bluuebunny/crossref_metadata_2025_split huggingface dataset:
Internet-connected cortical organoids for project-based stem cell and neuroscience education
Authors: Elliott Matthew A.T. , Schweiger Hunter E. , Robbins Ash , Vera-Choqqueccota Samira , Ehrlich Drew , Hernandez Sebastian , Voitiuk Kateryna , Geng Jinghui , Sevetson Jess L. , Rosen Yohei M. , Teodorescu Mircea , Wagner Nico O. , Haussler David , Mostajo-Radji Mohammed A. 
Published: July 2023

SUMMARYThe introduction of internet-connected technologies to the classroom has the potential to revolutionize STEM education by allowing students to perform experiments in complex models that are unattainable in traditional teaching laboratories. By connecting laboratory equipment to the cloud, we introduce students to experimentation in pluripotent stem cell-derived cortical organoids in two different settings: Using microscopy to monitor organoid growth in an introductory tissue culture course, and using high density multielectrode arrays to perform neuronal stimulation and recording in an advanced neuroscience mathematics course. We demonstrate that this approach develops interest in stem cell and neuroscience in the students of both courses. All together, we propose cloud technologies as an effective and scalable approach for complex project-based university training.HIGHLIGHTS- Development of cortical organoids as pedagogical tools for undergraduate education.- Organoids implemented in a tissue culture course through cloud-enabled microscopy.- Multielectrode arrays allow for live organoid manipulation in a mathematics course.- Students self-report increased interest in neuroscience and stem cells topics.
Information-theory analysis of mouse string-pulling agrees with Fitts’s Law: Increasing task difficulty engages multiple sensorimotor modalities in a dual oscillator behavior
Authors: Sandhu Pardeepak S. , Agha Behroo Mirza , Inayat Samsoon , Singh Surjeet , Ryait Hardeep S. , Mohajerani Majid H. , Whishaw Ian Q. 
Published: July 2023

AbstractMouse string pulling, in which a mouse reels in a string with hand-over-hand movements, can provide insights into skilled motor behavior, neurological status, and cognitive function. The task involves two oscillatory movements connected by the string. The snout tracks the pendulum movement of the string produced by hand-over-hand pulls and so guides the hands to grasp the string. The present study examines the allocation of time required to pull strings of varying diameter. Movement is also described with end-point measures, string-pulling topography with 2D markerless pose estimates based on transfer learning with deep neural networks, and Mat-lab image-segmentation and heuristic algorithms for object tracking. With reduced string diameter, mice took longer to pull 60cm long strings. They also made more pulling cycles, misses, and mouth engagements, and displayed changes in the amplitude and frequency of pull cycles. The time measures agree with Fitts’s law in showing that increased task difficulty slows behavior and engages multiple compensatory sensorimotor modalities. The analysis reveals that time is a valuable resource in skilled motor behavior and information-theory can serve as a measure of its effective use.
Arsenophonussymbiosis with louse flies: multiple origins, coevolutionary dynamics, and metabolic significance
Authors: Říhová Jana , Gupta Shruti , Darby Alistair C , Nováková Eva , Hypša Václav 
Published: July 2023

