bluuebunny/crossref_metadata_2025 huggingface dataset:
Implications of von Willebrand Factor in Inflammatory Bowel Diseases: Beyond Bleeding and Thrombosis
Authors: Lagrange Jérémy , Ahmed Muhammad Usman , Arnone Djésia , Lacolley Patrick , Regnault Véronique , Peyrin-Biroulet Laurent , Denis Cécile V
Published: July 2024

Inflammatory bowel disease (IBD) displays an increased venous and arterial thrombotic risk despite the common occurrence of intestinal bleeding. While some of the mechanisms leading to these thrombotic complications have been studied, other specific changes in the hemostasis profile of IBD patients have been less explored. One such example relates to von Willebrand factor (VWF) whose plasma levels have been reported to be modulated in IBD. Von Willebrand factor is a plasma glycoprotein crucial for hemostatic functions via roles both in platelet function and coagulation. High plasma VWF is a known risk factor for venous thromboembolism. In addition to its canonical roles in hemostasis, VWF is known to be directly or indirectly involved in other vascular processes such as maintenance of endothelial barrier integrity or proliferation of vascular smooth muscle cells. The purpose of this review is to recapitulate and update the existing data about VWF biology in IBD and to highlight its role both in the existing procoagulant phenotype and in vascular alterations that may occur in IBD.
A simple and easy-to-implement battery equalization strategy for photovoltaic-battery energy storage systems
Authors: Mao Yuexuan , Zhu Qingxiao , Fang Xuekao , Paul Williams
Published: July 2024

For renewable energy sources such as photovoltaic (PV), energy storage systems should be prioritized as they smooth the output well. Although lithium-ion battery energy storage systems are favored for their excellent performance, the large number of batteries connected in series and parallel may lead to inconsistent battery packs, which can cause system problems. Therefore, battery equalization techniques should be employed. This article proposes a battery equalization technique suitable for PV battery energy storage systems. In terms of the equalization circuit, we propose an equalization circuit consisting of a switch-selective circuit and a Cuk circuit, which is simple and easy to expand; in terms of the equalization strategy, we adopt a highly robust fuzzy logic control to better adapt to PV battery energy storage systems, we developed a set of control rules suitable for this equalization strategy. We have investigated the principle of the proposed battery equalization technique and verified it experimentally during the battery pack's resting, charging, and discharging. The consistency of the battery pack is significantly improved as a result.
Genomic Epidemiology and Evolution of Rhinovirus in Western Washington State, 2021–2022
Authors: Goya Stephanie , Wendm Seffir T , Xie Hong , Nguyen Tien V , Barnes Sarina , Shankar Rohit R , Sereewit Jaydee , Cruz Kurtis , Pérez-Osorio Ailyn C , Mills Margaret G , Greninger Alexander L
Published: July 2024

Background

Human rhinoviruses (RVs) primarily cause the common cold, but infection outcomes vary from subclinical to severe cases, including asthma exacerbations and fatal pneumonia in individuals who are immunocompromised. To date, therapeutic strategies have been hindered by the high diversity of serotypes. Global surveillance efforts have traditionally focused on sequencing VP1 or VP2/VP4 genetic regions, leaving gaps in our understanding of RV genomic diversity.

Methods

We sequenced 1078 RV genomes from nasal swabs of symptomatic and asymptomatic individuals to explore viral evolution during 2 epidemiologically distinct periods in Washington State: when the COVID-19 pandemic affected the circulation of other seasonal respiratory viruses except for RV (February–July 2021) and when the seasonal viruses reemerged with the severe outbreak of respiratory syncytial virus and influenza (November–December 2022). We constructed maximum likelihood and BEAST phylodynamic trees to characterize intragenotype evolution.

Results

We detected 99 of 168 known genotypes and observed intergenotypic recombination and genotype cluster swapping from 2021 to 2022. We found a significant association between the presence of symptoms and viral load but not with RV species or genotype. Phylodynamic trees, polyprotein selection pressure, and Shannon entropy revealed cocirculation of divergent clades within genotypes with high amino acid constraints throughout the polyprotein.

Conclusions

Our study underscores the dynamic nature of RV genomic epidemiology within a localized geographic region, as >20% of existing genotypes within each RV species cocirculated each studied month. Our findings also emphasize the importance of investigating correlations between RV genotypes and serotypes to understand long-term immunity and cross-protection.
Necrotising fasciitis, invasive Group A Streptococcus (iGAS) infection; a case series of 8 patients requiring surgical debridement in one trauma unit within 9 months
Authors: Salim Omar-Adam , Hillier-Smith Ryan , Ardolino Antonella
Published: July 2024

Necrotising fasciitis (NF) is a rare but life-threatening skin and soft tissue infection. It requires urgent surgical debridement. The most common cause of monomicrobial NF is invasive Group A Streptococcus (IGAS). We present eight patients who were all treated in a single trauma unit within a 9-month period. All cases required surgical debridement and had positive microbiology testing for IGAS. The eight patients did not present typically for NF, nor did they all have typical risk factors for the development of NF. The in-hospital mortality rate was 37.5%. This series represents an epidemiological spike of IGAS infections causing NF. The findings from this series could inform future practice if similar spikes were to be encountered.
Atraumatic splenic rupture as first presentation of hairy cell leukaemia—a case report
Authors: Wood Phoebe C , Simpson Fraser H , Lehane Katie , Yuide Peter , Franz Robert
Published: July 2024

