bluuebunny/crossref_metadata_2025 huggingface dataset:
Refining treat-to-target strategies in cryopyrin-associated periodic syndromes: the role of inflammatory markers
Authors: Satirer Özlem , Welzel Tatjana , Zapf Beate , Benseler Susanne M , Kuemmerle-Deschner Jasmin B
Published: July 2024

Objectives

Cryopyrin-associated periodic syndromes (CAPS) encompasses a spectrum of IL-1 driven systemic diseases with dramatic individual and societal burden. The study aimed to identify parameters and instruments to refine real-life treat-to-target (T2T) strategies and control CAPS disease activity.

Methods

A single-centre, longitudinal study of consecutive children and adults diagnosed with CAPS and treated with anti-IL-1 therapy was performed. Demographics, clinical phenotype and NLRP3 gene variants in addition to serial inflammatory markers and physician and patient/parent global assessments (PGA/PPGA) were captured. Effectiveness of anti-IL-1 T2T strategies and factors associated with therapy escalation were determined.

Results

A total of 54 CAPS patients with 759 follow-up visits were included; 31/54 (57%) were children; the median follow-up was 108 months (12–620). The moderate CAPS phenotype was present in 89%; overall 59% had pathogenic/likely pathogenic NLRP3 variants. Therapy adjustments were documented in 50/759 visits including 35 therapy escalations and 15 reductions; 74% of the therapy escalation visits were for children. At time of visit, 63% showed moderate, 37% severe clinical disease activity. Inflammatory markers remained largely normal. Significant improvement was observed in both PGA/PPGA throughout the study (P < 0.01). At the last follow-up, 96% of patients achieved remission.

Conclusion

Guidance for refining real-life T2T strategies in CAPS cohorts can be drawn from serial assessments of PGA and PPGA, reliably reflecting changes in disease activity. Individual parameters including age and NLRP3 gene variants are important predictors, while the sensitivity of inflammatory markers is limited due to the confounding anti-IL-1 therapy.
A systematic review of aspects of NUDT15 pharmacogenomic variants and thiopurine-induced myelosuppression
Authors: Palmer Rachel , Peters Jaime
Published: July 2024

Objectives

Evidence for NUDT15 pharmacogenomic variants and thiopurine-induced myelosuppression (TIM), consists predominantly of association data in Asian, mixed variant homozygote/heterozygote populations. We therefore sought evidence on; (i) NUDT15 genotype-guided thiopurine dosing. (ii) Association data for TIM in NUDT15 variant heterozygotes with inflammatory bowel disease. (iii) Association data for NUDT15 variants with TIM in Europeans. (iv) Health economic data for NUDT15 genotyping in inflammatory bowel disease.

Methods

A systematic review was conducted, consisting of database searches, screening against pre-defined inclusion/exclusion criteria, and assessment of risk of bias using study-specific appraisal tools.

Key findings

Titles/abstracts of 493 articles were screened, with 29 studies included. (i) Significant reductions in TIM with genotype-guided thiopurine dosing were reported by both trials and a cohort study. (ii) TIM rates were significantly higher in NUDT15*3 heterozygotes vs. wild type. Data were conflicting for rarer variants. (iii) Four of five studies reported an association with TIM for at least one or a combination of NUDT15 variants in Europeans (OR 9.5–38.2), but data were conflicting. (iv) Both health economic analyses found TPMT/NUDT15 genotyping cost-effective in Asian populations, but not when a European population was considered.

Conclusion

Limited data showed an association with TIM in NUDT15 variant heterozygotes and Europeans and the potential for genotype-guided dosing to reduce TIM. Studies were generally small, heterogenous, and of variable quality. The low prevalence of rarer NUDT15 variants/variants in Europeans likely contributed to contradictory findings. Further research on the clinical utility of genotyping in diverse populations will help inform future economic analyses.
A 10-Year Longitudinal Study of Brain Cortical Thickness in People with First-Episode Psychosis Using Normative Models
Authors: Berthet Pierre , Haatveit Beathe C , Kjelkenes Rikka , Worker Amanda , Kia Seyed Mostafa , Wolfers Thomas , Rutherford Saige , Alnaes Dag , Dinga Richard , Pedersen Mads L , Dahl Andreas , Fernandez-Cabello Sara , Dazzan Paola , Agartz Ingrid , Nesvåg Ragnar , Ueland Torill , Andreassen Ole A , Simonsen Carmen , Westlye Lars T , Melle Ingrid , Marquand Andre
Published: July 2024

Background

Clinical forecasting models have potential to optimize treatment and improve outcomes in psychosis, but predicting long-term outcomes is challenging and long-term follow-up data are scarce. In this 10-year longitudinal study, we aimed to characterize the temporal evolution of cortical correlates of psychosis and their associations with symptoms.

Design

Structural magnetic resonance imaging (MRI) from people with first-episode psychosis and controls (n = 79 and 218) were obtained at enrollment, after 12 months (n = 67 and 197), and 10 years (n = 23 and 77), within the Thematically Organized Psychosis (TOP) study. Normative models for cortical thickness estimated on public MRI datasets (n = 42 983) were applied to TOP data to obtain deviation scores for each region and timepoint. Positive and Negative Syndrome Scale (PANSS) scores were acquired at each timepoint along with registry data. Linear mixed effects models assessed effects of diagnosis, time, and their interactions on cortical deviations plus associations with symptoms.

