bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure-Activity Relationship Studies of Novel Gut-derived Lantibiotics Against Human Gut Commensals
Authors: Zhang Zhenrun J. , Wu Chunyu , Dorantes Darian , Pappas Téa , Sundararajan Anitha , Lin Huaiying , Pamer Eric G. , van der Donk Wilfred A. 
Published: September 2023

AbstractRecent advances in sequencing techniques unveiled the vast potential of ribosomally synthesized and post-translationally modified peptides (RiPPs) encoded in microbiomes. Class I lantibiotics such as nisin A, widely used as a food preservative, have been investigated for their efficacy in killing pathogens. However, the impact of nisin and nisin-like class I lantibiotics on commensal bacteria residing in the human gut remains unclear. Here, we report six gut-derived class I lantibiotics that are close homologs of nisin, four of which are novel. We applied an improved lantibiotic expression platform to produce and purify these lantibiotics for antimicrobial assays. We determined their minimal inhibitory concentration (MIC) against both Gram-positive human pathogens and gut commensals, and profiled the lantibiotic resistance genes in these pathogens and commensals. SAR studies with variants revealed key regions and residues that impact their antimicrobial properties. Our characterization and SAR studies of nisin-like lantibiotics against both pathogens and human gut commensals could shed light on the future development of lantibiotic-based therapeutics and food preservatives.
The association between cortical gyrification and sleep in adolescents and young adults
Authors: Santos João Paulo Lima , Hayes Rebecca , Franzen Peter L. , Goldstein Tina R. , Hasler Brant P. , Buysse Daniel J. , Siegle Greg J. , Dahl Ronald E. , Forbes Erika E. , Ladouceur Cecile D. , McMakin Dana L. , Ryan Neal D. , Silk Jennifer S. , Jalbrzikowski Maria , Soehner Adriane M 
Published: September 2023

ABSTRACTStudy objectivesHealthy sleep is important for adolescent neurodevelopment, and relationships between brain structure and sleep can vary in strength over this maturational window. Although cortical gyrification is increasingly considered a useful index for understanding cognitive and emotional outcomes in adolescence, and sleep is also a strong predictor of such outcomes, we know relatively little about associations between cortical gyrification and sleep.MethodsUsing Local gyrification index (lGI) of 34 bilateral brain regions and regularized regression for feature selection, we examined gyrification-sleep relationships in the Neuroimaging and Pediatric Sleep databank (252 participants; 9-26 years; 58.3% female) and identified developmentally invariant (stable across age) or developmentally specific (observed only during discrete age intervals) brain-sleep associations. Naturalistic sleep characteristics (duration, timing, continuity, and regularity) were estimated from wrist actigraphy.ResultsFor most brain regions, greater lGI was associated with longer sleep duration, earlier sleep timing, lower variability in sleep regularity, and shorter time awake after sleep onset. lGI in frontoparietal network regions showed associations with sleep patterns that were stable across age. However, in default mode network regions, lGI was only associated with sleep patterns from late childhood through early-to-mid adolescence, a period of vulnerability for mental health disorders.ConclusionsWe detected both developmentally invariant and developmentally specific ties between local gyrification and naturalistic sleep patterns. Default mode network regions may be particularly susceptible to interventions promoting more optimal sleep during childhood and adolescence.
Mechanistic Regulation of Planarian Shape During Growth and Degrowth
Authors: Ko Jason M. , Reginato Waverly , Lobo Daniel 
Published: September 2023

AbstractAdult planarians can grow when fed and degrow (shrink) when starved while maintaining their whole-body shape with correct proportions. Different planarian morphogens are expressed at the anterior-posterior poles, medio-lateral border, and midline to provide positional information signals for the specification of different tissues at the right locations. However, it is currently unknown how these signals are coordinated together during feeding or starvation and how they modulate the differential tissue growth or degrowth necessary to form correct whole-body shapes. Here we investigate the dynamics of planarian shape during growth and degrowth together with a theoretical study to evaluate the mechanisms that regulate whole-body proportions and shape. We found that the planarian body proportions scale isometrically following similar linear rates during growth and degrowth, but that fed worms are significantly wider than starved worms. By combining a descriptive model of planarian shape and size with a mechanistic model of anterior-posterior and medio-lateral signaling calibrated with a novel machine learning methodology, we demonstrate that the feedback loop between these positional information signals and the shape they control can regulate the planarian whole-body shape during growth. Furthermore, the model can predict the correct shape and size dynamics during degrowth due to an increase in apoptosis rate and pole signal during starvation. These results offer mechanistic insights into planarian shape and size dynamics and the regulation of whole-body morphologies.
Mapping the interaction sites of Influenza A viruses and human complement Factor H
Authors: Rabeeah Iman , Billington Elizabeth , Nal-Rogier Beatrice , Sadeyen Jean-Remy , Pathan Ansar , Iqbal Munir , Temperton Nigel , Zipfel Peter F. , Skerka Christine , Kishore Uday , Shelton Holly 
Published: September 2023

