bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum endocan, asymmetric dimethylarginine and lipid profile in children with familial Mediterranean fever
Authors: El Zayat Rania S. , Hassan Fahima M. , Aboelkhair Noran T. , Abdelhakeem Walaa F. , Abo Hola Ahmed S. 
Published: February 2024

Abstract
Background
Familial Mediterranean fever (FMF) is a chronic inflammatory disease, and it is thought that subclinical inflammation persists even when there are no attacks, eventually causing endothelial dysfunction (ED) and atherosclerosis. Limited data are available about serum endocan, asymmetric dimethylarginine (ADMA) and lipid profile in children with FMF, so we aimed to evaluate these markers in children with FMF during the attack-free period.

Methods
A total of 50 patients diagnosed with FMF and 50 age and sex-matched healthy children were recruited. Serum endocan, ADMA and lipid profiles were measured. Also, atherogenic indices (Castelli’s risk indices I and II [CRI I and II], atherogenic index of plasma [AIP] and atherogenic coefficient [AC]) were calculated.

Results
Serum endocan, ADMA levels, low-density lipoprotein cholesterol, triglycerides, CRI II and AIP of the FMF patients were significantly higher than controls (p < 0.001). Unlike serum endocan, serum ADMA showed a positive significant correlation with total cholesterol, non-high density lipoprotein cholesterol, CRI I, AIP and AC (p < 0.001, p < 0.001, p = 0.004, p = 0.028, p = 0.004 respectively).

Conclusion
Serum ADMA and lipid profile might be used as potential markers for endothelial dysfunction and increased cardiovascular risk in FMF patients.

Impact

Theoretically, serum ADMA may affect lipid profiles and serum endocan represents an intriguing biomarker related to inflammation. Coexistence of dyslipidemia represents an additional risk factor that contributes to the onset of early atherosclerosis.

A few studies investigated the role of changes in lipid profile and lipid ratios in accelerated atherosclerosis pathogenesis in FMF patients.

The relationship between colchicine and lipid profile is contradictory. Although colchicine can cause dyslipidemia, it also has anti-atherosclerosis effects.

Elevated ADMA level and atherogenic indices in FMF children reflect their potential role in the early detection of cardiovascular affection in FMF patients.
A multimodal deep learning approach for the prediction of cognitive decline and its effectiveness in clinical trials for Alzheimer’s disease
Authors: Wang Caihua , Tachimori Hisateru , Yamaguchi Hiroyuki , Sekiguchi Atsushi , Li Yuanzhong , Yamashita Yuichi ,   for Alzheimer’s Disease Neuroimaging Initiative
Published: February 2024

AbstractAlzheimer’s disease is one of the most important health-care challenges in the world. For decades, numerous efforts have been made to develop therapeutics for Alzheimer’s disease, but most clinical trials have failed to show significant treatment effects on slowing or halting cognitive decline. Among several challenges in such trials, one recently noticed but unsolved is biased allocation of fast and slow cognitive decliners to treatment and placebo groups during randomization caused by the large individual variation in the speed of cognitive decline. This allocation bias directly results in either over- or underestimation of the treatment effect from the outcome of the trial. In this study, we propose a stratified randomization method using the degree of cognitive decline predicted by an artificial intelligence model as a stratification index to suppress the allocation bias in randomization and evaluate its effectiveness by simulation using ADNI data set.
Update on the management of relapsed/refractory chronic lymphocytic leukemia
Authors: Bennett Rory , Seymour John F. 
Published: February 2024

AbstractChronic lymphocytic leukemia (CLL) predominantly affects older adults, characterized by a relapsing and remitting pattern with sequential treatments available for many patients. Identification of progressive/relapsed CLL should prompt close monitoring and early discussion about the next therapies when treatment indications are present. The intervening period represents an opportunity to optimize patient health, including establishing adequate vaccination and surveillance for second primary malignancies, and treating non-CLL-related comorbidities which may impact well-being and CLL therapy. We now see patients with relapsed/refractory (RR) CLL in the clinic who have been previously treated with chemoimmunotherapy (CIT) and/or one or more novel therapies. Continuous covalent inhibitors of Bruton’s tyrosine kinase (cBTKi) and fixed-duration venetoclax (Ven)-anti-CD20 monoclonal antibody (mAb) are preferred over CIT given the survival advantages associated with these therapies, although have never been evaluated head-to-head. While both classes are effective for RR CLL, potential side effects and the logistics of administration differ. Few randomized data demonstrate the sequential use of cBTKi and fixed-duration Ven-anti-CD20 mAb; however, they may be used in either sequence. Newer non-covalent BTKi, active against BTK C481 resistance mutations emerging with continuous cBTKi exposure, and novel approaches such as BTK degraders, bispecific antibodies, and chimeric antigen receptor T-cell therapies demonstrate impressive efficacy. In this review of RR CLL we explore relevant investigations, consideration of broader CLL- and non-CLL-related health needs, and evidence for efficacy and safety of B-cell receptor inhibitors and Ven, including available data to support drug sequencing or switching. We describe novel approaches to RR CLL, including rechallenging with fixed-duration therapies, allogeneic stem cell transplant indications in the novel therapy era, and highlight early data supporting the use of T-cell directing therapies and novel drug targets.
nNOS in Erbb4-positive neurons regulates GABAergic transmission in mouse hippocampus
Authors: Wan Chaofan , Xia Yucen , Yan Jinglan , Lin Weipeng , Yao Lin , Zhang Meng , Gaisler-Salomon Inna , Mei Lin , Yin Dong-Min , Chen Yongjun 
Published: February 2024