AbstractArsenophonusis a widespread insect symbiont with life strategies that vary from parasitism to obligate mutualism. In insects living exclusively on vertebrate blood, mutualisticArsenophonusstrains are presumed to provide B vitamins missing in the insect host diet. Hippoboscidae, obligate blood-feeders related to tsetse flies, were previously suggested to have acquiredArsenophonussymbionts in several independent events. Based on comparative genomic analyzes of eleven Hippoboscidae-associated strains, nine of them newly assembled, we reveal a wide range of their genomic characteristics and phylogenetic affiliations. Phylogenetic patterns and genomic traits split the strains into two different types. Seven strains display characteristics of obligate mutualists with significantly reduced genomes and long phylogenetic branches. The remaining four genomes cluster on short branches, and their genomes resemble those of free-living bacteria or facultative symbionts. Both phylogenetic positions and genomic traits indicate that evolutionary history of the Hippoboscidae-Arsenophonusassociations is a mixture of short-term coevolutions with at least four independent origins. The comparative approach to a reconstruction of B vitamin pathways across the availableArsenophonusgenomes produced two kinds of patterns. On one hand, it indicated the different importance of individual B vitamins in the host-symbiont interaction. While some (riboflavin, pantothenate, folate) seem to be synthesized by all Hippoboscidae-associated obligate symbionts, pathways for others (thiamine, nicotinamide, cobalamin) are mostly missing. On the other hand, the broad comparison produced patterns which can serve as bases for further assessments of the pathways’ completeness and functionality.ImportanceInsects that live exclusively on vertebrate blood utilize symbiotic bacteria as a source of essential compounds, e.g. B vitamins. In louse flies, the most frequent symbiont originated in genusArsenophonus, known from a wide range of insects. Here, we analyze genomic traits, phylogenetic origins, and metabolic capacities of elevenArsenophonusstrains associated with louse flies. We show that in louse fliesArsenophonusestablished symbiosis in at least four independent events, reaching different stages of symbiogenesis. This allowed for comparative genomic analysis, including convergence of metabolic capacities. The significance of the results is two-fold. First, based on a comparison of independently originatedArsenophonussymbioses, it determines the importance of individual B vitamins for the insect host. This expands our theoretical insight into insect-bacteria symbiosis. The second outcome is of methodological significance. We show that the comparative approach reveals artifacts that would be difficult to identify based on a single-genome analysis.
An expression-directed linear mixed model (edLMM) discovering low-effect genetic variants
Authors: Li Qing , Bian Jiayi , Qian Yanzhao , Kossinna Pathum , Gordon Paul MK , Zhou Xiang , Guo Xingyi , Yan Jun , Wu Jingjing , Long Quan 
Published: July 2023

AbstractDetecting genetic variants with low effect sizes using a moderate sample size is difficult, hindering downstream efforts to learn pathology and estimating heritability. In this work, by utilizing informative weights learned from training genetically predicted gene expression models, we formed an alternative approach to estimate the polygenic term in a linear mixed model (LMM). Our LMM estimates the genetic background by incorporating their relevance to gene expression. Our protocol, expression-directed linear mixed model (edLMM), enables the discovery of subtle signals of low-effect variants using moderate sample size. By applying edLMM to cohorts of around 5,000 individuals with either binary (WTCCC) or quantitative (NFBC1966) traits, we demonstrated its power gain at the low-effect end of the genetic etiology spectrum. In aggregate, the additional low-effect variants detected by edLMM substantially improved estimation of missing heritability. edLMM moves precision medicine forward by accurately detecting the contribution of low-effect genetic variants to human diseases.
A Recurrent Neural Circuit Mechanism of Temporal-scaling Equivariant Representation
Authors: Zuo Junfeng , Liu Xiao , Wu Ying Nian , Wu Si , Zhang Wen-Hao 
Published: July 2023

AbstractTime perception is fundamental in our daily life. An important feature of time perception is temporal scaling (TS): the ability to generate temporal sequences (e.g., movements) with different speeds. However, it is largely unknown about the mathematical principle underlying TS in the brain. The present theoretical study investigates temporal scaling from the Lie group point of view. We propose a canonical nonlinear recurrent circuit dynamics, modeled as a continuous attractor network, whose neuronal population responses embed a temporal sequence that is TS equivariant. We find the TS group operators can be explicitly represented by a time-invariant control input to the network, whereby the input gain determines the TS factor (group parameter), and the spatial offset between the control input and the network state on the continuous attractor manifold gives rise to the generator of the Lie group. The recurrent circuit’s neuronal responses are consistent with experimental data. The recurrent circuit can drive a feedforward circuit to generate complex sequences with different temporal scales, even in the case of negative temporal scaling (“time reversal”). Our work for the first time analytically links the abstract temporal scaling group and concrete neural circuit dynamics.
Beta-blocker exposure is associated with nonunion in a geriatric cohort of 253,266 extremity fractures
Authors: Steffenson Lillia , Martin Brook , Kantor Adam , O’Neill Dillon , Myhre Luke , Thorne Tyler , Rothberg David , Higgins Thomas , Haller Justin , Marchand Lucas 
Published: July 2023