AbstractThe complement system is an innate immune mechanism against microbial infection. It involves a cascade of effector molecules that is activated via classical, lectin and alternative pathways. Consequently, many pathogens bind to or incorporate in their structures host negative regulators of the complement pathways as an evasion mechanism. Factor H (FH) is a negative regulator of the complement alternative pathway that protects “self” cells of the host from non-specific complement attack. Viruses including human influenza A viruses (IAVs) have been shown to bind to FH. Here we show that IAVs of both human and avian origin can bind directly to human FH and the interaction is mediated via the IAV surface glycoprotein haemagglutinin (HA). HA bound to common pathogen binding footprints on the FH structure, complement control protein modules, CCP 5-7 and CCP 15-20. The FH binding to H1 and H3 showed that the interaction overlapped with the receptor binding site of both HAs but the footprint was more extensive for the H3 HA than the H1 HA. The HA - FH interaction impeded the initial entry of H1N1 and H3N2 IAV strains but its impact on viral multicycle replication in human lung cells was strain specific. The H3N2 virus binding to cells was significantly inhibited by preincubation with FH, whereas there was no alteration in replicative rate and progeny virus release for human H1N1 or avian H9N2 and H5N3 IAV strains. We have mapped the interaction between IAV and FH, the significance of which for the virus or host is yet to be elucidated.
Epidermal growth factor receptors in vascular endothelial cells contribute to functional hyperemia in the brain
Authors: Ferris Hannah R. , Hill-Eubanks David C. , Nelson Mark T. , Wellman George C. , Koide Masayo 
Published: September 2023

AbstractFunctional hyperemia – activity-dependent increases in local blood perfusion – underlies the on-demand delivery of blood to regions of enhanced neuronal activity, a process that is crucial for brain health. Importantly, functional hyperemia deficits have been linked to multiple dementia risk factors, including aging, chronic hypertension, and cerebral small vessel disease (cSVD). We previously reported crippled functional hyperemia in a mouse model of genetic cSVD that was likely caused by depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) in capillary endothelial cells (EC) downstream of impaired epidermal growth factor receptor (EGFR) signaling. Here, using EC-specific EGFR-knockout (KO) mice, we directly examined the role of endothelial EGFR signaling in functional hyperemia, assessed by measuring increases in cerebral blood flow in response to contralateral whisker stimulation using laser Doppler flowmetry. Molecular characterizations showed that EGFR expression was dramatically decreased in freshly isolated capillaries from EC-EGFR-KO mice, as expected. Notably, whisker stimulation-induced functional hyperemia was significantly impaired in these mice, an effect that was rescued by exogenous administration of PIP2, but not by the EGFR ligand, HB-EGF. These data suggest that the deletion of the EGFR specifically in ECs depletes PIP2and attenuates functional hyperemia, underscoring the central role of the endothelial EGFR signaling in cerebral blood flow regulation.
Pyruvate Kinase Activity Regulates Cystine Starvation Induced Ferroptosis through Malic Enzyme 1 in Pancreatic Cancer Cells
Authors: Ensink Elliot , Jordan Tessa , D Medeiros Hyllana C , Thurston Galloway , Pardal Anmol , Yu Lei , Lunt Sophia Y. 
Published: September 2023

AbstractPancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high mortality and limited efficacious therapeutic options. PDAC cells undergo metabolic alterations to survive within a nutrient-depleted tumor microenvironment. One critical metabolic shift in PDAC cells occurs through altered isoform expression of the glycolytic enzyme, pyruvate kinase (PK). Pancreatic cancer cells preferentially upregulate pyruvate kinase muscle isoform 2 isoform (PKM2). PKM2 expression reprograms many metabolic pathways, but little is known about its impact on cystine metabolism. Cystine metabolism is critical for supporting survival through its role in defense against ferroptosis, a non-apoptotic iron-dependent form of cell death characterized by unchecked lipid peroxidation. To improve our understanding of the role of PKM2 in cystine metabolism and ferroptosis in PDAC, we generated PKM2 knockout (KO) human PDAC cells. Fascinatingly, PKM2KO cells demonstrate a remarkable resistance to cystine starvation mediated ferroptosis. This resistance to ferroptosis is caused by decreased PK activity, rather than an isoform-specific effect. We further utilized stable isotope tracing to evaluate the impact of glucose and glutamine reprogramming in PKM2KO cells. PKM2KO cells depend on glutamine metabolism to support antioxidant defenses against lipid peroxidation, primarily by increased glutamine flux through the malate aspartate shuttle and utilization of ME1 to produce NADPH. Ferroptosis can be synergistically induced by the combination of PKM2 activation and inhibition of the cystine/glutamate antiporterin vitro. Proof-of-conceptin vivoexperiments demonstrate the efficacy of this mechanism as a novel treatment strategy for PDAC.Graphical AbstractHighlightsPKM2KO in pancreatic ductal adenocarcinoma (PDAC) cells produces enhanced defense against cystine starvation induced ferroptosis.Pharmacologic activation of pyruvate kinase (PK) activity promotes ferroptosis under cystine starvation, while inhibition promotes ferroptosis survival in PDAC cells.Decrease in PK activity reprograms glutamine metabolism to increase use of malic enzyme 1 and promote survival under cystine starvation in PDAC cells.Cystine starvation and activation of pyruvate kinase synergistically decreases progression of pancreatic cancerin vivo.
A three-genome ultraconserved element phylogeny of Cryptophytes
Authors: Greenwold Matthew J. , Merritt Kristiaän , Richardson Tammi L. , Dudycha Jeffry L. 
Published: September 2023

AbstractCryptophytes are single celled protists found in all aquatic environments. They are composed of a heterotrophic genus,Goniomonas, and a largely autotrophic group comprising many genera. Cryptophytes evolved through secondary endosymbiosis between a host eukaryotic heterotroph and a symbiont red alga. This merger resulted in a four-genome system that includes the nuclear and mitochondrial genomes from the host and a second nuclear genome (nucleomorph) and plastid genome inherited from the symbiont. Here, we make use of different genomes (with potentially distinct evolutionary histories) to perform a phylogenomic study of the early history of cryptophytes. Using ultraconserved elements from the host nuclear genome and symbiont nucleomorph and plastid genomes, we produce a three-genome phylogeny of 91 strains of cryptophytes. Our phylogenetic analyses find that that there are three major cryptophyte clades: Clade 1 comprisesChroomonasandHemiselmisspecies, Clade 2, a taxonomically rich clade, comprises at least twelve genera, and Clade 3, comprises the heterotrophicGoniomonasspecies. Each of these major clades include both freshwater and marine species, but subclades within these clades differ in degrees of niche conservatism. Finally, we discuss priorities for taxonomic revision to Cryptophyceae based on previous studies and in light of these phylogenomic analyses.
Effects of Polyphosphate metabolism Mutations on Biofilm, Capsule Formation and Virulence Traits in Hypervirulent ST23Klebsiella pneumoniaeSGH10
Authors: Rojas Diego , Marcoleta Andrés E. , Gálvez Matías , Varas Macarena A. , Díaz Mauricio , Hernández Mauricio , Vargas Cristian , Nourdin Guillermo , Koch Elard , Saldivia Pablo , Vielma Jorge , Gan Yunn-Hwen , Chen Yahua , Guiliani Nicolás , Chávez Francisco P. 
Published: September 2023

