bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing drug safety by identifying the axis of arrhythmia in cardiomyocyte electrophysiology
Authors: Heitmann Stewart , Vandenberg Jamie I , Hill Adam P
Published: December 2023

Many classes of drugs can induce fatal cardiac arrhythmias by disrupting the electrophysiology of cardiomyocytes. Safety guidelines thus require all new drugs to be assessed for pro-arrhythmic risk prior to conducting human trials. The standard safety protocols primarily focus on drug blockade of the delayed-rectifier potassium current (IKr). Yet the risk is better assessed using four key ion currents (IKr, ICaL, INaL, IKs). We simulated 100,000 phenotypically diverse cardiomyocytes to identify the underlying relationship between the blockade of those currents and the emergence of ectopic beats in the action potential. We call that relationship the axis of arrhythmia. It serves as a yardstick for quantifying the arrhythmogenic risk of any drug from its profile of multi-channel block alone. We tested it on 109 drugs and found that it predicted the clinical risk labels with an accuracy of 88.1–90.8%. Pharmacologists can use our method to assess the safety of novel drugs without resorting to animal testing or unwieldy computer simulations.
Shh from mossy cells contributes to preventing NSC pool depletion after seizure-induced neurogenesis and in aging
Authors: Noguchi Hirofumi , Arela Jessica Chelsea , Ngo Thomas , Cocas Laura , Pleasure Samuel
Published: December 2023

Epileptic seizures induce aberrant neurogenesis from resident neural stem cells (NSCs) in the dentate gyrus of the adult mouse hippocampus, which has been implicated in depletion of the NSC pool and impairment of hippocampal function. However, the mechanisms regulating neurogenesis after seizures remain unknown. Here, we demonstrate that Sonic hedgehog (Shh) from mossy cells is a major source of Shh signaling activity after seizures, by which mossy cells contribute to seizure-induced neurogenesis and maintenance of the NSC pool. Deletion of Shh from mossy cells attenuates seizure-induced neurogenesis. Moreover, in the absence of Shh from mossy cells, NSCs pool are prematurely depleted after seizure-induced proliferation, and NSCs have impaired self-renewal. Likewise, lack of Shh from mossy cells accelerates age-related decline of the NSC pool with accompanying reduction of self-renewal of NSCs outside the context of pathology such as seizures. Together, our findings indicate that Shh from mossy cells is critical to maintain NSCs and to prevent exhaustion from excessive consumption in aging and after seizures.
Optimal transport for automatic alignment of untargeted metabolomic data
Authors: Breeur Marie , Stepaniants George , Keski-Rahkonen Pekka , Rigollet Philippe , Viallon Vivian
Published: December 2023

Untargeted metabolomic profiling through liquid chromatography-mass spectrometry (LC-MS) measures a vast array of metabolites within biospecimens, advancing drug development, disease diagnosis, and risk prediction. However, the low throughput of LC-MS poses a major challenge for biomarker discovery, annotation, and experimental comparison, necessitating the merging of multiple datasets. Current data pooling methods encounter practical limitations due to their vulnerability to data variations and hyperparameter dependence. Here we introduce GromovMatcher, a flexible and user-friendly algorithm that automatically combines LC-MS datasets using optimal transport. By capitalizing on feature intensity correlation structures, GromovMatcher delivers superior alignment accuracy and robustness compared to existing approaches. This algorithm scales to thousands of features requiring minimal hyperparameter tuning. Applying our method to experimental patient studies of liver and pancreatic cancer, we discover shared metabolic features related to patient alcohol intake, demonstrating how GromovMatcher facilitates the search for biomarkers associated with lifestyle risk factors linked to several cancer types.
Working with my brain and not against it
Authors: Tamir Tigist
Published: December 2023

When attempts to capitalize on her undiagnosed ADHD traits led to repeated cycles of overwork and burnout, a postdoc re-evaluated how she faces the daily challenges of being a neurodivergent scientist.
How to Participate in Participatory Music Making at a Contemporary Folk Music Festival: Runosong Nests at the Viljandi Folk Music Festival and Pelimanni Evenings at the Kaustinen Folk Music Festival
Authors:   Estonian Folklore Archives, Estonian Literary Museum, Tartu, Estonia, Kõmmus Helen
Published: December 2023

The article studies, compares and analyses participatory music making at Estonian and Finnish folk music festivals. By comparing the empirical research materials collected during comprehensive fieldwork in 2004–2019 from the regilaulupesa (Eng. runosong nest) of the Viljandi Folk Music Festival (Est. Viljandi pärimusmuusika festival) in Estonia and from the pelimanni (Eng. folk musician, fiddler) evenings of the Kaustinen Folk Music Festival (Fin. Kaustisen kansanmusiikkijuhlat) in Finland, answers were sought to the following questions: What kind of participatory music making takes place at these folk music festivals? What are the social dynamics between and within the groups and individuals in participatory music making situations? How are the primary and secondary functions of music making formed? As a result of the qualitative comparative phenomenological research, it was found that although in participatory music situations at Estonian and Finnish folk music festivals the musical behaviour of participants and the social dynamics of groups could differ radically, they still strive for direct musical experience at a community and personal level and bring the older musical tradition closer to the contemporary people. During participatory music making the secondary function, that is, musical behaviour directed outside the group, could turn naturally into a primary function – musical activity that unites the community and fulfils its internal needs. Situations of participatory music making at Estonian and Finnish contemporary music festivals revealed the common music making as a cultural, social, creative, and emotional phenomenon which has symbolic and direct connections with traditional Finnic folk music culture.
Combining Archival and Academic Research in Dissident Manuscripts: The Ostrobothnian Mystics Project (Finland)
Authors: Mehtonen Päivi , Soiniola Tarja ,   Finnish Literature Society, Finland
Published: December 2023

