bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptome analyses describe the consequences of persistent HIF-1 over-activation inCaenorhabditis elegans
Authors: Feng Dingxia , Qu Long 
Published: November 2023

AbstractMetazoan animals rely on oxygen for survival, but during normal development and homeostasis, animals are often challenged by hypoxia (low oxygen). In metazoans, many of the critical hypoxia responses are mediated by the evolutionarily conserved hypoxia-inducible transcription factors (HIFs). The stability and activity of HIF complexes are strictly regulated. In the model organismC. elegans, HIF-1 stability and activity are negatively regulated by VHL-1, EGL-9, RHY-1 and SWAN-1. Importantly,C. elegansmutants carrying strong loss-of-function mutations in these genes are viable, and this provides opportunities to interrogate the molecular consequences of persistent HIF-1 over-activation. We find that the genome-wide gene expression patterns are compellingly similar in these mutants, supporting models in which RHY-1, SWAN-1 and EGL-9 function in common pathway(s) to regulate HIF-1 activity. These studies illuminate the diversified biological roles played by HIF-1, including metabolism, hypoxia and other stress responses, reproduction and development. Genes regulated by persistent HIF-1 over-activation overlap with genes responsive to pathogens, and they overlap with genes regulated by DAF-16. As crucial stress regulators, HIF-1 and DAF-16 converge on key stress-responsive genes and function synergistically to enable hypoxia survival.
Comparing natural language processing representations of disease sequences for prediction in the electronic healthcare record
Authors: Beaney Thomas , Jha Sneha , Alaa Asem , Smith Alexander , Clarke Jonathan , Woodcock Thomas , Majeed Azeem , Aylin Paul , Barahona Mauricio 
Published: November 2023

AbstractNatural language processing (NLP) is increasingly being applied to obtain unsupervised representations of electronic healthcare record (EHR) data, but their performance for the prediction of clinical endpoints remains unclear. Here we use primary care EHRs from 6,286,233 people with Multiple Long-Term Conditions in England to generate vector representations of sequences of disease development using two input strategies (212 disease categories versus 9,462 diagnostic codes) and different NLP algorithms (Latent Dirichlet Allocation, doc2vec and two transformer models designed for EHRs). We also develop a new transformer architecture, named EHR-BERT, which incorporates socio-demographic information. We then compare use of each of these representations to predict mortality, healthcare use and new disease diagnosis. We find that representations generated using disease categories perform similarly to those using diagnostic codes, suggesting models can equally manage smaller or larger vocabularies. Sequence-based algorithms perform consistently better than bag-of-words methods, with the highest performance for EHR-BERT.
Guided versus standard antiplatelet therapy in patients undergoing interventional intracranial aneurysm treatment using stents: protocol of a cluster randomized controlled cohort study
Authors: Zhou Yangyang , Li Wenqiang , Zhang Hongqi , Luo Bin , Wang Yang , Wang Jun , Zhang Pinyuan , Li Liang , Xiao Fushun , Mu Shiqing , Liu Jian , Zhao Yuanli , Yang Xinjian , Jiang Peng 
Published: November 2023

ABSTRACTBackgroundThe goal of standard dual antiplatelet therapy (SDAT) in patients undergoing endovascular interventional treatment of intracranial aneurysms is to prevent thrombosis; however, some patients have a poor response to these drugs, which increases the risk of cerebral infarction. This study aims to examine whether adjusting antiplatelet therapy based on light transmission aggregometry (LTA) can reduce the incidence of ischemic events compared with SDAT.MethodsWe will conduct a cluster randomized controlled trial using 16 treatment teams from eight hospitals in mainland China, enrolling 590 patients with unruptured intracranial aneurysms treated using endovascular stent placement. The treatment teams serving as clusters will be randomly assigned to either the test or control group at a 1:1 ratio. Test group patients will receive an antiplatelet regimen guided by LTA. Control group patients will receive SDAT. Patients will be followed for 1 month after the treatment period. The primary outcome measure is cerebral ischemic events within 30 days of stent placement, including stent thrombosis, ischemic stroke, and transient ischemic attack. The safety measure is all bleeding events within 30 days of treatment.DiscussionThe trial aims to determine whether LTA-guided antiplatelet therapy reduces the incidence of ischemic events without increasing the risk of bleeding in patients with intracranial aneurysms treated with endovascular stenting. Completion of this clinical trial may provide an individualized safe and effective regimen for antiplatelet therapy.Trial registration ClinicalTrials.gov,NCT05825391. Registered on April 11, 2023.What is already known on this topicDual antiplatelet therapy is administered to reduce thrombotic events in neurointerventional therapy of intracranial aneurysms. Platelet function testing is used to evaluate the antiplatelet effect of aspirin and clopidogrel.What this study addsThe trial aims to determine whether LTA-guided antiplatelet therapy reduces the incidence of ischemic events without increasing the risk of bleeding in patients with intracranial aneurysms treated with endovascular stenting.How this study might affect research, practice or policyFor stent neurointerventional therapy of unruptured intracranial aneurysms, this study could provide a promising method for adjusting appropriate antiplatelet therapy.
The antiviral protein Shiftless blocks p-body formation during KSHV infection
Authors: Hatfield David , Rodriguez William , Mehrmann Timothy , Muller Mandy 
Published: November 2023

