bluuebunny/crossref_metadata_2025_split huggingface dataset:
Broad-spectrum immune suppression encoded in self-amplifying RNA enables non-cytotoxic, non-immunostimulatory, externally controllable transgene expression
Authors: Lim Tony K.Y , Ritoux Anne , Paine Luke W. , Ferguson Larissa , Abdul Tawab , John Smith Ewan St. 
Published: September 2024

ABSTRACTSelf-amplifying RNA (saRNA) has the potential to provide durable, non-integrative transgene expression for transient gene therapy. However, its auto-replicative nature mimics viral infection, triggering innate immune responses that shutdown cap-dependent translation, degrade cellular mRNA, induce cell death, and release cytokines. In non-immunotherapy applications, this immune activation is undesirable as it limits transgene expression, depletes transfected cells, and induces inflammation, undermining therapeutic outcomes. Moreover, the use of exogenous immune suppressants to mitigate these effects often increases treatment complexity and the risk of unintended systemic side effects. To address these challenges, we developed a strategy to encode broad-spectrum innate immune suppression directly within saRNA. This approach leverages cap-independent translation to bypass saRNA-triggered translation shutdown, enabling the expression of multiple inhibitors targeting diverse double-stranded RNA-sensing and inflammatory signaling pathways. In mouse primary fibroblast-like synoviocytes—a cell type relevant to inflammatory joint diseases—this strategy eliminates the need for external immune inhibitors, reduces cytotoxicity and antiviral cytokine secretion, and enables sustained transgene expression that can be controlled with a small-molecule antiviral. These findings support the development of saRNA therapeutics that offer durable, non-integrative, externally controllable transgene expression without persistent immune activation or reliance on exogenous immune suppressants.GRAPHICAL ABSTRACT
Hematological phenotypes in GATA2 deficiency syndrome arise from secondary injuries and maladaptation to proliferation
Authors: Fernandez-Orth Juncal , Koyunlar Cansu , Weiss Julia M. , Gioacchino Emanuele , de Looper Hans , Andrieux Geoffroy , Borg Mariëtte Ter , Zink Joke , Gonzalez-Menendez Irene , Hoogenboezem Remco , Yigit Baris , Gussinklo Kirsten J , Mulet-Lazaro Roger , Wantzen Charlotte , Pfeiffer Sophie , Molnar Christian , Bindels Eric , Bohler Sheila , Sanders Mathijs , Quintanilla-Martinez Leticia , Wlodarski Marcin , Boerries Melanie , Touw Ivo P. , Niemeyer Charlotte , Erlacher Miriam , de Pater Emma 
Published: September 2024

AbstractThe GATA2 transcription factor is a pivotal regulator of hematopoiesis. Disruptions in theGATA2gene drive severe hematologic abnormalities and are associated with an increased risk of myelodysplastic syndromes and acute myeloid leukemia; however, the mechanisms underlying the pathophysiology of GATA2 deficiency remain still unclear. We developed two different mouse models that are based on serial and limiting donor cell transplantation of (aged) GATA2 haploinsufficient cells and mirror the symptoms of GATA2 deficiency. Similar to what has been observed in patients, our models show that GATA2 haploinsufficiency leads to B lymphopenia, monocytopenia, lethal bone marrow failure (BMF), myelodysplasia and leukemia. Leukemia arises exclusively as a result of BMF, driven by somatic aberrations and accompanied by increasedMyctarget expression and genomic instability. These findings were confirmed in human GATA2+/− K562 cell lines showing defects in cytokinesis and are in line with the fact that monosomy 7 and trisomy 8 are frequent events in patients with MDS.Key pointsIn a mouse model for GATA2 deficiency, leukemia emerges from bone marrow failureMaladaptation to proliferative signals and chromosomal segregation defects contribute to the hematological phenotypes in GATA2 deficiency
Evolution of transcription factor-containing superfamilies in Eukaryotes
Authors: Dubey Akshara , Muthu Ganesh , Seshasayee Aswin Sai Narain 
Published: September 2024