Atraumatic splenic rupture is a complex surgical pathology owing to its rarity, non-specificity of symptoms and gravity of possible outcomes. This case outlines the investigation and management of a patient with atraumatic splenic rupture secondary to undiagnosed hairy cell leukaemia. While the patient was initially managed conservatively, they went on to have a splenectomy owing to ongoing transfusion requirements. A review of the literature has also been performed and presented to highlight the potential causes of atraumatic splenic rupture and the various options for confirming diagnosis and definitive management.
Fragmentation in the European and Inter-American Human Rights Courts Regarding the Scope of Religious Autonomy: An Analysis of the Use of Sources and Methodologies
Authors: García Escobar Gabriela
Published: July 2024

Fragmentation in International Human Rights Law (IHRL) may affect the universality of human rights norms and their legitimacy. This article analyses a recent case of contradiction between the European and the Inter-American Court of Human Rights (IACHR) regarding employment contracts of religious education teachers and the scope of religious autonomy. These courts reached contradictory conclusions on key substantive issues because they used different ways of framing the issue at stake, and different legal sources and interpretative methodologies. The analysis reveals that while the European Court of Human Rights (ECHR) relied on the use of comparative law, a test of proportionality, and the margin of appreciation, the IACHR relied mainly on American domestic law and the opinions of two expert witnesses. In this case, the IACHR could learn from the approach of the ECHR to develop a more rigorous legal methodology in order to keep the coherence of the international legal system.
Association of Positive, Negative, and Disorganized Schizotypy With the Temporal Dynamics of Schizotypic Experiences in Daily Life
Authors: Kemp Kathryn C , Sperry Sarah H , Hernández Laura , Barrantes-Vidal Neus , Kwapil Thomas R
Published: July 2024

Background and Hypothesis

Schizotypy is a useful and unifying construct for examining the etiology, development, and expression of schizophrenia-spectrum psychopathology. The positive, negative, and disorganized schizotypy dimensions are associated with distinct patterns of schizophrenia-spectrum symptoms and impairment. Furthermore, they are differentiated by mean levels of psychotic-like, suspicious, negative, and disorganized schizotypic experiences in daily life, and by temporal dynamics of affect. The schizotypy dimensions were thus hypothesized to be differentiated by the temporal dynamics of schizotypic experiences in daily life.

Study Design

The present study employed experience sampling methodology in a large nonclinically ascertained sample (n = 693) to examine the associations of multidimensional schizotypy with psychotic-like, suspicious, negative, and disorganized schizotypic experiences in daily life, as well as with their temporal dynamics (variability, reactivity, inertia, and instability).

Study Results

We replicated the mean-level associations between multidimensional schizotypy and schizotypic experiences in daily life. Furthermore, positive, negative, and disorganized schizotypy demonstrated hypothesized, differential patterns of temporal dynamics of schizotypic experiences. Disorganized schizotypy demonstrated the most robust associations, including intensity, variability, and inertia of disorganized schizotypic experiences. Disorganized schizotypy also moderated reactivity of psychotic-like and disorganized schizotypic experiences following previously reported stress. Positive schizotypy was associated with intensity and variability of psychotic-like experiences. Negative schizotypy was associated with intensity and variability of negative schizotypic experiences.

Conclusions

The findings indicate that schizotypy dimensions can be differentiated by both mean levels and temporal patterns of psychotic-like, suspicious, negative, and disorganized schizotypic experiences in daily life, with disorganized schizotypy uniquely characterized by stress reactivity.
A 10-year mono-center study on patients with burns ≥70% TBSA: prediction model construction and multicenter validation – retrospective cohort
Authors: Huang Runzhi , Yao Yuntao , Li Linhui , Tong Xirui , Liu Yifan , Li Junqiang , Xu Dayuan , Wu Minjuan , Chang Zhengyan , Xu Long , Xian Shuyuan , Xie Sujie , Zhang Wei , Lu Jianyu , Lu Yuwei , Lu Bingnan , Wang Siqiao , Qian Weijin , Sun Hanlin , Jin Minghao , Huang Jie , Yang Yiting , Zhu Yushu , Li Yuanan , Guo Xinya , Gu Minyi , Jiang Luofeng , Luo Pengfei , Xiao Shichu , Ji Shizhao
Published: July 2024

Background:

Burn injuries with ≥70% total body surface area (TBSA) are especially acute and life-threatening, leading to severe complications and terrible prognosis, while a powerful model for the prediction of overall survival (OS) is lacking. The objective of this study is to identify prognostic factors for the OS of patients with burn injury ≥70% TBSA and construct and validate a feasible predictive model.

Materials and methods:

Patients diagnosed with burns ≥70% TBSA admitted and treated between 2010 and 2020 in our hospital were included. A cohort of the patients from the Kunshan explosion were assigned as the validation set. The χ
2 test and K-M survival analysis were conducted to identify potential predictors for OS. Then, multivariate Cox regression analysis was performed to identify the independent factors. Afterward, we constructed a nomogram to predict OS probability. Finally, the Kunshan cohort was applied as an external validation set.

