bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of flare-ups and impact of garetosmab in adults with fibrodysplasia ossificans progressiva: a post hoc analysis of the randomized, double-blind, placebo-controlled LUMINA-1 trial
Authors: Keen Richard , Dahir Kathryn M , McGinniss Jennifer , Sanchez Robert J , Mellis Scott , Economides Aris N , Di Rocco Maja , Orcel Philippe , Roux Christian , Tabarkiewicz Jacek , Bachiller-Corral Javier , Cheung Angela M , Al Mukaddam Mona , Mohammadi Kusha , Gu Jing , Srinivasan Dushyanth , Trotter Dinko Gonzalez , Eekhoff E Marelise W , Kaplan Frederick S , Pignolo Robert J
Published: August 2024

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder, characterized by progressive heterotopic ossification (HO) and painful soft-tissue inflammatory flare-ups. This was a post hoc analysis from a phase 2 (NCT03188666) trial in which adults with FOP received intravenous anti-activin A antibody garetosmab 10 mg/kg or placebo every 4 wk over 28 wk (Period 1), followed by a 28-wk open-label treatment and extension (Periods 2 and 3). Here we describe flare-ups, their relationship to new HO lesions, and the impact of garetosmab on flare-ups. Volume of new HO lesions was measured by CT. Patient-reported flare-ups were defined by any 2 of the following: new onset of pain, swelling, joint stiffness, decrease in movement, or perceived presence of HO. Flare-ups were experienced by 71% (17/24) of placebo-treated patients, 59% (10/17) of whom developed a new HO lesion irrespective of flare-up location; 24% of flare-ups location-matched new HO lesions. Twenty-nine new HO lesions occurred in the placebo cohort by week 28, of which 12 (41%) occurred in the same location as new or ongoing flare-ups. A higher volume of newly formed heterotopic bone (week 28) occurred in placebo-treated patients who had experienced a prior flare-up vs those without (median [Q1:Q3] of 16.6 [12.0:31.1] vs 3.2 cm3). Garetosmab was previously shown to decrease patient-reported flare-up frequency in Period 1; here, garetosmab reduced the median (Q1:Q3) duration of patient-reported flares (15.0 [6.0:82.0] vs 48.0 [15.0:1.00] d) and the severity of flare-ups vs placebo. Frequency of corticosteroid use was numerically reduced in those treated with garetosmab (40.0%) vs placebo (58.3%). In this analysis, 71% of placebo-treated adults with FOP experienced flare-ups over 28 wk, which were associated with an increased volume of newly formed heterotopic bone. Garetosmab reduced the severity and duration of flare-ups, with effects sustained during the entire trial.
Environmental factors affecting phenology and distribution of Tentyria species (Coleoptera: Tenebrionidae) in Doñana National Park (Southern Iberian Peninsula)
Authors: Cárdenas Ana M , Bujalance José Luis , Camacho Agustín
Published: August 2024

This research focuses on the effect of environmental factors on the phenology and distribution of the Tentyria species (Coleoptera: Tenebrionidae) from Doñana National Park (SW Iberian Peninsula). Data are derived from the results of a project carried out 20 years ago, aimed at inventorying the coleopteran of the park. This information provides a framework for comparison with current or future states since the time elapsed is long enough to detect variations. As the classification of Tentyria species is complex and controversial, the first aspect to be addressed was the taxonomical verification of the species. Indeed, they were T. platyceps Steven., T. subcostata Solier., T. bifida Bujalance, Cárdenas, Ferrer and Gallardo, and T. donanensis Bujalance, Cárdenas, Ferrer and Gallardo. Sampling consisted of 2 years of monthly pitfall trapping, encompassing the surface of the park and adjacent areas. Data on adult seasonal activity and spatial distribution of the species were obtained from the specific abundance in each sampling plot. Phenologically, the 4 species were mainly summer species, with unimodal or bimodal curves depending on the species. The distribution of the species was quite uneven: while T. donanensis was ubiquitous, T. subcostata was restricted to the southern coastal area of the park, and T. platyceps and T. bifida were recorded in the northern half, in marshes or inland forests, respectively. Our results also suggest that extreme temperatures may impose major constraints on the spatial distribution of Tentyria species, which could affect Doñana’s biodiversity in the future scenery of thermal rise linked to climate change.
A case of coinfection with dengue and parainfluenza virus after travel to Indonesia
Authors: Momoi Fumitaka , Yamamoto Chie , Hamashima Ryosuke , Furukawa Keitaro , Araki Ryo , Yamada Yukiji , Nakaya Takaaki , Nukui Yoko
Published: August 2024

We present a case of coinfection with dengue and parainfluenza viruses, a coinfection that has not been described in the literature to date. This case emphasizes that fever after travel is not always caused by a single disease. Appropriate research on fever sources and infection control measures should be implemented.
Research on the function of epigenetic regulation in the inflammation of non-alcoholic fatty liver disease
Authors: Sun Lin , Yue Zhensheng , Wang Lin
Published: August 2024