AbstractRegulation of gene expression helps determine various phenotypes in most cellular life forms. It is orchestrated at different levels and at the point of transcription initiation by transcription factors (TFs). TFs bind to DNA through domains that are evolutionarily related, by shared membership of the same superfamilies (TF-SFs), to those found in other nucleic acid binding and protein-binding functions (nTFs for non-TFs). Here we ask how TF DNA binding sequence families in eukaryotes have evolved in relation to their nTF relatives. TF numbers scale by power law with the total number of protein-coding genes differently in different clades, with fungi usually showing sub-linear powers whereas chordates show super-linear scaling. The LECA probably encoded a complex regulatory machinery with both TFs and nTFs, but with an excess of nTFs when compared to the relative distribution of TFs and nTFs in extant organisms. Losses drive the evolution of TFs and nTFs, with the possible exception of TFs in Animalia for some tree topologies. TFs are highly dynamic in evolution, showing higher gain and loss rates than nTFs though both are conserved to similar extents. Gains of TFs and nTFs are driven by the appearance of a large number of new sequence clusters in a small number of nodes, which determine the presence of as many as a third of extant TFs and nTFs as well as the relative presence of TFs and nTFs. Whereas nodes showing explosion of TF numbers belong to multicellular clades, those for nTFs lie among the fungi and the protists.
Endo-IP and Lyso-IP Toolkit for Endolysosomal Profiling of Human Induced Neurons
Authors: Hundley Frances V. , Gonzalez-Lozano Miguel A. , Gottschalk Lena M. , Cook Aslan N. K. , Zhang Jiuchun , Paulo Joao A. , Harper J. Wade 
Published: September 2024

AbstractPlasma membrane protein degradation and recycling is regulated by the endolysosomal system, wherein endosomes bud from the plasma membrane into the cytosol and mature into degradative lysosomes. As such, the endolysosomal system plays a critical role in determining the abundance of proteins on the cell surface, influencing cellular identity and function. Highly polarized cells, like neurons, rely on the endolysosomal system for axonal and dendritic specialization and synaptic compartmentalization. The importance of this system to neuronal function is reflected by the prevalence of risk variants in components of the system in several neurodegenerative diseases, ranging from Parkinson’s to Alzheimer’s disease. Nevertheless, our understanding of endocytic cargo and core endolysosomal machinery in neurons is limited, in part due to technical limitations. Here, we developed a toolkit for capturing EEA1-postive endosomes (Endo-IP) and TMEM192-positive lysosomes (Lyso-IP) in stem cell-derived induced neurons (iNeurons). We demonstrated its utility by revealing the endolysosomal protein landscapes for cortical-like iNeurons and stem cells. This allowed us to globally profile endocytic cargo, identifying hundreds of transmembrane proteins, including neurogenesis and synaptic proteins, as well as endocytic cargo with predicted SNX17 or SNX27 recognition motifs. By contrast, parallel lysosome profiling reveals a simpler protein repertoire, reflecting in part temporally controlled recycling or degradation for many endocytic targets. This system will facilitate mechanistic interrogation of endolysosomal components found as risk factors in neurodegenerative disease.
Gene coexpression network analysis of galactomannan biosynthesis and endosperm maturation in species of the genusCoffea
Authors: Dussert Stéphane , Stavrinides Anna K. , Serret Julien , Vaissayre Virginie , Combes Marie-Christine , Morcillo Fabienne , Lefort Eveline , Rialle Stéphanie , Etienne Hervé , Lashermes Philippe , Joët Thierry 
Published: September 2024

ABSTRACTIn a few important plant families and genera, including Arecaceae, Fabaceae and the genusCoffea, the main seed storage polysaccharide is not starch but cell wall galactomannans. Such seeds are albuminous with a persistent copious living endosperm that accumulates galactomannans. However, our understanding of the regulation of endosperm maturation, cell wall formation and galactomannan biosynthesis in albuminous seeds remains very limited. To gain insights into these processes, a large RNA-seq dataset was produced (14 coffee species × 5 endosperm developmental stages) and scrutinized using gene coexpression network analysis. The network revealed tight transcriptional coordination of the core galactomannan biosynthetic machinery for sucrose import, glycolysis, nucleotide sugar synthesis and transport, arabinogalactan protein and cellulose synthesis, and regulation of the trans-Golgi network. The orchestration of galactomannan and oil accumulation during endosperm maturation appeared to be exerted by the transcription factors FUSCA3, WRINKLED1, SHINE2 and DREB2D. The latter was the only coexpression partner of galactomannan biosynthetic genes. Numerous key genes of galactomannan biosynthesis were significantly upregulated in coffee somatic embryos overexpressing DREB2D, which showed increased production of UDP-galactose and diversion towards raffinose family oligosaccharides. Further, most genes of the galactomannan coexpression module were identified as DREB2D target genes by DAP-seq analysis.HighlightGene coexpression network analysis of the maturing endosperm identified the AP2/ERF transcription factor DREB2D as a major regulator of galactomannan accumulation in the cell walls of albuminous coffee seeds.
An Atlas of Linkage Disequilibrium Across Species
Authors: Zhu Tian-Neng , Huang Xing , Yang Meng-yuan , Qi Guo-An , Zhang Qi-Xin , Lin Feng , Zhang Wenjing , Zhang Zhe , Jin Xin , Zheng Hou-Feng , Xu Hai-Ming , Yu Shizhou , Chen Guo-Bo 
Published: September 2024