This article describes an interdisciplinary project set up for the collection of manuscripts produced during the period of ca. 1780–1830 by craftsmen and peasants along the coast of the Gulf of Bothnia in Finland (Ostrobothnian Mystics, literature and cultural history collection, the Finnish Literature Society). We briefly describe the nature of the material, discuss the specific aspects of the manuscript project which connected two fields of expertise – that of an archive researcher and a user of the particular collection – and conclude by arguing for the urgency of finding new ways and resources to preserve fragile items – both texts and material artefacts – in a specific field.
Predicting the final grade using a machine learning regression model: insights from fifty percent of total course grades in CS1 courses
Authors: Hidalgo Suarez Carlos Giovanny , Llanos Jose , Bucheli Víctor A.
Published: December 2023

This article introduces a model for accurately predicting students’ final grades in the CS1 course by utilizing their grades from the first half of the course. The methodology includes three phases: training, testing, and validation, employing four regression algorithms: AdaBoost, Random Forest, Support Vector Regression (SVR), and XGBoost. Notably, the SVR algorithm outperformed the others, achieving an impressive R-squared (R2) value ranging from 72% to 91%. The discussion section focuses on four crucial aspects: the selection of data features and the percentage of course grades used for training, the comparison between predicted and actual values to demonstrate reliability, and the model’s performance compared to existing literature models, highlighting its effectiveness.
Trainee psychotherapists’ emotion recognition accuracy during 1.5 years of psychotherapy education compared to a control group: no improvement after psychotherapy training
Authors: Döllinger Lillian , Letellier Isabelle , Högman Lennart , Laukka Petri , Fischer Håkan , Hau Stephan
Published: December 2023

The ability to recognize and work with patients’ emotions is considered an important part of most psychotherapy approaches. Surprisingly, there is little systematic research on psychotherapists’ ability to recognize other people’s emotional expressions. In this study, we compared trainee psychotherapists’ nonverbal emotion recognition accuracy to a control group of undergraduate students at two time points: at the beginning and at the end of one and a half years of theoretical and practical psychotherapy training. Emotion recognition accuracy (ERA) was assessed using two standardized computer tasks, one for recognition of dynamic multimodal (facial, bodily, vocal) expressions and one for recognition of facial micro expressions. Initially, 154 participants enrolled in the study, 72 also took part in the follow-up. The trainee psychotherapists were moderately better at recognizing multimodal expressions, and slightly better at recognizing facial micro expressions, than the control group at the first test occasion. However, mixed multilevel modeling indicated that the ERA change trajectories for the two groups differed significantly. While the control group improved in their ability to recognize multimodal emotional expressions from pretest to follow-up, the trainee psychotherapists did not. Both groups improved their micro expression recognition accuracy, but the slope for the control group was significantly steeper than the trainee psychotherapists’. These results suggest that psychotherapy education and clinical training do not always contribute to improved emotion recognition accuracy beyond what could be expected due to time or other factors. Possible reasons for that finding as well as implications for the psychotherapy education are discussed.
Backward Through the Veil: Individual and Group Identity in Dreams from My Father
Authors: Stearns Shep
Published: December 2023

This essay proposes that there is a common identity progression that structures the narratives of many works of Afro-American autobiography and fiction. This progression starts with a hegemonic Black group identitydesigned to contain and constrain a liberated conception of individual identity for the protagonist. After recognizing the falsity of this socially prescribed racist group identity, the protagonist cycles through alternative, ostensibly counter-hegemonic, group identities with the ultimate realization that these too are false and constricting. The affirmation and social recognition of a stable individual identity is seen as impossible in the context of the US racial identification system. Death, exile, or exit from the system in some other form is therefore the common resolution to these narratives. Barak Obama’s autobiography Dreams from My Father is treated as a negative case in this proposed trend. It is argued that Obama’s narrative basically reverses the traditional progression. This is claim is based on the idea that Obama’s work culminates not with his ownaffirmation of self-identity independent of the constraints of the US’s system of racial group identification, but with the affirmation of a self that is determined by Obama’s choice to identify and be identified with AfroAmericans as a group.
Judge, the Idiot, and Cormac McCarhty’s Critique of Violence in Blood Meridian
Authors: Zamorano Muñoz Rodrigo
Published: December 2023

The following paper examines the relation between the couple made up by Judge Holden and the Idiot in Cormac McCarthy’s Blood Meridian; or, The Evening Redness in the West. Set in the U.S.-Mexico borderlands during the mid-nineteenth century, McCarthy’s novel is an exploration of the violence underlying the march of American colonial westward expansion in which Judge Holden is a symbol of the desire to dominate others through the use of violence. As such, Holden is confronted and complemented by the figure of the Idiot. The latter works as a degraded, helpless and even more grotesque version of the Judge, and throughout the novel parallelisms and contrasts are established between the two characters. In many passages one mirrors the other; at other times, both make up a unity that reveals the full extent of Holden’s brutal ideology, with the idiot as its mute critic. Finally, the relations that this paper aims to expose may be read as a commentary on the irrationality of a philosophy that celebrates and legitimizes violence not only as a goal in itself, but also as the only way in which human beings can relate to one another.
Ambiguous Identities: The Subversion of Gender in Angela Carter’s The Passion of New Eve and Cristina Peri Rossi’s La Nave de los Locos
Authors: Ibarra Cordero Andrés
Published: December 2023

