bluuebunny/crossref_metadata_2025_split huggingface dataset:
Smell testing to identify early alpha-synucleinopathy among people with dream enactment behavior
Authors: Brown Ethan , Chahine Lana M , Videnovic Aleksandar , Marshall Micah J , Kurth Ryan , Caspell-Garcia Chelsea , Brumm Michael C , Coffey Christopher , Siderowf Andrew , Simuni Tanya , Marek Kenneth , Tanner Caroline M ,   The Parkinson’s Progression Markers Initiative
Published: December 2024

ABSTRACTBackgroundREM sleep behavior disorder (RBD) is an early manifestation of alpha-synucleinopathy in many cases. Dream enactment behavior (DEB), the clinical hallmark of RBD, has many etiologies and cannot be used alone to predict underlying alpha-synucleinopathy. We compared the proportion of people with alpha-synucleinopathy, as measured by CSF alpha-synuclein seed amplification assay (CSFasynSAA), between people with polysomnographic-confirmed RBD (RBD-PSG) and people who reported DEB on a questionnaire and were further selected with smell testing and DAT-SPECT.MethodsParticipants were enrolled in the Parkinson’s Progression Marker Initiative (PPMI) and ≥60 years old without a diagnosis of Parkinson’s disease. Participants had either RBD-PSG or self-reported DEB. Self-reported DEB participants had to have hyposmia (<10thpercentile for age/sex) and at least mild DAT-SPECT abnormality (<100% age/sex-expected). We compared CSFasynSAA between RBD-PSG and self-reported DEB with hyposmia (DEB+Hypos). RBD-PSG participants also underwent smell testing and DAT-SPECT; we determined the predictive value of these tests in RBD-PSG with regards to CSFasynSAA.ResultsCSFasynSAA was positive in 171/240 (71%) of RBD-PSG and %) 180/210 (86%) of DEB+Hypos participants. Among RBD-PSG, hyposmia strongly predicted CSFasynSAA+ (PPV: 92% [95% CI 87%-97%]). Smell identification was more accurate than DAT-SPECT in predicting CSFasynSAA+ in RBD-PSG (AUC for UPSIT: 0.89 [95% CI 0.84 – 0.94]; AUC for DAT-SPECT: 0.65 [95% CI 0.58 – 0.73]).ConclusionsSmell testing may be an effective and scalable method to identify people with alpha-synucleinopathy among those with self-reported DEB. Among individuals with RBD diagnosed by PSG, smell testing improved prediction of positive CSF alpha-synuclein biomarker.
Oropouche Virus Outbreak in Southeast, Brazil: Expanding Beyond the Amazonian Endemic Region
Authors: Delatorre Edson , de Colombo Gabriela Mendonça , Gatti Felipe Donateli , Có Anna Clara Gregório , Pereira Julia del Piero , Tavares Eric Arrivabene , Nodari Joana Zorzal , Rossi Agata , de Azevedo Suwellen Sardinha Dias , Sacchi Cláudio Tavares , Campos Karoline Rodrigues , Bugno Adriana , Alves Lyvia Neves Rebello , Bonela Lucas André Silva , Goulart Jaqueline Pegoretti , Souza Thiago de Jesus , Naveca Felipe Gomes , Ribeiro-Rodrigues Rodrigo 
Published: December 2024

AbstractThe Oropouche virus (OROV), historically endemic to the Amazon, has spread to nearly all Brazilian states in 2024, with Espírito Santo emerging as a significant transmission hotspot in the Atlantic Forest biome. We characterized the epidemiological factors driving OROV spread in non-endemic Southeast Brazil, analyzing environmental and agricultural conditions contributing to viral transmission. Samples from 29,000 suspected arbovirus-infected patients were tested by RT-qPCR for Dengue, Chikungunya, Zika, Mayaro, and Oropouche virus. Between March and June 2024, OROV cases in the state reached 339, demonstrating successful local transmission.Spatial analysis revealed that most cases clustered in municipalities with tropical climates and intensive cacao, robusta coffee, coconut, and pepper cultivation. Phylogenetic analysis identified the Espírito Santo OROV strains as part of the 2022-2024 Amazonian lineage. The rapid spread of OROV outside the Amazon highlights its adaptive potential and public health threat, emphasizing the need for enhanced surveillance and targeted control measures.
Rational design of19F NMR labelling sites to probe protein structure and interactions
Authors: Streit Julian O. , Chan Sammy H.S. , Daya Saifu , Christodoulou John 
Published: December 2024

