bluuebunny/crossref_metadata_2025_split huggingface dataset:
A large-scale bioinformatic study of graspimiditides and structural characterization of albusimiditide
Authors: Choi Brian , Acuna Arthur , Koos Joseph D. , Link A. James 
Published: June 2023

AbstractGraspetides are a class of ribosomally synthesized and post-translationally modified peptides (RiPPs) that exhibits an impressive diversity in patterns of side chain-to-side chain ω-ester or ω-amide linkages. Recent studies have uncovered a significant portion of graspetides to contain an additional post-translational modification involving aspartimidylation catalyzed by anO-methyltransferase, predominantly found in the genomes of Actinomycetota. Here, we present a comprehensive bioinformatic analysis focused on graspetides harboring aspartimide for which we propose the name graspimiditides. From Protein BLAST results of 5,000 methyltransferase sequences, we identified 962 unique putative graspimiditides, which we further classified into eight main clusters based on sequence similarity along with several smaller clusters and singletons. The previously studied graspimiditides, fuscimiditide and amycolimiditide, are identified in this analysis; fuscimiditide is a singleton while amycolimiditide is in the fifth largest cluster. Cluster 1, by far the largest cluster, contains 641 members, encoded almost exclusively in theStreptomycesgenus. To characterize an example of a graspimiditide in Cluster 1, we conducted experimental studies on the peptide fromStreptomyces albusJ1074, which we named albusimiditide. By tandem mass spectrometry, hydrazinolysis, and amino acid substitution experiments, we elucidated the structure of albusimiditide to be a large tetracyclic peptide with four ω-ester linkages generating a stem-loop structure with one aspartimide. The ester crosslinks form 22-, 46-, 22-, and 44-atom macrocycles, last of which, the loop, contains the enzymatically installed aspartimide. Furtherin vitroexperiments revealed that the aspartimide hydrolyzes in a 3:1 ratio of isoaspartate to aspartate residues. Overall, this study offers a comprehensive insight into the diversity and structural features of graspimiditides, paving the way for future investigations of this unique class of natural product.Abstract Figure
In vivovisualization of intracellular pH gradient in brain using PET imaging
Authors: Yamasaki Tomoteru , Mori Wakana , Ohkubo Takayuki , Hiraishi Atsuto , Zhang Yiding , Kurihara Yusuke , Nengaki Nobuki , Tashima Hideaki , Fujinaga Masayuki , Zhang Ming-Rong 
Published: June 2023

AbstractIntracellular pH (pHi) is a valuable index for predicting hypoxic brain damage. However, no positron emission tomography (PET) probe is currently available for monitoring pHiin vivo. In this study, we developed a new approach for visualizing monoacylglycerol lipase (MAGL) activity in the brain. This approach used PET with a new probe [11C]HC-A, an azetidine carbamate inhibitor, whose uptake and residence depended on the pHi gradient was evaluated within silico,in vitro, andin vivoassessments. Molecular dynamics simulations predicted that complex (complex-A) between HC-A and MAGL would be difficult to hydrolyze under acidic conditions.In vitroassessment using rat brain homogenate showed that [11C]HC-A reacted with MAGL to yield [11C]complex-A, which was rapidly hydrolyzed to liberate11CO2. The11CO2liberation rate was slower at lower pH. In PET with [11C]HC-A using ischemic rats, the radioactivity clearance rate, which reflects the production rate of11CO2in the brain, was lower in a remarkably hypoxic area than in the contralateral region. In conclusion, we successfully visualized the pHi gradient in the brain using PET imaging.
Review of spatial planning policy as an intervention for improving public health: protocol for a health-focused content review of local plans in England
Authors: Chang Michael , Carhart Neil 
Published: June 2023

