bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene–Genome Interactions
Authors: Kobow Katja , Mahoney John Matthew
Published: July 2024

The advent of high-throughput molecular technologies has fundamentally transformed epilepsy research. It is now possible to simultaneously measure tens of thousands of biomolecules in a stunning array of biological contexts to discern mechanistic drivers of molecular dysregulation in seizure disorders. Correspondingly, there has been an increased appreciation that the relationship between molecular perturbations (e.g., gene mutations) and their corresponding functional outcome is highly nonlinear and mediated through vast regulatory networks. Overcoming the immense complexity of biological systems to “reverse engineer” the pathological functioning of molecular networks is one of the fundamental tasks of epilepsy research over the next 10 years. This chapter discusses how to address the yet underappreciated gene–genome interactions. It provides a comprehensive overview of both specific experimental approaches and most recent advances in analytical methods to disentangle the nonlinear relationship between a complex molecular trait and its functional consequences leading to a specific phenotype, for example, epilepsy.
Progressive Myoclonus Epilepsy of Lafora
Authors: Serratosa José M. , Burgos Daniel F. , Zafra-Puerta Luis , Iglesias-Cabeza Nerea , Sanz Pascual , Sánchez Marina P.
Published: July 2024

Metformin is a biguanide drug that is commonly used as a first-line treatment for type 2 diabetes. This chemical works by activating the energy sensor AMPK that inhibits hepatic gluconeogenesis. Metformin’s therapeutic properties go beyond its use as an antidiabetic compound. As a result, a large number of publications have recently reported promising results in a variety of neurological diseases. Although several hypotheses have been formulated regarding the specific mechanisms of action of metformin in the central nervous system, such as a decrease of neuroinflammation or a reduction of oxidative stress, the underlying pathways of these positive effects remain obscure. In this chapter, we review the newly discovered benefits of metformin as a neuroprotective agent for Lafora disease, a rare form of progressive myoclonus epilepsy caused by mutations in the EPM2A or EPM2B genes. The aggregation of Lafora bodies, abnormal glycogen inclusions that accumulate in the brain and other tissues, is the major histopathological characteristic. Treatment with metformin in Lafora disease knockout mice reduced the number of Lafora bodies, decreased neuronal loss and reactive astrogliosis, and improved the functional and epileptic symptoms.
Antisense Oligonucleotide Therapy for Progressive Myoclonus Epilepsies
Authors: Nitschke Silvia , Minassian Berge A.
Published: July 2024

Progressive myoclonus epilepsies (PMEs) are genetic diseases that together account for about 1% of all epilepsies in childhood and adolescence. Even though the age of onset, symptom spectrum, and severity vary among different PMEs, all patients experience myoclonic seizures, generalized epilepsy, and progressive neurological decline, often intractable and fatal. Antisense oligonucleotides (ASOs) are synthetic single-stranded chemically modified nucleic acid polymers that target RNA to alter splicing, modulate translation, or promote/prevent mRNA degradation. Their gene-specific action and versatility has made ASO-based therapeutics one of the major pillars of drug development for genetic diseases with more than a dozen ASO drugs FDA-approved and many more in development and clinical trials. Advances in ASO technology already paved the way toward “N of 1” patient-customized therapies and hold great promise for personalized drug development that is much needed to treat rare genetic diseases such as PMEs. This chapter discusses the potential of ASO therapies for PMEs by giving an overview of the possible mechanisms of action employed to target disease genes and by reviewing ASO studies aimed to treat neuromuscular or neurodegenerative diseases, including PMEs.
What Rodent Models Teach Us about the Association of Autism and Epilepsy
Authors: Golshani Peyman
Published: July 2024