AbstractProteins are investigated in increasingly more complex biological systems, where19F NMR is proving highly advantageous due to its high gyromagnetic ratio and background-free spectra. Its application has, however, been hindered by limited chemical shift dispersions and an incomprehensive relationship between chemical shifts and protein structure. We exploit the sensitivity of19F chemical shifts to ring currents by designing labels with direct contact to a native or engineered aromatic ring. Fifty protein variants predicted by AlphaFold and molecular dynamics simulations show 80-90% success rates and direct correlations of their experimental chemical shifts with the magnitude of the engineered ring current. Our method consequently improves the chemical shift dispersion and through simple 1D experiments enables structural analyses of alternative conformational states, including ribosome-bound folding intermediates, and in-cell measurements of thermodynamics and protein-protein interactions. Our strategy thus provides a simple and sensitive tool to extract residue contact restraints from chemical shifts for previously intractable systems.
Deconstruction of a memory engram reveals distinct ensembles recruited at learning
Authors: Pouget Clément , Morier Flora , Treiber Nadja , García Pablo Fernández , Mazza Nina , Zhang Run , Reeves Isaiah , Winston Stephen , Brimble Mark A. , Kim Christina K. , Vetere Gisella 
Published: December 2024

AbstractHow are associative memories formed? Which cells represent a memory, and when are they engaged? By visualizing and tagging cells based on their calcium influx with unparalleled temporal precision, we identified non-overlapping dorsal CA1 neuronal ensembles that are differentially active during associative fear memory acquisition. We dissected the acquisition experience into periods during which salient stimuli were presented or certain mouse behaviors occurred and found that cells associated with specific acquisition periods are sufficient alone to drive memory expression and contribute to fear engram formation. This study delineated the different identities of the cell ensembles active during learning, and revealed, for the first time, which ones form the core engram and are essential for memory formation and recall.
Truncated and “double-headed” derivatives of TO1-B dye for Mango-based imaging systems with increased brightness and selectivity and large Stocks shift
Authors: Svetlova Julia I. , Slushko Georgy K. , Fayzieva Anna S. , Belyaev Evgeny S. , Kamzeeva Polina N. , Aralov Andrey V. 
Published: December 2024

ABSTRACTFluorogenic dyes that light up in complexes with genetically encodable RNA aptamers are increasingly used for intracellular RNA imaging. The growing toolbox of dyes and aptamers allows simultaneous or sequential monitoring of different RNAs. However, few orthogonal aptamer-dye pairs meet all the requirements of multiplex imaging in terms of brightness, contrast, etc., thus necessitating their optimization and further diversification. Here, we report new fluorogenic ligands for the Mango II aptamer, one of the most stable and widely used RNA tags. They are based on the cognate Mango ligand TO1-B, which is a thiazole orange (TO) derivative with a biotinylated tetraethylene glycol (TEG) residue attached via an amide linker, and its analogue with an isosteric triazolyl linker (TO1-triazolyl-TEG-biotin). Structural data suggested that the biotin residue might be dispensable for interactions with Mango, so we replaced it with a second TO residue or the alternative push-pull system, namely the dimethylaminophenyl (DMAP) group linked to the benzothiazolyl (BzT) group via the ethenyl linker. The resulting “double-headed” symmetric and asymmetric dyes showed reduced fluorescence in the free state due to intramolecular TO/TO or TO/DMAP-BzT interactions. The asymmetric dye exhibited intramolecular FRET in complex with Mango, resulting in a remarkably large (130 nm) Stocks shift, which may be advantageous for multiplex imaging. The main limitation of the “double-headed” dyes was their low brightness. To improve brightness, we further optimized the truncated (biotin-free) TO1-triazolyl-TEG dye by introducing a hydroxy or a methoxy group into the methylqunolinium (MQ) fragment of its push-pull system. The brightness of the methoxy-MQ derivative was increased by 40% compared to the reported TO1-triazolyl-TEG-biotin. Importantly, the methoxy-MQ derivative also showed increased selectivity for Mango over other noncanonical nucleic acids structures, making it a promising alternative to known TO-based dyes for high-contrast RNA imaging.
Rapamycin induced autophagy enhances lipid breakdown and ameliorates lipotoxicity in Atlantic salmon cells
Authors: Phadwal Kanchan , Haggarty Jennifer , Kurian Dominic , Marti Judit Aguilar , Houston Ross D. , Betancor Mónica B. , MacRae Vicky E. , Whitfield Phillip D. , Macqueen Daniel J. 
Published: December 2024