Results

LMEs revealed conditional main effects of diagnosis and time × diagnosis interactions in a distributed cortical network, where negative deviations in patients attenuate over time. In patients, symptoms also attenuate over time. LMEs revealed effects of anterior cingulate on PANSS total, and insular and orbitofrontal regions on PANSS negative scores.

Conclusions

This long-term longitudinal study revealed a distributed pattern of cortical differences which attenuated over time together with a reduction in symptoms. These findings are not in line with a simple neurodegenerative account of schizophrenia, and deviations from normative models offer a promising avenue to develop biomarkers to track clinical trajectories over time.
Effectiveness of targeted public university funding on universities’ start-up support: evidence from ‘EXIST—Potentials’
Authors: Mueller Christoph E , Eckardt Iris
Published: July 2024

Universities play a crucial role in the creation and promotion of academic spin-offs, which is why public funding programmes are implemented to improve start-up support there. So far, however, there has been little robust evidence as to whether such programmes actually improve start-up support mechanisms at universities. Against this backdrop, the present study makes a contribution by examining the effects of a large German university funding programme entitled ‘EXIST—Potentials’ on the start-up support of the funded universities. Using an indicator that measures start-up support at universities very broadly and employing a before-and-after comparison group design, reliable results on the effectiveness of the programme are presented. The findings suggest that the programme is effective in improving start-up support mechanisms at universities.
Changes in higher order cognitive function between four watch keeping schedules
Authors: Guzzetti Jacob R , Marando Isabella , Matthews Raymond W , Owen Mikaela S , Yates Crystal , Banks Siobhan
Published: July 2024

Maritime industries utilize many different watch keeping schedules to maintain vigilance and crew safety around the clock. These schedules can be fatiguing, negatively impacting vigilant attention. This has led to the consideration of schedules that might allow for more sleep time, but how these schedules impact higher order cognitive function remains unclear. These schedules require assessment with tasks that are relevant to real-world operations on maritime vessels. This study investigated the effect of four schedules on higher order cognitive function. N = 27 (16 female) participants were recruited to a 10-day laboratory study, comparing four schedules. The schedules investigated were eight-on/eight-off/four-on/four-off (8/8/4/4) with sleep from 09:30 to 16:00 (condition A); six-on/six-off (6/6) with sleep from 08:30 to 12:30 and 21:30 to 00:00 (condition B); four-on/four-off (4/4/4/4/4/4) with sleep from 18:00 to 00:30 (condition C); and four-on/four-off (4/4/4/4/4/4) with sleep from 01:30 to 08:00 (condition D). Higher order cognitive function was assessed 2–3× daily whilst “on watch” using tests of visual scanning, learning, working memory, mental flexibility, and visuomotor control. Conditions were ranked and stability of performance on watch was compared between conditions using Kruskal–Wallis tests. Cognitive function within condition B was ranked the worst for most of the tasks. However, the stability of higher order cognitive function was poorest across the waking day within condition A. These findings highlight the variability in cognitive capacities during different watch keeping schedules.
Exploring Phylogenetic Signal in Multivariate Phenotypes by Maximizing Blomberg’s K
Authors: Mitteroecker Philipp , Collyer Michael L , Adams Dean C
Published: July 2024

Due to the hierarchical structure of the tree of life, closely related species often resemble each other more than distantly related species; a pattern termed phylogenetic signal. Numerous univariate statistics have been proposed as measures of phylogenetic signal for single phenotypic traits, but the study of phylogenetic signal for multivariate data, as is common in modern biology, remains challenging. Here, we introduce a new method to explore phylogenetic signal in multivariate phenotypes. Our approach decomposes the data into linear combinations with maximal (or minimal) phylogenetic signal, as measured by Blomberg’s K. The loading vectors of these phylogenetic components or K-components can be biologically interpreted, and scatterplots of the scores can be used as a low-dimensional ordination of the data that maximally (or minimally) preserves phylogenetic signal. We present algebraic and statistical properties, along with 2 new summary statistics, KA and KG, of phylogenetic signal in multivariate data. Simulation studies showed that KA and KG have higher statistical power than the previously suggested statistic Km⁢u⁢l⁢t, especially if phylogenetic signal is low or concentrated in a few trait dimensions. In 2 empirical applications to vertebrate cranial shape (crocodyliforms and papionins), we found statistically significant phylogenetic signal concentrated in a few trait dimensions. The finding that phylogenetic signal can be highly variable across the dimensions of multivariate phenotypes has important implications for current maximum likelihood approaches to phylogenetic signal in multivariate data.
Poland: Tax labyrinths and legal landscapes—the odyssey of family foundations in Poland
Authors: Krzywański Tomasz , Gajdziński Krzysztof
Published: July 2024

The Polish Family Foundation Law, introduced in May 2023, was designed to facilitate the preservation and management of family wealth. Its success has exceeded expectations with over 1,500 foundations established in its first year. This article examines the law’s impact, its reception, and the practicalities of establishing a Polish foundation. It also explores the implications for existing foreign foundations, analyzing the challenges posed by the exit tax regulations, Controlled Foreign Corporation rules and withholding tax developments. The article further discusses potential legal adjustments needed to align the law with European Union principles and the opportunities for foreign foundations related to it.
Phytocytokine StPep1-Secreting Bacteria Suppress Potato Powdery Scab Disease
Authors: Moroz Natalia , Colvin Benjamin , Jayasinghe Samodya , Gleason Cynthia , Tanaka Kiwamu
Published: July 2024