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver condition, characterized by a spectrum that progresses from simple hepatic steatosis to nonalcoholic steatohepatitis, which may eventually lead to cirrhosis and hepatocellular carcinoma. The precise pathogenic mechanisms underlying NAFLD and its related metabolic disturbances remain elusive. Epigenetic modifications, which entail stable transcriptional changes without altering the DNA sequence, are increasingly recognized as pivotal. The principal forms of epigenetic modifications include DNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs. These alterations participate in the regulation of hepatic lipid metabolism, insulin resistance, mitochondrial injury, oxidative stress response, and release of inflammatory cytokines, all of which are associated with the onset and progression of NAFLD. This review discussed recent advances in understanding the potential epigenetic regulation of inflammation in NAFLD. Unraveling these epigenetic mechanisms may facilitate the identification of early diagnostic biomarkers and the development of targeted therapeutic strategies for NAFLD.
Global weather map reveals persistent top-of-atmosphere features on the nearest brown dwarfs
Authors: Chen Xueqing , Biller Beth A , Vos Johanna M , Crossfield Ian J M , Mace Gregory N , Hood Callie E , Tan Xianyu , Allers Katelyn N , Martin Emily C , Bubb Emma , Fortney Jonathan J , Morley Caroline V , Hammond Mark
Published: August 2024

Brown dwarfs and planetary-mass companions display rotationally modulated photometric variability, especially those near the L/T transition. This variability is commonly attributed to top-of-atmosphere (TOA) inhomogeneities, with proposed models including patchy thick and thin clouds, planetary-scale jets, or chemical disequilibrium. Surface mapping techniques are powerful tools to probe their atmospheric structures and distinguish between models. One of the most successful methods for stellar surface mapping is Doppler imaging, where the existence of TOA inhomogeneities can be inferred from their varying Doppler shifts across the face of a rotating star. We applied Doppler imaging to the nearest brown dwarf binary WISE 1049AB (also known as Luhman 16AB) using time-resolved, high-resolution spectroscopic observations from Gemini IGRINS, and obtained for the first time H- and K-band simultaneous global weather map for brown dwarfs. Compared to the only previous Doppler map for a brown dwarf in 2014 featuring a predominant mid-latitude cold spot on WISE 1049B and no feature on WISE 1049A, our observations detected persistent spot-like structures on WISE 1049B in the equatorial to mid-latitude regions on two nights, and revealed new polar spots on WISE 1049A. Our results suggest stability of atmospheric features over time-scale of days and possible long-term stable or recurring structures. H- and K-band maps displayed similar structures in and out of CO bands, indicating the cold spots not solely due to chemical hotspots but must involve clouds. Upcoming 30-m extremely large telescopes will enable more sensitive Doppler imaging of dozens of brown dwarfs and even a small number of directly imaged exoplanets.
Biologically inspired heterogeneous learning for accurate, efficient and low-latency neural network
Authors: Wang Bo , Zhang Yuxuan , Li Hongjue , Dou Hongkun , Guo Yuchen , Deng Yue
Published: August 2024

The pursuit of artificial neural networks that mirror the accuracy, efficiency and low latency of biological neural networks remains a cornerstone of artificial intelligence (AI) research. Here, we incorporated recent neuroscientific findings of self-inhibiting autapse and neuron heterogeneity for innovating a spiking neural network (SNN) with enhanced learning and memorizing capacities. A bi-level programming paradigm was formulated to respectively learn neuron-level biophysical variables and network-level synapse weights for nested heterogeneous learning. We successfully demonstrated that our biologically inspired neuron model could reproduce neural statistics at both individual and group levels, contributing to the effective decoding of brain–computer interface data. Furthermore, the heterogeneous SNN showed higher accuracy (1%–10% improvement), superior efficiency (maximal 17.83-fold reduction in energy) and lower latency (maximal 5-fold improvement) in performing several AI tasks. For the first time, we benchmarked SNN for conducting cell type identification from scRNA-seq data. The proposed model correctly identified very rare cell types associated with severe brain diseases where typical SNNs failed.
The activities, competencies and conditions necessary for public-health policy advisers in a Dutch local government setting to contribute to a healthier living environment: a qualitative multiple-case study
Authors: Mourits Kristine , Spitters Hilde , van der Velden Koos , Bekker Marleen , Molleman Gerard
Published: August 2024

The inclusion of health considerations in the design of the physical living environment can contribute to solving wicked health problems, such as obesity and mental health. Such projects demand an integrated approach and strong collaboration between policy domains. At the level of local government, public-health policy advisers can play an important role in this regard. The aim of this study is to explore how public-health policy advisers in the Netherlands deploy cross-border activities to promote a healthy living environment and to identify the organizational dynamics under which they operate. Drawing on the theory of boundary spanning, a qualitative multiple-case study was conducted in three Dutch pioneering local governments, based on a combination of semi-structured interviews and in-depth project analysis. The results indicate that public-health policy advisers engage in a wide range of boundary-spanning activities at the political-administrative, strategic, tactical and operational levels, including participating in spatial-planning processes, understanding the language of the physical domain and providing the right knowledge about health in relation to the environment. Further, this study demonstrates that creating a healthier living environment is the shared responsibility of the entire local government system, thereby calling for leadership, collective accountability, an integrated approach, coordination, and sufficient staffing capacity. Within this context, policy advisers perform guiding, signaling and connecting roles by undertaking a variety of boundary-spanning activities.
Rapid Vacuolar Sorting of the Borate Transporter BOR1 Requires the Adaptor Protein Complex AP-4 in Arabidopsis
Authors: Yoshinari Akira , Shimizu Yutaro , Hosokawa Takuya , Nakano Akihiko , Uemura Tomohiro , Takano Junpei
Published: August 2024