ABSTRACTP-bodies (PB) are non-membranous foci involved in determining mRNA fate by affecting translation and mRNA decay. In this study, we identify the anti-viral factor SHFL as a potent disassembly factor of PB. We show that PBs remain sparse in the presence of SHFL even in the context of oxidative stress, a major trigger for PB induction. Mutational approaches revealed that SHFL RNA binding activity is not required for its PB disassembly function. However, we have identified a new region of SHFL which bridges two distant domains as responsible for PB disassembly. Furthermore, we show that SHFL ability to disrupt PB formation is directly linked to its anti-viral activity during KSHV infection. While WT SHFL efficiently restricts KSHV lytic cycle, PB disruption defective mutants no longer lead to reactivation defects. SHFL-mediated PB disassembly also leads to increased expression of key anti-viral cytokines, further expanding SHFL dependent anti-viral state. Taken together, our observations suggest a role of SHFL in PB disassembly, which could have important anti-viral consequences during infection.
Molecular mechanisms of re-emerging chloramphenicol susceptibility in extended-spectrum beta-lactamase producing Enterobacterales
Authors: Graf Fabrice E , Goodman Richard N , Gallichan Sarah , Forrest Sally , Picton-Barlow Esther , Fraser Alice J , Phan Minh-Duy , Mphasa Madalitso , Hubbard Alasdair T M , Musicha Patrick , Schembri Mark A , Roberts Adam P , Edwards Thomas , Lewis Joseph M , Feasey Nicholas A 
Published: November 2023

AbstractInfections with Enterobacterales (E) are increasingly difficult to treat due to antimicrobial resistance. After ceftriaxone replaced chloramphenicol (CHL) as empiric therapy for suspected sepsis in Malawi in 2004, ESBL-E rapidly emerged. Concurrently, resistance to CHL inEscherichia coliandKlebsiellaspp. decreased, raising the possibility of CHL re-introduction. However, many phenotypically susceptible isolates still carry CHL acetyltransferase (CAT) genes.We used a combination of genomics, phenotypic susceptibility assays, experimental evolution and functional assays for CAT activity to understand the molecular mechanisms and stability of this re-emerging CHL susceptibility.Of 840 Malawian isolates, 31% had discordant CHL susceptibility genotype-phenotype, and we selected 42 isolates for in-depth analysis. Stable degradation ofcatgenes by insertion sequences led to re-emergence of CHL susceptibility. Our study suggests CHL could be reintroduced as reserve agent for critically ill patients with ESBL-E infections in Malawi and similar settings and highlights the ongoing challenges in inferring antimicrobial resistance from sequence data.
Establishment of an intragastric surgical model using C57BL/6 mice to study the vaccine efficacy of OMV-based immunogens againstHelicobacter pylori
Authors: Das Sanjib , Halder Prolay , Banerjee Soumalya , Mukhopadhyay Asish Kumar , Dutta Shanta , Koley Hemanta 
Published: November 2023