Powdery scab is an important potato disease caused by the soilborne pathogen Spongospora subterranea f. sp. subterranea. Currently, reliable chemical control and resistant cultivars for powdery scab are unavailable. As an alternative control strategy, we propose a novel approach involving the effective delivery of a phytocytokine to plant roots by the rhizobacterium Bacillus subtilis. The modified strain is designed to secrete the plant elicitor peptide StPep1. In our experiments employing a hairy root system, we observed a significant reduction in powdery scab pathogen infection when we directly applied the StPep1 peptide. Furthermore, our pot assay, which involved pretreating potato roots with StPep1-secreting B. subtilis, demonstrated a substantial decrease in disease symptoms, including reduced root galling and fewer tuber lesions. These findings underscore the potential of engineered bacteria as a promising strategy for safeguarding plants against powdery scab.
MiR398b Targets Superoxide Dismutase Genes in Soybean in Defense Against Heterodera glycines via Modulating Reactive Oxygen Species Homeostasis
Authors: Zhang Xiaoyu , Zhu Xiaofeng , Chen Lijie , Fan Haiyan , Liu Xiaoyu , Yang Ning , Duan Yuxi , Wang Yuanyuan
Published: July 2024

MicroRNAs play crucial roles in plant defense responses. However, the underlying mechanism by which miR398b contributes to soybean responses to soybean cyst nematode ( Heterodera glycines) remains elusive. In this study, by using Agrobacterium rhizogenes-mediated transformation of soybean hairy roots, we observed that miR398b and target genes GmCCS and GmCSD1b played vital functions in soybean− H. glycines interaction. The study revealed that the abundance of miR398b was downregulated by H. glycines infection, and overexpression of miR398b enhanced the susceptibility of soybean to H. glycines. Conversely, silencing of miR398b improved soybean resistance to H. glycines. Detection assays revealed that miR398b rapidly senses stress-induced reactive oxygen species, leading to the repression of target genes GmCCS and GmCSD1b and regulating the accumulation of plant defense genes against nematode infection. Moreover, exogenous synthetic ds-miR398b enhanced soybean sensitivity to H. glycines by modulating H2O2 and O2− levels. Functional analysis demonstrated that overexpression of GmCCS and GmCSD1b in soybean enhanced resistance to H. glycines. RNA interference-mediated repression of GmCCS and GmCSD1b in soybean increased susceptibility to H. glycines. RNA sequencing revealed that a majority of differentially expressed genes in overexpressed GmCCS were associated with oxidative stress. Overall, the results indicate that miR398b targets superoxide dismutase genes, which negatively regulate soybean resistance to H. glycines via modulating reactive oxygen species levels and defense signals.
Validation of Fungicide Spray Strategies and Selection for Fenhexamid Resistance in Botrytis cinerea on Greenhouse-Grown Grapevines
Authors: Boushell Stephen C. , Hu Mengjun
Published: July 2024

In this study, in planta assays were conducted to assess the effects of fungicide spray tactics, such as the reduction of the labeled fungicide dose and mixture with a multisite fungicide, on fungicide resistance selection and disease control using Vitis vinifera ‘Cabernet Sauvignon’ grown in a greenhouse for 2 years. The entire clusters were inoculated with Botrytis cinerea isolates at varying frequencies of fenhexamid resistance, followed by fungicide sprays and disease and fenhexamid resistance investigations at critical phenological stages. Our findings indicate that the lower dose of the at-risk fungicide, fenhexamid, effectively managed fenhexamid resistance and disease as well as the higher, labeled dose. In addition, a mixture with the multisite fungicide captan generally resulted a net-positive effect on both resistance management and disease control.
Role of the Electrocardiogram for Identifying the Development of Atrial Fibrillation
Authors: Montazerin Sahar Memar , Ekmekjian Zareh , Kiwan Chrystina , Correia Joaquim J. , Frishman William H. , Aronow Wilbert S.
Published: July 2024

Atrial fibrillation (AF), a prevalent cardiac arrhythmia, is associated with increased morbidity and mortality worldwide. Stroke, the leading cause of serious disability in the United States, is among the important complications of this arrhythmia. Recent studies have demonstrated that certain clinical variables can be useful in the prediction of AF development in the future. The electrocardiogram (ECG) is a simple and cost-effective technology that is widely available in various healthcare settings. An emerging body of evidence has suggested that ECG tracings preceding the development of AF can be useful in predicting this arrhythmia in the future. Various variables on ECG especially different P wave parameters have been investigated in the prediction of new-onset AF and found to be useful. Several risk models were also introduced using these variables along with the patient’s clinical data. However, current guidelines do not provide a clear consensus regarding implementing these prediction models in clinical practice for identifying patients at risk of AF. Also, the role of intensive screening via ECG or implantable devices based on this scoring system is unclear. The purpose of this review is to summarize AF and various related terminologies and explain the pathophysiology and electrocardiographic features of this tachyarrhythmia. We also discuss the predictive electrocardiographic features of AF, review some of the existing risk models and scoring system, and shed light on the role of monitoring device for screening purposes.
A rare case report of osteochondroma of the left medial cuneiform
Authors: Shrestha Rohit , Maharjan Sandesh S. , Pandey Abhishek , Pradhananga Kriti , Pandey Archana
Published: July 2024

Introduction and importance:

Osteochondroma is a benign skeletal neoplasm presenting with the proliferation of bony tissue. Osteochondroma of the foot is uncommon, and that of the cuneiform is an extremely rare entity.