ABSTRACTPreviously published animal studies have shown positive skeletal effects with local or systemic administration of beta blockers (BBs). However, population studies have shown mixed effects on bone mineral density (BMD) and fracture risk with BB use. The goal of this study was to evaluate whether exposure to BB is associated with fracture nonunion. Fee-for-service Medicare beneficiaries with an extremity fracture were identified by International Classification of Diseases (ICD)-10 and current procedural terminology (CPT) codes from 2016-2019. Charlson Comorbidity Index (CCI) was assigned using diagnoses prior to index fracture and nonunion identified by ICD-10 or CPT codes within one year from index fracture diagnosis. Patients were classified by BB exposure based on Part D (Pharmacy) claims between 90 days prior to and one year following index fracture. Chi square and Student’s T-tests were performed on categorical and continuous variables, respectively. Logistic regression was performed to evaluate the association between BB use and nonunion, controlling for age, sex, race, and comorbidity. Total number of fractures meeting inclusion criteria was 253,266 with 45% of patients having used a BB during the study period. The incidence of nonunion was 3.9% overall. BBs were associated with a 13% increase in non-union for all fracture types, after controlling for age, sex, fracture location, and CCI (OR 1.13 [CI 1.06-1.20], p<.001). Results of this study suggest a negative influence of BB on bone healing, contrary to results of previously published animal models and epidemiologic observations, and demonstrate that BB use during fracture care is associated with significant increase in incidence of nonunion.
Dynamics of T-cell responses following COVID-19 mRNA vaccination and breakthrough infection in older adults
Authors: Datwani Sneha , Kalikawe Rebecca , Mwimanzi Francis , Speckmaier Sarah , Liang Richard , Sang Yurou , Waterworth Rachel , Yaseen Fatima , Lapointe Hope R. , Barad Evan , DeMarco Mari L. , Holmes Daniel T. , Simons Janet , Montaner Julio S.G. , Romney Marc G. , Brumme Zabrina L. , Brockman Mark A. 
Published: July 2023

ABSTRACTIntroductionWhile older adults generally mount weaker antibody responses to a primary COVID-19 vaccine series, T-cell responses remain less well characterized in this population. We compared SARS-CoV-2 spike-specific T-cell responses after two- and three-dose COVID-19 mRNA vaccination and subsequent breakthrough infection in older and younger adults.MethodsWe quantified CD4+ and CD8+ T-cells reactive to overlapping peptides spanning the ancestral SARS-CoV-2 spike protein in 40 older adults (median age 79) and 50 younger health care workers (median age 39), all COVID-19 naive, using an activation induced marker assay. T-cell responses were further assessed in 24 participants, including 8 older adults, who subsequently experienced their first SARS-CoV-2 breakthrough infection.ResultsA third COVID-19 mRNA vaccine dose significantly boosted spike-specific CD4+ and CD8+ T-cell frequencies to above two-dose levels in older and younger adults. T-cell frequencies did not significantly differ between older and younger adults after either dose. Multivariable analyses adjusting for sociodemographic, health and vaccine-related variables confirmed that older age was not associated with impaired cellular responses. Instead, the strongest predictors of CD4+ and CD8+ T-cell frequencies post-third-dose were their corresponding post-second-dose frequencies. Breakthrough infection significantly increased both CD4+ and CD8+ T cell frequencies, to comparable levels in older and younger adults. Exploratory analyses revealed an association between HLA-A*02:03 and higher post-vaccination CD8+ T-cell frequencies, which may be attributable to numerous strong-binding HLA-A*02:03-specific CD8+ T-cell epitopes in spike.ConclusionOlder adults mount robust T-cell responses to two- and three-dose COVID-19 mRNA vaccination, which are further boosted following breakthrough infection.
Are medical students aware of SUDEP? A survey in Turkey
Authors: Aslan Feyza Sule , Ismayilova Aylin , Hasanli Shams , Angelopoulou Efthalia , Baydili Kursad Nuri , Akyuz Enes 
Published: July 2023