This paper discusses issues of gender identity and dystopia in Angela Carter’s The Passion of New Eve and Cristina Peri Rossi’s La Nave de los Locos. It compares both women writer’s concerns in the creation of normative gender identities and how those identities are, at the same time, undermined by subversive characters. Carter and Peri Rossi present a variety of micro-worlds, which correlate with the different positions that women occupy in a variety of discursive orders. It also points to how social technologies, mythical representations and social practices constantly endorse essential representations of femininity and masculinity. As a result this paper argues that these novels, though from different socio-cultural contexts, give evidence of the artificial construction of gender and engage in gender performance and parody to provide a subject position outside the normative binaries of sexual difference, and flirting with androgyny as a possible sexual utopia.
Shaulamhu
Authors: Beavers Danette
Published: December 2023

A breathing word that inhales hope and exhales despair for a girl who cries like the western winds that keen through Sierra Nevada and shrill through cracks in the walls of galash dungal, her house.
Select Poems by Roberto Onell
Authors: Concilio Arielle
Published: December 2023

DANZA Minutos desvestidos, la lumbre de otros miembros y el domingo infinito.
La gramática funcional al servicio de la escritura. Una propuesta curricular y didáctica para trabajar con estructuras sintácticas en la Educación Básica
Authors:   , Abarca Ferrando María Celeste
Published: December 2023

La enseñanza de la gramática dentro del enfoque comunicativo se denomina como una del tipo funcional, es decir, está a disposición del usuario para que tome decisiones conscientes en la producción de sus discursos, con el objetivo de cumplir con su propósito comunicativo de manera exitosa. Sin embargo, esta concepción de la gramática no ha sido desarrollada de manera curricular en el contexto nacional, ya que predomina una visión normativa por sobre una funcional. Por esta razón, el objetivo de este TFE es proponer una progresión de objetivos de aprendizaje de 1° a 6° básico basado en una gramática funcional, con el contenido central de estructuras sintácticas, además de incluir una propuesta de secuencia didáctica gramatical como guía para los docentes de cómo trabajar estos objetivos en el aula, específicamente en el nivel de 4° año básico. Para el diseño de estos productos, se inició primeramente con una etapa de investigación y recolección de datos para sustentar teóricamente los productos realizados. Se comenzó con la producción de la progresión de objetivos de aprendizaje, para luego continuar con el diseño de la secuencia didáctica. Ambos productos fueron sometidos a un juicio de expertos conformados por dos profesoras expertas en didáctica de la gramática y una profesora especialista en lenguaje que ejerce actualmente en el aula. A modo de síntesis, las mayores dificultades que se presentó luego de la revisión de datos, fue el lograr una evidente incorporación de la reflexión metalingüística en los estudiantes, además de asegurar una enseñanza explícita de la gramática para aportar en la toma de decisiones conscientes por parte de estos en la producción escrita de un cuento breve.
Respuesta de una plataforma de pilotes verticales bajo cargas de oleaje regular e irregular considerando interacción suelo-estructura
Authors:   , Tobar Fuentes Kevin Jordi
Published: December 2023

Debido a los múltiples factores que componen el estudio de estructuras marítimas, estas encuentran en continua investigación en muchos países alrededor del mundo. Investigaciones previas se han centrado en estructuras con sistemas de fundación específicos, como monopilotes, jackets y jack-ups. En este trabajo, a diferencia de estudios previos, aborda la respuesta de una plataforma con pilotes verticales, un sistema comúnmente utilizado en Chile y propone factores de corrección para obtener una estimación de la respuesta alcanzada mediante métodos más sofisticados. Esta investigación estudia estructuras marítimas tipo marco frente a cargas de oleaje, mediante la respuesta de desplazamiento del tablero y del momento flector en pilotes. Se consideran parámetros estructurales, hidráulicos y geotécnicos. Se analizan 8 estructuras compuestas por distintos números de pilotes y de diferente altura. Se utilizan 6 olas con diversas características, variando el periodo de estas y la altura media de agua. Se consideran 4 stratigrafías, dos arenas y dos arcillas, de distinta densidad y consistencia. Se realizan análisis estructurales estáticos y dinámicos, con condiciones de oleaje regular e irregular y modelación del suelo mediante apoyo empotrado y resortes no lineales. Se ha observado que los casos de oleaje irregular presentan un comportamiento diferente a los de oleaje regular, destacando la importancia de considerar los efectos dinámicos y de resonancia en el diseño de estructuras marítimas, alcanzando un factor de amplificación por oleaje irregular máximo de 3.9 en la respuesta de desplazamiento y de 3.2 en la respuesta de momento flector. Además, se han propuesto factores de corrección para estimar la respuesta de un análisis estructural dinámico, con cargas de oleaje irregular y con el suelo modelado mediante resortes no lineales.
Masculinidades jóvenes: Representaciones de salud desde la inserción a servicios en Santiago de Chile
Authors:   , Seoane Ponce Tania
Published: December 2023