AbstractChronic gastritis is one of the major symptoms of gastro-duodenal disorders typically induced byHelicobacter pylori(H. pylori).To date, no suitable model is available to study pathophysiology and therapeutic measures accurately. Here, we have presented a successful surgical infection model ofH. pylori-induced gastritis in C57BL/6 mice that resembles features similar to human infection. The proposed model does not require any preparatory treatment other than surgical intervention. C57BL/6 mice were injected with wild-type SS1 (Sydney strain 1, reference strain) directly into the stomach. Seven days post infection, infected animals showed alterations in cytokine responses along with inflammatory cell infiltration in the lamina propria, depicting a prominent inflammatory response due to infection. To understand the immunogenicity and protective efficacy, the mice were immunized with outer membrane vesicles (OMVs) isolated from an indigenous strain with putative virulence factors ofH. pylori[A61C (1),cag+/vacA s1m1]. In contrast to the nonimmunized cohort, the OMV-immunized cohort showed a gradual increase in serum immunoglobulin(s) levels on the 35thday after the first immunization. This conferred protective immunity against subsequent challenge with the reference strain (SS1). Direct inoculation ofH. pyloriinto the stomach influenced infection in a short time and, more importantly, in a dose-dependent manner, indicating the usefulness of the developed model for pathophysiology, therapeutic and prophylactic studies.
Cell-specific α-tubulin TBA-6 and pan-ciliary IFT cargo RAB-28 generate a non-canonical transition zone
Authors: Akella Jyothi Shilpa , Silva Malan S. , Nguyen Ken C. Q. , Hall David H. , Barr Maureen M. 
Published: November 2023

AbstractThe transition zone (TZ) regulates cilia composition and function. Canonical TZs with 9 doublet microtubules (MTs) are common but non-canonical TZs that vary from 9 MT symmetry also occur and arise through unknown mechanisms. Cilia on the quadrant inner labial type 2 (IL2Q) neurons ofC. eleganshave a specialized non-canonical TZ with fewer than 9 doublet MTs. We previously showed that non-canonical TZs in IL2Q cilia arise via MT loss and reorganization of canonical TZs. Here, we identify structural events and mechanisms that generate non-canonical TZs. Cell-specific α-tubulin TBA-6 and pan-ciliary IFT cargo RAB-28 regulate IL2QTZ MT loss without affecting ciliary assembly. Our results reveal a role for the tubulin code in generating non-canonical TZs and contribute towards understanding ciliary functional specialization.Author summaryCiliary microtubules are exquisitely diverse in arrangements and composition. Studies on how ciliary ultrastructural diversity is generated are essential to our understanding of cilia function in diverse healthy and pathological contexts. Despite its clinical relevance, the ultrastructural diversity of the transition zone and its microtubules remains understudied. Here, we uncover mechanisms contributing to generating ultrastructural diversity in the transition zone and in cilia. A subset of sensory cilia inC. eleganscontain a non-canonical transition zone with 7 and fewer doublet microtubules. We previously showed that this distinct transition zone is generated through microtubule loss in a canonical transition zone with 9 doublet microtubules, a process that occurs asynchronously during animal development. Here, we identify roles for the tubulin code and for an IFT cargo in generating a distinct transition zone. Sculpting of the distinct transition zone occurs in fully assembled cilia and transition zones and is independent of general ciliogenesis mechanisms. Our results demonstrate how specialized transition zones can be generated from canonical transition zones and provide insight into mechanisms of ciliary ultrastructural diversity and post-ciliogenesis restructuring. Such mechanisms hold the key to understanding ciliary function and to restoration of function in ciliopathies with ciliary ultrastructural defects.
The explosive radiation of the NeotropicalTillandsiasubgenusTillandsia(Bromeliaceae) has been facilitated by pervasive hybridization
Authors: Yardeni Gil , Barfuss Michael H. J. , Till Walter , Thornton Matthew R. , Groot Crego Clara , Lexer Christian , Leroy Thibault , Paun Ovidiu 
Published: November 2023