Results:

Sex, the percentage of third-degree and fourth-degree burns as well as organ dysfunction were identified as significant independent factors. A nomogram only based on the factors of the individuals was built and evidenced to have promising predictive accuracy, accordance, and discrimination by both internal and external validation.

Conclusions:

This study recognized significant influencing factors for the OS of patients with burns ≥70% TBSA. Furthermore, our nomogram proved to be an effective tool for doctors to quickly evaluate patients’ outcomes and make appropriate clinical decisions at an early stage of treatment.
Accelerated High-Resolution Deep Learning Reconstruction Turbo Spin Echo MRI of the Knee at 7 T
Authors: Marth Adrian Alexander , von Deuster Constantin , Sommer Stefan , Feuerriegel Georg Constantin , Goller Sophia Samira , Sutter Reto , Nanz Daniel
Published: July 2024

Objectives

The aim of this study was to compare the image quality of 7 T turbo spin echo (TSE) knee images acquired with varying factors of parallel-imaging acceleration reconstructed with deep learning (DL)–based and conventional algorithms.

Materials and Methods

This was a prospective single-center study. Twenty-three healthy volunteers underwent 7 T knee magnetic resonance imaging. Two-, 3-, and 4-fold accelerated high-resolution fat-signal-suppressing proton density (PD-fs) and T1-weighted coronal 2D TSE acquisitions with an encoded voxel volume of 0.31 × 0.31 × 1.5 mm3 were acquired. Each set of raw data was reconstructed with a DL-based and a conventional Generalized Autocalibrating Partially Parallel Acquisition (GRAPPA) algorithm. Three readers rated image contrast, sharpness, artifacts, noise, and overall quality. Friedman analysis of variance and the Wilcoxon signed rank test were used for comparison of image quality criteria.

Results

The mean age of the participants was 32.0 ± 8.1 years (15 male, 8 female). Acquisition times at 4-fold acceleration were 4 minutes 15 seconds (PD-fs, Supplemental Video is available at http://links.lww.com/RLI/A938) and 3 minutes 9 seconds (T1, Supplemental Video available at http://links.lww.com/RLI/A939). At 4-fold acceleration, image contrast, sharpness, noise, and overall quality of images reconstructed with the DL-based algorithm were significantly better rated than the corresponding GRAPPA reconstructions (P < 0.001). Four-fold accelerated DL-reconstructed images scored significantly better than 2- to 3-fold GRAPPA-reconstructed images with regards to image contrast, sharpness, noise, and overall quality (P ≤ 0.031). Image contrast of PD-fs images at 2-fold acceleration (P = 0.087), image noise of T1-weighted images at 2-fold acceleration (P = 0.180), and image artifacts for both sequences at 2- and 3-fold acceleration (P ≥ 0.102) of GRAPPA reconstructions were not rated differently than those of 4-fold accelerated DL-reconstructed images. Furthermore, no significant difference was observed for all image quality measures among 2-fold, 3-fold, and 4-fold accelerated DL reconstructions (P ≥ 0.082).

Conclusions

This study explored the technical potential of DL-based image reconstruction in accelerated 2D TSE acquisitions of the knee at 7 T. DL reconstruction significantly improved a variety of image quality measures of high-resolution TSE images acquired with a 4-fold parallel-imaging acceleration compared with a conventional reconstruction algorithm.
Decision-making Considerations in Revisional Bariatric Surgery
Authors: Chen Sheena , Chiang Jessica , Ghanem Omar , Ferzli George
Published: July 2024

Objective:

With drastic variations in bariatric practices, consensus is lacking on an optimal approach for revisional bariatric surgeries.

Materials and Methods:

The authors reviewed and consolidated bariatric surgery literature to provide specific revision suggestions based on each index surgery, including adjustable gastric band (AGB), sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion with duodenal switch (BPD-DS), single anastomosis duodenal-ileal bypass with sleeve (SADI-S), one anastomosis gastric bypass (OAGB), and vertical banded gastroplasty (VBG).

Results:

AGB has the highest weight recurrence rate and can be converted to RYGB, SG, and BPD-DS. After index SG, common surgical options include a resleeve or RYGB. The RYGB roux limb can be distalized and pouch resized in context of reflux, and the entire anatomy can be revised into BPD-DS. Data analyzing revisional surgery after a single anastomosis duodenal-ileal bypass with sleeve was limited. In patients with one anastomosis gastric bypass and vertical banded gastroplasty anatomy, most revisions were the conversion to RYGB.

Conclusions:

As revisional bariatric surgery becomes more common, the best approach depends on the patient’s indication for surgery and preexisting anatomy.
U-shaped Relationship Between Body Mass Index and Intracerebral Hemorrhage-Related Functional Decline
Authors: Kanejima Yuji , Ogawa Masato , Ishihara Kodai , Yoshida Naofumi , Nakai Michikazu , Kanaoka Koshiro , Sumita Yoko , Emoto Takuo , Sakai Yoshitada , Iwanaga Yoshitaka , Miyamoto Yoshihiro , Yamashita Tomoya , Hirata Kenichi , Izawa Kazuhiro P.
Published: July 2024

BACKGROUND

Intracerebral hemorrhage (ICH) has a high mortality rate, and even if patients survive, they are likely to have severe disability. Body mass index (BMI) is associated with ICH risk, and extremely low and high BMIs are associated with the site of ICH, which affects functional decline. However, few reports exist on ICH-related functional decline and BMI. This study aimed to clarify the relationship between BMI and stroke-related disability of patients with ICH.