Autism is strongly associated with epilepsy, but the mechanisms that drive this association are poorly understood. Are autism-related behaviors and epilepsy different manifestations of pathological excitability or altered synaptic transmission induced by the same genetic changes in different brain structures? Or do early-life seizures themselves drive activity-dependent changes in circuits and induce or exacerbate deficits in social interaction? This chapter will review work done in the last 10 years in mouse models of Dravet syndrome, CACNA1a deficiency, several potassium channelopathies, and the CNTNAP2 knockout model of cortical dysplasia focal epilepsy syndrome to dissect mechanisms that drive the epilepsy and autism-relevant behaviors. It will also review the evidence for the causal role of epilepsy in autism. To conclude, it will discuss new directions for research in the coming decade, driven by the development of new technologies.
Drug Combinations for Antiepileptogenesis
Authors: Löscher Wolfgang
Published: July 2024

Prevention of epilepsy in patients at risk is an urgent global unmet need. In theory, the latent period between an epileptogenic brain insult and the onset of epilepsy may offer a therapeutic window to interfere with epileptogenesis. Numerous preclinical and a few clinical studies on antiepileptogenesis have been performed in the past 20-plus years. The vast majority of these studies used treatments with single, often highly selective drugs shortly after epileptogenic brain injuries, mostly without any success. The negative results may be due to the complex mechanisms of epileptogenesis, which complicate any strategy to interfere with this process. It was therefore proposed to apply principles of network pharmacology to the search for antiepileptogenic treatments. Here the outcome of preclinical studies using rationally chosen drug combinations for antiepileptogenesis is reviewed. Of 24 drug combinations that are discussed here, only four exerted persistent antiepileptogenic efficacy in rodent models of acquired epilepsy. For three of these effective combinations, clinically approved drugs were used, which would facilitate translation into clinical trials. The chapter also discusses future advancements in the search for antiepileptogenic drugs or drug combinations, including the subsequent use of in silico, in vitro, and in vivo platforms as well as “big data” mining approaches and machine learning.
Purinergic Signaling in Epilepsy
Authors: Engel Tobias , Dale Nicholas
Published: July 2024

Despite the availability of numerous antiseizure drugs (ASDs), treatment of epilepsy remains a clinical challenge, with over 30% of patients not responding to any pharmacological intervention. In addition, ASDs are mainly symptomatic without significantly impacting on disease progression. Thus, there is a strong focus on the identification of drug targets with a novel mechanism of action that are independent on GABAergic and glutamatergic neurotransmission and that possess a disease-modifying potential. That extracellular released purines such as adenosine triphosphate (ATP) and adenosine act as signaling molecules in the brain has been known for decades. While the anticonvulsant potential of adenosine is well established, increasing evidence suggests also an important role for ATP during the generation of seizures and the development of epilepsy. Usually present at low extracellular concentrations, ATP is released in response to several pathological stimuli including increased neuronal activity acting as danger signal and activating specific purinergic P2 receptors divided into the metabotropic P2Y and ionotropic P2X receptors. Suggesting a role during seizures and epilepsy, data from experimental models and patients show widespread expression changes of both P2Y and P2X receptor family members during epilepsy and, critically, drugs targeting both receptor subtypes, in particular, the P2Y1 and P2X7 receptors, confer both anticonvulsive and antiepileptic effects. This chapter provides a detailed summary of the current evidence suggesting ATP-gated receptors as novel drug targets for epilepsy, discusses the possible mechanisms for how these receptors contribute to increased hyperexcitability, and briefly outlines how the purinergic system can be used as novel tool for the diagnosis of epilepsy.
Targeted Augmentation of Nuclear Gene Output (TANGO)
Authors: Isom Lori L. , Knupp Kelly G.
Published: July 2024