AbstractNeuronal nitric oxide synthase (nNOS, gene name Nos1) orchestrates the synthesis of nitric oxide (NO) within neurons, pivotal for diverse neural processes encompassing synaptic transmission, plasticity, neuronal excitability, learning, memory, and neurogenesis. Despite its significance, the precise regulation of nNOS activity across distinct neuronal types remains incompletely understood. Erb-b2 receptor tyrosine kinase 4 (ErbB4), selectively expressed in GABAergic interneurons and activated by its ligand neuregulin 1 (NRG1), modulates GABA release in the brain. Our investigation reveals the presence of nNOS in a subset of GABAergic interneurons expressing ErbB4. Notably, NRG1 activates nNOS via ErbB4 and its downstream phosphatidylinositol 3-kinase (PI3K), critical for NRG1-induced GABA release. Genetic removal of nNos from Erbb4-positive neurons impairs GABAergic transmission, partially rescued by the NO donor sodium nitroprusside (SNP). Intriguingly, the genetic deletion of nNos from Erbb4-positive neurons induces schizophrenia-relevant behavioral deficits, including hyperactivity, impaired sensorimotor gating, and deficient working memory and social interaction. These deficits are ameliorated by the atypical antipsychotic clozapine. This study underscores the role and regulation of nNOS within a specific subset of GABAergic interneurons, offering insights into the pathophysiological mechanisms of schizophrenia, given the association of Nrg1, Erbb4, Pi3k, and Nos1 genes with this mental disorder.
Ferroptotic alveolar epithelial type II cells drive TH2 and TH17 mixed asthma triggered by birch pollen allergen Bet v 1
Authors: Ma Linyi , He Ying , Xie Huancheng , Wang Jing , Chen Jiaqian , Song Shijie , Zhang Le , Li Linmei , Lai He , Liu Yongping , Chen Huifang , Zhang Xueyan , Liu Xueting , Zou Zehong , Zhang Qingling , Yan Jie , Tao Ailin 
Published: February 2024

AbstractAsthma is a common allergic disease characterized by airway hypersensitivity and airway remodeling. Ferroptosis is a regulated death marked by iron accumulation and lipid peroxidation. Several environmental pollutants and allergens have been shown to cause ferroptosis in epithelial cells, but the relationship between birch pollinosis and ferroptosis in asthma is poorly defined. Here, for the first time, we have identified ferroptosis of type II alveolar epithelial cells in mice with Bet v 1-induced asthma. Further analysis revealed that treatment with ferrostatin-1 reduced TH2/TH17-related inflammation and alleviated epithelial damage in mice with Bet v 1-induced asthma. In addition, ACSL4-knocked-down A549 cells are more resistant to Bet v 1-induced ferroptosis. Analysis of clinical samples verified higher serum MDA and 4-HNE concentrations compared to healthy individuals. We demonstrate that birch pollen allergen Bet v 1 induces ferroptosis underlaid TH2 and TH17 hybrid asthma. Lipid peroxidation levels can be considered as a biomarker of asthma severity, and treatment with a specific ferroptosis inhibitor could be a novel therapeutic strategy.
Runx1+ vascular smooth muscle cells are essential for hematopoietic stem and progenitor cell development in vivo
Authors: Gonzalez Galofre Zaniah N. , Kilpatrick Alastair M. , Marques Madalena , Sá da Bandeira Diana , Ventura Telma , Gomez Salazar Mario , Bouilleau Léa , Marc Yvan , Barbosa Ana B. , Rossi Fiona , Beltran Mariana , van de Werken Harmen J. G. , van IJcken Wilfred F. J. , Henderson Neil C. , Forbes Stuart J. , Crisan Mihaela 
Published: February 2024