METHODS

Patients with ICH registered in the Japanese Registry Of All Cardiac and Vascular Diseases Diagnosis Procedure Combination (JROAD-DPC) database from April 2016 to March 2020 were included. BMI was defined according to the World Health Organization Asia-Pacific classification. Functional disability was assessed using the modified Rankin Scale (mRS). ICH-related functional decline was defined as an increase in mRS score at discharge compared with that of the pre-stroke assessment.

RESULTS

This study included 155,211 patients with ICH whose median age was 72.0 years and mean BMI was 22.3 kg/m2. The ratio of patients with ICH who experience functional decline was 74.9%. The spline curve between BMI and ICH-related functional decline was U-shaped, revealing that the Normal to Obese I BMI groups (BMI: 22.2–30.4 kg/m2) exhibited reduced odds ratios for ICH-related functional decline. Hospitalization cost and BMI showed similar U-shaped patterns, with a BMI of 25.0 kg/m2as the lowest point, regardless of age group.

CONCLUSION

In patients with ICH, those with both extremely low and high BMIs were more likely to experience functional decline after ICH onset, which resulted in increased hospitalization costs. To reduce ICH-related functional decline, patients should be managed at a normal to slightly obese BMI.
Differential Antibody Response To Polysaccharide Vaccines Following Allogeneic Stem Cell Transplantation; A Dynamical Systems Perspective
Authors: Zelikson Viktoriya , Khan Maheen , Horton Morgan , Ho Thuy , Roberts Catherine , Toor Amir
Published: July 2024

Bacterial polysaccharide vaccination is generally commenced within 6 months to 1 year following SCT. Antibody responses to these vaccines tend to be variable, raising concerns for inadequate protection from infection and the potential for repeated vaccination. This landmark analysis was performed to evaluate pathogen specific antibody titers, as well as helper T cell and B cell recovery from transplant and post-vaccination amongst patients surviving at least 6 months post allogeneic SCT. Antibody titers to various pneumococcal serotypes and Hemophilus influenza type B (HiB) followed a Power Law distribution in each individual at all time points evaluated. Distinct serotype vaccine responses were observed and antibody titer hierarchy developed early after vaccination and was maintained over time. When B cell recovery was modeled as a function of helper T cell reconstitution over time, the robustness of the antibody response was dependent on threshold values of cellular immune recovery. These suggest that antibody responses are a highly regulated dynamical system.
Measuring the effect of RFID and Marker Recognition tags on cockroach behaviour using AI aided tracking
Authors: McLean Callum J , Fisher David N
Published: July 2024

RFID technology and marker recognition algorithms can offer an efficient and non-intrusive means of tracking animal positions. As such, they have become important tools for invertebrate behavioural research. Both approaches require fixing a tag or marker to the study organism, and so it is useful to quantify the effects such procedures have on behaviour before proceeding with further research. However, frequently studies do not report doing such tests. Here, we demonstrate a time-efficient and accessible method for quantifying the impact of tagging on individual movement using open-source automated video tracking software. We tested the effect of RFID tags and tags suitable for marker recognition algorithms on the movement of Argentinian wood roaches (Blapicta dubia) by filming tagged and untagged roaches in laboratory conditions. We employed DeepLabCut on the resultant videos to track cockroach movement and extract measures of behavioural traits. We found no statistically significant differences between RFID tagged and untagged groups in average speed over the trial period, the number of unique zones explored, and the number of discrete walks. However, groups that were tagged with labels for marker recognition had significantly higher values for all three metrics. We therefore support the use of RFID tags to monitor the behaviour ofB. dubiabut note that the effect of using labels suitable for label recognition to identify individuals should be taken into consideration when measuringB.dubiabehaviour. We hope that this study can provide an accessible and viable roadmap for further work investigating the effects of tagging on insect behaviour.
Reticulate leaf venation inPilea peperomioidesis a Voronoi diagram
Authors: Zheng Xingyu , Venezia Matthew , Blum Elijah , Pedmale Ullas V. , Jackson Dave , Prusinkiewicz Przemyslaw , Navlakha Saket
Published: July 2024

Reticulate leaf venation, characterized by the presence of loops, is a distinguishing feature of many flowering plants. However, our understanding of both the geometry and the morphogenesis of reticulate vein patterns is far from complete. We show that in the Chinese money plant (Pilea peperomioides), major veins form an approximate Voronoi diagram surrounding secretory pores known as hydathodes. We also propose a mechanistic model based on polar transport of the plant hormone auxin to produce Voronoi patterns. In contrast with classical models where veins directly connect auxin sources to sinks, our model generates veins that bisect the space between adjacent auxin sources, collectively forming loops. The paradigm change offered by this model may open the door to study reticulate vein formation in other species.
Load-dependent and load-independent effects on longitudinal motor training in human continuous hand movements
Authors: Wang Xiaolu , Liang Xuan , Ku Yixuan , Zhan Yinwei , Song Rong
Published: July 2024