Most development and epileptic encephalopathies (DEEs) are genetic in origin. Drug-resistant epilepsy is often the most notable feature of the DEEs, although numerous other symptoms are present that have significant impact on patients’ quality of life. Despite novel, third-generation antiseizure drug treatment options becoming available over the last several years, seizure freedom is often not attained and nonseizure symptoms remain. Therapeutic approaches such as antisense oligonucleotides and adeno-associated virus delivered gene modulation offers realistic hope for seizure freedom in some DEEs with an underlying genetic etiology, with several approaches demonstrating preclinical success and now transitioning to clinical trials. Several of these therapeutic strategies risk the exacerbation of gain-of-function variants and may not be reversible, thus emphasizing the need for functional testing of variants and more reliable prediction tools for pathogenicity. Dravet syndrome, Rett syndrome, and Angelman syndrome are presented here as examples of how these techniques are being applied and the nuances and challenges of each unique genetic disorder. Additionally, with so many gene regulatory therapeutic options on the horizon, there will be a need to understand how to select appropriate patients for each treatment, whether treatments are complementary or adverse to each other, and long-term risks of the treatment. Nevertheless, precision therapeutics hold tremendous potential to provide long-lasting seizure freedom and even complete cures for this devastating disease.
Warps and breaks in circumbinary discs
Authors: Rabago Ian , Zhu Zhaohuan , Lubow Stephen , Martin Rebecca G
Published: July 2024

Disc warping, and possibly disc breaking, has been observed in protoplanetary discs around both single and multiple stars. Large warps can break the disc, producing multiple observational signatures. In this work, we use comparisons of disc time-scales to derive updated formulae for disc breaking, with better predictions as to when and where a disc is expected to break and how many breaks could occur. Disc breaking is more likely for discs with small inner cavities, cooler temperatures, and steeper power-law profiles, such that thin, polar-aligning discs are more likely to break. We test our analytical formulae using three-dimensional grid-based simulations of protoplanetary discs warped by the gravitational torque of an inner binary. We reproduce the expected warp behaviours in different viscosity regimes and observe disc breaking at locations in agreement with our derived equations. As our simulations only show disc breaking when disc viscosity is low, we also consider a viscous criterion for disc breaking, where rapid alignment to the precession vector can prevent a break by reducing the maximum misalignment between neighbouring rings. We apply these results to the GW Orionis circumtriple disc and find that the precession induced from the central stars can break the disc if it is relatively thin. We expect repeated or multiple disc breaking to occur for discs with sufficiently steep power-law profiles. We simulate a polar-aligning disc around an eccentric binary with steep power-law profiles and observe two separate breaking events at locations in rough agreement with our analytical predictions.
Radiation hydrodynamical simulations of super-Eddington mass transfer and black hole growth in close binaries
Authors: Toyouchi Daisuke , Hotokezaka Kenta , Inayoshi Kohei , Kuiper Rolf
Published: July 2024

Radiation-driven outflows play a crucial role in extracting mass and angular momentum from binary systems undergoing rapid mass transfer at super-Eddington rates. To study the mass transfer process from a massive donor star to a stellar-mass black hole (BH), we perform multidimensional radiation-hydrodynamical simulations that follow accretion flows from the first Lagrange point down to about a hundred times the Schwarzschild radius of the accreting BH. Our simulations reveal that rapid mass transfer occurring at over a thousand times the Eddington rate leads to significant mass-loss from the accretion disc via radiation-driven outflows. Consequently, the inflow rates at the innermost radius are regulated by two orders of magnitude smaller than the transfer rates. We find that convective motions within the accretion disc drive outward energy and momentum transport, enhancing the radiation pressure in the outskirts of the disc and ultimately generating large-scale outflows with sufficient energy to leave the binary. Furthermore, we observe strong anisotropy in the outflows, which occur preferentially toward both the closest and furthest points from the donor star. However, when averaged over all directions, the specific angular momentum of the outflows is nearly comparable to the value predicted in the isotropic emission case. Based on our simulation results, we propose a formula that quantifies the mass growth rates on BHs and the mass-loss rates from binaries due to radiation-driven outflows. This formula provides important implications for the binary evolution and the formation of merging binary BHs.
A critical review of recent Gaia wide binary gravity tests
Authors: Hernandez X , Chae Kyu-Hyun , Aguayo-Ortiz A
Published: July 2024