AbstractIntroductionEach local authority in England is required to create a statutory local plan that sets out their land use priorities as the basis of decision-making on urban development. Only recently has there been an explicit recognition the local plan is capable of being a legal determinant of and important public policy intervention in influencing population physical and mental health and wellbeing. But there is a lack of comprehensive understanding of whether and how local plans have integrated wider determinants of health. The objective of this research is to identify and understand the state of current local plans in relation to health by undertaking a census.Methods and analysisThe review for England will involve a census of all local plans, and content and thematic analyses of a sample of local plans. This is subject to developing a review framework as the basis for gathering findings using a combination of query functions in PDF documents and data presentation in Excel, supported latterly by the computerassisted qualitative data analysis software, NVivo. The review framework will include a range of search parameters for identifying explicit health references across specified policy topics and wider determinants of health indicators as they relate to spatial planning based on an established evidence publication. A sampling strategy identifies inclusion and exclusion criteria to focus on local plans in England used in planning decision making. Results will be collected in qualitative and quantitative data formats. The results will be synthesised and discussed using a combination of qualitative data analytical strategies.Ethics and disseminationThe review is desktop based using publicly available policy documents on local authority websites, so ethics approval is not required. The results of the review will be reported in journal articles and for policy makers to improve national and local policy development.
Single nucleotide variation catalogue from clinical isolates mapped on tertiary and quaternary structures of ESX-1 related proteins reveals critical regions as putative Mtb therapeutic targets
Authors: Tzfadia Oren , Siroy Axel , Vujkovic Alexandra , Gijsbers Abril , Snobre Jihad , Vargas Roger , Mulders Wim , Meehan Conor J. , Farhat Maha , Peters Peter J. , de Jong Bouke C. , Ravelli Raimond B.G. 
Published: June 2023

AbstractProteins encoded by the ESX-1 genes of interests are essential for full virulence in allMycobacterium tuberculosiscomplex (MTBc) lineages, the pathogens with the highest mortality worldwide. Identifying critical regions in these ESX-1 related proteins could provide preventive or therapeutic targets for MTB infection, the game changer needed for tuberculosis control. We analysed a compendium of whole genome sequences of clinical MTB isolates from all lineages from >32,000 patients and identified single nucleotide variations (SNV). When mutations corresponding to all nonsynonymous SNPs were mapped on the surface of known and AlphaFold-predicted ternary protein structures, fully conserved regions emerged. Some could be assigned to known quaternary structures, whereas others could be predicted to be involved in yet-to-be-discovered interactions. Some mutants had clonally expanded (found in >1% of the isolates): these were mostly located at the surface of globular domains, remote from known intra- and inter-molecular protein–protein interactions. Fully conserved intrinsically disordered regions (IDRs) of proteins were found, suggesting that these are crucial for the pathogenicity of the MTBc. Altogether, our findings provide an evolutionary structural perspective on MTB virulence and highlight fully conserved regions of proteins as attractive vaccine antigens and drug targets. Extending this approach to other pathogens can provide a novel critical resource for the development of innovative tools for pathogen control.
MX2 restricts HIV-1 and herpes simplex virus type 1 by forming cytoplasmic biomolecular condensates that mimic nuclear pore complexes
Authors: Moschonas George D. , Delhaye Louis , Cooreman Robin , Hüsers Franziska , Bhat Anayat , Sutter Delphine De , Parthoens Eef , Desmet Anne-Sophie , Maciejczuk Aleksandra , Grzesik Hanna , Lippens Saskia , Debyser Zeger , Sodeik Beate , Eyckerman Sven , Saelens Xavier 
Published: June 2023

SummaryHuman myxovirus resistance 2 (MX2) can potently restrict HIV-1 and herpesviruses at a post-entry step by a process that requires MX2 interaction with the capsids of these viruses. The involvement of other host cell factors in this process, however, remains poorly understood. Here, we mapped the proximity interactome of MX2 revealing strong enrichment of phenylalanine-glycine (FG)-rich proteins related to the nuclear pore complex as well as proteins that are part of cytoplasmic ribonucleoprotein granules. MX2 interacted with these proteins to form multiprotein cytoplasmic biomolecular condensates that were essential for its anti-HIV-1 and -herpes simplex virus-1 (HSV-1) activity. MX2 condensate formation required the disordered N-terminal region of MX2 and its dimerization. Incoming HIV-1 and HSV-1 capsids associated with MX2 at these dynamic cytoplasmic biomolecular condensates. Our results demonstrate that MX2 forms cytoplasmic condensates that act as nuclear pore decoys, which trap capsids and induce premature viral genome release, and thereby interfere with nuclear targeting of HIV-1 and HSV-1.
Transcriptomic profiling of murine GnRH neurons reveals developmental trajectories linked to human reproduction
Authors: Zouaghi Yassine , Alpern Daniel , Gardeux Vincent , Russeil Julie , Deplancke Bart , Santoni Federico , Pitteloud Nelly , Messina Andrea 
Published: June 2023