AbstractAutophagy is a highly conserved cellular recycling process essential for homeostasis in all eukaryotic cells. Lipid accumulation and its regulation by autophagy are key areas of research for understanding metabolic disorders in human and model mammals. However, the role of autophagy in lipid regulation remains poorly characterised in non-model fish species of importance to food production, which could be important for managing health and welfare in aquaculture. Addressing this knowledge gap, we investigate the role of autophagy in lipid regulation using a macrophage-like cell line (SHK-1) from Atlantic salmon (Salmo salarL.), the world’s most commercially valuable farmed finfish. Multiple lines of experimental evidence reveal that the autophagic pathway responsible for lipid droplet breakdown is conserved in Atlantic salmon cells. We employed global lipidomics and proteomics analyses on SHK-1 cells subjected to lipid overload, followed by treatment with rapamycin to induce autophagy. This revealed that activating autophagy via rapamycin enhances storage of unsaturated triacylglycerols and suppresses key lipogenic proteins, including fatty acid elongase 6 and acid sphingomyelinase. Moreover, fatty acid elongase 6 was identified as cargo for autophagosomes, suggesting a critical role for autophagy in lipid metabolism in fish. Together, this study establishes a novel model of lipotoxicity and advances understanding of lipid autophagy in fish cells, with significant implications for addressing fish health issues in aquaculture.
AKR1C mediates the acquired resistance to T-Dxd in a HER-2 positive gastric cancer line
Authors: Wang Dong , Huang Qinqin , Wang Peili , Tang Feng , Han Yuhe , Wang Xiangyi , Huang Jingwei , Shi Liqi , Cao Weiqun , Zhang Zhixiang , Gu Qingyang 
Published: December 2024

AbstractTrastuzumab deruxtecan (T-Dxd), an anti-HER2 antibody–drug conjugate, has significantly enhanced clinical outcomes for patients as a HER2-directed therapy compared to previous standards of care. However, acquired resistance is always a concern, necessitating further investigation into the underlying resistance mechanism. In this study, we successfully established T-Dxd-resistant cell line (N87-R) by exposing HER2-positive N87 gastric cancer cells to increasing concentrations of T-Dxd, and demonstrated its resistance phenotype bothin vitroandin vivo. While there were no changes in HER2 expression or T-Dxd binding in N87-R, a signature of drug metabolism genes were found upregulated, among which AKR1C played a critical role in the resistance mechanism. The resistance phenotype of N87-R cells was mitigated by both siRNA-mediated knockdown of AKR1C and pharmacological inhibition of its enzymatic activity. Our preclinical study underscores the critical role of AKR1C function in mediating T-Dxd resistance and suggests potential therapeutic innovation for combating T-Dxd resistance.
RNA encodes physical information
Authors: Seim Ian , Zhang Vita , Jalihal Ameya P. , Stormo Benjamin M. , Cole Sierra J. , Ekena Joanne , Nguyen Hung T. , Thirumalai D. , Gladfelter Amy S. 
Published: December 2024

AbstractMost amino acids are encoded by multiple codons, making the genetic code degenerate. Synonymous mutations affect protein translation and folding, but their impact on RNA itself is often neglected. We developed a genetic algorithm that introduces synonymous mutations to control the diversity of structures sampled by an mRNA. The behavior of the designed mRNAs reveals a physical code layered in the genetic code. We find that mRNA conformational heterogeneity directs physical properties and functional outputs of RNA-protein complexes and biomolecular condensates. The role of structure and disorder of proteins in biomolecular condensates is well appreciated, but we find that RNA conformational heterogeneity is equally important. This feature of RNA enables both evolution and engineers to build cellular structures with specific material and responsive properties.
Regimen comprising clarithromycin, clofazimine and bedaquiline is more efficacious than monotherapy in a mouse model of chronicMycobacterium aviumlung infection
Authors: Rimal Binayak , Howe Ruth A. , Panthi Chandra , Lamichhane Gyanu 
Published: December 2024