Plants maintain nutrient homeostasis by controlling the activities and abundance of nutrient transporters. In Arabidopsis thaliana, the borate (B) transporter BOR1 plays a role in the efficient translocation of B under low-B conditions. BOR1 undergoes polyubiquitination in the presence of sufficient B and is then transported to the vacuole via multivesicular bodies (MVBs) to prevent B accumulation in tissues at a toxic level. A previous study indicated that BOR1 physically interacts with µ subunits of adaptor protein complexes AP-3 and AP-4, both involved in vacuolar sorting pathways. In this study, we investigated the roles of AP-3 and AP-4 subunits in BOR1 trafficking in Arabidopsis. The lack of AP-3 subunits did not affect either vacuolar sorting or polar localization of BOR1-GFP, whereas the absence of AP-4 subunits resulted in a delay in high-B-induced vacuolar sorting without affecting polar localization. Super-resolution microscopy revealed a rapid sorting of BOR1-GFP into AP-4-positive spots in the trans-Golgi network (TGN) upon high-B supply. These results indicate that AP-4 is involved in sequestration of ubiquitinated BOR1 into a TGN-specific subdomain ‘vacuolar-trafficking zone’, and is required for efficient sorting of MVB and vacuole. Our findings have thus helped elucidate the rapid vacuolar sorting process facilitated by AP-4 in plant nutrient transporters.
A Kinesin-Like Protein, KAC, is Required for Light-Induced and Actin-Based Chloroplast Movement in Marchantia polymorpha
Authors: Yamamoto-Negi Yoshiko , Higa Takeshi , Komatsu Aino , Sasaki Kanta , Ishizaki Kimitsune , Nishihama Ryuichi , Gotoh Eiji , Kohchi Takayuki , Suetsugu Noriyuki
Published: August 2024

Chloroplasts accumulate on the cell surface under weak light conditions to efficiently capture light but avoid strong light to minimize photodamage. The blue light receptor phototropin regulates the chloroplast movement in various plant species. In Arabidopsis thaliana, phototropin mediates the light-induced chloroplast movement and positioning via specialized actin filaments on the chloroplasts, chloroplast-actin filaments. KINESIN-LIKE PROTEIN FOR ACTIN-BASED CHLOROPLAST MOVEMENT (KAC) and CHLOROPLAST UNUSUAL POSITIONING 1 (CHUP1) are pivotal for actin-based chloroplast movement and positioning in land plants. However, the mechanisms by which KAC and CHUP1 regulate chloroplast movement and positioning remain unclear. In this study, we characterized KAC and CHUP1 orthologs in the liverwort Marchantia polymorpha, MpKAC and MpCHUP1, respectively. Their knockout mutants, Mpkacko and Mpchup1ko, impaired the light-induced chloroplast movement. Although Mpchup1ko showed mild chloroplast aggregation, Mpkacko displayed severe chloroplast aggregation, suggesting the greater contribution of MpKAC to the chloroplast anchorage to the plasma membrane. Analysis of the subcellular localization of the functional MpKAC-Citrine indicated that MpKAC-Citrine formed a punctate structure on the plasma membrane. Structure–function analysis of MpKAC revealed that the deletion of the conserved C-terminal domain abrogates its targeting to the plasma membrane and its function. The deletion of the N-terminal motor domain retains the plasma membrane targeting but abrogates the formation of punctate structure and shows a severe defect in the light-induced chloroplast movement. Our findings suggest that the formation of the punctate structure on the plasma membrane of MpKAC is essential for chloroplast movement.
Transcendental idealism and Kant's reconciliation of determinism and libertarianism
Authors: Beizaei Banafsheh
Published: August 2024

Kant famously argues that transcendental idealism allows us to solve the problem of free will. The basic outlines of the solution are as follows: while freedom and determinism are incompatible, we can consistently predicate them of one and the same being if we take the former to be a quality of the human being as it is in itself and the latter a quality of the human being as it appears. In this paper, I look at three different readings of transcendental idealism—the two-object reading, the two-property reading, and the epistemological reading—and argue that none of them—at least in their standard forms—are able to make sense of this solution. I then draw on my alternative, semantic reading of transcendental idealism to propose a new way of understanding Kant's solution.
The anglicization of science in China
Authors: Li Kai , Zheng Xiang , Ni Chaoqun
Published: August 2024

The preeminence of English as the lingua franca in global science has led to English-dominant publication practices, even in non-English-speaking countries. We examine the complex dynamics of language use in scientific publications in China, a major contributor to global scientific output, and the tensions between English and the native language. By analyzing 2,209,987 multilingual publications from 183,457 projects funded by the National Natural Science Foundation of China, we reveal a strong preference for English as the publication language in China, with 66.2% of publications in English versus 33.8% in Chinese. Key projects and natural sciences and engineering projects favor English more; regional projects and social sciences projects use Chinese more. However, English has a growing prevalence over the years across all research fields, project types, and publication venues. There is a negative correlation between the shares of English usage in journals and conference proceedings. We find only a minor overlap between English and Chinese-language publications, indicating unique contributions rather than repetitive content. However, Chinese-language publications are more likely to be similar to English-language publications. For highly similar cross-language publication pairs, the Chinese version tends to be published earlier. The findings underscore the risk of underestimating China’s scientific output by only counting English-language publications. We highlight the importance of creating a comprehensive multilingual database and the significant role of non-English-language research in global scientific discourse.