Durante los últimos años se ha reconocido la importancia de considerar las diferencias de género en la salud, tanto desde una perspectiva biológica como sociocultural. En Chile, se han identificado diferencias epidemiológicas entre hombres y mujeres, como, por ejemplo, una menor esperanza de vida. Sin embargo, el sistema de salud chileno en algunas ocasiones presenta limitaciones en el abordaje de la salud masculina. Objetivo: Explorar las percepciones, representaciones y prácticas de salud, en hombres jóvenes de la zona sur oriente de Santiago que están insertos en centros sanitarios del sector. Metodología: Se realizó un estudio cualitativo por medio de 12 entrevistas a hombres cisgénero de entre 15 y 24 años. Se realizó un análisis temático. Resultados: los participantes tienen un concepto de salud que se centra en la imagen corporal y el cuidado físico, priorizando un cuerpo atlético. Tienden a descuidar su salud y adoptar conductas de riesgo. Los jóvenes tienden a no preocuparse demasiado por su salud, dependiendo del apoyo otorgado por su familia para asistir a centros de salud. Conclusión: La presente investigación reafirmó la disparidad de género existente entre hombre y mujeres, además de tener un acercamiento sobre las representaciones en la juventud sobre los procesos de salud-enfermedad en ellos, las diferencias significativas entre ellos y las mujeres, además de conectar el apoyo social desde las representaciones sociales particulares que necesitan para sobrellevar una atención en salud.
Analyzing the Impact of Rainfall Patterns on Agriculture, Economy and Tourism in India: A Statistical Approach
Authors: Sneha Babu R.  , Uma G.
Published: December 2023

The current study examines rainfall trends in India, encompassing its effect on various economic aspects and forecasting for 2023-2030. The Mann-Kendall test and Sen’s slope estimator are utilized to analyze annual and seasonal rainfall patterns. Results reveal a pronounced winter decline (2001-2022) alongside significant pre- monsoon, monsoon, and post-monsoon increases. Annual rainfall consistently de- creases, contrasting with rising pre-monsoon, monsoon, and post-monsoon trends. Annual rainfall exhibits the steepest decline (-1.0891 mm/year), while the monsoon season displays the highest increase (3.2538 mm/year). Further, the present study explores relationships between rainfall and economic growth, tourism, and agriculture. A statistically insignificant yet positive correlation is found between annual rainfall and per-capita GDP, indicating other economic drivers. Tourism shows a weak, statistically insignificant link with annual rainfall. In contrast, a robust statistically significant correlation emerges between annual rainfall and food- grain production, highlighting its role in agriculture. Finally, the present research forecasts annual rainfall (2023-2030) using the ARIMA (1,0,0) model, predicting a continued decline. This has profound implications for water resources, agriculture, and the economy, necessitating proactive measures such as water conservation, drought-resistant farming, and alternative energy investments.
An Energy Efficient Cluster Head Selection in WSN Based on Enhanced Chicken Swarm Optimization
Authors: M. Prakash , A. Prakash
Published: December 2023

Clustering of data are ab effective energy saving method for wireless sensor networks (WSN). However, they incur additional costs in data collections from sensor nodes and sending them to base station (BS) after aggregations. Cluster heads (CHs) in hierarchical cluster-based WSNs use more energy. Therefore, choosing a suitable CHs is essential to conserve energy for sensor nodes and prolong the life of the WSN. Provide energy-saving cluster head selection techniques in this work. where enhanced fuzzy means clustering is used to perform the first cluster construction. Enhanced Chick Swarm optimization (ECSO) selects CHs which is evaluated strictly for varying WSN scenarios and counts of CHs and nodes for values of remaining energies of sensor nodes, sink distances, and distances within clusters. To demonstrate that the proposed technique is superior, the results are compared with those of several other currently used algorithms.
Racial and Ethnic Differences in Hospice Use Among Medicaid-Only and Dual-Eligible Decedents
Authors: Robison Julie , Shugrue Noreen , Dillon Ellis , Migneault Deborah , Charles Doreek , Wakefield Dorothy , Richards Bradley
Published: December 2023

Importance

Hospice care enhances quality of life for people with terminal illness and is most beneficial with longer length of stay (LOS). Most hospice research focuses on the Medicare-insured population. Little is known about hospice use for the racially and ethnically diverse, low-income Medicaid population.

Objective

To compare hospice use and hospice LOS by race and ethnicity among Medicaid-only individuals and those with dual eligibility for Medicare and Medicaid (duals) in the Connecticut Medicaid program who died over a 4-year period.

Design, Setting, and Participants

This retrospective population-based cohort study used Medicaid and traditional Medicare enrollment and claims data for 2015 to 2020. The study included Connecticut Medicaid recipients with at least 1 of 5 most common hospice diagnoses who died from 2017 to 2020.

Exposure

Race and ethnicity.

Main Outcomes and Measures

Hospice use (yes/no) and hospice LOS (1-7 days vs ≥8 days.) Covariates included sex, age, and nursing facility stay within 60 days of death.