AbstractHematopoietic stem cells (HSCs) produce all essential cellular components of the blood. Stromal cell lines supporting HSCs follow a vascular smooth muscle cell (vSMC) differentiation pathway, suggesting that some hematopoiesis-supporting cells originate from vSMC precursors. These pericyte-like precursors were recently identified in the aorta-gonad-mesonephros (AGM) region; however, their role in the hematopoietic development in vivo remains unknown. Here, we identify a subpopulation of NG2+Runx1+ perivascular cells that display a sclerotome-derived vSMC transcriptomic profile. We show that deleting Runx1 in NG2+ cells impairs the hematopoietic development in vivo and causes transcriptional changes in pericytes/vSMCs, endothelial cells and hematopoietic cells in the murine AGM. Importantly, this deletion leads also to a significant reduction of HSC reconstitution potential in the bone marrow in vivo. This defect is developmental, as NG2+Runx1+ cells were not detected in the adult bone marrow, demonstrating the existence of a specialised pericyte population in the HSC-generating niche, unique to the embryo.
A convergent evolutionary pathway attenuating cellulose production drives enhanced virulence of some bacteria
Authors: Nhu Nguyen Thi Khanh , Rahman M. Arifur , Goh Kelvin G. K. , Kim Seung Jae , Phan Minh-Duy , Peters Kate M. , Alvarez-Fraga Laura , Hancock Steven J. , Ravi Chitra , Kidd Timothy J. , Sullivan Matthew J. , Irvine Katharine M. , Beatson Scott A. , Sweet Matthew J. , Irwin Adam D. , Vukovic Jana , Ulett Glen C. , Hasnain Sumaira Z. , Schembri Mark A. 
Published: February 2024

AbstractBacteria adapt to selective pressure in their immediate environment in multiple ways. One mechanism involves the acquisition of independent mutations that disable or modify a key pathway, providing a signature of adaptation via convergent evolution. Extra-intestinal pathogenic Escherichia coli (ExPEC) belonging to sequence type 95 (ST95) represent a global clone frequently associated with severe human infections including acute pyelonephritis, sepsis, and neonatal meningitis. Here, we analysed a publicly available dataset of 613 ST95 genomes and identified a series of loss-of-function mutations that disrupt cellulose production or its modification in 55.3% of strains. We show the inability to produce cellulose significantly enhances ST95 invasive infection in a rat model of neonatal meningitis, leading to the disruption of intestinal barrier integrity in newborn pups and enhanced dissemination to the liver, spleen and brain. Consistent with these observations, disruption of cellulose production in ST95 augmented innate immune signalling and tissue neutrophil infiltration in a mouse model of urinary tract infection. Mutations that disrupt cellulose production were also identified in other virulent ExPEC STs, Shigella and Salmonella, suggesting a correlative association with many Enterobacteriaceae that cause severe human infection. Together, our findings provide an explanation for the emergence of hypervirulent Enterobacteriaceae clones.
Adjuvant dendritic cell therapy in stage IIIB/C melanoma: the MIND-DC randomized phase III trial
Authors: Bol Kalijn F. , Schreibelt Gerty , Bloemendal Martine , van Willigen Wouter W. , Hins-de Bree Simone , de Goede Anna L. , de Boer Annemiek J. , Bos Kevin J. H. , Duiveman-de Boer Tjitske , Olde Nordkamp Michel A. M. , van Oorschot Tom G. M. , Popelier Carlijn J. , Pots Jeanne M. , Scharenborg Nicole M. , van de Rakt Mandy W. M. M. , de Ruiter Valeska , van Meeteren Wilmy S. , van Rossum Michelle M. , Croockewit Sandra J. , Koeneman Bouke J. , Creemers Jeroen H. A. , Wortel Inge M. N. , Angerer Caroline , Brüning Mareke , Petry Katja , Dzionek Andrzej , van der Veldt Astrid A. , van Grünhagen Dirk J. , Werner Johanna E. M. , Bonenkamp Johannes J. , Haanen John B. A. G. , Boers-Sonderen Marye J. , Koornstra Rutger H. T. , Boomsma Martijn F. , Aarntzen Erik H. J. , Gotthardt Martin , Nagarajah James , de Witte Theo J. M. , Figdor Carl G. , de Wilt Johannes H. W. , Textor Johannes , de Groot Jan Willem B. , Gerritsen Winald R. , de Vries I. Jolanda M. 
Published: February 2024