Keywords: multilingual publishing; scientific communication; language policy; academic multilingualism; bibliometrics; quantitative analysis.
Evaluation of electric field (E) exposure levels and its relationship with the sleep quality of residents around the BTS antennas in Sabzevar, Iran
Authors: Malvandi Hassan , Fallahi Majid , Saghi Mohammad Hossien , Hassanzadeh Nasrin
Published: August 2024

Mobile devices and base transceiver station (BTS) are the main sources of human exposure to radio frequency electromagnetic fields (RF-EMFs). Therefore, the aim of the present study was to evaluate the levels of exposure to RF-EMF in three different time intervals and three different distances from BTS antennas in Sabzevar. Additional goals were to investigate the electric field (E) difference between different microenvironments, between the suburbs and downtown, and evaluating the sleep quality of residents around BTS antennas at different distances. The results showed significant differences between the values of E Avg and E max Avg at different times (T1, T2, and T3), different distances (50, 100, and 300 m) from BTS antennas, and between BTS antennas located in the suburbs and downtown. No significant differences were observed between the values of E Avg and E max Avg in terms of microenvironments. Poor sleep quality (>5) was recorded in the residents around the BTS antennas at different distances, and a significant difference was observed between the sleep quality of the residents at a distance of ˂100 m compared to the residents at a distance of ˃300 m. The recorded levels of E in all places and times were below the human safety limits set by the Iranian National Standardization Organization, the Information and Communication Technologies Authority and the International Commission on Non-Ionizing Radiation Protection, indicating the absence of potential risk due to exposure to E in the study area.
Anti-LGI1 Antibody-Associated Encephalitis Misdiagnosed as Schizophrenia: A Case Report
Authors: Zhang Jin-he , Fu Bing-bing , Wang Wei , Sun Cong-cong , Xu Jin-jie
Published: August 2024

Anti-leucine-rich glioma-inactivated 1 (LGI1) antibody-associated encephalitis is a rare but clinically significant form of autoimmune encephalitis, predominantly affecting middle-aged men. Its heterogeneous clinical presentation often leads to misdiagnosis, commonly as other neurological or psychiatric disorders. This report details the case of a 46-year-old male who initially presented with depressive symptoms, personality changes, and visual hallucinations. Over time, his condition progressed to include memory impairment, disorganized behavior, and seizures. Initially misdiagnosed with schizophrenia, the correct diagnosis of LGI1 antibody-associated encephalitis was eventually established through positive serum and cerebrospinal fluid (CSF) tests for LGI1 antibodies. Neuroimaging findings revealed characteristic bilateral temporal lobe lesions. The patient demonstrated marked improvement following treatment with methylprednisolone and intravenous immunoglobulin, ultimately achieving significant recovery. This case highlights the critical importance of comprehensive antibody testing and neuroimaging in patients presenting with nonspecific psychiatric and neurological symptoms to prevent misdiagnosis and delays in appropriate treatment. The article also reviews the pathogenesis, clinical manifestations, diagnostic approaches, and therapeutic strategies for LGI1 antibody-associated encephalitis, aiming to enhance clinical awareness and optimize patient outcomes.
Refining sleep staging accuracy: transfer learning coupled with scorability models
Authors: Ganglberger Wolfgang , Nasiri Samaneh , Sun Haoqi , Kim Soriul , Shin Chol , Westover M Brandon , Thomas Robert J
Published: August 2024

Study Objectives

This study aimed to (1) improve sleep staging accuracy through transfer learning (TL), to achieve or exceed human inter-expert agreement and (2) introduce a scorability model to assess the quality and trustworthiness of automated sleep staging.

Methods

A deep neural network (base model) was trained on a large multi-site polysomnography (PSG) dataset from the United States. TL was used to calibrate the model to a reduced montage and limited samples from the Korean Genome and Epidemiology Study (KoGES) dataset. Model performance was compared to inter-expert reliability among three human experts. A scorability assessment was developed to predict the agreement between the model and human experts.

Results

Initial sleep staging by the base model showed lower agreement with experts (κ = 0.55) compared to the inter-expert agreement (κ = 0.62). Calibration with 324 randomly sampled training cases matched expert agreement levels. Further targeted sampling improved performance, with models exceeding inter-expert agreement (κ = 0.70). The scorability assessment, combining biosignal quality and model confidence features, predicted model-expert agreement moderately well (R² = 0.42). Recordings with higher scorability scores demonstrated greater model-expert agreement than inter-expert agreement. Even with lower scorability scores, model performance was comparable to inter-expert agreement.