AbstractLinkage disequilibrium (LD) is a key metric that characterizes populations in flux. To reach a genomic scale LD illustration, which has a substantial computational cost of𝒪(nm2), we introduce a framework with two novel algorithms for LD estimation: X-LD, with a time complexity of𝒪(n2m) suitable for small sample sizes (n <104); X-LDR, a stochastic algorithm with a time complexity of𝒪(nmB) for biobank-scale data (Biterations);nthe sample size, andmthe number of SNPs. These methods can refine the entire genome into high-resolution LD grids, such as more than 9 million grids for UK Biobank samples (∼4.2 million SNPs). The efficient resolution for genome-wide LD leads to intriguing biological discoveries.I)High-resolution LD illustrations revealed how the pericentromeric regions and the HLA region lead to intense and extended LD patterns.II)Two universal LD patterns, identified as Norm I and Norm II patterns, provide insights on the evolutionary history of populations and can also highlight genomic regions of deviation, such as chromosomes 6 and 11 or ncRNA regions.III)The results of our innovative LD decay method aligned with the LD decay scores of 59.5 for Europeans, 60.2 for East Asians, and 33.2 for Africans; correspondingly, the length of the LD was approximately 2.85 Mb, 2.18 Mb, and 1.58 Mb for these three ethnicities. Rare or imputed variants universally increased LD.IV)An unprecedented LD atlas for 25 reference populations contoured interspecies diversity in terms of their Norm I and Norm II LD patterns, highlighting the impact of refined population structure, quality of reference genomes, and uncovered a profoundstatus quoof these populations. The algorithms have been implemented in C++ and are freely available (https://github.com/gc5k/gear2).
Effect of Mutations on Smlt1473 Binding to Various Substrates Using Molecular Dynamics Simulations
Authors: Mondal Kinjal , Felton Samantha , Berger Bryan W. , Klauda Jeffery B. 
Published: September 2024

AbstractSmlt1473 is a polysaccharide lyase fromStenotrophomonas maltophiliawhose crystal structure was solved recently using X-ray crystallography. There was an effort to study the effect of mutations on the activity of Smlt1473 binding to various substrates like hyaluronic acid(HA), mannuronic acid(ManA), and alginate. In this study, we use molecular docking and molecular dynamics simulations to investigate the effect of binding of various substrates (HA and ManA) to Smlt1473 and two of its mutants H221F and R312L. We further studied the stability in the binding of Smlt1473 to its various substrates as well as the role of fluctuations. Machine-Learning based clustering algorithms were used to group the entire simulation trajectory into various stable states. The molecular interactions Smlt1473 to the substrates were calculated and the importance of specific residues were tested with observed activity assays due to residue mutations. Overall, we find that the R218 plays an important role in substrate binding and thus impacting the activity due to the H221F mutant and R/L312 itself plays an important role in the R312 mutation. In addition, we have also found three more residues K56, R107, and R164 important for substrate binding which we further proceed to confirm using wet lab mutagenesis studies.
Variability in proliferative and migratory defects in Hirschsprung disease-associatedRETpathogenic variants
Authors: Fries Lauren E , Dharma Sree , Chakravarti Aravinda , Chatterjee Sumantra 
Published: September 2024

AbstractDespite the extensive genetic heterogeneity of Hirschsprung disease (HSCR; congenital colonic aganglionosis) 72% of patients harbor pathogenic variants in 10 genes that form a gene regulatory network (GRN) controlling the development of the enteric nervous system (ENS). Among these genes, the receptor tyrosine kinase gene RET is the most significant contributor, accounting for pathogenic variants in 12%-50% of patients depending on phenotype. RET plays a critical role in the proliferation and migration of ENS precursors, and defects in these processes lead to HSCR. However, despite the gene’s importance in HSCR, the functional consequences of RET pathogenic variants and their mechanism of disease remain poorly understood. To address this, we investigated the proliferative and migratory phenotypes in a RET-dependent neural crest-derived cell line harboring one of five missense (L56M, E178Q, Y791F, S922Y, F998L) or three nonsense (Y204X, R770X, Y981X) pathogenic heterozygous variants. Using a combination of cDNA-based and CRISPR-based PRIME editing coupled with quantitative proliferation and migration assays, we detected significant losses in cell proliferation and migration in three missense (E178Q, S922Y, F998L) and all nonsense variants. Our data suggests that the Y791F variant, whose pathogenicity has been debated, is likely not pathogenic. Importantly, the severity of migration loss did not consistently correlate with proliferation defects, and the phenotypic severity of nonsense variants was independent of their position within the RET protein. This study highlights the necessity and feasibility of targeted functional assays to accurately assess the pathogenicity of HSCR-associated variants, rather than relying solely on machine learning predictions, which could themselves be refined by incorporating such functional data.
GPR30 in spinal cholecystokinin-positive neurons modulates neuropathic pain via mediating descending facilitation
Authors: Chen Qing , Wu Hui , Xie Shulan , Zhu Fangfang , Xu Fang , Xu Qi , Sun Lihong , Yang Yue , Xie Linghua , Xie Jiaqian , Li Hua , Dai Ange , Zhang Wenxin , Wang Luyang , Jiao Cuicui , Zhang Honghai , Xu Zhen-Zhong , Chen Xinzhong 
Published: September 2024