Motor learning involves complex interactions between the cognitive and sensorimotor systems, which is susceptible to different levels of task load. While the mechanism underlying load-dependent regulations in cognitive functions has been extensively investigated, their influence on downstream execution in motor skill learning remains less understood. The current study extends the understanding of how load levels affect motor learning by a longitudinal functional near-infrared spectroscopy (fNIRS) study in which 30 participants (15 females) engaged in extensive practice on a two-dimensional continuous hand tracking task with varying task difficulties. We propose the index of difficulty (ID) as a quantitative estimate of task difficulty, which is positively correlated with psychometric measure of subjective workload level. Results shows that as behavioral performance improved over time, participants adopted a direction-specific and load-independent (i.e., consistent across different load levels) control strategy, shifting from feedback-dominant to feedforward-dominant control in the vertical direction as training progressed. Crucially, we provide robust evidence of the learning-induced alteration in load-dependent cortical activation patterns, suggesting that effective motor skill learning may lead to shift towards an inverted-U relationship between activation and load level in the pre-motor and supplementary motor areas. In addition, brain-behavior relationship in the frontoparietal network was strengthened after training. Taken together, our findings provide new insights into the learning-induced plasticity in brain and behavior associated with load-dependent and load-independent contributions to motor skill learning.
Rhythmic modulation of subthalamo-pallidal interactions depends on synaptic rewiring through inhibitory plasticity
Authors: Asl Mojtaba Madadi , Lea-Carnall Caroline A.
Published: July 2024

Rhythmic stimulation offers a paradigm to modulate brain oscillations and, therefore, influence brain function. A growing body of evidence indicates that reciprocal interactions between the neurons of the subthalamic nucleus (STN) and globus pallidus externus (GPe) play a central role in the emergence of abnormal synchronous beta (15-30 Hz) oscillations in Parkinson’s disease (PD). The proliferation of inhibitory GPe-to-STN synapses following dopamine loss exacerbates this pathological activity. Rhythmic modulation of the STN and/or GPe, for example, by deep brain stimulation (DBS), can restore physiological patterns of activity and connectivity. Here, we tested whether dual targeting of STN-GPe by rhythmic stimulation can modulate pathologically strong GPe-to-STN synapses through inhibitory spike-timing-dependent plasticity (iSTDP). More specifically, we examined how time-shifted paired stimuli delivered to the STN and GPe can lead to inter-population synaptic rewiring. To that end, we first theoretically analysed the optimal range of stimulation time shift and frequency for effective synaptic rewiring. Then, as a minimal model for generating subthalamo-pallidal oscillations in healthy and PD conditions, we considered a biologically inspired STN-GPe loop comprised of conductance-based spiking neurons. Consistent with the theoretical predictions, rhythmic stimulation with appropriate time shift and frequency modified GPe-to-STN interactions through iSTDP, i.e., by long-lasting rewiring of pathologically strong synaptic connectivity. This ultimately caused desynchronising after-effects within each population such that excessively synchronous beta activity in the PD state was suppressed, resulting in a decoupling of the STN-GPe network and restoration of healthy dynamics in the model. Decoupling effects of the dual STN-GPe stimulation can be realised by time-shifted continuous and intermittent stimuli, as well as monopolar and bipolar simulation waveforms. Our findings demonstrate the critical role of neuroplasticity in shaping long-lasting stimulation effects and may contribute to the optimisation of a variety of multi-site stimulation paradigms aimed at reshaping dysfunctional brain networks by targeting plasticity.
Mapping the Learning Curves of Deep Learning Networks
Authors: Jiang Yanru , Dale Rick
Published: July 2024

There is an important challenge in systematically interpreting the internal representations of deep neural networks. This study introduces a multi-dimensional quantification and visualization approach which can capture two temporal dimensions of a model learning experience: the "information processing trajectory" and the "developmental trajectory." The former represents the influence of incoming signals on an agent's decision-making, while the latter conceptualizes the gradual improvement in an agent's performance throughout its lifespan. Tracking the learning curves of a DNN enables researchers to explicitly identify the model appropriateness of a given task, examine the properties of the underlying input signals, and assess the model's alignment (or lack thereof) with human learning experiences. To illustrate the method, we conducted 750 runs of simulations on two temporal tasks: gesture detection and natural language processing (NLP) classification, showcasing its applicability across a spectrum of deep learning tasks. Based on the quantitative analysis of the learning curves across two distinct datasets, we have identified three insights gained from mapping these curves: nonlinearity, pairwise comparisons, and domain distinctions. We reflect on the theoretical implications of this method for cognitive processing, language models and multimodal representation.
A Drug-Elicitable Alternative-Splicing Module (DreAM) for Tunable AAV Expression and Controlled Myocardial Regeneration
Authors: Chen Zhan , Yang Luzi , Zhang Yueyang , Li Yue , Chen Gonglie , Wang Ze , Li Jiting , Yang Yuhan , Zhao Dongyu , Pu William T , Yang Ke , Dong Erdan , Guo Yuxuan
Published: July 2024