ABSTRACTObjectiveSudden unexpected death in epilepsy (SUDEP) has been recognized as an important cause of death in patients with epilepsy. In order to inform patients with epilepsy and their relatives correctly, it is necessary to increase the awareness of students about SUDEP from the early stages of medical education. The aim of this study was to identify the level of knowledge and awareness of medical students in Turkey about SUDEP.MethodsMedical students (23±7 years old; n=793) in Turkey participated in the online SUDEP awareness survey. The survey included demographic evidence, followed by questions about their awareness of epilepsy, seizure knowledge and about the definition, awareness of SUDEP.ResultsThe majority of medical students (95%) claimed that they had heard about epileptic seizures. Half of the participants (49.9%) mentioned that they had heard about tonic-clonic seizures. However, two-thirds of the students (67%) have never heard about SUDEP, while 85% of the students stated that they did not have sufficient knowledge about SUDEP. Concerning the potential prevention of SUDEP, 80.8% of the students did not know about this topic. Furthermore, most participants (82%) expressed their interest and willingness to learn about SUDEP.ConclusionKnowledge about SUDEP plays a key role in identifying patients at risk and informing patients and their relatives. The limited awareness of SUDEP in medical education may pose risks for patients diagnosed with epilepsy and their relatives, and the effective incorporation of lectures and training in SUDEP into the curriculum of medical school is of paramount importance.
Incorporating Social Determinants of Health in the Prediction of Chronic Kidney Disease Progression in a National Cohort of US Veterans
Authors: Singh Karandeep , Bragg-Gresham Jennifer , Han Yun , Gillespie Brenda , Weitzel William , Crowley Susan , Saran Rajiv 
Published: July 2023

ABSTRACTBackgroundAs new therapies such as Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors become available that may be effective earlier in the course of chronic kidney disease (CKD), newer risk prediction tools are required earlier in the course of CKD, and also to evaluate whether social determinants of health play a role in addition to individual-level risk factors.MethodsWe examined CKD progression among US Veterans who had known CKD in the VA health system using data from 2006-2016. CKD progression was defined based on two separate outcomes: 1) rapid CKD progression based on the eGFR slope < −3.7 mL/min/1.73m2as a binary outcome, and 2) time-to-end stage kidney disease (ESKD) as a survival outcome. Veterans whose eGFR values were declining more steeply than −3.7 per year were considered “fast progressors,” representing 9.8% of the overall cohort. ESKD was identified by linking the VA data with US Renal Data System (USRDS) data, a national ESKD registry. After randomly dividing the dataset into a training, tuning, and testing set, tree ensemble models were trained and evaluated.ResultsWe identified 1,550,526 patients meeting inclusion criteria, of which 930,615 patients were assigned to a training cohort, 309,831 to a tuning cohort, and 310,044 to a testing cohort. Tree ensemble models predicted fast progression with a C-statistic of 0.79 and time to ESKD with a C-statistic of 0.90. Baseline eGFR was the most important variable in predicting both outcomes, though social determinants constituted more of the important variables in rapid progressionConclusionsCKD progression can be accurately predicted, though the predictors differ for fast progression and ESKD onset.
RNase T2-involved selective autophagy of ribosomes induced by starvation in yeast
Authors: Minami Atsushi , Nishi Kohei , Yamada Rikusui , Jinnai Gai , Shima Hikari , Oishi Sakiko , Akagawa Hirofumi , Aono Toshihiro , Hidaka Makoto , Masaki Haruhiko , Kuzuyama Tomohisa , Noda Yoichi , Ogawa Tetsuhiro 
Published: July 2023