Results

Overall, 2407 Medicaid only and 23 857 duals were included. Medicaid-only decedents were younger (13.8% ≥85 vs 52.5%), more likely to be male (50.6% vs 36.4%), more racially and ethnically diverse (48.7% non-Hispanic White vs 79.9%), and less likely to have a nursing facility stay (34.9% vs 56.1%). Race and ethnicity were significantly associated with hospice use and LOS in both populations: non-Hispanic Black and Hispanic decedents had lower odds of using hospice than non-Hispanic White decedents, and Hispanic decedents had higher odds of a short LOS. In both populations, older age and female sex were also associated with more hospice use. For duals only, higher age was associated with lower odds of short LOS. For decedents with nursing facility stays, compared with those without, Medicaid-only decedents had higher odds of using hospice (odds ratio [OR], 1.49; 95% CI, 1.24-1.78); duals had lower odds (OR, 0.60; 95% CI, 0.57-0.63). Compared with decedents without nursing facility stays, duals with a nursing facility stay had higher odds of short LOS (OR, 2.63; 95% CI, 2.43-2.85).

Conclusions and Relevance

Findings raise concerns about equity and timing of access to hospice for Hispanic and non-Hispanic Black individuals in these understudied Medicaid populations. Knowledge about, access to, and acceptance of hospice may be lacking for these low-income individuals. Further research is needed to understand barriers to and facilitators of hospice use for people with nursing facility stays.
Subcutaneous batoclimab in generalized myasthenia gravis: Results from a Phase 2a trial with an open‐label extension
Authors: Nowak Richard J. , Breiner Ari , Bril Vera , Allen Jeffrey A. , Khan Shaida , Levine Todd , Jacobs Daniel H. , Sahagian Gregory , Siddiqi Zaeem A. , Xu Jing , Macias William L. , Benatar Michael ,   ASCEND MG Study Group
Published: December 2023

Objectives

To assess the safety, tolerability, and key pharmacodynamic effects of subcutaneous batoclimab, a fully human anti‐neonatal Fc receptor monoclonal antibody, in patients with generalized myasthenia gravis and anti‐acetylcholine receptor antibodies.

Methods

A Phase 2a, proof‐of‐concept, randomized, double‐blind, placebo‐controlled trial is described. Eligible patients were randomized (1:1:1) to receive once‐weekly subcutaneous injections of batoclimab 340 mg, batoclimab 680 mg, or matching placebo for 6 weeks. Subsequently, all patients could enter an open‐label extension study where they received batoclimab 340 mg once every 2 weeks for 6 weeks. Primary endpoints were safety, tolerability, and change from baseline in total immunoglobulin G, immunoglobulin G subclasses, and anti‐acetylcholine receptor antibodies at 6 weeks post‐baseline. Secondary endpoints included changes from baseline to 6 weeks post‐baseline for Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, Myasthenia Gravis Composite, and revised 15‐item Myasthenia Gravis Quality of Life scores.

Results

Seventeen patients were randomized to batoclimab 680 mg (n = 6), batoclimab 340 mg (n = 5), or placebo (n = 6). Batoclimab was associated with significantly greater reductions in total immunoglobulin G and anti‐acetylcholine receptor antibodies from baseline to 6 weeks post‐baseline than placebo. Reductions in immunoglobulin G subclasses were generally consistent with total immunoglobulin G. While clinical measures showed directionally favorable improvements over time, the study was not powered to draw conclusions about therapeutic efficacy. No safety issues were identified.

Interpretation

The safety profile, pharmacodynamics, and preliminary clinical benefits observed in this study support further investigation of subcutaneous batoclimab injections as a potential patient‐administered therapy for seropositive generalized myasthenia gravis.
Seizures and electrophysiological features in familial cortical myoclonic tremor with epilepsy 1
Authors: Ding Yao , Cen Zhidong , Zheng Yang , Qiu Xia , Ye Yumao , Chen Xinhui , Hu Lingli , Wang Bo , Wang Zhongjin , Yin Houmin , Shen Chunhong , Ming Wenjie , Ge Yi , Xie Fei , Yang Dehao , Ouyang Zhiyuan , Wang Haotian , Wu Sheng , Ding Meiping , Wang Shuang , Luo Wei
Published: December 2023

Objectives

To investigate and characterize epileptic seizures and electrophysiological features of familial cortical myoclonic tremor with epilepsy (FCMTE) type 1 patients in a large Chinese cohort.

Methods

We systematically evaluated 125 FCMTEtype 1 patients carrying the pentanucleotide (TTTCA) repeat expansion in the SAMD12 gene in China.

Results

Among the 28 probands, epileptic seizures (96.4%, 27/28) were the most common reason for an initial clinic visit. Ninety‐seven (77.6%, 97/125) patients had experienced seizures. The seizures onset age was 36.5 ± 9.0 years, which was 6.9 years later than cortical tremors. The seizures were largely rare (<1/year, 58.8%) and occasional (1–6/year, 37.1%). Prolonged prodromes were reported in 57.7% (56/97). Thirty‐one patients (24.8%, 31/125) reported photosensitivity history, and 79.5% (31/39) had a photoparoxysmal response. Interictal epileptiform discharges (IEDs) were recorded in 69.1% (56/81) of patients. Thirty‐three patients showed generalized IEDs and 72.7% (24/33) were occipitally dominant, while 23 patients presented with focal IEDs with 65.2% (15/23) taking place over the occipital lobe. Overnight EEG of FCMTE patients displayed paradoxical sleep–wake fluctuation, with a higher average IED index of 0.82 ± 0.88/min during wakefulness and a lower IED index of 0.04 ± 0.06/min during non‐rapid eye movement sleep stages I–II.