Conclusions

Fine-tuning a pretrained neural network through targeted TL significantly enhances sleep staging performance for an atypical montage, achieving and surpassing human expert agreement levels. The introduction of a scorability assessment provides a robust measure of reliability, ensuring quality control and enhancing the practical application of the system before deployment. This approach marks an important advancement in automated sleep analysis, demonstrating the potential for AI to exceed human performance in clinical settings.
In-Furrow Application of Biologicals for Control of Rhizoctonia Diseases in Snap Bean
Authors: Liu Qingchun , Zhang Shouan
Published: August 2024

Florida ranks first in the production of fresh-market snap bean in the United States. Rhizoctonia diseases, including damping-off and root rot caused by Rhizoctonia solani, are important diseases in snap bean, particularly if there is heavy rainfall during the first month after seeding. Growers usually use seeds treated with fungicides to control soilborne pathogens including R. solani. However, there are concerns about resistance development in R. solani and the impacts of chemicals on the environment. In this study, three biological products (Howler, Theia, and Double Nickel LC) applied as an in-furrow spray at seeding and/or foliar sprays after emergence were evaluated in the field for their efficacy in controlling R. solani on snap bean. When nontreated seeds were used, Howler at 5 lb./acre and Double Nickel LC at 16 fl. oz./acre each applied as an in-furrow spray at seeding significantly ( P < 0.05) reduced disease incidence compared with the untreated control. However, weekly foliar sprays after emergence showed effectiveness in disease reduction only at a high inoculum level. The highest disease reduction of 95.4% was observed in the treatment with Howler at 5 lb./acre in the 2022 trial, and 32.8% for Double Nickel LC was observed at 16 fl. oz./acre in 2023. Both biologicals also significantly increased the pod yield, by 85.6% with Howler in 2022 and doubled by Double Nickel LC in 2023 when compared with the untreated control. Results from these field trials reveal the potential of these biologicals in the control of Rhizoctonia root rot in snap bean production.
Promotion of endoplasmic reticulum retrotranslocation by overexpression of E3 ubiquitin‐protein ligase synoviolin 1 reduces endoplasmic reticulum stress and preserves cone photoreceptors in cyclic nucleotide‐gated channel deficiency
Authors: Yang Fan , Ma Hongwei , Boye Sanford L. , Boye Shannon E. , Ding Xi‐Qin
Published: August 2024

Cone photoreceptor cyclic nucleotide‐gated (CNG) channels play an essential role in phototransduction and cellular Ca2+ homeostasis. Mutations in genes encoding the channel subunits CNGA3 and CNGB3 are associated with achromatopsia, progressive cone dystrophy, and early‐onset macular degeneration. Cone loss in patients with achromatopsia and cone dystrophy associated with CNG channel mutations has been documented by optical coherence tomography and in mouse models of CNG channel deficiency. Cone death in CNG channel‐deficient retinas involves endoplasmic reticulum (ER) stress‐associated apoptosis, dysregulation of cellular/ER Ca2+ homeostasis, impaired protein folding/processing, and impaired ER‐associated degradation (ERAD). The E3 ubiquitin‐protein ligase synoviolin 1 (SYVN1) is the primary component of the SYVN1/SEL1L ER retrotranslocon responsible for ERAD. Previous studies have shown that manipulations that protect cones and reduce ER stress/cone death in CNG channel deficiency, such as increasing ER Ca2+ preservation or treatment with an ER chaperone, increase the expression of SYVN1 and other components of the ER retrotranslocon. The present work investigated the effects of SYVN1 overexpression. Intraocular injection of AAV5‐IRBP/GNAT2‐Syvn1 resulted in overexpression of SYVN1 in cones of CNG channel‐deficient mice. Following treatment, cone density in Cnga3−/− mice was significantly increased, compared with untreated controls, outer segment localization of cone opsin was improved, and ER stress/apoptotic cell death was reduced. Overexpression of SYVN1 also led to increased expression levels of the retrotranslocon components, degradation in ER protein 1 (DERL1), ERAD E3 ligase adaptor subunit (SEL1L), and homocysteine inducible ER protein with ubiquitin‐like domain 1 (HERPUD1). Moreover, overexpression of SYVN1 likely enhanced protein ubiquitination/proteasome degradation in CNG channel‐deficient retinas. This study demonstrates the role of SYVN1/ERAD in cone preservation in CNG channel deficiency and supports the strategy of promoting ERAD for cone protection.
Fc immunoreceptors promote autophagy to regulate monocyte functions
Authors: Nugue Mathilde , D’Allemagne Marie , Koumantou Despoina , Vetillard Mathias , Cragg Mark S , Bourdely Pierre , Lotersztajn Sophie , Saveanu Loredana
Published: August 2024

Receptors for the Fc fragment of immunoglobulin G (FcyRs) are critical in the defense against pathogens and in monoclonal antibody-based therapies. When activated by immune complexes or opsonized particles, FcyRs are endocytosed. Components of the endocytosis machinery are used during autophagy, a process which is triggered by starvation or by activation of specific receptors. In this work, we demonstrate that activation of FcyRs initiates autophagy, characterized by formation of p62 protein puncta and activation of ULK1, a major component of the autophagy initiation complex. Autophagy induction downstream of FcyRs activation involves the protein phosphatase Pp2a and its enzymatic activity, as demonstrated byin situprotein labeling. In animal models in which autophagy was inactivated or enhanced in myeloid cells, autophagy negatively regulates pro-inflammatory cytokine production downstream of FcyRs receptors, while being required for FcyRs -mediated antibody-induced cell phagocytosis and myeloid cell survival. Our results suggest that, for antibody-based therapeutic strategies that target the activation of FcyRs, an additional level of control can be obtained by manipulation of autophagy.
Learning to Move and Plan like the Knight: Sequential Decision Making with a Novel Motor Mapping
Authors: Velázquez-Vargas Carlos A. , Taylor Jordan A.
Published: August 2024

