bluuebunny/crossref_metadata_2025_split huggingface dataset:
How the prospect of a clinical trial impacts decision-making for predictive genetic testing in amyotrophic lateral sclerosis
Authors: Fontaine Myriam , Horowitz Kayla , Anoja Nancy , Genge Angela , Salmon Kristiana 
Published: October 2024

AbstractObjectiveGenetic testing practices are rapidly evolving for people living with, or at-risk for, amyotrophic lateral sclerosis (ALS), due to emerging genotype-driven therapies. This study explored how individuals at-risk for familial ALS (fALS) perceive the opportunity to participate in a clinical trial, and to better understand how that may influence the decision-making process for predictive genetic testing.MethodsThis study used both quantitative and qualitative data analyses. Data were collected through an online questionnaire, followed by semi-structured interviews conducted with twelve (n=12) individuals at-risk for eitherSOD1-orC9orf72-ALS who had predictive testing prior to study participation. Interview data were analyzed using reflexive thematic analysis.ResultsThree overarching themes were conceptualized from the data: i) the psychosocial impact of fALS; ii) perspectives of at-risk individuals on research involvement; and iii) predictive genetic counselling and testing considerations. These results contribute perspectives of the lived experience to inform predictive genetic counselling and testing practices for individuals at-risk for fALS.ConclusionIndividuals at-risk for fALS view potential participation in a presymptomatic clinical trial as an actionable measure that may increase their desire for predictive genetic testing. Genetic counselling was identified as a critical component of the predictive testing process given the life-changing implications associated with a positive result. Increased access to genetic counselling, and in a timely manner, is a significant need in the ALS population given potential access to gene-specific therapies in the presymptomatic stage.
Generalizable gesture recognition using magnetomyography
Authors: Yun Richy , Csaky Richard , Dash Debadatta , Gerrard Isabel , Gonzalez Gabriel , Kittle Evan , Taylor David , Soroushmojdehi Rahil , Labanowski Dominic , Deka Nishita 
Published: October 2024

AbstractThe progression of human-computer interfaces into immersive and touchless realities requires new ways of interacting with machines that are correspondingly intuitive and seamless. Among these are gesture-based systems that use natural hand movements to interact with and control digital devices. Today, these systems are most commonly implemented through the use of cameras or inertial sensors, which have drawbacks in environments that are poorly lit, in conditions where the hands are obscured, or for applications that require fine motor control. More recent studies have advocated for the use of surface electromyography (sEMG) to capture gesture information by sensing electrical activity generated by muscle contraction. While promising demonstrations have been shown, studies have also outlined limitations in sEMG when it comes to generalization across a population, largely due to physiological differences between individuals. Magnetomyography (MMG) is an alternative modality for measuring the same motor signals at the muscle, but is impervious to distortions caused by tissue, hair, and moisture; this indicates potential for lower variability caused by physiological differences and changes in skin conductivity, making MMG a promising generalizable solution for gesture control. To test this theory, we developed wristbands with magnetic sensors and implemented a signal processing pipeline for gesture classification. Using this system, we measured MMG across 30 participants performing a gesture task consisting of nine discrete gestures. We demonstrate average single-participant classification accuracy of 95.4%, rivaling state-of-the-art accuracy with sEMG. In addition, we achieved higher cross-session and cross-participant accuracy compared to sEMG studies. Given that these results were obtained with a non-ideal recording system, we anticipate significantly better results with better sensors. Together, these findings suggest that MMG can provide higher performance for control systems based on gesture recognition by overcoming limitations of existing techniques.
Longitudinal analysis of B- and T-cell responses to SARS-CoV-2 recombinant S-protein vaccine S-268019-b in phase 1/2 priming and booster study
Authors: Fujitani Masaya , Lu Xiuyuan , Shinnakasu Ryo , Inoue Takeshi , Kidani Yujiro , Seki Naomi M. , Ishida Satoru , Mitsuki Shungo , Ishihara Takeshi , Aoki Miwa , Suzuki Akio , Takahashi Koji , Takayama Masahiro , Ota Takeshi , Iwata Satoshi , Shibata Risa Yokokawa , Sonoyama Takuhiro , Ariyasu Mari , Kitano Ayumi , Terooatea Tommy , Villa Jordan Kelly , Yamashita Kazuo , Yamasaki Sho , Kurosaki Tomohiro , Omoto Shinya 
Published: October 2024