Interpretation

FCMTE type 1 has a benign course of epilepsy and distinct clinical and electrophysiological features. In addition to a positive family history and cortical myoclonus tremor, the seizure prodromes, specific seizure triggers, photosensitivity, distribution of IEDs, and unique fluctuations during sleep–wake cycle are cues for proper genetic testing and an early diagnosis of FCMTE.
A Novel Approach to Increase Glial Cell Populations in Brain Microphysiological Systems
Authors: Morales Pantoja Itzy E. , Ding Lixuan , Leite Paulo E. C. , Marques Suelen A. , Romero July Carolina , Alam El Din Dowlette‐Mary , Zack Donald J. , Chamling Xitiz , Smirnova Lena
Published: December 2023

Brain microphysiological systems (bMPS) recapitulate human brain cellular architecture and functionality more closely than traditional monolayer cultures and have become increasingly relevant for the study of neurological function in health and disease. Existing 3D brain models vary in reflecting the relative populations of different cell types present in the human brain. Most models consist mainly of neurons, while glial cells represent a smaller portion of the cell populations. Here, by means of a chemically defined glial‐enriched medium (GEM), an improved method to expand the population of astrocytes and oligodendrocytes without compromising neuronal differentiation in bMPS, is presented. An important finding is that astrocytes also change in morphology when cultured in GEM, more closely recapitulating primary culture astrocytes. GEM bMPS are electro‐chemically active and show different patterns of calcium staining and flux. Synaptic vesicles and terminals observed by electron microscopy are also present. No significant changes in neuronal differentiation are observed by gene expression, however, GEM enhanced neurite outgrowth and cell migration, and differentially modulated neuronal maturation in two different cell lines. These results have the potential to significantly improve functionality of bMPS for the study of neurological diseases and drug discovery, contributing to the unmet need for safe human models.
Treatment with Cerebrolysin Prolongs Lifespan in a Mouse Model of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy
Authors: Kastberger Birgit , Winter Stefan , Brandstätter Hemma , Biller Janina , Wagner Wolfgang , Plesnila Nikolaus
Published: December 2023

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare familial neurological disorder caused by mutations in the NOTCH3 gene and characterized by migraine attacks, depressive episodes, lacunar strokes, dementia, and premature death. Since there is no therapy for CADASIL the authors investigate whether the multi‐modal neuropeptide drug Cerebrolysin may improve outcome in a murine CADASIL model. Twelve‐month‐old NOTCH3R169C mutant mice (n=176) are treated for nine weeks with Cerebrolysin or Vehicle and histopathological and functional outcomes are evaluated within the subsequent ten months. Cerebrolysin treatment improves spatial memory and overall health, reduces epigenetic aging, and prolongs lifespan, however, CADASIL‐specific white matter vacuolization is not affected. On the molecular level Cerebrolysin treatment increases expression of Calcitonin Gene‐Related Peptide (CGRP) and Silent Information Regulator Two (Sir2)‐like protein 6 (SIRT6), decreases expression of Insulin‐like Growth Factor 1 (IGF‐1), and normalizes the expression of neurovascular laminin. In summary, Cerebrolysin fosters longevity and healthy aging without specifically affecting CADASIL pathology. Hence, Cerebrolysin may serve a therapeutic option for CADASIL and other disorders characterized by accelerated aging.
Biomimetic Chiral Nanotopography for Manipulating Immunological Response
Authors: He Yide , Zhang Xige , Meng Fanhui , Wang Jinjin , Li Yi , Zhang Yan , Song Wen , Li Tianjie , Zhang Yumei
Published: December 2023

Immune response regulates implanted biomaterial−tissue integration and tissue regeneration, in which macrophages play a key role due to their plasticity and polarization. Chirality, an inherent property of carbon‐based life, can also exist in biomaterials such as gold monolayer. Constructing chiral nanostructured surfaces of implants can imitate the chirality of extracellular environment in a biomimetic manner, but the manipulation and mechanism of chiral nanotopography on macrophages remain poorly understood. Here, highly ordered gold nanoparticle arrays with 300 or 900 nm spacing are fabricated and modified with L‐ or D‐chirality. The D‐nanoarrays can promote M2 polarization and related cytokine secretion of macrophages, thus facilitating the reduction of inflammatory reaction and promoting tissue healing and regeneration. The mechanistic analysis further suggests that D‐nanoarrays proceeded these regulations through enhancing the expression of integrin αv/α8/β3‐p‐FAK pathway in macrophages, which may be largely attributed to its higher stereo‐affinity for fibronectin as revealed by quantitative experiments and molecular dynamics simulations. Overall, this study demonstrates that biomimetic chiral nanotopography can promote biomaterial−tissue integration by manipulating macrophage phenotype, bringing a novel strategy for immunomodulation.
Cotton Fibers with a Lactic Acid‐Like Surface for Re‐establishment of Protective Lactobacillus Microbiota by Selectively Inhibiting Vaginal Pathogens
Authors: Wu Yuzheng , Liu Pei , Liao Qing , Jin Tao , Wu Zhengwei , Wang Guomin , Wang Huaiyu , Chu Paul K.
Published: December 2023