AbstractThe recent rapid radiation ofTillandsiasubgenusTillandsia(Bromeliaceae) provides an attractive system to study the drivers and limits of species diversification. This species-rich Neotropical monocot clade includes predominantly epiphytic species displaying vast phenotypic diversity. Recent in-depth phylogenomic work revealed that the subgenus originated within the last 7 MY while expanding through one major event from South into Central America within the last 5 MY. However, disagreements between phylogenies and lack of resolution at shallow nodes suggested that hybridization occurred throughout the radiation, together with frequent incomplete lineage sorting and/or considerable gene family evolution. We used whole-genome resequencing data and a newly available reference genome to explore the evolutionary history of 34 representative ingroup species employing both a tree-based and a network approach. Our results indicate that lineage co-occurrence does not predict relatedness and confirm significant deviations from a tree-like structure, coupled with pervasive gene tree discordance. Focusing on hybridization, ABBA-BABA and related statistics were used to infer the rates and relative timing of introgression, while topology weighting uncovered high heterogeneity of the phylogenetic signal along the genome. High rates of hybridization within and among clades suggest that, in contrast to previous hypotheses, the expansion of subgenusTillandsiainto Central America proceeded in several dispersal events, punctuated by episodes of diversification and gene flow. Network analysis revealed reticulation as a prominent propeller during radiation and establishment in different ecological niches. This work contributes a plant example of prevalent hybridization during rapid species diversification, supporting the hypothesis that interspecific gene flow facilitates explosive diversification.
Microinjection, gene knockdown, and CRISPR-mediated gene knock-in in the hard coral,Astrangia poculata
Authors: Warner Jacob F. , Besemer Ryan , Schickle Alicia , Borbee Erin , Changsut Isabella V. , Sharp Koty , Babonis Leslie S. 
Published: November 2023

AbstractCnidarians have become valuable models for understanding many aspects of developmental biology including the evolution of body plan diversity, novel cell type specification, and regeneration. Most of our understanding of gene function during early development in cnidarians comes from a small number of experimental systems including the sea anemone,Nematostella vectensis. Few molecular tools have been developed for use in hard corals, limiting our understanding of this diverse and ecologically important clade. Here, we report the development of a suite of tools for manipulating and analyzing gene expression during early development in the northern star coral,Astrangia poculata. We present methods for gene knockdown using short hairpin RNAs, gene overexpression using exogenous mRNAs, and endogenous gene tagging using CRISPR-mediated gene knock-in. Combined with our ability to control spawning in the laboratory, these tools makeA. poculataa tractable experimental system for investigative studies of coral development. Further application of these tools will enable functional analyses of embryonic patterning and morphogenesis across Anthozoa and open new frontiers in coral biology research.Summary StatementThis study reports the development of the first transgenic knock-in coral, providing the opportunity to track the behavior of various cell types during early coral development.
Monocyte-derived microglia withDnmt3amutation cause motor pathology in aging mice
Authors: Kim Jung-Seok , Trzebanski Sébastien , Shin Sun-Hye , Ilani Noa Chapal , Kaushansky Nathali , Scheller Marina , Solomon Aryeh , Liu Zhaoyuan , Aust Oliver , Boura-Halfon Sigalit , Amann Lukas , Prinz Marco , Ginhoux Florent , Avraham Roi , Müller-Tidow Carsten , Uderhardt Stefan , Milenkovic Ivan , Shlush Liran , Jung Steffen 
Published: November 2023

AbstractMicroglia are established in embryogenesis forming a self-containing cellular compartment resisting seeding with cells derived from adult definitive hematopoiesis. We report that monocyte-derived macrophages (MoMΦ) accumulate in the brain of aging mice with distinct topology, including the nigrostriatum and medulla, but not the frontal cortex. Parenchymal MoMΦ adoptbona fidemicroglia expression profiles. Unlike microglia, these monocyte-derived microglia (MoMg) are due to their hematopoietic origin targets of clonal hematopoiesis (CH). Using a chimeric transfer model, we show that hematopoietic expression of DNMT3AR822H, a prominent mutation in human CH, renders MoMg pathogenic promoting motor deficits resembling atypical Parkinsonian disorders. Collectively, these data establish in a mouse model that MoMg progressively seed the brains of aging healthy mice, accumulate in selected areas, and, when carrying a somatic mutation associated with CH, can contribute to brain pathology.
Glia detect and mount a protective response to loss of dendrite substructure integrity inC. elegans
Authors: Varandas Katherine C. , Hodges Brianna M. , Lubeck Lauren , Farinas Amelia , Liang Yupu , Lu Yun , Shaham Shai 
Published: November 2023