ABSTRACTThe emergence of hypervirulentKlebsiella pneumoniae(hvKP) strains poses a significant threat to public health due to their high mortality rates and propensity to cause severe community-acquired infections in otherwise healthy individuals. The ability of hvKP to form biofilms and produce a protective capsule contributes to its enhanced virulence and is a significant challenge to effective antibiotic treatment. Therefore, understanding the molecular mechanisms underlying hvKP virulence and biofilm formation is crucial for developing new therapeutic strategies. Polyphosphate Kinase 1 (PPK1) is an enzyme responsible for inorganic polyphosphate synthesis and plays a vital role in regulating various physiological processes in bacteria. In this study, we investigated the impact of polyP metabolism on the biofilm and capsule formation and virulence traits in hvKP usingDictyostelium discoideumamoeba as a model host. We found that the PPK1 null-mutant was impaired in biofilm and capsule formation and showed attenuated virulence inD. discoideumcompared to the wild-type strain. We performed a shotgun proteomic analysis of the PPK1 mutant and wild-type strain to gain further insight into the underlying molecular mechanism. The results revealed that the PPK1 mutant had a differential expression of proteins (DEP) involved in capsule synthesis (Wzi - Ugd), biofilm formation (MrkC-D-H), synthesis of the colibactin genotoxin precursor (ClbB), as well as proteins associated with the synthesis and modification of lipid A (ArnB -LpxC - PagP). These proteomic findings corroborate the phenotypic observations and indicate that the PPK1 mutation is associated with impaired biofilm and capsule formation and attenuated virulence in hypervirulentK. pneumoniae. Overall, our study highlights the importance of polyP synthesis in regulating extracellular biomolecules and virulence inK. pneumoniaeand provides insights into potential therapeutic targets for treatingK. pneumoniaeinfections.
Androgen blockade primes NLRP3 in macrophages to induce tumor phagocytosis
Authors: Chaudagar Kiranj , Rameshbabu Srikrishnan , Mei Shenglin , Hirz Taghreed , Hu Ya-Mei , Argulian Anna , Labadie Brian , Desai Kunal , Grimaldo Sam , Kahramangil Doga , Nair Rishikesh , DSouza Sabina , Zhou Dylan , Li Mingyang , Doughan Farah , Chen Raymond , Shafran Jordan , Loyd Mayme , Xia Zheng , Sykes David B. , Moran Amy , Patnaik Akash 
Published: September 2023

ABSTRACTImmune-based therapies induce durable remissions in subsets of patients across multiple malignancies. However, there is limited efficacy of immunotherapy in metastatic castrate-resistant prostate cancer (mCRPC), manifested by an enrichment of immunosuppressive (M2) tumor- associated macrophages (TAM) in the tumor immune microenvironment (TME). Therefore, therapeutic strategies to overcome TAM-mediated immunosuppression are critically needed in mCRPC. Here we discovered that NLR family pyrin domain containing 3 (NLRP3), an innate immune sensing protein, is highly expressed in TAM from metastatic PC patients treated with standard-of-care androgen deprivation therapy (ADT). Importantly,ex vivostudies revealed that androgen receptor (AR) blockade in TAM upregulates NLRP3 expression, but not inflammasome activity, and concurrent AR blockade/NLRP3 agonist (NLRP3a) treatment promotes cancer cell phagocytosis by immunosuppressive M2 TAM. In contrast, NLRP3a monotherapy was sufficient to enhance phagocytosis of cancer cells in anti-tumor (M1) TAM, which exhibit highde novoNLRP3 expression. Critically, combinatorial treatment with ADT/NLRP3a in a murine model of advanced PC resulted in significant tumor control, with tumor clearance in 55% of mice via TAM phagocytosis. Collectively, our results demonstrate NLRP3 as an AR-regulated “macrophage phagocytic checkpoint”, inducibly expressed in TAM by ADT and activated by NLRP3a treatment, the combination resulting in TAM-mediated phagocytosis and tumor control.
Imprinting but not cytonuclear interactions affects parent-of-origin effect on seed size inArabidopsishybrids
Authors: June Viviana , Song Xiaoya , Chen Z. Jeffrey 
Published: September 2023