Failure to reconstruct the Lactobacillus microbiota is the major reason for the recurrence of vaginal infection. However, most empiric therapies focus on the efficacy of pathogen elimination but do not sufficiently consider the viability of Lactobacillus. Herein, cotton fibers with a lactic acid‐like surface (LC) are fabricated by NaIO4 oxidation and L‐isoserine grafting. The lactic acid analog chain ends and imine structure of LC can penetrate cell walls to cause protein cleavage in Escherichia coli and Candida albicans and inhibit vaginal pathogens. Meanwhile, the viability of Lactobacillus acidophilus is unaffected by the LC treatment, thus revealing a selective way to suppress pathogens as well as provide a positive route to re‐establish protective microbiota in the vaginal tract. Moreover, LC has excellent properties such as good biosafety, antiadhesion, water absorption, and weight retention. The strategy proposed here not only is practical, but also provides insights into the treatment of vaginal infections.
A Conformable Organic Electronic Device for Monitoring Epithelial Integrity at the Air Liquid Interface
Authors: Barron Sarah L. , Oldroyd Sophie V. , Saez Janire , Chernaik Alice , Guo Wenrui , McCaughan Frank , Bulmer David , Owens Róisín M.
Published: December 2023

Air liquid interfaced (ALI) epithelial barriers are essential for homeostatic functions such as nutrient transport and immunological protection. Dysfunction of such barriers are implicated in a variety of autoimmune and inflammatory disorders and, as such, sensors capable of monitoring barrier health are integral for disease modelling, diagnostics and drug screening applications. To date, gold‐standard electrical methods for detecting barrier resistance require rigid electrodes bathed in an electrolyte, which limits compatibility with biological architectures and is non‐physiological for ALI. This work presents a flexible all‐planar electronic device capable of monitoring barrier formation and perturbations in human respiratory and intestinal cells at ALI. By interrogating patient samples with electrochemical impedance spectroscopy and simple equivalent circuit models, disease‐specific and patient‐specific signatures are uncovered. Device readouts are validated against commercially available chopstick electrodes and show greater conformability, sensitivity and biocompatibility. The effect of electrode size on sensing efficiency is investigated and a cut‐off sensing area is established, which is one order of magnitude smaller than previously reported. This work provides the first steps in creating a physiologically relevant sensor capable of mapping local and real‐time changes of epithelial barrier function at ALI, which will have broad applications in toxicology and drug screening applications.
Optically Manipulated Micromirrors for Precise Excitation of WGM Microlasers
Authors: Plaskocinski Tomasz , Yan Libin , Schubert Marcel , Gather Malte C. , Di Falco Andrea
Published: December 2023

Whispering gallery mode microlasers are highly sensitive refractive index sensors widely explored for biophotonic and biomedical applications. Microlaser excitation and collection of the emitted light typically utilize microscope objectives at normal incidence, limiting the choice of the oscillation plane of the modes. Here, a platform that enables the excitation of microlasers from various directions using an optically manipulated micromirror is presented. The scheme enables precise sensing of the environment surrounding the microlasers along different well‐controlled planes. The capability of the platform to perform a time‐resolved experiment of dynamic sensing using a polystyrene probe bead orbiting the microlaser is further demonstrated.
Enhanced Interband Transition in FeCoNiAlTi High‐Entropy Alloy for Ultrafast Nonlinear Optical Applications
Authors: Liu Xiang , Li Jinfeng , Li Zongsheng , Chu Hongwei , Pan Zhongben , Pan Han , Zhao Shengzhi , Li Dechun
Published: December 2023

High‐entropy alloys (HEAs) possess superior mechanical, thermal, and electronic properties, which attract great interest in the fields of photothermal, electrocatalysis, and magnetic applications. Herein, the nonlinear optical properties of FeCoNiAlTi HEA with a large specific surface area for the first time is investigated. Owing to the strong d–d interaction, the interband transition near the Fermi level could be enhanced in HEAs, leading to broadband optical absorption. Excitation with the picosecond laser source, the FeCoNiAlTi HEA possesses saturable absorption with a large modulation depth of 7.61% and 30.47% at 1 and 1.5 µm, respectively. Furthermore, at the higher excitation level at 1.5 µm, the saturable absorber exhibits a typical reverse saturable absorption property. Subsequently, the FeCoNiAlTi HEA on the tapered fiber first serves as the saturable absorber in the Yb‐doped fiber laser and the Er‐doped fiber laser, leading to the noise‐like pulses at 1 µm, and the stable Q‐switching, conventional soliton, and dissipative soliton resonance mode‐locking operations at 1.5 µm. This work confirms that the enhanced saturable absorption in HEAs can endow the high‐performance ultrashort pulse generation.
Facile Fabrication Technique of Polymeric Ionic Liquids‐Coated Core–Shell Nanoparticles for Polymer Electrolyte Membranes
Authors: Tabata Keisuke , Makino Tsutomu , Matsuo Yoshimasa , Sinkus Rose , Masuhara Akito
Published: December 2023