AbstractGonadotropin-releasing hormone (GnRH) neurons play a crucial role in human reproduction and are associated with a spectrum of conditions. However, the underlying biological mechanisms remain elusive due to their small number and sparse distribution. We performed transcriptomic profiling of GnRH neurons during mouse embryonic development, revealing their molecular identity and gene expression dynamics. Our findings show that GnRH neurons undergo a profound transcriptional shift as they migrate from the nose to the brain and that distinct expression trajectories are associated with critical biological processes, including cell migration, neuronal projections, and synapse formation. Cell-to-cell communication analysis revealed timely and spatially restricted modulation of signaling pathways involving known molecules, such as Semaphorins and Plexins, and novel candidates, such as Neurexins and Endothelins. Using GWAS genes linked to human reproductive onset, we found a specific association with GnRH neuron trajectories rising in late developmental stages and involved in neuron maturation and connectivity. Finally, analysis of the genetic burden in a large cohort of patients with congenital GnRH deficiency revealed specific GnRH neuron trajectories with a significant mutation load compared to controls.In conclusion, this study revealed the gene expression dynamics underlying GnRH neuron embryonic development and provides novel insights linking GnRH neuron biology to human reproduction.
The influence of diet on gut microbiome and body mass dynamics in a capital-breeding migratory bird
Authors: Jones Isabelle L , Marsh Kirsty J , Handby Tess , Hopkins K , Slezasek J , Bearhop Stuart , Harrison Xavier A 
Published: June 2023

AbstractGut-associated microbial communities are known to play a vital role in the health and fitness of their hosts. Though studies investigating the factors associated with among-individual variation in microbiome structure in wild animal species are increasing, knowledge of this variation at the individual level is scarce, despite the clear link between microbiome and nutritional status uncovered in humans and model organisms. Here, we combine detailed life history, foraging preference, and faecal microbiome data to investigate the relationship between diet, microbiome stability and rates of body mass gain in a migratory capital-breeding bird, the light-bellied Brent goose (Branta bernicla hrota). Our findings suggest that there is a significant relationship between foraging and the diversity, composition and stability of the faecal microbiome. We also suggest a link between foraging phenotype and the rates of mass gain during the spring staging of a capital breeder. This study offers rare insight into individual-level temporal dynamics of the gut microbiome of a wild host. Further work is needed to uncover the functional link between individual dietary choices, gut microbiome structure and stability, and the implications this has for the reproductive success of this capital breeder.
Tirzepatide inhibits tumor growth in mice with diet-induced obesity
Authors: Huang Linxuan , Zeng Jibin , Wang Ye , Pollak Michael 
Published: June 2023

AbstractTirzepatide, a drug used in management of type II diabetes, is an activator of both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptors. Tirzepatide treatment leads to weight loss in murine models of obesity, and clinical trials have shown the drug can lead to weight loss up to ∼ 20% in overweight patients. Obesity has been shown to increase risk and/or to worsen prognosis of certain common cancers, including colon cancer, but the effect of tirzepatide on neoplasia has not been examined in detail. We studied the effects of this drug on the murine MC38 colon cancer model, which has previously shown to exhibit accelerated growth in hosts with diet-induced obesity. Tirzepatide did not cause tumor regression, but reduced tumor growth rates by ∼ 50%. This was associated with substantial reductions in food intake, and in circulating levels of insulin and leptin. Tirzepatide had no effect on MC38 cancer cell proliferationin vitro, and the effect of tirzepatide on tumor growthin vivocould be phenocopied in placebo treated mice simply by restricting food intake to the amount consumed mice receiving the drug. This provides evidence that the drug acts indirectly to inhibit tumor growth. Our findings raise the possibility that use of tirzepatide or similar agents may benefit patients with obesity-related cancers.
Deciphering the genetic interactions between Pou4f3, Gfi1, and Rbm24 in maintaining cochlear hair cell survival
Authors: Wang Guangqin , Gu Yunpeng , Liu Zhiyong 
Published: June 2023