SummaryThe durability of vaccine-induced immune memory to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for preventing infection, especially severe disease. This follow-up report from a phase 1/2 study of S-268019-b (a recombinant spike protein vaccine) after homologous booster vaccination confirms its long-term safety, tolerability, and immunogenicity. Booster vaccination with S-268019-b resulted in an enhancement of serum neutralizing antibody (NAb) titers and a broad range of viral neutralization. Single-cell immune profiling revealed persistent and mature antigen-specific memory B cells and T follicular helper cells, with increased B-cell receptor diversity. The expansion of B- and T-cell repertoires and presence of cross-reactive NAbs targeting conserved epitopes within the receptor-binding domain following a booster accounted for the broad-spectrum neutralizing activity. These findings highlight the potential of S-268019-b to provide broad and robust protection against a range of SARS-CoV-2 variants, addressing a critical challenge in the ongoing fight against coronavirus disease 2019 (COVID-19).
Sex differences in the clinical manifestation of autosomal dominant frontotemporal dementia
Authors: Memel Molly , Staffaroni Adam M , Ilan-Gala Ignacio , Castro Jesús Garcia , Kornak John , Tartaglia Carmela M , Saloner Rowan , VandeBunte Anna M , Paolillo Emily W , Cadwallader Claire J , Chen Coty , Gorno-Tempini Maria Luisa , Mandelli Malu , Apostolova Liana , Graff-Radford Neil , Litvan Irene , Bayram Ece , Pressman Peter S , Miyagawa Toji , Mackenzie Ian , Goldman Jill , Darby Richard R. , Appleby Brian S , Petrucelli Len , Gendron Tania , Heuer Hilary W , Forseberg Leah K , Rojas Julio C , Boeve Brad F , Brushaber Nellie , Domoto-Reilly Kimiko , Ghoshal Nupur , Lapid Maria , Pascual Belen , Lee Suzee , Ramos Eliana Marisa , Ramanan Vijay , Rademakers Rosa , Rascovsky Katya , Pantelyat Alex , Masdeu Joseph C , Snyder Allison , Boxer Adam L , Rosen Howard J , Casaletto Kaitlin 
Published: October 2024

AbstractINTRODUCTIONSex differences are apparent in neurodegenerative diseases, but have not been comprehensively characterized in frontotemporal dementia (FTD).METHODSParticipants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to six years. Linear mixed-effects models investigated how sex and disease stage associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL).RESULTSWhile sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that attenuated in symptomatic participants.DISCUSSIONIn genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD-causing mutations.
Top-down feedback matters: Functional impact of brainlike connectivity motifs on audiovisual integration
Authors: Tugsbayar Mashbayar , Li Mingze , Muller Eilif B. , Richards Blake 
Published: October 2024

AbstractArtificial neural networks (ANNs) are an important tool for studying neural computation, but many features of the brain are not captured by standard ANN architectures. One notable missing feature in most ANN models is top-down feedback, i.e. projections from higher-order layers to lower-order layers in the network. Top-down feedback is ubiquitous in the brain, and it has a unique modulatory impact on activity in neocortical pyramidal neurons. However, we still do not understand its computational role. Here we develop a deep neural network model that captures the core functional properties of top-down feedback in the neocortex, allowing us to construct hierarchical recurrent ANN models that more closely reflect the architecture of the brain. We use this to explore the impact of different hierarchical recurrent architectures on an audiovisual integration task. We find that certain hierarchies, namely those that mimic the architecture of the human brain, impart ANN models with a light visual bias similar to that seen in humans. This bias does not impair performance on the audiovisual tasks. The results further suggest that different configurations of top-down feedback make otherwise identically connected models functionally distinct from each other, and from traditional feedforward-only models. Altogether our findings demonstrate that modulatory top-down feedback is a computationally relevant feature of biological brains, and that incorporating it into ANNs affects their behavior and helps to determine the solutions that the network can discover.
A simple action reduces high fat diet intake and obesity in mice
Authors: Barrett M. R. , Pan Y. , Murrell Chantelle , Karolczak Eva O. , Wang Justin , Fang Lisa , Thompson Jeremy M. , Chang Yu-Hsuan , Casey Eric , Czarny J. , So Wang Lok , Reichenbach Alex , Stark Romana , Taghipourbibalan Hamid , Penna Suzanne R. , McCullough Katherine B. , Westbrook Sara , Matikainen-Ankney Bridget , Cazares Victor A , Delevich Kristen , Fobbs Wambura , Maloney Susan , Sutton Hickey Ames , McCutcheon James E. , Andrews Zane , Creed Meaghan C. , Krashes Michael J. , Kravitz Alexxai V. 
Published: October 2024