Case presentation:

We present the case of a 22-year-old woman with osteochondroma of the left medial cuneiform who was having pain in the first ray of the left foot.

Clinical discussion:

Most cases of osteochondromas are nontender and painless masses with a benign asymptomatic course; however, progression to inflammation and neurovascular complications may cause considerable morbidity. The majority of cases are treated conservatively, while some severe cases require surgical management.

Conclusion:

Operative treatment of osteochondroma with excision of the mass remains a safe and successful alternative to conservative management whenever required.
Central neurological manifestations in a sample of Syrian patients with systemic lupus erythematosus: cross-sectional study
Authors: Kudsi Maysoun , Achmeh Bassel , Khalayli Naram , Rabah Karam , Rabah Nour , Al_Darwish Lama , Alghawe Fatima Alzahraa
Published: July 2024

Introduction:

The authors aimed to study systemic lupus erythematosus (SLE) central neurological patterns and their correlations with the disease activity.

Patients and methods:

The authors’ retrospective observational study was carried out on admitted SLE patients. The patients’ demographic data, clinical examinations, laboratory tests, imaging studies, and systemic lupus erythematosus disease activity index (SLEDAI) were recorded.

Results:

Thirty-six SLE patients had neurological manifestations from 203 patients, but 8 patients were excluded. 90.2% were females. The age of neuro-lupus manifestation was 24.1+2.9 years. Neurological manifestations were the initial presentation in 25% of patients. General seizures were the frequent manifestation. SLEDAI was 29.51±18.43, while it was 18.3±9.2 among patients without neuropsychiatric systemic lupus erythematosus (NPSLE). Twenty-five percent of patients had pleocytosis on cerebrospinal fluid (CSF) analysis. Small lesions were seen in 57.1% of patients on brain MRIs, and large lesions were observed in 10.6%. These findings were compatible with the disease activity.

Discussion:

Central nervous system involvement ranged between 10 and 80%, and much more with active disease. The frequent finding was general seizures. Psychosis and cognitive impairment were relatively frequent. Adult NPSLE manifestations had developed before or around the time of SLE diagnosis and within the first year after diagnosis. These manifestations were directly correlated to the disease activity. Abnormality in CSF is characterized by slight pleocytosis, and elevation of protein with normal fructose. MRI is the neuroimaging test of choice for NPSLE in clinical practice.

Conclusion:

Central neurological involvement in SLE was seen early in the course of the disease, and correlating to the disease activity.
Local Ablation Therapy for Hepatocellular Carcinoma
Authors: Lee Min Woo , Han Seungchul , Gu Kyowon , Rhim Hyunchul
Published: July 2024

Local ablation therapy, encompassing radiofrequency ablation (RFA), microwave ablation, and cryoablation, has emerged as a crucial strategy for managing small hepatocellular carcinomas (HCCs), complementing liver resection and transplantation. This review delves into the clinical significance of tumor size, location, and biology in guiding treatment decisions for HCCs undergoing local ablation therapy, with a focus on tumors smaller than 3 cm. Tumor size significantly influences treatment outcomes, with larger tumors associated with poorer local tumor control due to challenges in creating sufficient ablative margins and the likelihood of microvascular invasion and peritumoral satellite nodules. Advanced ablation techniques such as centripetal or no-touch RFA using multiple electrodes, cryoablation using multiple cryoprobes, and microwave ablation offer diverse options for HCC treatment. Notably, no-touch RFA demonstrates superior local tumor control compared with conventional RFA by achieving sufficient ablative margins, making it particularly promising for hepatic dome lesions or tumors with aggressive biology. Laparoscopic RFA proves beneficial for treating anterior subphrenic HCCs, whereas artificial pleural effusion–assisted RFA is effective for controlling posterior subphrenic HCCs. However, surgical resection generally offers better survival outcomes for periportal HCCs compared with RFA. Cryoablation exhibits a lower incidence of vascular or biliary complications than RFA for HCCs adjacent to perivascular or periductal regions. Additionally, aggressive tumor biology, such as microvascular invasion, can be predicted using magnetic resonance imaging findings and serum tumor markers. Aggressive HCC subtypes frequently exhibit Liver Imaging Reporting and Data System M features on magnetic resonance imaging, aiding in prognosis. A comprehensive understanding of tumor size, location, and biology is imperative for optimizing the benefits of local ablation therapy in managing HCCs.
“Magnetic Sand”: Illusions of Interactivity
Authors: Shimojo Shinsuke , Shimojo Kensuke , Shimojo Eiko , Zheng Shengjie , Wu Daw-An
Published: July 2024