ABSTRACTThe parent-of-origin effect on seed size can result from imprinting or a combinational effect between cytoplasmic and nuclear genomes, but their relative contributions remain unknown. To discern these confounding effects, we generated cytoplasmic-nuclear substitution (CNS) lines using recurrent backcrossing in theArabidopsis thalianaecotypes Col-0 and C24. These CNS lines differ only in the nuclear genome (imprinting) or in the cytoplasm. The CNS reciprocal hybrids with the same cytoplasm display a ∼20% seed size difference as observed in the conventional hybrids. However, seed size is similar between the reciprocal cybrids with fixed imprinting. Transcriptome analyses in the endosperm of CNS hybrids using laser-capture microdissection have identified 104 maternally expressed genes (MEGs) and 90 paternally-expressed genes (PEGs). These imprinted genes are involved in pectin catabolism and cell wall modification in the endosperm.HDG9, an epiallele and one of 11 cross-specific imprinted genes, controls seed size. In the embryo, a handful of imprinted genes is found in the CNS hybrids but only one is expressed higher in the embryo than endosperm.AT4G13495encodes a long-noncoding RNA (lncRNA), but no obvious seed phenotype is observed in the lncRNA knockout lines.NRPD1, encoding the largest subunit of RNA Pol IV, is involved in the biogenesis of small interfering RNAs. Seed size and embryo is larger in the cross usingnrpd1as the maternal parent than in the reciprocal cross. In spite of limited ecotypes tested, these results suggest potential roles of imprinting andNRPD1-mediated small RNA pathway in seed size variation in hybrids.
Phosphate starvation regulates cellulose synthesis to modify root growth
Authors: Khan Ghazanfar Abbas , Dutta Arka , Van de Meene Allison , Frandsen Kristian EH. , Ogden Michael , Whelan James , Persson Staffan 
Published: September 2023

AbstractIn the model plantArabidopsis thaliana, the absence of the essential macro-nutrient phosphate reduces primary root growth through decreased cell division and elongation, requiring alterations to the polysaccharide-rich cell wall surrounding the cells. Despite its significance, the regulation of cell wall synthesis in response to low phosphate levels is not well understood. In this study, we show that plants increase cellulose synthesis in roots under limiting phosphate conditions, which leads to changes in the thickness and structure of the cell wall. These changes contribute to the reduced growth of primary roots in low phosphate conditions. Furthermore, we found that the cellulose synthase complex activity at the plasma membrane increases during phosphate deficiency. Moreover, we show that this increase in the activity of the cellulose synthase complex is likely due to alterations in the phosphorylation status of cellulose synthases in low phosphate conditions. Specifically, phosphorylation of CELLULOSE SYNTHASE 1 at the S688 site decreases in low phosphate conditions. Phosphomimic versions of CELLULOSE SYNTHASE 1 with an S688E mutation showed significantly reduced cellulose induction and primary root length changes in low phosphate conditions. Protein structure modelling suggests that the phosphorylation status of S688 in CELLULOSE SYNTHASE 1 could play a role in stabilizing and activating the cellulose synthase complex. This mechanistic understanding of root growth regulation under limiting phosphate conditions provides potential strategies for changing root responses to soil phosphate content.
Comparison of image registration techniques in functional ultrasound imaging
Authors: Zhong Shan , Agyeman Kofi , Syed Shanze , Tobing Richard , Choi Wooseong , Liu Charles , Lee Darrin , Christopoulos Vassilios 
Published: September 2023

AbstractFunctional Ultrasound Imaging (fUSI) is an emerging hemodynamic-based functional neuroimaging technique that combines high spatiotemporal resolution and sensitivity, as well as extensive brain coverage, enabling a range of applications in both control and disease animal models. Based on power Doppler (pD) imaging, fUSI measures changes in cerebral blood volume (CBV) by detecting the back-scattered echoes from red blood cells moving within its field of view (FOV). However, the expansion of fUSI technology is partly limited by the challenge to co-register pD vascular maps acquired across different sessions or animals to one reference; an approach that could widen the scope of experimental paradigms and enable advanced data analysis tools. In this study, we seek to address this critical limitation. We evaluate six image registration techniques, predominantly used in other neuroimaging studies, using 2D sagittal whole-brain fUSI data from 82 anesthetized mice, and tested the quality of registration using multiple metrics. Our findings indicate a substantial enhancement in the alignment of fUSI images post registration. Among the tested techniques, the non-rigid registration algorithmImregdeformyielded superior performance. We offer the first comparative study of image registration techniques for a 2D fUSI brain dataset, paving a way for improved utilization of fUSI in future pre-clinical research applications.