Adeno-associated virus (AAV) is a major vector for gene therapy. A technique to fine-tune the time and level of AAV expression is lacking, which greatly restricts indication choice, therapeutic efficacy and safety. To solve this problem, here we developed a drug-elicitable alternative-splicing module (DreAM) responsive to risdiplam, an FDA-approved alternative splicing modulator. Risdiplam activates DreAM-regulated AAV expression in a dose-dependent manner with an over 2000-fold inducible change depending on the inducer dosage and the organ of interests. With a temporally resolution of a couple of days, DreAM could repeatedly activate AAV expression, determined by the frequency and duration of risdiplam administration. As an example of DreAM-realized gene therapy, this technique was used to control AAV-based cardiac delivery of YAP5SA, a potent cardiomyocyte regeneration factor. DreAM transiently activated AAV-YAP5SA, establishing the dedifferentiation-proliferation-redifferentiation cycle in cardiomyocytes. Consequently, DreAM fulfilled the regenerative capacity of AAV-YAP5SAin myocardial infarction while circumventing toxicity associated with prolonged AAV-YAP5SAexpression. Together, these data demonstrated a tremendous potential of DreAM to enhance the efficacy, safety and applicable scope of gene therapy.
Dynamic functional connectivity correlates of trait mindfulness in early adolescence
Authors: Treves Isaac N , Marusak Hilary A , Decker Alexandra , Kucyi Aaron , Hubbard Nicholas A , Bauer Clemens C.C. , Leonard Julia , Grotzinger Hannah , Giebler Melissa A , Camacho Torres Yesi , Imhof Andrea , Romeo Rachel , Calhoun Vince , Gabrieli John D.E.
Published: July 2024

Background: Trait mindfulness, the tendency to attend to present-moment experiences without judgement, is negatively correlated with adolescent anxiety and depression. Understanding the neural mechanisms underlying trait mindfulness may inform the neural basis of psychiatric disorders. However, few studies have identified brain connectivity states that correlate with trait mindfulness in adolescence, nor have they assessed the reliability of such states. Methods: To address this gap in knowledge, we rigorously assessed the reliability of brain states across 2 functional magnetic resonance imaging (fMRI) scan from 106 adolescents aged 12 to 15 (50% female). We performed both static and dynamic functional connectivity analyses and evaluated the test-retest reliability of how much time adolescents spent in each state. For the reliable states, we assessed associations with self-reported trait mindfulness. Results: Higher trait mindfulness correlated with lower anxiety and depression symptoms. Static functional connectivity (ICCs from 0.31-0.53) was unrelated to trait mindfulness. Among the dynamic brains states we identified, most were unreliable within individuals across scans. However, one state, an hyperconnected state of elevated positive connectivity between networks, showed good reliability (ICC=0.65). We found that the amount of time that adolescents spent in this hyperconnected state positively correlated with trait mindfulness. Conclusions: By applying dynamic functional connectivity analysis on over 100 resting-state fMRI scans, we identified a highly reliable brain state that correlated with trait mindfulness. The brain state may reflect a state of mindfulness, or awareness and arousal more generally, which may be more pronounced in those who are higher in trait mindfulness.
HIV Coreceptors Related Genes (CCR5 and CXCR4) Promoter Methylation: Original Research
Authors: Esman Anna , Salamaikina Svetlana , Kirichenko Alina , Vinokurov Michael , Fomina Darya , Sikamov Kirill , Syrkina Arina , Pokrovskaya Anastasiya , Akimkin Vasily
Published: July 2024

The persistence of human immunodeficiency virus (HIV) within viral reservoirs poses significant challenges to eradication efforts. Epigenetic alterations, including DNA methylation, are potential factors influencing HIV latency and persistence. This study details the development and application of techniques to assess CpG methylation in the promoter regions of theCCR5andCXCR4genes, key HIV-1 coreceptors. Using both Sanger sequencing and pyrosequencing methods, we examined 51 biological samples from 17 HIV-1-infected individuals at three time points: baseline (Week 0) and post-antiretroviral therapy (ART) at Weeks 24 and 48. Our results revealed thatCXCR4promoter CpG sites were largely unmethylated, whileCCR5promoter CpGs exhibited significant variability in methylation levels. Specifically,CCR5CpG 1 showed a significant decrease in methylation from Week 0 to Week 48, whileCXCR4CpG 3 displayed a significant decrease between Week 0 and Week 24. These differences were statistically significant when compared with non-HIV-infected controls. These findings demonstrate distinct methylation patterns betweenCCR5andCXCR4promoters in HIV-1 positive individuals over time, suggesting that epigenetic modifications may play a role in regulating HIV-1 persistence. Our techniques provide a reliable framework for assessing gene promoter methylation and could be applied to further research in HIV epigenetics.
Intra- and interspecific variations in flight performance of oak-associated Agrilinae (Coleoptera: Buprestidae) using computerised flight mills
Authors: Le Souchu Elodie , Sallé Aurélien , Bankhead-Dronnet Stéphanie , Laparie Mathieu , Sauvard Daniel
Published: July 2024