Many skills that humans acquire throughout their lives, such as playing video games or sports, require substantial motor learning and multi-step planning. While both processes are typically studied separately, they are likely to interact during the acquisition of complex motor skills. In this work, we studied this interaction by assessing human performance in a sequential decision-making task that requires the learning of a non-trivial motor mapping. Participants were tasked to move a cursor from start to target locations in a grid world, using a standard keyboard. Notably, the specific keys were arbitrarily mapped to a movement rule resembling the Knight chess piece. In Experiment 1, we showed the learning of this mapping in the absence of planning, led to significant improvements in the task when presented with sequential decisions at a later stage. Computational modeling analysis revealed that such improvements resulted from an increased learning rate about the state transitions of the motor mapping, which also resulted in more flexible planning from trial to trial (less perseveration or habitual responses). In Experiment 2, we showed that incorporating mapping learning into the planning process, allows us to capture (1) differential task improvements for distinct planning horizons and (2) overall lower performance for longer horizons. Additionally, model analysis suggested that participants may limit their search to three steps ahead. We hypothesize that this limitation in planning horizon arises from capacity constraints in working memory, and may be the reason complex skills are often broken down into individual subroutines or components during learning.
Epigenomic anomalies in induced pluripotent stem cells from Alzheimer’s disease cases
Authors: Flamier Anthony , Katbe Alisar , Serhani Dounya , Hamam Rimi , Hogan Ryan , Tavares Erika , Héon Élise , Hanna Roy , Bernier Gilbert
Published: August 2024

Reprogramming of adult somatic cells into induced pluripotent stem cells (iPSCs) resets the aging clock. However, primed iPSCs can retain cell-of-origin epigenomic marks, especially those linked to heterochromatin and lamina-associated regions. Here we show that iPSCs produced from dermal fibroblasts of late-onset sporadic Alzheimer’s disease (AD) cases retain epigenomic anomalies that supersede developmental defects and neurodegeneration. When compared to iPSCs from elderly controls, AD iPSCs show reducedBMI1expression, lower H3K9me3 levels, and an altered DNA methylome. Gene Ontology analysis of differentially methylated DNA regions (DMRs) reveals terms linked to cell-cell adhesion and synapse, with the cognitive resilience-associated MEF2 family of transcription factors being the most enriched at DMRs. Upon noggin exposure, AD iPSCs show lesser efficient neural induction and forebrain specification, together with increased ZIC2, ZIC5 and WNT-related gene expression. Long-term AD neuronal cultures present a dedifferentiation and loss-of-cell identity phenotype. Despite these epigenomic anomalies, AD iPSCs generate cortical neurons in normal proportion and readily form cerebral organoids developing amyloid and Tau pathology. BMI1 overexpression in AD neurons mitigates amyloid and tau accumulation, heterochromatin fragmentation, and G4 DNA induction. These findings implicate reprogramming resistant epigenomic anomalies or uncharacterized genetic alterations working in trans on the epigenome in AD pathophysiology.
Determining the off-target activity of antibiotics and novel translation initiation sites in mitochondria
Authors: Marks James , Young Emma , Hafner Markus
Published: August 2024

Mitochondria translate the 13 mitochondrially encoded proteins using a dedicated translation system that closely resembles the one found in prokaryotes. Consequently, many bacterial protein synthesis inhibitors, used as antibiotics, exhibit mitochondrial toxicity as off-target effects. However, whether these antibiotics act through the same mechanisms in mitochondria as in bacteria remains unclear. To address this, we characterized the impact of a panel of bacterial translation and elongation inhibitors on mitochondrial translation through mitoribosome profiling. We found that the mechanism of action for every antibiotic, except telithromycin, is the same in both bacteria and mitochondria. Additionally, mitoribosome profiling data showed thatMT-ND1andMT-ND5have incorrectly annotated translation initiation sites and suggested several novel mitochondrial translation events. Careful study of the mechanisms of mitochondrial translation inhibition can guide development of antibiotics with increased target specificity and reduced mitochondrial toxicity.
DEVELOPMENT OF AN IDENTIFICATION METHOD FORLeishmaniaspp BASED ON REAL-TIME PCR WITH HIGH-RESOLUTION MELTING
Authors: Villareal Julio Rafael , Ordoñez Brayan E. , Pérez Gabriel A. , Manjarrez Valeria , Julio Katia Villarreal , Muskuz Carlos
Published: August 2024

Introduction

Leishmaniasisis a disease caused by parasites of the genusLeishmania. In Colombia, 6 pathogenic species have been reported. Traditional parasitological diagnosis based on the observation of parasites does not allow the species to be identified, which is why biochemical or molecular methods must be used, including conventional PCR, but this has some limitations and requires long periods of time to obtain results., which are sometimes inconclusive.

General Objective

Implement a methodology based on PCR-HRM, which allows the simultaneous detection and identification of parasites of theLeishmaniagenus in clinical samples from patients or parasites in cultures.

Materials and methods

A PCR-HRM was standardized, through which 237 clinical samples were evaluated, 98 classified as positive and 139 as parasitologically negative by direct and/or culture. The typings were compared with a previously standardized PCR-RFLP.

