), without requiring KatG. However, we recently showed that inside mycobacterial cells, IQG-607 activity depends on KatG. Hence, this compound might also be activated by KatG to inhibit InhA. We evaluated whether recombinant MtKatG uses IQG-607 as a substrate in oxidation reactions and adduct formation with NAD+. A recombinant MtKatG was produced inE. coliand purified in a 3-step protocol to obtain a homogeneous protein. An HPLC method was optimized to monitor both oxidation and adduct products, and our assay system was validated by performing control reactions using INH as a substrate. We found that the metal-based compound IQG-607 is not a substrate for recombinant MtKatG under all conditions tested.
Molecular insights into the stimulation of SNM1A nuclease activity by CSB during interstrand crosslink processing
Authors: Roddan Rebecca , Nathan William J. , Newman Joseph A. , El-Sagheer Afaf , Wilson David M. , Brown Tom , Schofield Christopher J. , McHugh Peter J. 
Published: September 2024

AbstractThe SNM1A exonuclease plays a key role in repair of interstrand crosslinks (ICLs) which represent a particularly toxic class of DNA damage. Previous work suggests that the SWI/SNF family ATP-dependent, chromatin remodeler, Cockayne Syndrome B protein (CSB) interacts with SNM1A, during transcription-coupled DNA interstrand crosslink repair (TC-ICL repair). Here, we validate this interaction using purified proteins and demonstrate that the ubiquitin-binding and winged-helix domains of CSB are required for interaction with the catalytic domain of SNM1A. The winged helix domain is essential for binding, although high-affinity SNM1A binding requires the entire CSB C-terminal region (residues 1187-1493), where two copies of the C-terminal domain of CSB are necessary for a stable interaction with SNM1A. CSB stimulates SNM1A nuclease activity on varied model DNA repair intermediate substrates. Importantly, CSB was observed to stimulate digestion through ICLsin vitro, implying a key role of the interaction in ‘unhooking’ during TC-ICL repair. AlphaFold3 models of CSB constructs complexed with the SNM1A catalytic domain enabled mapping of the molecular contacts required for the CSB-SNM1A interaction. This identified specific protein-protein interactions necessary for CSB’s stimulation of SNM1A’s activity that we confirmed experimentally. Additionally, our studies reveal the C-terminal region of CSB as a novel DNA binding region that also is involved in stimulation of SNM1A-mediated ICL repair. Moreover, targeting protein-protein interactions that are vital for specific nuclease activities, such as CSB’s stimulation of SNM1A’s nuclease activity, may be a productive alternative therapeutic strategy to nuclease active site inhibition.
Structural Basis for Dimerization and Activation of UvrD-family Helicases
Authors: Chadda Ankita , Nguyen Binh , Lohman Timothy M. , Galburt Eric A. 
Published: September 2024

AbstractUvrD-family helicases are superfamily 1A motor proteins that function during DNA replication, recombination, repair, and transcription. UvrD family monomers translocate along single stranded (ss) DNA but need to be activated by dimerization to unwind DNA in the absence of force or accessory factors. However, prior structural studies have only revealed monomeric complexes. Here, we report the first structures of a dimeric UvrD-family helicase,Mycobacterium tuberculosisUvrD1, both free and bound to a DNA junction. In each structure, the dimer interface occurs between the 2B subdomains of each subunit. The apo UvrD1 dimer is observed in symmetric compact and extended forms indicating substantial flexibility. This symmetry is broken in the DNA-bound dimer complex with leading and trailing subunits adopting distinct conformations. Biochemical experiments reveal that theE. coliUvrD dimer shares the same 2B-2B interface. In contrast to the dimeric structures, an inactive, auto-inhibited UvrD1 DNA-bound monomer structure reveals 2B subdomain-DNA contacts that are likely inhibitory. The major re-orientation of the 2B subdomains that occurs upon UvrD1 dimerization prevents these duplex DNA interactions, thus relieving the auto-inhibition. These structures reveal that the 2B subdomain serves a major regulatory role rather than participating directly in DNA unwinding.
Structural characterization of Mpn444, an essential lipoprotein ofMycoplasma pneumoniae
Authors: Keles Irem , Manger Sina , Mantanya Mbuso S. , Frangakis Achilleas S. 
Published: September 2024