ABSTRACTMammals harbor a limited number of sound-receptor hair cells (HCs) that cannot be regenerated after damage. Thus, investigating the underlying molecular mechanisms that maintain HC survival is crucial for preventing hearing impairment. Intriguingly,Pou4f3-/-orGfi1-/-HCs form initially but then rapidly degenerate, whereasRbm24-/-HCs degenerate considerably later. However, the transcriptional cascades involving Pou4f3, Gfi1, and Rbm24 remains undescribed. Here, we demonstrate thatRbm24expression is completely repressed inPou4f3-/-HCs but unaltered inGfi1-/-HCs, and further that the expression of both POU4F3 and GFI1 is intact inRbm24-/-HCs. Moreover, by usingin vivomouse transgenic reporter assays, we identify threeRbm24enhancers to which POU4F3 binds. Lastly, throughin vivogenetic testing of whether Rbm24 restoration alleviates the degeneration ofPou4f3-/-HCs, we show that ectopic Rbm24 alone cannot preventPou4f3-/-HCs from degenerating. Collectively, our findings provide new molecular and genetic insights into how HC survival is regulated.
Ninein domains required for its localization, association with partners dynein and ensconsin, and microtubule organization
Authors: Tillery Marisa M. L. , Zheng Chunfeng , Zheng Yiming , Megraw Timothy L. 
Published: June 2023

AbstractNinein (Nin) is a microtubule (MT) anchor at the subdistal appendages of mother centrioles and the pericentriolar material (PCM) of centrosomes that also functions to organize microtubules at non-centrosomal microtubule-organizing centers (ncMTOCs). In humans, theNINgene is mutated in Seckel syndrome, an inherited developmental disorder. Here we dissect the protein domains involved in Nin’s localization and interactions with dynein and ensconsin (ens/MAP7) and show that the association with ens cooperatively regulates microtubule assembly inDrosophilafat body cells. We define domains of Nin responsible for its localization to the ncMTOC on the fat body cell nuclear surface, localization within the nucleus, and association with Dynein light intermediate chain (Dlic) and ens, respectively. We show that Nin’s association with ens synergistically regulates MT assembly. Together, these findings reveal novel features of Nin function and its regulation of a ncMTOC.
EARLY MATURITY 7modifies the circadian clock and photoperiod sensitivity in barley
Authors: Helmsorig Gesa , Walla Agatha , Rütjes Thea , Buchmann Gabriele , Schüller Rebekka , Hensel Götz , von Korff Maria 
Published: June 2023

AbstractBreeding for variation in photoperiod response is crucial to adapt crop plants to novel environments. Plants measure changes in day length by the circadian clock, an endogenous timekeeper that allows plants to anticipate changes in diurnal and seasonal light-dark cycles. Here, we describe theearly maturity 7(eam7) mutation in barley, which interacts with natural variation atPHOTOPERIOD 1(Ppd-H1) to cause early flowering independent of the photoperiod. We identifyLIGHT-REGULATED WD 1 (LWD1)as a putative candidate to underly theeam7locus in barley as supported by genetic mapping and CRISPR-Cas9 generatedlwd1mutants. Mutations ineam7cause a significant phase advance and a misregulation of core clock and clock output genes under diurnal conditions. Early flowering correlated with an upregulation ofPpd-H1during the night and consequent induction of the florigenFLOWERING LOCUS T1under short days. We propose thatEAM7controls photoperiodic flowering in barley by controlling the light input into the clock and diurnal expression patterns of the major photoperiod response genePpd-H1.
African swine fever virus I196L is a virulence determinant and its deletant induces robust protection in Domestic pig
Authors: Fan Jiaqi , Zhu Rongnian , Li Nan , Yang Jinjin , Yue Huixian , Zhang Yanyan , Zhou Xintao , Ke Junnan , Wang Yu , Li Qixuan , Qi Yu , Miao Faming , Li Min , Chen Teng , Hu Rongliang 
Published: June 2023