Results

It was possible to implement a PCR-HRM for the diagnosis and identification ofLeishmaniaspecies, obtaining 100% agreement with the typings obtained by PCR-RFLP. It was even possible to detect and identify the parasite in samples diagnosed as negative by conventional methods. It was found that, with a reliability percentage greater than 95%, 91 samples out of 98 were typed, of which 81.63% of the cases were L. panamensis, 11.22% were L. braziliensis and 7.14 were indeterminate.% of cases.

Conclusions

PCR-HRM is a good method that allows the identification of the most prevalent species in Colombia, comparing specific mean denaturation temperatures according to theLeishmaniaspecies involved.
Exome sequencing identifiesABCA7as an important gene for familial AD cases from Eastern India
Authors: Sadhukhan Dipanwita , Mukherjee Adreesh , Bhattacharyya Bidisha , Mishra Smriti , Banerjee Tapas Kumar , Das Gautam , Sinharoy Uma , Hui Subhra Prakash , Gupta Soma , Biswas Atanu , Biswas Arindam
Published: August 2024

Introduction

AD is the most complex disorder leading to dementia worldwide. Despite the disease burden among Indians the mutation spectrum in our subcontinent is not well examined.

Methods

To identify probable causal variants for AD, in a total of 29 clinically diagnosed, majorly familial and young onset AD cases from Eastern India, whole exome analysis in Illumina NovoSeq. 6000 sequencing platform was performed as per standard methodology. Next, the coding variants were prioritised based on the literature and our bioinformatic analyses for genotype-to-phenotype correlation.

Results

A total of 25 missense variants and 4 nonsense variants in 17 genes among 23 AD cases were identified as probable damaging ones in our study cohort. Amongst all,ABCA7account for the maximum number of pathogenic variants (5/29). A lowering in the age of onset was observed for mutation carriers and cases belonging to the posterior cortical atrophy (PCA) subgroup. Our further comparative analyses suggested that variants in APP metabolism pathway genes are more common in PCA, frontal AD, and young-onset multi-domain amnestic phenotypes than dysexecutive and typical AD.

Conclusion

Our study suggests that whole exome sequencing among Indian AD patients holds the potential to identify the most common gene as well as clinically relevant new causal variants which may highlight new insight into disease mechanism through future research.
The social determinants of maternal and congenital syphilis at the Colombia-Venezuela border: A qualitative study of twenty mothers of newborns with congenital syphilis
Authors: Parada Doris , Wirtz Andrea , Olarte Rafael , Pedraza Magaly , Hoffmann Bert , Blofield Merike
Published: August 2024

Humanitarian crises and resulting out-migration have created contexts in which treatable diseases such as syphilis have expanded in prevalence. Untreated syphilis can have potentially irreversible and devastating consequences, especially for infants born with congenital syphilis. Our study aimed to understand the experiences of postpartum mothers whose newborns have been diagnosed with congenital syphilis and explore the social determinants of maternal and congenital syphilis. The setting of our study is the main public hospital in Cúcuta, Colombia, at the border with Venezuela, which provides emergency care to everyone regardless of documentation and thus receives a high share of Venezuelan migrants. We conducted twenty in-depth interviews with women who had their newborns hospitalized with a diagnosis of congenital syphilis. Sampling was conducted purposively at the hospital, between March and June 2023. Study participants were mostly Venezuelan migrants and Colombian returnees, from their teens to their forties. We used a grounded theory technique to conduct thematic analysis. Four major themes emerged: 1) experiencing a pregnancy in the context of a lack of resources, violence and ignorance; 2) guilt with and reinfection of syphilis; 3) challenges and limitations in accessing health care; and 4) limited support networks and machismo. Reported challenges were intertwined with the high costs of health care in the country of origin, the lack of knowledge of sexually transmitted infections, the limited public health education targeting this population group, and the absence of Colombian public policies that promote care for the non-regularized migrant population.
Predictors of successful weaning from Veno-Arterial Extracorporeal Membrane Oxygenation (V-A ECMO): A Systematic Review and Meta-analysis
Authors: Hsu Henry R. , Sekhar Praba , Grover Jahnavi , Tian David H. , Downey Ciaran , Maudlin Ben , Dissanayake Chathuri , Dennis Mark
Published: August 2024

Background

Venoarterial extracorporeal membrane oxygenation (V-A ECMO) use to support patients in cardiac failure is increasing. Despite this increased use, predicting successful weaning from ECMO can be challenging, no uniform guidelines on weaning exist. Therefore, we completed a systematic review to evaluate prognostic factors that predict successful weaning from V-A ECMO.

Methods

Following the PRIMSA guidelines, a systematic literature search of Medline, Embase, SCOPUS and CENTRAL identified original research studies of patients requiring V-A ECMO where weaning was attempted. Data was collected on demographic factors and weaning protocol, biomarkers, haemodynamic, echocardiographic factors for the successfully weaned (SW) and not successfully weaned (NSW) groups. Two investigators reviewed studies for relevance, extracted data, and assessed risk of bias using the ROBINS-I tool. The study was registered on the international prospective register of systematic reviews (PROSPERO ID# CRD42022366153).