ABSTRACTMycobacterium avium, a leading non-tuberculous mycobacterium (NTM) pathogen, causes chronic pulmonary infections, particularly in individuals with underlying lung conditions or immunosuppression. Current treatments involve prolonged multi-drug regimens with poor outcomes and significant side effects, highlighting the urgent need for improved therapies. Using a BALB/c mouse model of chronicM. aviumpulmonary disease, we evaluated the efficacy of individual antibiotics— clarithromycin, clofazimine, and rifabutin—and combination regimens including clarithromycin+bedaquiline and clarithromycin+clofazimine+bedaquiline. Clarithromycin demonstrated potent bactericidal activity, reducing lung bacterial burden by 2.2 log10CFU, while clofazimine transitioned from bacteriostatic to bactericidal, achieving a 1.7 log10CFU reduction. Rifabutin was bacteriostatic againstM. aviumMAC 101 but ineffective against MAC 104. The triple-drug regimen of clarithromycin+clofazimine+bedaquiline was the most effective, achieving a 3.3 log10CFU reduction in bacterial load, with 98% clearance within the first week and continued efficacy over eight weeks. Gross pathology confirmed these results, with granulomatous lesions observed only in untreated or rifabutin-treated mice. Combination therapy demonstrated enhanced efficacy compared to monotherapy. The findings underscore the potential of oral clarithromycin+clofazimine+bedaquiline or clarithromycin+clofazimine regimen as a promising therapeutic strategy forM. aviumpulmonary disease.
Vibrio choleraeO1 El Tor A1552 encodes two functional ornithine lipid synthases and induces ornithine lipid formation under low phosphate and under low salinity growth conditions
Authors: Vences-Guzmán Miguel Ángel , Olea-Ozuna Roberto Jhonatan , Martínez-Méndez Raquel , Escobedo-Hinojosa Wendy Itzel , Castro-Santillán Marlene , Guan Ziqiang , Zamorano-Sánchez David , Sohlenkamp Christian 
Published: December 2024

ABSTRACTOrnithine lipids (OLs) are phosphorus-free membrane lipids that can be formed by a wide range of bacteria. The presence of OLs is frequently related to the resistance to abiotic stress conditions, and its synthesis is often induced as part of various stress responses. Two different pathways for synthesizing OLs are currently known: the OlsBA pathway first described inSinorhizobium meliloti, and the OlsF pathway first described inSerratia proteamaculans. We identified in the genome ofVibrio choleraeO1 El Tor A1552 two genes encoding OlsF homologs, VC0489 is located on chromosome 1, whereas VCA0646 is located on chromosome 2. Both synthases, when expressed inEscherichia coli, caused the synthesis of OLs. Single mutants deficient in each of the OL synthases, double mutants deficient in both OL synthases, and mutants deficient in the transcriptional regulator PhoB were constructed and characterized. We corroborated that VC0489 is solely responsible for the synthesis of OLs under phosphate-limitation. The deletion of VC0489 reduced the growth velocity compared to the wildtype under phosphate-limiting conditions but not under phosphate-replete conditions. The expression of VCA0646 is favored under low salt growth conditions, and its deletion abrogates OL synthesis at low salinities. The absence of VCA0646 and, therefore, the lack of OLs under low salt conditions makes the respective mutant more susceptible to polymyxin than OL-forming strains. None of the mutants was affected in biofilm formation, swimming, or virulence assays usingCaenorhabditis elegansorGalleria mellonella. Here, we describe two functional OL synthases present in a single bacterium for the first time, and we show evidence that OLs have an important function during theV. choleraelifecycle.
In-depth Characterization of S-Glutathionylation in Ventricular Myosin Light Chain 1 Across Species by Top-Down Proteomics
Authors: Chapman Emily A. , Rogers Holden T. , Gao Zhan , Chan Hsin-Ju , Alvarado Francisco J. , Ge Ying 
Published: December 2024

AbstractS-glutathionylation (SSG) is increasingly recognized as a critical signaling mechanism in the heart, yet SSG modifications in cardiac sarcomeric proteins remain understudied. Here we identified SSG of the ventricular isoform of myosin light chain 1 (MLC-1v) in human, swine, and mouse cardiac tissues using top-down mass spectrometry (MS)-based proteomics. Our results enabled the accurate identification, quantification, and site-specific localization of SSG in MLC-1v across different species. Notably, the endogenous SSG of MLC-1v was observed in human and swine cardiac tissues but not in mice. Treating non-reduced cardiac tissue lysates with GSSG elevated MLC-1v SSG levels across all three species.
Mental health and weight loss in men: an exploratory mixed methods study of the Game of Stones trial
Authors: Torrens Claire E , Turner Katrina , Swingler James , O’Dolan Catriona , MacLean Alice , Macaulay Lisa , Dombrowski Stephan U , Avenell Alison , Cotton Seonaidh , McKinley Michelle C , Hunt Kate , Gray Cindy , Kee Frank , MacLennan Graeme , Hoddinott Pat 
Published: December 2024