Nanoparticles and nanofibers are widely used as components of polymer electrolytes for membranes in fuel cells, and many surface modification methods are reported. However, some fabrication techniques are complicated, and it is necessary to develop a simplified and precise control method. Herein, a facile fabrication method is reported for core–shell nanoparticles hierarchically coated with polymeric ionic liquids (PIL) and hydrophobic polymers as a material for polymer electrolytes. A hierarchical polymer layer on the surface of the SiO2 nanoparticles is easily constructed by repeating the facile polymer‐coating technique based on precipitation polymerization several times. The highest proton conductivity of the core–shell nanoparticles is 1.3 × 10−2 S cm−1 at 80 °C and 95% relative humidity. Although the hydrophobic polymers coated as a protective layer reduce the proton conductivity, the formation of the PIL enhances the proton conductivity in various temperature and humidity environments. Therefore, the proposed method enables the facile fabrication of polymer layers with multiple functions, such as a proton‐conductive PIL layer and hydrophobic polymer layers as protective layers on the surface of the nanoparticles. Furthermore, they are expected to be applied to energy supply and gas separation, including polyelectrolytes, for the realization of a sustainable society.
From Theory to Therapy: The Advancements of Extracellular Vesicles in Immunotherapy
Authors: Piernitzki Nils , Staufer Oskar
Published: December 2023

Extracellular vesicles (EVs) are lipid‐membrane‐enclosed particles released from cells, playing a pivotal role in cellular communication, particularly within the immune system. The fundamental molecular mechanisms through which EVs offer unique functionality for immunotherapeutic benefits are identified and reviewed. The focus is on three essential features, all rooted in the EV lipid membrane: immune receptor–ligand interactions at the EV membrane interface, the shielding of immunogenic cargo within the EVs, and the fusion of EVs with target cell membranes for direct cargo delivery. From this, how these distinct EV attributes, from their initial description and analysis in immune communication, have led to the development of novel immunotherapeutic strategies is traced. This review delves into how these strategies are applied in various immunotherapies, such as cancer immunotherapy, autoimmune diseases, infections, vaccinations, and graft‐versus‐host diseases, to modulate communication among different cell types for immune regulation. It is concluded by reviewing clinical trials involving EVs in immunotherapy that have effectively harnessed EVs' unique molecular mechanisms in clinical settings. Research and standardization efforts to maximize the potential impact of EVs on immunotherapy are further suggested.
Efferocyte‐Derived MCTRs Metabolically Prime Macrophages for Continual Efferocytosis via Rac1‐Mediated Activation of Glycolysis
Authors: Koenis Duco Steven , de Matteis Roberta , Rajeeve Vinothini , Cutillas Pedro , Dalli Jesmond
Published: December 2023

Clearance of multiple rounds of apoptotic cells (ACs) through continual efferocytosis is critical in the maintenance of organ function, the resolution of acute inflammation, and tissue repair. To date, little is known about the nature of mechanisms and factors that govern this fundamental process. Herein, the authors reported that breakdown of ACs leads to upregulation of 12‐lipoxygenase in macrophages. This enzyme converts docosahexaenoic acid to maresin conjugates in tissue regeneration (MCTRs). The levels of these autacoids are elevated at sites of high apoptotic burden in vivo and in efferocytosing macrophages in vitro. Abrogation of MCTR production using genetic approaches limits the ability of macrophages to perform continual efferocytosis both in vivo and in vitro, an effect that is rescued by add‐back of MCTRs. Mechanistically, MCTR‐mediated priming of macrophages for continual efferocytosis is dependent on alterations in Rac1 signalling and glycolytic metabolism. Inhibition of Rac1 abolishes the ability of MCTRs to increase glucose uptake and efferocytosis in vitro, whereas inhibition of glycolysis limits the MCTR‐mediated increases in efferocytosis and tissue repair. Together, these findings demonstrate that upregulation of MCTRs by efferocytosing macrophages plays a central role in the regulation of continual efferocytosis via the autocrine and paracrine modulation of metabolic pathways.
Polaron Vibronic Progression Shapes the Optical Response of 2D Perovskites
Authors: Dyksik Mateusz , Beret Dorian , Baranowski Michal , Duim Herman , Moyano Sébastien , Posmyk Katarzyna , Mlayah Adnen , Adjokatse Sampson , Maude Duncan K. , Loi Maria Antonietta , Puech Pascal , Plochocka Paulina
Published: December 2023

The optical response of 2D layered perovskites is composed of multiple equally‐spaced spectral features, often interpreted as phonon replicas, separated by an energy Δ ≃ 12 − 40 meV, depending upon the compound. Here the authors show that the characteristic energy spacing, seen in both absorption and emission, is correlated with a substantial scattering response above ≃ 200 cm−1 (≃ 25 meV) observed in resonant Raman. This peculiar high‐frequency signal, which dominates both Stokes and anti‐Stokes regions of the scattering spectra, possesses the characteristic spectral fingerprints of polarons. Notably, its spectral position is shifted away from the Rayleigh line, with a tail on the high energy side. The internal structure of the polaron consists of a series of equidistant signals separated by 25–32 cm−1 (3–4 meV), depending upon the compound, forming a polaron vibronic progression. The observed progression is characterized by a large Huang‐Rhys factor (S > 6) for all of the 2D layered perovskites investigated here, indicative of a strong charge carrier – lattice coupling. The polaron binding energy spans a range ≃ 20–35 meV, which is corroborated by the temperature‐dependent Raman scattering data. The investigation provides a complete understanding of the optical response of 2D layered perovskites via the direct observation of polaron vibronic progression. The understanding of polaronic effects in perovskites is essential, as it directly influences the suitability of these materials for future opto‐electronic applications.