Results

1219 records were screened, of which 20 studies were deemed sufficient to be included in the statistical analysis based on pre-specified criteria. Factors associated with successful weaning were higher left ventricular ejection fraction (LVEF) (MD 9.0, 95% CI 4.1 – 13.8; p<0.001) and left ventricular outflow tract velocity time integral (LVOT VTI) at time of weaning, (MD 1.35, 95% CI 0.28 – 2.40 lactate at admission (MD -2.5, 95%CI -3.8 – -1.1, p<0.001;), and CK-MB at admission (MD -4.11, 95%CI -6.6 to -1.6, p=0.001). Critical appraisal demonstrated moderate-high risk of bias owing to confounding and low sample sizes.

Conclusion

In patients on V-A ECMO support being assessed for weaning multi-parametric assessment is required. Moderate-high heterogeneity and low sample sizes warrant higher-quality studies to help guide decisions to wean patients from V-A ECMO.
Coupled stack-up volume RF coils for low-field open MR imaging
Authors: Zhao Yunkun , Bhosale Aditya A , Zhang Xiaoliang
Published: August 2024

Background

Low-field open magnetic resonance imaging (MRI) systems, typically operating at magnetic field strengths below 1 Tesla, has greatly expanded the accessibility of MRI technology to meet a wide range of patient needs. However, the inherent challenges of low-field MRI, such as limited signal-to-noise ratios and limited availability of dedicated radiofrequency (RF) coils, have prompted the need for innovative coil designs that can improve imaging quality and diagnostic capabilities.

Purpose

In response to these challenges, we introduce the coupled stack-up volume coil, a novel RF coil design that addresses the shortcomings of conventional birdcage in the context of low-field open MRI.

Methods

The proposed coupled stack-up volume coil design utilizes a unique architecture that optimizes both transmit/receive efficiency and RF field homogeneity and offers the advantage of a simple design and construction, making it a practical and feasible solution for low-field MRI applications. This paper presents a comprehensive exploration of the theoretical framework, design considerations, and experimental validation of this innovative coil design.

Results

We demonstrate the superior performance of the coupled stack-up volume coil in achieving 47.7% higher transmit/receive efficiency and 68% more uniform magnetic field distribution compared to traditional birdcage coils in electromagnetic simulations. Bench tests results show that the B1 field efficiency of coupled stack-up volume coil is 57.3% higher compared with that of conventional birdcage coil.

Conclusions

The proposed coupled stack-up volume coil outperforms the conventional birdcage coil in terms of B1 efficiency, imaging coverage, and low-frequency operation capability. This design provides a robust and simple solution to low-field MR RF coil design.
Studying Veteran food insecurity longitudinally using electronic health record data and natural language processing
Authors: Chapman Alec B. , Panadero Talia , Dalrymple Rachel , Cohen Alicia , Kamdar Nipa , Pethani Farhana , Kalvesmaki Andrea , Nelson Richard E. , Butler Jorie
Published: August 2024

Food insecurity is an important social risk factor that is directly linked to patient health and well-being. The Department of Veterans Affairs (VA) aims to identify and resolve food insecurity through social and clinical interventions. However, evaluating the impact of such interventions is made challenging by the lack of follow-up data on Veteran food insecurity status. One potential solution is to leverage documentation of food insecurity in electronic health records (EHRs). In this paper, we developed and validated a natural language processing system to identify food insecurity status from clinical notes and applied it to study longitudinal trajectories of food insecurity among a large cohort of food insecure Veterans. Our analyses provide insight into the timing and persistence of Veteran food insecurity; in the future, our methods will be used to evaluate food insecurity interventions and evaluate VA policy.
Hungry catfish – effect of prey availability on movement dynamics of a top predator
Authors: Říha Milan , Rabaneda-Bueno Rubén , Vejřík Lukáš , Jarić Ivan , Prchalová Marie , Šmejkal Marek , Čech Martin , Draštík Vladislav , Blabolil Petr , Holubová Michaela , Jůza Tomáš , Gjelland Karl Ø. , Sajdlová Zuzana , Kočvara Luboš , Tušer Michal , Peterka Jiří
Published: August 2024

The availability and spatial distribution of prey determines the energetic costs of predators foraging and largely drives their space use, activity level and foraging timing. Consequently, predators in ecosystems with different prey availability and distribution should adjust their movement patterns to optimise their foraging success in order to maximise efficiency.

The aim of this study was to investigate the ability of a top predator, European catfish (Silurus glanis), to adapt its space use, temporal activity and diet patterns in environments with varying prey density and distribution, and to examine the consequences for the catfish’s body growth.

Catfish activity, tracked with high-resolution acoustic telemetry positioning systems deployed in two oligotrophic lakes with limited fish prey and one eutrophic reservoir with abundant fish prey, showed clear differences in their spatial and foraging behaviour. In oligotrophic, prey-poor lakes, catfish showed larger space use, altered diurnal activity patterns, reduced use of the open water, increased variability in inter- and intra-individual space use and had a more diverse diet compared to their conspecifics in the eutrophic, prey-rich reservoir. However, despite these behavioural alterations the reduced food availability in prey-poor lakes ultimately led to a reduced catfish growth, as these behavioural changes could not fully compensate for the lower prey fish abundance.

The study showed that top predators can combine different behavioural mechanisms and individual strategies to adapt to different ecological contexts. The observed ability of catfish to optimize activity, space use and diet highlights the evolutionary need to maximise foraging efficiency and overall fitness in different habitats, giving catfish a significant competitive advantage. Such competitive abilities are prerequisites for the actual catfish success as an invasive species within a Europe.