SUMMARYNeurons have elaborate structures that determine their connectivity and functions. Changes in neuronal structure accompany learning and memory formation and are hallmarks of neurological disease. Here we show that glia monitor dendrite structure and respond to dendrite perturbation. InC. elegansmutants with defective sensory-organ dendrite cilia, adjacent glia accumulate extracellular matrix-laden vesicles, secrete excess matrix around cilia, alter gene expression, and change their secreted protein repertoire. Inducible cilia disruption reveals that this response is acute. DGS-1, a 7-transmembrane domain neuronal protein, and FIG-1, a multifunctional thrombospondin-domain glial protein, are required for glial detection of cilia integrity, and exhibit mutually-dependent localization to and around cilia, respectively. While inhibiting glial secretion disrupts dendritic cilia properties, hyperactivating the glial response protects against dendrite damage. Our studies uncover a homeostatic protective dendrite-glia interaction and suggest that similar signaling occurs at other sensory structures and at synapses, which resemble sensory organs in architecture and molecules.
Whole-brain Mechanism of Neurofeedback Therapy: Predictive Modeling of Neurofeedback Outcomes on Repetitive Negative Thinking in Depression
Authors: Misaki Masaya , Tsuchiyagaito Aki , Guinjoan Salvador M. , Rohan Michael L. , Paulus Martin P. 
Published: November 2023

AbstractReal-time fMRI neurofeedback (rtfMRI-NF) has emerged as a promising intervention for psychiatric disorders, yet its clinical efficacy remains underexplored due to limited controls and an incomplete mechanistic understanding. This study aimed to elucidate the whole-brain mechanisms underpinning the effects of rtfMRI-NF on repetitive negative thinking in depression. In a double-blind randomized controlled trial, forty-three depressed individuals underwent NF training targeting the functional connectivity (FC) between the posterior cingulate cortex and the right temporoparietal junction, linked to rumination severity. Participants were randomly assigned to active or sham groups, with the sham group receiving synthesized feedback mimicking real NF signal patterns. The active group demonstrated a significant reduction in brooding rumination scores (p<0.001, d=-1.52), whereas the sham group did not (p=0.503, d=- 0.23). While the target FC did not show discernible training effects or group differences, we found that the interaction between brain activities during regulation and the response to the feedback signal was the critical factor in explaining treatment outcomes. Connectome-based predictive modeling (CPM) analysis, incorporating this interaction, successfully predicted rumination changes across both groups. The FCs significantly contributing to the prediction were distributed across broad brain regions, notably the frontal control, salience network, and subcortical reward processing areas. These results underscore the importance of considering the interplay between brain regulation activities and brain response to the feedback signal in understanding the therapeutic mechanisms of rtfMRI-NF. The study not only affirms the potential of rtfMRI-NF as a therapeutic intervention for repetitive negative thinking in depression but also highlights the need for a more nuanced understanding of the whole-brain mechanisms contributing to its efficacy.
Intranasal GHK peptide enhances resilience to cognitive decline in aging mice
Authors: Tucker Matthew , Keely Addison , Park Joo Young , Rosenfeld Manuela , Wezeman Jackson , Mangalindan Ruby , Ratner Dan , Ladiges Warren 
Published: November 2023

AbstractBrain aging and cognitive decline are aspects of growing old. Age-related cognitive impairment entails the early stages of cognitive decline, and is extremely common, affecting millions of older people. Investigation into early cognitive decline as a treatable condition is relevant to a wide range of cognitive impairment conditions, since mild age-related neuropathology increases risk for more severe neuropathology and dementia associated with Alzheimer’s Disease. Recent studies suggest that the naturally occurring peptide GHK (glycyl-L-histidyl-L-lysine) in its Cu-bound form, has the potential to treat cognitive decline associated with aging. In order to test this concept, male and female C57BL/6 mice, 20 months of age, were given intranasal GHK-Cu, 15 mg/kg daily, for two months. Results showed that mice treated with intranasal GHK-Cu had an enhanced level of cognitive performance in spatial memory and learning navigation tasks, and expressed decreased neuroinflammatory and axonal damage markers compared to mice treated with intranasal saline. These observations suggest that GHK-Cu can enhance resilience to brain aging, and has translational implications for further testing in both preclinical and clinical studies using an atomizer device for intranasal delivery.