Abstract

Several Agrilinae species (Coleoptera: Buprestidae) are secondary pests of broadleaf forests, and some of them are also major invasive pests. These thermophilous borers are expected to be favoured by climate change and the global deterioration of forest health, and ultimately expand their range and damage. Flight behaviour and performance of these insects are poorly known despite their critical role in dispersal inside and outside native ranges and their relevance for management purposes. This study aimed to assess intra- and interspecific variability in active flight of several Agrilinae species and effects of sex and mass on this variability to contribute to filling this gap. We assessed the flight performance of eleven species associated with oaks (nineAgrilus, oneCoraebusand oneMeliboeus) plus oneAgrilusspecies associated with the herbaceous layer. Computer-monitored flight mills were used to measure flight parameters, including periods, durations, distances and velocity in 250 beetles. Overall, flight capacities were rather homogeneous among species, with a dominance of poor flyers and onlyCoraebus undatusshowed outstanding performance. Beetles generally performed several short flight bouts within one trial, and only a few individuals sustained long flight. The maximal total distance covered across multiple assays until death ranged from 170 to 16 097 m depending on the species, with a median between 35 and 966 m (excluding individuals that never flew). On top of this interspecific variability, flight distances also varied greatly among individuals, but were not influenced by sex. Preflight body mass had mixed effects depending on the species, presumably related to different dispersal patterns. In our experimental conditions, most species had limited average dispersal capacities over multiple flight trials. Overall, dispersal over long distances and colonisation events probably depend mainly on a small proportion of individuals which largely exceeded the median performance.
A 3D human iPSC-derived multi-cell type neurosphere system to model cellular responses to chronic amyloidosis
Authors: Wendt Stefan , Lin Ada J. , Ebert Sarah N. , Brennan Declan J. , Cai Wenji , Bai Yanyang , Sorrentino Stefano , Groten Christopher J. , Lee Christopher , Frew Jonathan , Choi Hyun B. , Karamboulas Konstantina , Delhaye Mathias , MacKenzie Ian , Kaplan David R. , Miller Freda , MacVicar Brian A. , Nygaard Haakon B.
Published: July 2024

Background: Alzheimer's Disease (AD) is characterized by progressive amyloid beta (Aβ) deposition in the brain, with eventual widespread neurodegeneration. While the cell-specific molecular signature of end-stage AD is reasonably well characterized through autopsy material, less is known about the molecular pathways in the human brain involved in the earliest exposure to Aβ. Human model systems that not only replicate the pathological features of AD but also the transcriptional landscape in neurons, astrocytes and microglia are crucial for understanding disease mechanisms and for identifying novel therapeutic targets. Methods: In this study, we used a human 3D iPSC-derived neurosphere model to explore how resident neurons, microglia and astrocytes and their interplay are modified by chronic amyloidosis induced over 3 to 5 weeks by supplementing media with synthetic Aβ1-42 oligomers. Neurospheres under chronic Aβ exposure were grown with or without microglia to investigate the functional roles of microglia. Neuronal activity and oxidative stress were monitored using genetically encoded indicators, including GCaMP6f and roGFP1, respectively. Single nuclei RNA sequencing (snRNA-seq) was performed to profile Aβ and microglia driven transcriptional changes in neurons and astrocytes, providing a comprehensive analysis of cellular responses. Results: Microglia efficiently phagocytosed Aβ inside neurospheres and significantly reduced neurotoxicity, mitigating amyloidosis-induced oxidative stress and neurodegeneration following different exposure times to Aβ. The neuroprotective effects conferred by the presence of microglia was associated with unique gene expression profiles in astrocytes and neurons, including several known AD-associated genes such as APOE. These findings reveal how microglia can directly alter the molecular landscape of AD. Conclusions: Our human 3D neurosphere culture system with chronic Aβ exposure reveals how microglia may be essential for the cellular and transcriptional responses in AD pathogenesis. Microglia are not only neuroprotective in neurospheres but also act as key drivers of Aβ-dependent APOE expression suggesting critical roles for microglia in regulating APOE in the AD brain. This novel, well characterized, functional in vitro platform offers unique opportunities to study the roles and responses of microglia to Aβ modelling key aspects of human AD. This tool will help identify new therapeutic targets, accelerating the transition from discovery to clinical applications.
Genomic prediction of heterosis, inbreeding control, and mate allocation in outbred diploid and tetraploid populations
Authors: Endelman Jeffrey B.
Published: July 2024

Breeders have long appreciated the need to balance selection for short-term genetic gain with maintaining genetic variance for long-term gain. For outbred populations, the method called Optimum Contribution Selection (OCS) chooses parental contributions to maximize the average breeding value at a prescribed inbreeding rate. With Optimum Mate Allocation (OMA), the contribution of each mating is optimized, which allows for specific combining ability due to dominance. To enable OCS and OMA in polyploid species, new theoretical results were derived to (1) predict mid-parent heterosis due to dominance and (2) control inbreeding in a population of arbitrary ploidy. A new Convex optimization framework for OMA, named COMA, was developed and released as public software. Under stochastic simulation of a genomic selection program, COMA maintained a target inbreeding rate of 0.5% using either pedigree or genomic IBD kinship. Significantly more genetic gain was realized with pedigree kinship, which is consistent with previous studies showing the selective advantage of an individual under OCS is dominated by its Mendelian sampling term. Despite the higher accuracy (+0.2–0.3) when predicting mate performance with OMA compared to OCS, there was little long-term gain advantage. The sparsity of the COMA mating design and flexibility to incorporate mating constraints offer practical incentives over OCS. In a potato breeding case study with 170 candidates, the optimal solution at 0.5% inbreeding involved 43 parents but only 43 of the 903 possible matings.
Pollinators differentially respond to local and landscape grassland features
Authors: Lichtenberg Elinor M. , Heiser Jaclyn , Baum Kristen A. , Neff John L. , Jha Shalene
Published: July 2024