AbstractNeuropathic pain, a major health problem affecting 7 - 10% of the global population, lacks effective treatment due to its elusive mechanisms. Cholecystokinin-positive (CCK+) neurons in the spinal dorsal horn (SDH) are critical for neuropathic pain, yet the underlying molecular mechanisms remain unclear. Here we showed that the membrane estrogen receptor G-protein coupled estrogen receptor (GPER/GPR30) in spinal was significantly upregulated in chronic constriction injury (CCI) mice and that inhibition of GPR30 in CCK+neurons reversed CCI-induced neuropathic pain. Besides, GPR30 in spinal CCK+neurons was essential for the enhancement of AMPA-mediated excitatory synaptic transmission in CCI mice. Furthermore, GPR30 was expressed in the spinal CCK+neurons receiving direct projection from the primary sensory cortex (S1-SDH). Chemogenetic inhibition of S1-SDH post-synaptic neurons alleviated CCI-induced neuropathic pain. Conversely, chemogenetic activation of these neurons mimicked neuropathic pain symptoms, which were attenuated by spinal inhibition of GPR30. Finally, we confirmed that GPR30 in S1-SDH post-synaptic neurons is required for CCI-induced neuropathic pain. Taken together, our findings suggest that GPR30 in spinal CCK+neurons is pivotal for neuropathic pain and mediates descending facilitation by corticospinal direct projections, thereby representing a promising therapeutic target for neuropathic pain.
Alzheimer’s neuropathology and longitudinal change in subjective cognitive complaints
Authors: Bannerjee Alisa , Elkins Wendy , Resnick Susan M. , Bilgel Murat 
Published: September 2024

AbstractINTRODUCTIONSubjective cognitive complaints often precede declines in objective measures of cognitive performance. Incipient AD neuropathology may be associated with subjective cognitive complaints prior to detectable associations with neuropsychological testing among cognitively normal individuals.METHODSWe examined the independent associations of PET measures of amyloid-β and tau pathology with longitudinal change in subjective complaints and memory among 91 cognitively normal Baltimore Longitudinal Study of Aging participants using linear mixed effects models. Subjective complaints and memory performance were assessed with the Cognitive Failures Questionnaire and the California Verbal Learning Test, respectively.RESULTSGreater parahippocampal tau, independent of amyloid, was associated with higher subjective complaints (estimate=0.203, SE=0.0825,p=0.016), while greater entorhinal tau corresponded to an attenuated increase in complaints over time (estimate=-0.0629, SE=0.0299,p=0.040). Hippocampal tau was associated with steeper memory decline (estimate=-0.0279, SE=0.0135,p=0.043).CONCLUSIONSubjective cognitive complaints may serve as early indicators of cerebral tau pathology in cognitively normal individuals.
Detection of Mpox and other Orthopoxviruses using a Lateral Flow Device as a Point of Care diagnostic
Authors: Laidlaw Stephen M. , Ulaeto David , Lonsdale Steve , Clark Graeme , Sumner Rebecca , Edwards Thomas , Adams Emily , Logist Anne-Sophie , Holm Bram Van , Maluquer de Motes Carlos , Horby Peter , Maes Piet , Carroll Miles W. 
Published: September 2024