AbstractDiets that are high in fat cause over-eating and weight gain in multiple species of animals, suggesting that high dietary fat is sufficient to cause obesity. However, high-fat diets are typically provided freely to animals in obesity experiments, so it remains unclear if high-fat diets would still cause obesity if they required more effort to obtain. We hypothesized that unrestricted and easy access is necessary for high-fat diet induced over-eating, and the corollary that requiring mice to perform small amounts of work to obtain high-fat diet would reduce high-fat diet intake and associated weight gain. To test this hypothesis, we developed a novel home-cage based feeding device that either provided high-fat diet freely, or after mice poked their noses into a port one time – a simple action that is easy for them to do. We tested the effect of this intervention for six weeks, with mice receiving all daily calories from high-fat diet, modifying only how they accessed it. Requiring mice to nose-poke to access high-fat diet reduced intake and nearly completely prevented the development of obesity. In follow up experiments, we observed a similar phenomenon in mice responding for low-fat grain-based pellets that do not induce obesity, suggesting a general mechanism whereby animals engage with and consume more food when it is freely available vs. when it requires a simple action to obtain. We conclude that unrestricted access to food promotes overeating, and that a simple action such as a nose-poke can reduce over-eating and weight gain in mice. This may have implications for why over-eating and obesity are common in modern food environments, which are often characterized by easy access to low-cost unhealthy foods.
Tunable ligand discrimination via kinetic sorting
Authors: Dixit Purushottam , Goetz Andrew , Madsen Ralitsa 
Published: October 2024

AbstractKinetic proofreadingis a class of non-equilibrium mechanisms that allow biochemical sensing networks to discriminate between cognate and non-cognate ligands. Proofreading is typically invoked in the context of error correction and therefore is often inflexible in its discrimination in favor of the cognate ligand. This discrimination is achieved when a multi-step and energy consuming reaction pathway is irreversibly restarted with a rate proportional to the thermodynamic stability of the ligand-bound complex. Here, we present a novel non-equilibrium and tunablekinetic sortingmechanism that allows signaling networks to modulate ligand discrimination in direction as well as in magnitude. In our model, the ‘restart cycle’ associated with traditional proofreading is coupled with a topologically distinct and ligand-identity independent cycle, e.g., through receptor degradation or activity-induced desensitization. The signaling network cankinetically sortthe non-equilibrium flux of receptors bound to one of the ligands towards degradation/desensitization and the other through the restart cycle. This preferential diversion of the non-equilibrium flux allows the network to switch its ligand discrimination by altering biochemical processes that are not specific to the identity of the bound ligand, thereby allowing cells to respond to ligands in a context-specific manner. Our model recapitulates several observations related to paradoxical ligand discrimination by the Epidermal Growth Factor pathway. Given the ubiquity of receptor degradation, activity-induced desensitization, and other similar cycles in cellular signaling networks, tunable ligand discrimination usingkinetic sortingis likely to be broadly applicable.
Efficacy of photodynamic therapy using 5-aminolevulinic acid-induced photosensitization is enhanced in pancreatic cancer cells with acquired drug resistance
Authors: Liu Yiran , Mensah Sally Kyei , Farias Sergio , Khan Shakir , Hasan Tayyaba , Celli Jonathan P. 
Published: October 2024