Over the last couple of years, the appearance of the third data release from the Gaia satellite has triggered various wide binary low acceleration gravity tests. Wide binaries with typical total masses $\approx 1.0 - 1.6\,\mathrm{ M}_{\odot }$ and separations above a few thousand au probe the low acceleration $a \lesssim a_{0}$ regime, where at galactic and larger scales gravitational anomalies typically attributed to the presence of an as yet undetected dark matter component appear, where $a_{0} \approx 1.2\times 10^{-10}$ m s$^{-2}$ is the acceleration scale of Modified Newtonian Dynamics (MOND). Thus, studies of the relative velocities and separations on the plane of the sky, $v_{2\mathrm{ D}}$ and $s_{2\mathrm{ D}}$, respectively, of wide binary stars extending to separations above a few kau, provide an independent approach on the empirical study of gravity in the interesting $a \lesssim a_{0}$ acceleration range. Two independent groups, through complementary approaches, have obtained evidence for a departure from Newtonian predictions in the low acceleration regime, in consistency with MOND expectations for wide binary orbits in the Solar Neighbourhood. Two other groups however, have instead reported results showing a clear preference for Newtonian gravity over various MOND alternatives tested, over the same low acceleration regime. We here take a critical look at the various studies in question, from sample selection to statistical treatment of the wide binary relative velocities obtained. We discover a couple of critical problems in the formal design and statistical implementation shared by the two latter groups, and show explicitly how these yield biased conclusions.
Digitalizing Specialist Smoking Cessation Support in Pregnancy: Views of Pregnant Smokers
Authors: Belderson Pippa , McDaid Lisa , Emery Joanne , Coleman Tim , Leonardi-Bee Jo , Naughton Felix
Published: July 2024

Introduction

Unsupported attempts to quit smoking during pregnancy have a low success rate. Chances of quitting successfully are higher with an interpersonal treatment program but there is low uptake of this in the United Kingdom. Delivering a pregnancy-specific treatment program digitally may provide an alternative treatment route. This study explored pregnant smokers’ perceptions of barriers and facilitators to using digital cessation support, along with identifying modes of delivery and engagement enhancers.

Aims and Methods

Semi-structured interviews were carried out with an ethnically and socioeconomically diverse sample of 25 participants with recent experience of attempting to quit smoking in pregnancy, aged 20–40, from the United Kingdom. An inductive thematic analysis approach was used.

Results

Digital smoking cessation support, particularly a smartphone app, for pregnancy was felt to overcome many barriers to engaging with interpersonal support, being viewed as more convenient, and nonjudgmental, providing better consistency of advice, and enhancing privacy and autonomy. However, some participants felt that removing access to a human could undermine a digital support package and reduce engagement. Popular engagement enhancers included self-monitoring (eg, digital recording of smoking; smartphone-linked carbon monoxide monitoring), online communities, and remote access to nicotine substitution options. Digital support was viewed as having potential as a stand-alone intervention or working in conjunction with standard interpersonal treatment.

Conclusions

The findings support the investigation of a digital support package as both a stand-alone and adjunct to standard interpersonal cessation support in pregnancy to increase the proportion of pregnant smokers who make a supported quit attempt.