ABSTRACTIntroductionIn 2022 the WHO declared the worldwide outbreak of mpox to be a public health emergency of international concern (PHEIC). The causative monkeypox virus (MPXV) belonged to Clade IIb and transmitted through sexual contact with a low case fatality rate (0.1%), which together with underdetection, all contributed to a rapid global spread particularly within the MSM (men who have sex with men) community. As MPXV Clade II remains circulating worldwide, a new outbreak of the more fatal Clade I disease has been declared in Central and East Africa and remains uncontrolled in part due to the lack of Point of Care (POC) diagnostics for rapid decisions on treatment and self-isolation.AimTo address the lack of POC solutions for mpox we have designed and evaluated an orthopoxvirus-specific lateral flow device (LFD) that could be used for diagnosis of mpox.ResultsUsing an LFD comprising four monoclonal antibodies against the A27 protein we demonstrate sensitivity to 3×105pfu/ml. This sensitivity is expected to be sufficient for detection of MPXV from lesion sites and may also be sufficient for other sample types such as saliva and urine. However, sample collection buffer may have a detrimental impact on sensitivity for clinical material.ConclusionPoint of care (POC) diagnosis of mpox may be possible using a LFD to reduce delays arising from sample shipment to centralised laboratory testing facilities.
Interest in and preference for long-acting injectable PrEP among men who have sex with men, trans* individuals, and cis-gender heterosexual women: a global systematic review and meta-analysis
Authors: Wang Haoyi , Kolstee Johann , Adriaque Lozano Alejandro , Aphami Liana , Gaetani Marco , Zimmermann Hanne M.L. , Jonas Kai J. 
Published: September 2024

SummaryBackgroundLong-acting injectable HIV pre-exposure prophylaxis (LAI-PrEP) offers potentials for expanding PrEP coverage and improving public health outcomes. This study synthesises global evidence on the prevalence and determinants of interest in and preference for LAI-PrEP among men-who-have-sex-with-men (MSM), trans* individuals, and cis-gender heterosexual women.MethodsWe conducted a global systematic review and meta-analysis, building on quantitative studies from a previous review (January 1, 2010, to September 27, 2021) and new studies published in PubMed, Web of Science, and Embase (September 27, 2021, to December 31, 2023). Studies presenting data on LAI-PrEP interest, preference, and their determinants were included. Data were assessed for risk of bias and publication bias. We used a random-effects meta-analysis to pool prevalence of LAI-PrEP interest and preference, and narratively synthesized their determinants across all key populations. This study is registered with PROSPERO, CRD42023488350.FindingsWe included 41 articles (18 from the previous systematic review and 23 from the new search). 74% (95%CI 71-78) of MSM showed interest in using LAI-PrEP and 37% (95%CI 29-44) of them preferring LAI-PrEP over other HIV prevention methods. The prevalence of interest and preference were even higher among current oral PrEP users (77% (95%CI 70-84), and 43% (95%CI 28-58), respectively). Interest in LAI-PrEP among trans* individuals was similarly high at 72% (95%CI 67-78), with one study reported that 57% of transgender women preferred for LAI-PrEP. Cis-gender heterosexual women also showed a high preference for LAI-PrEP (55%, 95%CI 40-70)). Overall, people who have more resources and who are already aware and using oral PrEP are likely more interested in LAI-PrEP when it becomes available.InterpretationContinued research is essential to effectively deploy LAI-PrEP and address HIV prevention gaps. As more countries adopt LAI-PrEP, understanding its impact and reaching underserved populations will be critical to maximising public health benefits.FundingNone.
Time-dependent LSTM for Survival Prediction and Patient Subtyping in Kidney Disease Trajectory
Authors: Shi Pumeng , Fu Chunmei 
Published: September 2024

ABSTRACTChronic kidney disease (CKD) affects over 10% of the global population and is projected to become the fifth leading cause of years of life lost (YLL) by 2040. Accurate prediction of CKD progression to end-stage kidney failure (ESKF) is critical for timely interventions that can slow or halt disease progression. However, current models often fail to address the complexities of time-varying biomarkers like estimated glomerular filtration rate (eGFR) and the irregular nature of longitudinal health data, resulting in suboptimal predictions. In this study, we develop a Time-dependent Long Short-Term Memory (TdLSTM) network to analyze longitudinal eGFR data and predict time-to-ESKF. Our model is specifically designed to handle irregular time intervals and temporal dynamics, capturing nuanced patterns of CKD progression. We conducted experiments on two independent CKD cohorts, MASTERPLAN and NephroTest, using patient data including age, gender, eGFR, UACR, and diagnosis. The TdLSTM model outperformed traditional and state-of-the-art predictive models, demonstrating superior accuracy in estimating time-to-ESKF and identifying subtypes of CKD progression through unsupervised clustering. By leveraging the temporal dynamics of biomarkers, our approach offers a robust tool for personalized survival prediction and risk stratification. These findings highlight the potential of deep learning in improving CKD management and identifying high-risk patients in time for effective intervention.