AbstractMycoplasma pneumoniaeis a human pathogen causing atypical community-acquired pneumonia. It is a model for a minimal cell, known for its non-canonical use of surface proteins for host-cell adhesion through ectodomain shedding and antigenic variation to evade the host cell immune response. Mpn444 is an essential mycoplasma surface protein implicated in both processes. It is one of 46 lipoproteins ofM. pneumoniae, none of which have been structurally or functionally characterized. Here, we report the structure of Mpn444 at 3.04 Å as well as the molecular architecture of the trimeric Mpn444 complex. Our experimental structure displays striking similarity to structure predictions of several other essential lipoproteins inM. pneumoniaeand other relatedMycoplasmaspecies, suggesting it to have a specialized and conserved function. The essentiality and involvement of Mpn444 in host immune evasion makes our structure a target for the development of new treatment strategies against mycoplasma infections.
Widespread occurrence of benzimidazole resistance single nucleotide polymorphisms in the canine hookworm,Ancylostoma caninum, in Australia
Authors: Abdullah Swaid , Stocker Thomas , Kang Hyungsuk , Scott Ian , Hayward Douglas , Jaensch Susan , Ward Michael P. , Jones Malcolm K. , Kotze Andrew C. , Šlapeta Jan 
Published: September 2024

AbstractCanine hookworm (Ancylostoma caninum), a gastrointestinal nematode of domestic dogs, principally infects the small intestine of dogs and has the potential to cause zoonotic disease. In greyhounds and pet dogs in the USA,A. caninumhas been shown to be resistant to multiple anthelmintics. We conducted a molecular survey of benzimidazole resistance inA. caninumfrom dogs at veterinary diagnostic centers in Australia and New Zealand. First, we implemented an internal transcribed spacer (ITS)-2 rDNA deep amplicon metabarcoding sequencing approach to ascertain the species of hookworms infecting dogs in the region. Then, we evaluated the frequency of the canonical F167Y and Q134H isotype-1 β-tubulin mutations, which confer benzimidazole resistance, using the same sequencing approach. The most detected hookworm species in diagnostic samples wasA. caninum(90%; 83/92); the related Northern hookworm (Uncinaria stenocephala) was identified in 11% (10/92) of the diagnostic samples. There was a single sample with coinfection byA. caninumandU. stenocephala. Both isotype-1 β-tubulin mutations were present inA. caninum, 49% and 67% for Q134H and F167Y, respectively. Mutation F167Y in the isotype-1 β-tubulin mutation was recorded inU. stenocephalafor the first known time. Canonical benzimidazole resistance codons 198 and 200 mutations were absent. Egg hatch assays performed on a subset of theA. caninumsamples showed significant correlation between 50% inhibitory concentration (IC50) to thiabendazole and F167Y, with an increased IC50for samples with >75% F167Y mutation. We detected 14% of dogs with >75% F167Y mutation inA. caninum. Given that these samples were collected from dogs across various regions of Australia, the present study suggests that benzimidazole resistance inA. caninumis widespread. Therefore, to mitigate the risk of resistance selection and further spread, adoption of a risk assessment-based approach to limit unnecessary anthelmintic use should be a key consideration for future parasite control.
A simple immunohistochemical method for perinatal mammalian ovaries revealed different kinetics of oocyte apoptosis caused by DNA damage and asynapsis
Authors: Kogo Hiroshi , Iizuka-Kogo Akiko , Yamamoto Hanako , Ikezawa Maiko , Tajika Yukiko , Matsuzaki Toshiyuki 
Published: September 2024