We found a series of new illusions, in which actions performed near a random white-noise display lead to the perception that the display is altered interactively with the observer’s actions. The perceptions resemble interactions with a box of magnetic sand, where the hand can leave traces, or attract and repulse grains in its vicinity. 1) the observer puts a finger very close to a dynamic noise display, slowly moving as though drawing a letter or a shape. A trace appears left in the finger’s path, decaying within 500 ms or so. 2) When the observer moves their palm toward and away from the display, opening and closing their fingers as if grabbing and releasing grains of sand, the random dots appear as though they were magnetically attracted to or repelled by the fingers. 3) When an open hand close to the display is slowly moved back and forth laterally, the nearby dots appear to get attracted to or captured by the fingers and thus appear to move with them. 4) The same kind of action capture occurs even when the hand is not visible, moving behind the display. These illusions are robust across a wide range of parameters, including frame rate, luminance contrast, dot size (spatial frequency), and finger movement factors. Inter-subject variability is not correlated across illusion types, and the illusions also diverge in behavior across dynamic and static noise conditions. This indicates that multiple mechanisms are involved to different extents across illusions. Several known visual motion detectors and other low-level mechanisms may be involved in seeding the perceptual phenomena. However, a complete explanation would require mechanisms of action capture, whereby the internal model of the person’s actions and their predicted consequences organizes visual attention and processing of the random stimulus components.
Genetic liability underlying reward-related comorbidity in psychiatric disorders involves the coincident functions of autism-linked ADGRL1 and hevin
Authors: Correoso-Braña Kerlys G. , Anesio Augusto , Dumas Sylvie , Valjent Emmanuel , Heck Nicolas , Vialou Vincent , Boucard Antony A.
Published: July 2024

Comorbidity between psychiatric traits is thought to involve overlapping pleiotropic effects from sets of genes. Notably, substance abuse is a shared comorbid condition among various neurodevelopmental disorders with externalizing symptoms such as autism spectrum disorder and attention-deficit hyperactivity disorder, thus hinting at the nucleus accumbens (NAc) as a site for predisposition underlying convergence of genetic influences in reward-related comorbidity. Here, we identify the autism-related gene encoding the adhesion G protein-coupled receptor (aGPCR) Latrophilin-1/ADGRL1 as an essential transducer of reward mechanisms in the NAc. We found that ADGRL1 mRNA is ubiquitously expressed throughout major NAc neuronal populations in mice. A mouse model of pan-neuronal Adgrl1 deficiency in the NAc displayed cocaine-seeking impairments in adult individuals denoting its role in drug-induced reinforcement and reward. Connecting molecular pathways of cocaine-induced learning, we uncover that ADGRL1 constitutes a functional receptor for autism-related cocaine effector molecule hevin/SPARCL1. Indeed, hevin interacts with membrane-expressed ADGRL1 and induces its internalization while stabilizing its uncleaved fraction. Moreover, hevin alters the formation of intercellular adhesion contacts mediated by ADGRL1 and Neurexin-1. Importantly, the functional constitutive coupling between ADGRL1 and various G protein pathways is selectively modulated by hevin stimulation with a bias toward Gi3, Gs, and G13 proteins. These findings unveil the dual role of ADGRL1 and hevin as genetic risk factors for both psychiatric disorders and substance abuse to define the molecular etiology of comorbidity.
Altered B Cell Metabolic Pathways Characterize Type 1 Diabetes Progression
Authors: Conway Holly , Perez Dianna , Swar-Eldahab Mugtaba , Piganelli Jon , Evans-Molina Carmella , Felton Jamie
Published: July 2024

Type 1 diabetes (T1D) results in immune-mediated destruction of insulin-producing beta cells in the pancreas. B cells have been identified as critical, pathogenic antigen presenting cells and their specificity drives disease progression. At the same time, immunosuppressive, IL-10- producing regulatory B cells (Bregs) have been shown to play protective roles in mouse models of several autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. In these models, microenvironmental stimuli induce regulatory B cell differentiation. Specifically, signaling through hypoxia-inducible factor 1α (HIF-1α) drives a glycolytic flux that facilitates Breg expansion. While Breg frequencies are decreased in individuals with T1D compared to healthy controls, the role B regs play, how microenvironmental stimuli influence their differentiation, and whether this is altered in T1D progression, which is characterized by progressive, systemic hyperglycemia, are less clear. Here we examine the relationship between B cell differentiation, cellular metabolism, and HIF-1α to reveal that in a mouse model of autoimmune diabetes, B cells have distinct metabolic characteristics that change with disease progression. Further, response to hypoxia in autoimmune B cells is distinct from the response by non-autoimmune, control B cells. Together, these data suggest that dysregulated HIF signaling may skew the B cell repertoire toward inflammatory, rather than regulatory B cell subsets to drive T1D development. Consequently, HIF-1α activation to expand regulatory B cell populations may be a viable option for immune modulation.
Reproductive success of inbred strain MV31 of the ctenophoreMnemiopsis leidyiin a self-sustaining inland laboratory culture system
Authors: Garg Pranav , Frey Cameron , Browne William E. , Plotkin Steven S.
Published: July 2024