AbstractThe worldwide pandemic of African swine fever virus (ASFV) has a profound impact on the global pig industry. ASFV is a complex multilayered structure and the functions of unknown genes are being revealed. Here we deleted I196L from virulent ASFV SY18 with different length and obtained two recombinant viruses. The replication efficiency of the two recombinant viruses were similar but significantly lower than parental SY18. The pigs all survived the two recombinant viruses with 106.0TCID50except one pig occurred sudden death and the suvived pigs all resisted the challenge without fever after intramuscularly injecting a lethal dose (102.0TCID50) of ASFV SY18. The recombinant viruses induced a strong anti-p54 humoral immune response. Meanwhile, the pigs also inevitably appeared moderate to high viremia throughout the observation period and presented a gradually downward trend. The results show that deleting I196L gene is a potential and effective vaccine that protects pigs from ASFV.IMPORTANCEThe worldwide outbreak of African swine fever (ASF) cannot be effectively prevented due to no availably commercial vaccine. Many different types of vaccine candidates are researched and reported, which is a hopeful trend to develop safety and efficacy vaccine. Here we report on an unknown functional gene, I196L, which affects the virulence and replication of ASFV. When I196L was deleted from ASFV SY18, the recombinant virus decreased virulence and resisted the challenge of parental strain. This is a novel, effective, potential live attenuated vaccine (LAVs) for ASF.
Multi-omics analysis ofBacillus. subtilisspores formed at different environmental temperatures reveal differences at the morphological and molecular level
Authors: Huang Yixuan , Roseboom Winfried , Brul Stanley , Kramer Gertjan 
Published: June 2023

AbstractSpore-forming bacteria play an essential role in the food industry and public health. Through sporulation, bacteria can withstand extreme environmental conditions that vegetative cells cannot survive. Although it is well established that the same environmental factors that affect the growth of vegetative cells also profoundly influence sporulation, the mechanisms of how growth conditions affect spore structure and function remain unknown. Prior research has shown that spores prepared at higher temperatures are more heat resistant than those prepared at lower temperatures. The present study examines, both at metabolomic and proteomic levels, the effect of different sporulation temperatures (25, 37 and 42°C) on the small molecule and protein composition of spores (strain PY79) of the model organismB. subtilis. Through differential harvesting times, spores of the same developmental stage were obtained for each temperature regime. The heat resistance, dipicolinic acid content, germination kinetics and spore morphology were assayed to compare spore properties. Metabolome and proteome analysis yielded unparalleled broad molecular detail of the spores formed at different environmental temperatures. Our findings indicate that peptidoglycan biosynthesis and 28 outer-layer proteins play a crucial role in the functional diversity of spores produced byB. subtilisunder varying temperatures.
Longitudinal development of thalamocortical functional connectivity in 22q11.2 deletion syndrome
Authors: Schleifer Charles H. , O’Hora Kathleen P. , Jalbrzikowski Maria , Bondy Elizabeth , Kushan-Wells Leila , Lin Amy , Uddin Lucina Q. , Bearden Carrie E. 
Published: June 2023

AbstractBackground22q11.2 Deletion Syndrome (22qDel) is a genetic Copy Number Variant (CNV) that strongly increases risk for schizophrenia and other neurodevelopmental disorders. Disrupted functional connectivity between the thalamus and somatomotor/frontoparietal cortex has been implicated in cross-sectional studies of 22qDel, idiopathic schizophrenia, and youth at clinical high risk (CHR) for psychosis. Here, we use a novel functional atlas approach to investigate longitudinal age-related changes in network-specific thalamocortical functional connectivity (TCC) in 22qDel and typically developing (TD) controls.MethodsTCC was calculated for nine functional networks derived from resting-state functional magnetic resonance imaging (rs-fMRI) scans collected from n=65 22qDel participants (63.1% female) and n=69 demographically matched TD controls (49.3% female), ages 6 to 23 years. Analyses included 86 longitudinal follow-up scans. Non-linear age trajectories were characterized with general additive mixed models (GAMMs).ResultsIn 22qDel, TCC in the frontoparietal network increases until approximately age 13, while somatomotor and cingulo-opercular TCC decrease from age 6 to 23. In contrast, no significant relationships between TCC and age were found in TD controls. Somatomotor connectivity in 22qDel is significantly higher than TD in childhood, but lower in late adolescence. Frontoparietal TCC shows the opposite pattern.Conclusions22qDel is associated with aberrant development of functional network connectivity between the thalamus and cortex. Younger individuals with 22qDel have lower frontoparietal connectivity and higher somatomotor connectivity than controls, but this phenotype may normalize or partially reverse by early adulthood. Altered maturation of this circuitry may underlie elevated neuropsychiatric disease risk in this syndrome.