AbstractOocytes having meiotic defects are assumed to be eliminated by apoptosis in perinatal period. However, the oocyte apoptosis caused by meiotic defects has not been well analyzed, partly due to the great technical demands for tissue sectioning of perinatal ovaries. In the present study, we applied a squash method for immunohistochemical analysis of perinatal mouse ovaries as a substitute for tissue sectioning. As a result, we could show different kinetics of apoptosis caused by DMC1- and SPO11-deficiencies, indicating that DNA damage-induced apoptosis precedes asynapsis-induced apoptosis in mouse oocytes. Double mutant analysis revealed that only asynapsis-induced apoptosis was significantly dependent on HORMAD2. The present method is simple, easy, and able to analyze a sufficient number of oocytes for detecting infrequent events in a single specimen, accelerating detailed immunohistochemical analyses of mammalian ovaries during the fetal and perinatal periods.
Divergent inflammatory and neurology-related plasma protein profiles in individuals with long COVID following primary and breakthrough SARS-CoV-2 infections
Authors: Bansal Amit , Olechnowicz Sam W.Z. , Kiernan-Walker Nicholas , Cumming Jacob , Mazhari Ramin ,   COVID PROFILE consortium, Cox Rebecca J. , Mueller Ivo , Bowden Rory , Eriksson Emily M. 
Published: September 2024

AbstractLong COVID is a complex condition where symptoms persist for more than 3 months after SARS-CoV-2 infection and affects an estimated 5-30% of individuals. While the pathobiology of long COVID is still evolving, persistent inflammation has emerged as an important feature of this condition. However, it is unclear if immune responses from COVID-19 vaccination or SARS-CoV-2 re-infection exacerbate or mirror the initial inflammatory responses. To address this question, we quantified 182 inflammatory and neurology-related proteins in plasma using multiplexed affinity proteomics. Plasma samples were collected 6-9 months after first infection, but before COVID-19 vaccination from individuals who had recovered from COVID-19 (n=21) or from individuals with long COVID (n=12). This was benchmarked against plasma from unvaccinated, SARS-CoV-2 naive individuals (n=24). In addition to this cross-sectional analysis, we performed longitudinal analysis in a subset of individuals (n=34), where paired samples collected 2-4 weeks after a third COVID-19 vaccine dose and after SARS-CoV-2 breakthrough infection were available. Boruta feature selection and lasso regression models identified a distinct plasma profile in long COVID individuals, characterised by elevated IL-20, HAGH, NAAA, CLEC10A, LXN, and MCP-1 and reduced TRAIL, G-CSF, NBL1, and CCL23 protein concentrations. Notably, longitudinal analysis demonstrated that neither COVID-19 booster vaccination nor breakthrough infection replicated inflammatory and neurology-related plasma protein profiles observed after primary infection suggesting an altered immune response outcome in individuals with long COVID upon re-exposure.
Chyme Reinfusion Practices in the Neonatal Population
Authors: Lim Alexandria H , Tinawi Georges , Harrington Taylor , Ludlow Emma , Evans Helen , Bissett Ian , Keane Celia 
Published: September 2024

AbstractIntroductionThe utilisation of chyme reinfusion therapy (CRT) by returning the output from the proximal limb into the distal limb of double enterostomies is a safe and effective method to improve nutritional uptake and maintain intestinal integrity in adult populations. This technique is also particularly suitable for neonatal patients with life-threatening conditions such as congenital bowel abnormalities and necrotising enterocolitis (NEC). Despite its promise, it has only had irregular uptake in neonatal patients. We aimed to identify the frequency, methodology and adverse events associated with CRT in the appropriate neonatal population.MethodsA ten-year retrospective cohort study was conducted using database searches at two major paediatric hospitals in New Zealand. All patients with suitable anatomy were identified, and data on CRT methodology and outcomes were recorded.ResultsOf the 49 neonates identified with double enterostomy 23 (47%) underwent CRT for high stoma output, risk of short gut syndrome or as a routine protocol before re-anastomosis. A nasogastric feeding tube was inserted into the distal limb and collected chyme was reinfused via manual bolus or automated syringe driver. The median (IQR) weight gain increased from 13.9 (3.50 - 22.89) to 24.37 (19.68 - 29.99) g/day during CRT (p = 0.04). 18 infections requiring medical intervention but unrelated to CRT occurred in 13 patients (56%). The rate of non-infectious adverse events was 24, with 7% remaining free from any adverse events.ConclusionChyme reinfusion is an underutilised method of improving nutrition in neonates with intestinal failure. Premature neonates requiring double enterostomy formation are at high risk of infectious and non-infectious complications, but few of these are related to CRT. Standardised protocols providing clear eligibility criteria and detailed methodology for CRT are required to promote uniform utilisation of this practice.