Ctenophores are an attractive lineage for studying animal evolution due to their early divergence from other metazoans. Among Ctenophora,Mnemiopsis leidyiis a model system for developmental, cellular, molecular genetic, and evolutionary studies. Until recently, many of these studies were conducted on wild-caught animals, limiting access to researchers on the coast. Here we present significant advancements towards culturingM. leidyiin laboratories without coastal access, enabling its wider use as an experimental and genetic model system. We detail updated feeding regimes that take advantage of co-culturingBrachionusrotifers withApocyclopscopepods, and quantify the reproductive output of ourM. leidyilab strain on this diet. Our updated feeding regime maintains reproductive fitness comparable to wild-caught individuals. Importantly, we have eliminated the logistical complexities and costs of regularly feeding live larval fish toM. leidyi. Our updated protocols make it feasible to maintain continuous ctenophore cultures independent of access to both coastal populations of wildM. leidyiand larval fish culturing facilities.
Active Loop Extrusion guides DNA-Protein Condensation
Authors: Takaki Ryota , Savich Yahor , Brugués Jan , Jülicher Frank
Published: July 2024

The spatial organization of DNA involves DNA loop extrusion and the formation of protein-DNA condensates. While the significance of each process is increasingly recognized, their interplay remains unexplored. Using molecular dynamics simulation and theory we investigate this interplay. Our findings reveal that loop extrusion can enhance the dynamics of condensation and promotes coalescence and ripening of condensates. Further, the DNA loop enables condensate formation under DNA tension and position condensates. The concurrent presence of loop extrusion and condensate formation results in the formation of distinct domains similar to TADs, an outcome not achieved by either process alone.
Diverse Calcium Signaling in Astrocytes: Insights from a Computational Model
Authors: Bezerra Thiago Ohno , Roque Antonio C.
Published: July 2024

Astrocytes are complex cells that influence a variety of brain functions and behaviors. They are active cells that show a sharp increase in intracellular Ca2+concentration in response to neurotransmitters (events called Ca2+signals). The main source of intracellular Ca2+is the stores in endoplasmic reticulum (ER), released by the activation of IP3 receptor channels on the ER membrane. As neurons, astrocytes from different brain regions show distinct Ca2+signals. In addition, astrocytes can also show different patterns of Ca2+responses. It is not yet clear how the diversity of astrocyte response emerge from the same mech-anisms. Here we present a two variable astrocyte compartmental model for the Ca2+and IP3 dynamics. We show that Ca2+signals with different characteristics can emerge from changing the parameters associated with the Ca2+and IP3 dynamics and the transmembrane current. We also show that global Ca2+signals are required for the model to trigger different patterns of Ca2+responses. The model present here can be used to simulate astrocytes from different brain regions and with distinct types of response.
High-Resolution Multimodal Profiling of Human Epileptic Brain Activity via Explanted Depth Electrodes
Authors: Dwiwedi Anuj Kumar , Mahesh Arun , Sanfeliu Albert , Larkin Julian , Siwicki Rebecca , Sweeney Kieron J. , O’Brien Donncha F. , Widdess-Walsh Peter , Picelli Simone , Henshall David C. , Tiwari Vijay K.
Published: July 2024

Understanding neurological disorders necessitates systems-level approaches that integrate multimodal data, but progress has been hindered by limited sample availability, and the absence of combined electrophysiological and molecular data from live patients. Here, we demonstrate that intracranial stereoelectroencephalography (SEEG) electrodes used for identifying the seizure focus in epilepsy patients enable the integration of RNA sequencing, genomic variants and epigenome maps with in vivo recordings and brain imaging. Specifically, we report a method, MoPEDE (Multimodal Profiling of Epileptic Brain Activity via Explanted Depth Electrodes) that recovers extensive protein-coding transcripts, DNA methylation and mutation profiles from explanted SEEG electrodes matched with electrophysiological and radiological data allowing for high-resolution reconstructions of brain structure and function in human patients. Our study shows that epilepsies of different aetiologies have distinct molecular landscapes and identify transcripts correlating with neurophysiological signals, including immediate early genes, inflammation markers, and axon guidance molecules. Additionally, we identify DNA methylation profiles indicative of transcriptionally permissive or restrictive chromatin states. While gene expression gradients corresponded with the assigned epileptogenicity index, we found outlier molecular fingerprints in some electrodes, potentially indicating seizure generation or propagation zones not detected during electroclinical assessments. These findings validate that RNA profiles, genetic variation and genome-wide epigenetic data from explanted SEEG electrodes offer high-resolution surrogate molecular landscapes of brain activity. Our transformative MoPEDE approach has the potential to enhance diagnostic decisions and deepen our understanding of epileptogenic network processes in the human brain.
Quantifying compositional variability in microbial communities with FAVA
Authors: Morrison Maike L. , Xue Katherine S. , Rosenberg Noah A.
Published: July 2024

Microbial communities vary across space, time, and individual hosts, presenting new challenges for the development of statistics measuring the variability of community composition. To understand differences across microbiome samples from different host individuals, sampling times, spatial locations, or experimental replicates, we present FAVA, a new normalized measure for characterizing compositional variability across multiple microbiome samples. FAVA quantifies variability across many samples of taxonomic or functional relative abundances in a single index ranging between 0 and 1, equaling 0 when all samples are identical and equaling 1 when each sample is entirely comprised of a single taxon. Its definition relies on the population-genetic statisticFST, with samples playing the role of “populations” and taxa playing the role of “alleles.” Its convenient mathematical properties allow users to compare disparate data sets. For example, FAVA values are commensurable across different numbers of taxonomic categories and different numbers of samples considered. We introduce extensions that incorporate phylogenetic similarity among taxa and spatial or temporal distances between samples. We illustrate how FAVA can be used to describe across-individual taxonomic variability in ruminant microbiomes at different regions along the gastrointestinal tract. In a second example, a longitudinal analysis of gut microbiomes of healthy human adults taking an antibiotic, we use FAVA to quantify the increase in temporal variability of microbiomes following the antibiotic course and to measure the duration of the antibiotic’s influence on microbial variability. We have implemented this tool in an R package,FAVA, which can fit easily into existing pipelines for the analysis of microbial relative abundances.