ABSTRACTThe use of 5-aminolevulinic acid (ALA) as a precursor for protoporphyrin IX (PpIX) is an established photosensitization strategy for photodynamic therapy (PDT) and fluorescence guided surgery. Ongoing studies are focused on identifying approaches to enhance PpIX accumulation as well as to identify tumor sub-types associated with high PpIX accumulation. In this study, we investigated PpIX accumulation and PDT treatment response with respect to nodule size in 3D cultures of pancreatic cancer cells (Panc1) and a derivative subline (Panc1OR), which has acquired drug resistance and exhibits increased epithelial mesenchymal transition. In monolayer and 3D culture dose response studies the Panc1OR cells exhibit significantly higher cell killing at lower light doses than the drug naïve cells. Panc1OR also exhibits increased PpIX accumulation. Further analysis of cell killing efficiency per molecule of intracellular PpIX indicates that the drug resistant cells are intrinsically more responsive to PDT. Additional investigation using exogenous delivery of PpIX also shows higher cell killing in drug resistant cells, under conditions which achieve approximately the same intracellular PpIX. Overall these results are significant as they demonstrate that this example of drug-resistant cells associated with aggressive disease progression and poor clinical outcomes, show increased sensitivity to ALA-PDT.
mRNA expression is co-regulated by non-nucleolar RNA polymerase I
Authors: Carter Lucas M , Gong Ruyi , Acosta Nicolas , Li Wing Shun , Pujadas Liwag Emily , Kuo Tiffany , Minh Uyen Phan Lam , MacQuarrie Kyle , Huang Sui , Kanemaki Masato T. , Almassalha Luay , Backman Vadim 
Published: October 2024

AbstractThe relationship between gene transcription and chromatin organization is an area of active study. Due to its role in mRNA synthesis, many studies have focused on the regulaton of RNA polymerase II (Pol-II) function by supranucleosomal structure and vice-versa. In contrast, there is little work on the function of RNA polymerase I (Pol-I) in non-nucleolar chromatin. Prior work has shown that Pol-I engages with components of Pol-II on rDNA, but it’s role in global transcription and chromatin structure beyond the nucleolus has largely been ignored. By pairing auxin-inducible degron technology with nanoscopic imaging, RNA-Seq, and Hi-C, we found that Pol-I and Pol-II co-regulate conformationally defined chromatin domains and mRNA synthesis. Mechanistically, Pol-I maintains the positioning of intronic and intergenic chromatin within domains for the proper expression of exon elements. Consequently, Pol-I loss disrupts genome connectivity,in situchromatin domains, and the expression of mRNA, genome-wide.
A stableNetrin-1fluorescent reporter chicken reveals cell-specific molecular signatures during optic fissure closure
Authors: Chan Brian Ho Ching , Hardy Holly , Requena Teresa , Findlay Amy , Ioannidis Jason , Meunier Dominique , Toms Maria , Moosajee Mariya , Raper Anna , McGrew Mike , Rainger Joe 
Published: October 2024

ABSTRACTNTN1is expressed in a wide range of developmental tissues and is essential for normal development. Here we describe the generation of a Netrin-1 reporter chicken line (NTN1-T2A-eGFP) by targeting green fluorescent protein into theNTN1locus using CRISPR/Cas9 methodology. Our strategy gave 100% transmission of heterozygous (NTN1T2A-eGFP/+) embryos in which GFP localisation faithfully replicated endogenousNTN1expression in the optic fissure and neural tube floorplate. Furthermore, allNTN1T2A-eGFP/+embryos and hatched birds appeared phenotypically normal. We applied this resource to a pertinent developmental context - coloboma is a structural eye malformation characterised by failure of epithelial fusion during optic fissure closure (OFC) andNTN1is specifically expressed in fusion pioneer cells at the edges of the optic fissure. We therefore optimised the isolation of GFP expressing cells from embryonicNTN1T2A-eGFP/+eyes using spectral fluorescence cell-sorting and applied transcriptomic profiling of pioneer cells, which revealed multiple new OFC markers and novel pathways for developmental tissue fusion and coloboma. This work provides a novel fluorescentNTN1chicken reporter line with broad experimental utility and is the first to directly molecularly characterise pioneer cells during OFC.
Robust Bayesian analysis of animal networks subject to biases in sampling intensity and censoring
Authors: Sosa Sebastian , Brooke McElreath Mary , Redhead Daniel , Ross Cody T. 
Published: October 2024