AbstractAutologous natural dendritic cells (nDCs) treatment can induce tumor-specific immune responses and clinical responses in cancer patients. In this phase III clinical trial (NCT02993315), 148 patients with resected stage IIIB/C melanoma were randomized to adjuvant treatment with nDCs (n = 99) or placebo (n = 49). Active treatment consisted of intranodally injected autologous CD1c+ conventional and plasmacytoid DCs loaded with tumor antigens. The primary endpoint was the 2-year recurrence-free survival (RFS) rate, whereas the secondary endpoints included median RFS, 2-year and median overall survival, adverse event profile, and immunological response The 2-year RFS rate was 36.8% in the nDC treatment group and 46.9% in the control group (p = 0.31). Median RFS was 12.7 months vs 19.9 months, respectively (hazard ratio 1.25; 90% CI: 0.88−1.79; p = 0.29). Median overall survival was not reached in both treatment groups (hazard ratio 1.32; 90% CI: 0.73−2.38; p = 0.44). Grade 3−4 study-related adverse events occurred in 5% and 6% of patients. Functional antigen-specific T cell responses could be detected in 67.1% of patients tested in the nDC treatment group vs 3.8% of patients tested in the control group (p < 0.001). In conclusion, while adjuvant nDC treatment in stage IIIB/C melanoma patients generated specific immune responses and was well tolerated, no benefit in RFS was observed.
Multi-omics analysis in human retina uncovers ultraconserved cis-regulatory elements at rare eye disease loci
Authors: Lopez Soriano Victor , Dueñas Rey Alfredo , Mukherjee Rajarshi ,   Genomics England Research Consortium, Inglehearn Chris F. , Coppieters Frauke , Bauwens Miriam , Willaert Andy , De Baere Elfride 
Published: February 2024

AbstractCross-species genome comparisons have revealed a substantial number of ultraconserved non-coding elements (UCNEs). Several of these elements have proved to be essential tissue- and cell type-specific cis-regulators of developmental gene expression. Here, we characterize a set of UCNEs as candidate CREs (cCREs) during retinal development and evaluate the contribution of their genomic variation to rare eye diseases, for which pathogenic non-coding variants are emerging. Integration of bulk and single-cell retinal multi-omics data reveals 594 genes under potential cis-regulatory control of UCNEs, of which 45 are implicated in rare eye disease. Mining of candidate cis-regulatory UCNEs in WGS data derived from the rare eye disease cohort of Genomics England reveals 178 ultrarare variants within 84 UCNEs associated with 29 disease genes. Overall, we provide a comprehensive annotation of ultraconserved non-coding regions acting as cCREs during retinal development which can be targets of non-coding variation underlying rare eye diseases.
Anomalously bright single-molecule upconversion electroluminescence
Authors: Luo Yang , Kong Fan-Fang , Tian Xiao-Jun , Yu Yun-Jie , Jing Shi-Hao , Zhang Chao , Chen Gong , Zhang Yang , Zhang Yao , Li Xiao-Guang , Zhang Zhen-Yu , Dong Zhen-Chao 
Published: February 2024

AbstractEfficient upconversion electroluminescence is highly desirable for a broad range of optoelectronic applications, yet to date, it has been reported only for ensemble systems, while the upconversion electroluminescence efficiency remains very low for single-molecule emitters. Here we report on the observation of anomalously bright single-molecule upconversion electroluminescence, with emission efficiencies improved by more than one order of magnitude over previous studies, and even stronger than normal-bias electroluminescence. Intuitively, the improvement is achieved via engineering the energy-level alignments at the molecule−substrate interface so as to activate an efficient spin-triplet mediated upconversion electroluminescence mechanism that only involves pure carrier injection steps. We further validate the intuitive picture with the construction of delicate electroluminescence diagrams for the excitation of single-molecule electroluminescence, allowing to readily identify the prerequisite conditions for producing efficient upconversion electroluminescence. These findings provide deep insights into the microscopic mechanism of single-molecule upconversion electroluminescence and organic electroluminescence in general.
Motility of an autonomous protein-based artificial motor that operates via a burnt-bridge principle
Authors: Korosec Chapin S. , Unksov Ivan N. , Surendiran Pradheebha , Lyttleton Roman , Curmi Paul M. G. , Angstmann Christopher N. , Eichhorn Ralf , Linke Heiner , Forde Nancy R. 
Published: February 2024