AbstractObjectiveWeight management interventions can affect mental health. Mental health can affect engagement with weight loss interventions or services. This study explored mental health and wellbeing outcomes, retention and participant experiences of mental health within the Game of Stones trial.MethodsMixed methods process evaluation within a 3-group randomised controlled trial: behavioural text messages with financial incentives, texts alone, and waiting list control, for 585 men with obesity. Secondary outcomes analysed descriptively included: Warwick-Edinburgh Mental Wellbeing Scale, Weight Self-Stigma Questionnaire, EQ-5D-5L, EQ-5D-5L anxiety and depression subscale, Patient Health Questionniare-4, and retention. Three categories of participants were compared: ever diagnosed with a mental health condition (n=146; 25.0%), latent mental health condition (n=142; 24.3%) no mental health condition (n=295; 50.6%). Semi-structured interviews (n=54) were conducted after 12 months and analysed using Framework method.ResultsA higher proportion of men who self-reported ever having a mental health condition had a disability, multiple long-term conditions, were under financial strain and were single compared to those with those with a latent mental health condition and no mental health condition. Improvements from baseline were shown for weight stigma, wellbeing and PHQ-4 at 12 months for men in intervention groups with a mental health condition and latent mental health condition. EQ-5D-5L Visual Analogue Scale scores improved across all mental health categories and trial groups, but EQ-5D-5L and EQ-5D-5L-AD scores were inconsistent. Retention at 12 months was 76.0% (mental health condition), 70.4% (latent mental health condition) and 72.5% (no mental health condition). The qualitative evidence indicated that stress, anxiety and depression were experienced in different ways by men during the programme. Mental health difficulties were unique to the individual, could be episodic, recurrent, cyclical or ongoing and were a barrier to behaviour change for some but not for others.ConclusionThe trial was able to engage and retain men regardless of mental health category. Behavioural text messages with or without incentives helped some men lose weight, but not others. Observed heterogeneity for mental health and wellbeing measures is problematic for weight management trials with men.
Remote Real Time Digital Monitoring fills a Critical Gap in the Management of Parkinson’s disease
Authors: Negi Aarushi S. , Karjagi Shreesh , Parisi Laura , Daley Kerry W. , Abay Annie K. , Gala Aryaman S. , Wilkins Kevin B. , Hoffman Shannon L. , Ferris Margaret S. , Zahed Hengameh , Chattree Gaurav , Palushaj Bianca , Bronte-Stewart Helen M. 
Published: December 2024

AbstractBackground and ObjectivesPeople with Parkinson’s disease (PWP) face significant gaps in care. Limited neurologist access, infrequent clinic visits, and inadequate symptom measurement culminate in suboptimal therapy and high morbidity. Quantitative Digitography (QDG) addresses these care gaps by providing validated, quantitative metrics of all motor signs in Parkinson’s disease (PD) in real-time through a 30-second repetitive alternating finger tapping (RAFT) task. We investigated the feasibility and clinical relevance of remote QDG monitoring in individuals with movement disorders.MethodsIn this prospective cohort study, participants with suspected or clinically established PD were referred by neurologists from Stanford Movement Disorders Clinic, with one participant recruited outside Stanford. Participants were asked to complete at-home QDG-RAFT for 30 days and were administered usability and quality-of-life questionnaires throughout testing; descriptive statistics summarized compliance and questionnaire responses, and a Spearman correlation assessed the relationship between QDG Mobility Score and MDS-UPDRS Part II scores. The primary outcome was compliance with once-daily testing for at least 16/30 days of remote monitoring.Results30 participants (24 with clinically diagnosed and 6 with suspected PD at time of referral) were included. 100% of participants demonstrated compliance with once-daily testing for at least 16/30 days. Adherence rates for once-daily and twice-daily testing were 96.2% and 82.2%, respectively, with 96% of participants rating once-daily testing as easy. The QDG Mobility Score correlated strongly with patients’ self-reported impact of motor symptoms on Activities of Daily Living (ADLs) per the MDS-UPDRS II (ρ=-0.61 [−0.88, −0.16], p=0.004). QDG-RAFT documented motor asymmetry and impairment from 1-month pre-diagnosis to 20-years duration of PD. The QDG Mobility Score reflected motor improvement and deterioration after adding or removing respectively a single tablet of carbidopa/levodopa.DiscussionParticipants showed excellent compliance with remote QDG monitoring and found the system easy to use. The QDG Mobility Score was highly correlated with ADLs, captured motor complexities across a broad disease duration range, and detected responses to minor therapy adjustments. A pivotal advancement in PD care, QDG offers providers an accessible, comprehensive tool to remotely monitor motor symptoms, optimize treatment regimens, and bridge care gaps created by infrequent clinic visits and subjective symptom assessment.