Significance statement

Studies of microbial community composition across time, space, or biological replicates often rely on summary statistics that analyze just one or two samples at a time. Although these statistics effectively summarize the diversity of one sample or the compositional dissimilarity between two samples, they are ill-suited for measuring variability across many samples at once. Measuring compositional variability among many samples is key to understanding the temporal stability of a community across multiple time points, or the heterogeneity of microbiome composition across multiple experimental replicates or host individuals. Our proposed measure, FAVA, meets the need for a statistic summarizing compositional variability across many microbiome samples all at once.
A discrete sarcomere model reveals internal unbinding dynamics and conditions for regularity of spontaneous oscillatory contractions
Authors: Warmington Benjamin , Rossiter Jonathan , Gadêlha Hermes Bloomfield
Published: July 2024

Using a discrete modelling approach for myosin systems we demonstrate how structural differences between single myosin filaments and sarcomeres allow for self similarity during sarcomeric spontaneous oscillatory contractions (SPOC). The form of our modelled SPOC recapitulates the subtleties ofin vitroSPOCs more closely than prior modelling methods, suggesting we are capturing internal dynamics of the sarcomere that are either not generally considered or previously unknown. These results reinforce the value of discretely modelling molecular motor systems.
Recombination landscape and karyotypic variations revealed by linkage mapping in the grapevine downy mildew pathogenPlasmopara viticola
Authors: Dvorak Etienne , Mazet Isabelle D. , Couture Carole , Delmotte François , Foulongne-Oriol Marie
Published: July 2024

Plasmopara viticola, the causal agent of grapevine downy mildew, is a biotrophic oomycete engaged in atight coevolutionary relationship with its host. Rapid adaptation of the pathogen is favored by annual sexual reproduction which generates genotypic diversity. With the aim of studying the recombination landscape across theP. viticolagenome, we generated two half-siblings F1 progenies (N=189 and 162). Offspring were genotyped by targeted sequencing of a set of 5,000 informative SNPs. This enabled the construction of unprecedented high-density linkage maps for this species. The reference genome could be assembled into 17 pseudo-chromosomes, anchoring 88% of its physical length. We observed a strong collinearity between parental genomes and extensive synteny with the downy mildewPeronospora effusa. In the consensus map, the median recombination rate was 13.8 cM/Mb. The local recombination rate was highly variable along chromosomes and recombination was suppressed in putative centromeric regions. Recombination rate was found negatively correlated with repeats coverage and positively correlated with gene coverage. However, genes encoding secreted proteins and putative effectors were under-represented in highly recombining regions. In both progenies, about 5% of the individuals presented karyotypic anomalies. Aneuploidies and triploidies almost exclusively originated from the male-transmitted chromosomes. Triploids resulted from fertilization by diploid gametes, but also from dispermy. Obligatory sexual reproduction each year may explain the lower level of karyotypic variation inP. viticolacompared to other oomycetes. The linkage maps will be useful to guide futurede novochromosome-scale assemblies ofP. viticolagenomes and to perform forward genetics.

Sexual reproduction contributes to the rapid adaptation of plant pathogens thanks to the recombination of genetic variants. By crossing strains of grapevine downy mildew, we built a set of linkage maps and describe the recombination landscape along the 17 chromosomes of the genome. The recombination rate varied greatly and was higher in gene-rich regions, but not in effector-rich regions. We observed an abnormal number of chromosomes in 5% of the offspring, which was mostly due to the male parent.
A lasting impact of serotonergic psychedelics on visual processing and behavior
Authors: West Chloe L. , Bastos Georgia , Duran Annabel , Nadeem Samen , Ricci David , Rader Groves Anna M. , Wargo Joseph A. , Peterka Darcy S. , Van Leeuwen Neil , Hamm Jordan P.
Published: July 2024

Serotonergic psychedelics (e.g., psilocybin) have shown potential for treating psychiatric disorders, with therapeutic effects lasting weeks after a single dose. Predictive processing theories posit that psychedelics work by loosening priors or high-level beliefs, including ingrained biases that have become pathological, leading to shifts in bottom-up vs top-down information processing that reconfigure perception, cognition, and mood. Because 5-HT2A receptors, the primary target of psychedelics, are enriched in visual cortices, we investigated whether psychedelics alter visual processing in a manner consistent with predictive processing theories. People who recently (<3 weeks) used 5-HT2A-agonist psychedelics (psilocybin, LSD) exhibited slowed response latencies and increased cortical involvement in generating saccades to targets in predictable locations, along with a generalization of sensory prediction errors (i.e., deviance detection) during passive visual processing. Individuals who recently used a 5-HT1A- selective psychedelic (5-MeO-DMT) displayed similar changes in saccade production, but unaltered deviance detection, suggesting circuit-specific effects. Mice administered DOI (5- HT2A-agonist) exhibited altered deviance detection within primary visual cortex (V1), along with weakened top-down feedback to V1 from higher cortical area ACa. These results concord with the hypothesis that psychedelics shift the balance from top-down to bottom-up in sensory cortical circuits – an effect that persists beyond the acute exposure period.
The Role of Glucocorticoid and Nicotinic Acetylcholine Receptors in the Reward-Enhancing Effects of Nicotine in the ICSS Procedure in Male and Female Rats
Authors: Chellian Ranjithkumar , Behnood-Rod Azin , Bruijnzeel Adriaan W.
Published: July 2024