ABSTRACTRNase T2 is ubiquitous across diverse organisms, playing essential roles despite its simple enzymatic activity. InSaccharomyces cerevisiae, RNase T2, known as Rny1p, localizes in vacuoles and mediates rRNA degradation during autophagy of ribosomes. In this study, we elucidated novel aspects of ribosome degradation mechanisms and the function of Rny1p. First, we discovered that most ribosomes are degraded by selective autophagy, where Rsa1p is the specific receptor of ribosomes to be degraded. Complex structure prediction suggested that Rsa1p also interacts with Atg8p. Furthermore, we observed that the accumulation of rRNA in vacuoles, due to the lack of Rny1p, leads to a decrease in bulk autophagic activity. This decrease in autophagic activity may explain the inability of Rny1p-deficient strains to adapt to starvation conditions. Second, our structural prediction and biochemical analyses indicate that a C-terminal extension, characteristic in fungal RNase T2 including Rny1p, is not necessary for rRNA degradation but for anchoring to the cell wall. Together with molecular phylogenetic analysis, a species-specific role of RNase T2 conferred by the C-terminal extension is suggested.
NGFR regulates germinal center B-cell activation and negative selection
Authors: Hernández-Barranco Alberto , Mazariegos Marina S. , Santos Vanesa , Caleiras Eduardo , Nogués Laura , Mourcin Frédéric , Léonard Simon , Oblet Christelle , Genebrier Steve , Rossille Delphine , Benguría Alberto , Vazquez Enrique , Dopazo Ana , Efeyan Alejo , Ortega-Molina Ana , Cogne Michel , Tarte Karin , Peinado Héctor 
Published: July 2023

AbstractThe expression of the Nerve growth factor receptor (NGFR) has been described in follicular dendritic cells (FDCs), the major lymphoid stromal cell (LSC) compartment regulating B-cell activation within germinal centers (GCs). However, the role of NGFR in humoral response is not well defined. In this work, we have studied the effect ofNgfrKO in LNs organization and function.NgfrKO led to spontaneous GC formation and expansion of GC B-cell compartment which were related toNgfrdepletion in non-hematopoietic radioresistant compartment. In agreement,NgfrKO mice showed alterations in LSC with an increased frequency of FDCs harboring an activated phenotype characterized by the overexpression of CD21/35, MAdCAM-1, and VCAM-1. Moreover,NgfrKO mice showed GC ectopic location, loss of polarization, impaired high-affinity antibody production, and increased circulating autoantibodies. In addition,NgfrKO/Bcl2Tg mice displayed increased levels of autoantibodies, higher incidence of autoimmunity, and decreased overall survival. Our work shows that NGFR maintains GC structure and functionality, being involved in the regulation of antibody production and immune tolerance.
Neural stimulation hardware for the selective intrafascicular modulation of the vagus nerve
Authors: Strauss I. , Agnesi F. , Zinno C. , Giannotti A. , Dushpanova A. , Casieri V. , Terlizzi D. , Bernini F. , Gabisonia K. , Wu Y. , Jiang D. , Paggi V. , Lacour S. , Recchia F. , Demosthenous A. , Lionetti V. , Micera S. 
Published: July 2023

AbstractThe neural stimulation of the vagus nerve is able to modulate various functions of the parasympathetic response in different organs. The stimulation of the vagus nerve is a promising approach to treating inflammatory diseases, obesity, diabetes, heart failure, and hypertension. The complexity of the vagus nerve requires highly selective stimulation, allowing the modulation of target-specific organs without side effects. Here, we address this issue by adapting a neural stimulator and developing an intraneural electrode for the particular modulation of the vagus nerve. The neurostimulator parameters such as amplitude, pulse width, and pulse shape were modulated. Single-, and multi-channel stimulation was performed at different amplitudes. For the first time, I polyimide thin-film neural electrode was designed for the specific stimulation of the vagus nerve. In vivo experiments were performed in the adult minipig to validate to elicit electrically evoked action potentials and to modulate physiological functions selectively, validating the selectivity of intraneural stimulation. Electrochemical tests of the electrode and the neurostimulator showed that the stimulation hardware was working correctly. Stimulating the porcine vagus nerve resulted in selective modulation of the vagus nerve. Alpha, beta, and theta waves could be distinguished during single- and multi-channel stimulation. We have shown that the here presented system is able to activate the vagus nerve selectively and can therefore modulate the heart rate, diastolic pressure, and systolic pressure. The here presented system may be used to restore the cardiac loop after denervation by implementing biomimetic stimulation patterns. Presented methods may be used to develop intraneural electrodes adapted for various applications.