Predicting how habitat composition alters communities of mobile ecosystem service providers remains a major challenge in community ecology. This is partially because separate taxonomic groups that provide the same service may respond uniquely to changes in habitat and associated resource availability. Further, the spatial scale at which habitat features impact each group can vary. Failure to account for these differences significantly limits the ability to quantify shared versus contrasting responses to habitat for important ecosystem service-providing groups.

We investigated the impacts of local (habitat patch level) and landscape features in the US Southern Great Plains on groups of pollinating insects with different basic biologies: Coleoptera, Diptera, Hymenoptera, and Lepidoptera. Habitat features included local flower and shelter resources as well as landscape-scale semi-natural habitat.

We found that bare ground supported more Hymenoptera and Lepidoptera but fewer Diptera, while more diverse flower communities supported more Hymenoptera but fewer Coleoptera. Interestingly, given that this study occurred in a grassland system, forest cover in the surrounding landscape more strongly affected pollinator diversity than grassland cover did. Landscapes with more woodland had higher Coleoptera and Diptera richness.

Our results highlight that pollinator conservation and sustainable land management depend on understanding the habitat needs, including shelter, of diverse pollinators. Because taxa can have opposite responses to specific habitat features or scales, providing a range of grassland management practices (e.g., variety in the timing and type of biomass removal) may be the most effective approach to support the broader pollinator community.
The CCT chaperonin and actin modulate the ER and RNA-binding protein condensation during oogenesis to maintain translational repression of maternal mRNA and oocyte quality
Authors: Elaswad Mohamed T. , Gao Mingze , Tice Victoria E. , Bright Cora G. , Thomas Grace M. , Munderloh Chloe , Trombley Nicholas J. , Haddad Christya N. , Johnson Ulysses G. , Cichon Ashley N. , Schisa Jennifer A.
Published: July 2024

The regulation of maternal mRNAs is essential for proper oogenesis, the production of viable gametes, and to avoid birth defects and infertility. Many oogenic RNA-binding proteins have been identified with roles in mRNA metabolism, some of which localize to dynamic ribonucleoprotein granules and others that appear dispersed. Here, we use a combination ofin vitrocondensation assays and thein vivo C. elegansoogenesis model to determine the intrinsic properties of the conserved KH-domain MEX-3 protein and to identify novel regulators of MEX-3 and the Lsm protein, CAR-1. We demonstrate that MEX-3 undergoes liquid-liquid phase separation and appears to have intrinsic gel-like propertiesin vitro. We also identify novel roles for the CCT chaperonin and actin in preventing ectopic RNA-binding protein condensates in maturing oocytes that appear to be independent of MEX-3 folding. CCT and actin also oppose the expansion of ER sheets that may promote ectopic condensation of RNA-binding proteins that are associated with de-repression of maternal mRNA. This regulatory network is essential to preserve oocyte quality, prevent infertility, and may have implications for understanding the role of hMex3 phase transitions in cancer.

Significance statement:

The molecular mechanisms that regulate phase transitions of oogenic RNA-binding proteins are critical to elucidate but are not fully understood.

We identify novel regulators of RNA-binding protein phase transitions in maturing oocytes that are required to maintain translational repression of maternal mRNAs and oocyte quality.

This study is the first to elucidate a regulatory network involving the CCT chaperonin, actin, and the ER for phase transitions of RNA-binding proteins during oogenesis. Our findings for the conserved MEX-3 protein may also be applicable to better understanding the role of hMex3 phase transitions in cancer.
BaCoN (Balanced Correlation Network) improves prediction of gene buffering
Authors: Rohde Thomas , Demirtas Talip Yasir , Shaw Angela Helen , Billmann Maximilian
Published: July 2024

Buffering between genes is fundamental for robust cellular functions. While experimentally testing all possible gene pairs is infeasible, gene buffering can be predicted genome-wide under the assumption that a gene’s buffering capacity depends on its expression level and the absence of this buffering capacity primes a severe fitness phenotype of the buffered gene. We developed BaCoN (BalancedCorrelationNetwork), a post-hoc unsupervised correction method that amplifies specific signals in expression-vs-fitness effect correlation-based networks. We quantified 147 million potential buffering relationships by associating CRISPR-Cas9-screening fitness effects with transcriptomic data across 1019 Cancer Dependency Map (DepMap) cell lines. BaCoN outperformed state-of-the-art methods including multiple linear regression, based on our newly compiled metrics for gene buffering predictions. Combining BaCoN with batch correction or Cholesky data whitening further boosts predictive performance. We characterized a high-confidence list of 899 buffering predictions and found that while buffering genes overall are often syntenic, buffering paralogs are on different chromosomes. BaCoN performance increases with more screens and genes considered, making it a valuable tool for gene buffering predictions from the constantly growing DepMap.