AbstractData collection biases are a persistent issue for studies of social networks. This issue has been particularly important in Animal Social Network Analysis (ASNA), where data are unevenly sampled and such biases may potentially lead to incorrect inferences about animal social behavior. Here, we address the issue by developing a Bayesian generative model, which not only estimates network structure, but also explicitly accounts for sampling and censoring biases. Using a set of simulation experiments designed to reflect various sampling and observational biases encountered in real-world scenarios, we systematically validate our model and evaluate it’s performance relative to other common ASNA methodologies. By accounting for differences in node-level censoring (i.e., the probability of missing an individual interaction.), our model permits the recovery of true latent social connections, even under a wide range of conditions where some key individuals are intermittently unobserved. Our model outperformed all other existing approaches and accurately captured network structure, as well as individual-level and dyad-level effects. Antithetically, permutation-based and simple linear regression aprroaches performed the worst across many conditions. These results highlight the advantages of generative network models for ASNA, as they offer greater flexibility, robustness, and adaptability to real-world data complexities. Our findings underscore the importance of generative models that jointly estimate network structure and adjust for measurement biases typical in empirical studies of animal social behaviour.
Detecting the body’s reproductive hormonal brake against tissue overgrowth: micrin/SgII-70
Authors: Hart John E , Davies Keith G , Mundy Christopher R , Hart Aurelia C , Howlett David R , Newton Russell P 
Published: October 2024

AbstractA new humoral factor has been detected, within a project aiming to disclose the body’s reproductive hormonal brake against tissue overgrowth, micrin (‘my-crin’). It is hypothesized that micrin braking, gonadal and hypothalamic, is lifted at puberty and wanes with age, bringing on prostatic enlargement and cancers. Factor purification has involved fractionation of ovine and bovine ovarian follicular fluid and blood plasma and serum, with evaluation via rat bioassays in vivo and in vitro. Analysis averse, the molecular effector provided a chemical conundrum. Evidence from mass spectrometry (MS) has been problematic, with spectra from MALDI-TOF, the only productive MS modality, confused by a target polypeptide exhibiting artefacts during processing, storage and MALDI set-up in terms of C-terminal truncation and water losses, together with N-terminal grand fragmentations and dimerizations (factor fragments doubled up). Evidence from chemical sequencing of amino acid (aa) residues was likewise baffling, but consistent with a spiralised depolymerisation within the Edman reaction chamber of a unitary polypeptide. Data decryption has overcome molecular intractability, supported by the results of tryptic digestion and epitope mapping using immunohistochemistry (IHC). The detected inhibitory factor is sleuthed to relate to secretogranin II (SgII), the neurosecretory prohormone, in the form of a secreted acidic 70-aa polypeptide derivative called here SgII-70 (‘sig two seventy’). The product of peptide splicing, micrin/SgII-70 is potentially an amphipathic molecular ampersand (&), with ends entwined (via salt bridging), the knotty totality compromising Edman and MALDI analyses and molecular modelling whilst conferring protease and heat resistance. The two ends of the factor are conceptualised as binding at the same time to a dimeric cellular receptor, to stoichiometric effect, providing fewer smaller cells within a counting mechanism of tissue-mass regulation. Hexapeptide mimetics simulating both ends of the hormone together have been demonstrated in different species and settings, in the cause of antiorganotrophism (tissue reduction) and reproductive modulation. Therapeutic exploitation beckons for mimetics of the body’s hormonal brake, micrin/SgII-70, in tissue overgrowth conditions such as endometriosis, PCOS, BPH and cancer, and in infertility.