AbstractInspired by biology, great progress has been made in creating artificial molecular motors. However, the dream of harnessing proteins – the building blocks selected by nature – to design autonomous motors has so far remained elusive. Here we report the synthesis and characterization of the Lawnmower, an autonomous, protein-based artificial molecular motor comprised of a spherical hub decorated with proteases. Its “burnt-bridge” motion is directed by cleavage of a peptide lawn, promoting motion towards unvisited substrate. We find that Lawnmowers exhibit directional motion with average speeds of up to 80 nm/s, comparable to biological motors. By selectively patterning the peptide lawn on microfabricated tracks, we furthermore show that the Lawnmower is capable of track-guided motion. Our work opens an avenue towards nanotechnology applications of artificial protein motors.
Structural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy
Authors: Hoogenboezem Ella N. , Patel Shrusti S. , Lo Justin H. , Cavnar Ashley B. , Babb Lauren M. , Francini Nora , Gbur Eva F. , Patil Prarthana , Colazo Juan M. , Michell Danielle L. , Sanchez Violeta M. , McCune Joshua T. , Ma Jinqi , DeJulius Carlisle R. , Lee Linus H. , Rosch Jonah C. , Allen Ryan M. , Stokes Larry D. , Hill Jordan L. , Vickers Kasey C. , Cook Rebecca S. , Duvall Craig L. 
Published: February 2024

AbstractThe high potential of siRNAs to silence oncogenic drivers remains largely untapped due to the challenges of tumor cell delivery. Here, divalent lipid-conjugated siRNAs are optimized for in situ binding to albumin to improve pharmacokinetics and tumor delivery. Systematic variation of the siRNA conjugate structure reveals that the location of the linker branching site dictates tendency toward albumin association versus self-assembly, while the lipid hydrophobicity and reversibility of albumin binding also contribute to siRNA intracellular delivery. The lead structure increases tumor siRNA accumulation 12-fold in orthotopic triple negative breast cancer (TNBC) tumors over the parent siRNA. This structure achieves approximately 80% silencing of the anti-apoptotic oncogene MCL1 and yields better survival outcomes in three TNBC models than an MCL-1 small molecule inhibitor. These studies provide new structure-function insights on siRNA-lipid conjugate structures that are intravenously injected, associate in situ with serum albumin, and improve pharmacokinetics and tumor treatment efficacy.
Design of target specific peptide inhibitors using generative deep learning and molecular dynamics simulations
Authors: Chen Sijie , Lin Tong , Basu Ruchira , Ritchey Jeremy , Wang Shen , Luo Yichuan , Li Xingcan , Pei Dehua , Kara Levent Burak , Cheng Xiaolin 
Published: February 2024

AbstractWe introduce a computational approach for the design of target-specific peptides. Our method integrates a Gated Recurrent Unit-based Variational Autoencoder with Rosetta FlexPepDock for peptide sequence generation and binding affinity assessment. Subsequently, molecular dynamics simulations are employed to narrow down the selection of peptides for experimental assays. We apply this computational strategy to design peptide inhibitors that specifically targetβ-catenin and NF-κB essential modulator. Among the twelveβ-catenin inhibitors, six exhibit improved binding affinity compared to the parent peptide. Notably, the best C-terminal peptide bindsβ-catenin with an IC50of 0.010 ± 0.06 μM, which is 15-fold better than the parent peptide. For NF-κB essential modulator, two of the four tested peptides display substantially enhanced binding compared to the parent peptide. Collectively, this study underscores the successful integration of deep learning and structure-based modeling and simulation for target specific peptide design.
Global evaluation of lineage-specific human papillomavirus capsid antigenicity using antibodies elicited by natural infection
Authors: Kamuyu Gathoni , Coelho da Silva Filomeno , Tenet Vanessa , Schussler John , Godi Anna , Herrero Rolando , Porras Carolina , Mirabello Lisa , Schiller John T. , Sierra Mónica S. , Kreimer Aimée R. , Clifford Gary M. , Beddows Simon 
Published: February 2024

AbstractHuman Papillomavirus (HPV) type variants have been classified into lineages and sublineages based upon their whole genome sequence. Here we have examined the specificity of antibodies generated following natural infection with lineage variants of oncogenic types (HPV16, 18, 31, 33, 45, 52 and 58) by testing serum samples assembled from existing archives from women residing in Africa, The Americas, Asia or Europe against representative lineage-specific pseudoviruses for each genotype. We have subjected the resulting neutralizing antibody data to antigenic clustering methods and created relational antigenic profiles for each genotype to inform the delineation of lineage-specific serotypes. For most genotypes, there was evidence of differential recognition of lineage-specific antigens and in some cases of a sufficient magnitude to suggest that some lineages should be considered antigenically distinct within their respective genotypes. These data provide compelling evidence for a degree of lineage specificity within the humoral immune response following natural infection with oncogenic HPV.