Tobacco use disorder is a chronic disorder that affects more than one billion people worldwide and causes the death of millions each year. The rewarding properties of nicotine are critical for the initiation of smoking. Previous research has shown that the activation of glucocorticoid receptors (GRs) plays a role in nicotine self-administration in rats. However, the role of GRs in the acute rewarding effects of nicotine are unknown. In this study, we investigated the effects of the GR antagonist mifepristone and the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine on the reward-enhancing effects of nicotine using the intracranial self-stimulation (ICSS) procedure in adult male and female rats. The rats were prepared with ICSS electrodes in the medial forebrain bundle and then trained on the ICSS procedure. Nicotine lowered the brain reward thresholds and decreased response latencies similarly in male and female rats. These findings suggest that nicotine enhances the rewarding effects of ICSS and has stimulant properties. Treatment with the GR antagonist mifepristone did not affect the reward-enhancing effects of nicotine but increased response latencies, suggesting a sedative effect. Mecamylamine did not affect the brain reward thresholds or response latencies of the control rats, but prevented the nicotine-induced decrease in brain reward thresholds and reward latencies. These findings indicate that the rewarding effects of nicotine are mediated via the activation of nAChRs, and that the activation of GRs does not contribute to the acute rewarding effects of nicotine. These studies enhance our understanding of the neurobiological mechanisms underlying tobacco use disorder.
Dissecting cell-free DNA fragmentation variation in tumors using cell line-derived xenograft mouse
Authors: Fu Ruiqing , Su He Amy , Tian Yafei , Chen Hongyan , Lu Daru
Published: July 2024

Cell-free DNA (cfDNA) is increasingly studied for its diverse applications in non-invasive detection. Non-randomly cleaved by nucleases and released into the bloodstream, cfDNA exhibits a variety of intrinsic fragmentation patterns indicative of cell status. Particularly, these fragmentation patterns have recently been demonstrated to be effective in predicting cancer and its tissue-of-origin, owing to increased variation of fragmentation features observed in tumor patients. However, there remains a lack of detailed exploration of altered cfDNA fragmentation profiles in tumors, which consist of a mixture of both non-tumor cfDNA and circulating tumor DNA (ctDNA). Hence, we leveraged the human tumor cell line-derived xenograft (CDX) mouse model, where different tumor cell lines were implanted into different anatomical sites, to isolate pure ctDNA and separately investigate the fragment properties of CDX-induced cfDNA and ctDNA. We found an enrichment of short cfDNA fragments in both CDX-induced cfDNA and ctDNA compared to normal plasma cfDNA, with more elevated short fragments in ctDNA. Moreover, the CDX-induced cfDNA fragmentation features distinguished between CDX models of different tumor cell lines, while the ctDNA fragmentation features conversely discriminate between CDX models of different anatomical sites. The results suggested that both non-tumor cfDNA and ctDNA contribute to the increased variation observed in tumors, and that cfDNA fragmentation may be highly variable and susceptible to regulations by both original cells and cells within the local niche.
Social clues in risky pools: Perceived conspecific rivals strongly modify individual oviposition decisions in response to larval predation and competition
Authors: Ramesh Ashwini , Sharma Manvi , Isvaran Kavita
Published: July 2024

Reproductive choices are imperative in shaping organismal fitness across diverse taxa. Such choices are particularly critical in organisms with biphasic lifecycles, as females must maximize offspring survival pre-oviposition, with no parental care extended afterward. Consequently, females face strong site selection pressures to effectively respond to offspring competition and predation risks. Ovipositing females encounter yet another challenge during site selection: assessing future competition for their offspring from potential conspecific rivals. Our current knowledge, based on average social versus solitary behaviours, fails to clarify how social signals influence individual behavior within groups. To address these challenges, we leveraged the unique oviposition biology of the mosquitoAedes aegyptiwhere only blood-fed females can lay eggs. By tracking individual behaviour in a social setting, we ask: how does social information from perceived conspecific rivals influence an individual’s oviposition site selection? In our lab-based experiment, we examined oviposition strategies at two spatial scales under varying larval competition and predation risk. Our findings reveal that social information exerts a stronger influence on egg-laying behavior at larger spatial scales, i.e., at the scale of pool networks, than between neighboring pools. Social cues facilitated oviposition with increasing larval predation, as social females transitioned from rejecting to accepting pool networks. Conversely, under larval competition, social cues led to inhibition, with females withholding their eggs likely in anticipation of future competition. At finer spatial scales, social information only weakly modified oviposition behavior despite potential negative fitness consequences for the offspring. Thus, perceived conspecific risk strongly modifies oviposition—facilitation, inhibition, or no effect—and is scale-dependent.