Implications

In many countries like the United Kingdom, there are few smoking cessation options routinely available that provide effective support for smoking cessation in pregnancy. To maximize impact, health services need an effective range of strategies to engage with and support quit attempts made by all pregnant smokers, particularly as interpersonal support options are not often well used. Development of a pregnancy-specific digital support package for smoking cessation in pregnancy may represent a means to help address this gap.
Transcriptomic response to nitrogen availability reveals signatures of adaptive plasticity during tetraploid wheat domestication
Authors: Pieri Alice , Beleggia Romina , Gioia Tania , Tong Hao , Di Vittori Valerio , Frascarelli Giulia , Bitocchi Elena , Nanni Laura , Bellucci Elisa , Fiorani Fabio , Pecchioni Nicola , Marzario Stefania , De Quattro Concetta , Limongi Antonina Rita , De Vita Pasquale , Rossato Marzia , Schurr Ulrich , David Jacques L , Nikoloski Zoran , Papa Roberto
Published: July 2024

The domestication of crops, coupled with agroecosystem development, is associated with major environmental changes and provides an ideal model of phenotypic plasticity. Here, we examined 32 genotypes of three tetraploid wheat (Triticum turgidum L.) subspecies, wild emmer, emmer, and durum wheat, which are representative of the key stages in the domestication of tetraploid wheat. We developed a pipeline that integrates RNA-Seq data and population genomics to assess gene expression plasticity and identify selection signatures under diverse nitrogen availability conditions. Our analysis revealed differing gene expression responses to nitrogen availability across primary (wild emmer to emmer) and secondary (emmer to durum wheat) domestication. Notably, nitrogen triggered the expression of twice as many genes in durum wheat compared to that in emmer and wild emmer. Unique selection signatures were identified at each stage: primary domestication mainly influenced genes related to biotic interactions, whereas secondary domestication affected genes related to amino acid metabolism, in particular lysine. Selection signatures were found in differentially expressed genes (DEGs), notably those associated with nitrogen metabolism, such as the gene encoding glutamate dehydrogenase (GDH). Overall, our study highlights the pivotal role of nitrogen availability in the domestication and adaptive responses of a major food crop, with varying effects across different traits and growth conditions.
[Ca2+]cyt-ASSOCIATED PROTEIN KINASE 1 and NIMA-RELATED KINASE 2 interact during root hair cell morphogenesis
Authors: Yang Hong , Huang Chongzheng , Dong Nannan , Xu Yifei , Zheng Yiling , Xu Lushun , Guo Sasa , Zhang Xin , Ma Xiaonan , Bai Ling
Published: July 2024

Root hair growth has been studied to understand the principles underlying the regulation of directional growth. Arabidopsis (Arabidopsis thaliana) [Ca2+]cyt-ASSOCIATED PROTEIN KINASE 1 (CAP1) maintains normal vesicle trafficking and cytoskeleton arrangement during root hair growth in response to ammonium signaling. In the current study, we identified CAP1 SUPPRESSOR 1 (CAPS1) as a genetic suppressor of the cap1-1 mutation. The CAPS1 mutation largely rescued the short root hair phenotype of cap1-1. Loss of CAPS1 function resulted in significantly longer root hairs in cap1-1. MutMap analysis revealed that CAPS1 is identical to NIMA (NEVER IN MITOSIS A)-RELATED KINASE 2 (NEK2). In addition, our studies showed that NEK2 is expressed in root and root hairs. Its distribution was associated with the pattern of microtubule (MT) arrangement and partially colocalized with CAP1. Further biochemical studies revealed that CAP1 physically interacts with NEK2 and may enhance its phosphorylation. Our study suggests that NEK2 acts as a potential phosphorylation target of CAP1 in maintaining the stability of root hair MTs to regulate root hair elongation.
A simple method to visualize pre-mRNA splicing with the naked eye using a genetically encoded visual splicing reporter
Authors: Prasad Kasavajhala V S K , Cheema Amandeep , Scanlon William , Matthews Allison , Sharifova Saida , Huq Enamul , Reddy Anireddy S N
Published: July 2024

A genetically encoded splicing reporter allows naked-eye visualization of pre-mRNA splicing and requires no expensive equipment or substrate.
Structure of the intact Tom20 receptor in the human translocase of the outer membrane complex
Authors: Su Jiayue , Tian Xuyang , Wang Ziyi , Yang Jiawen , Sun Shan , Sui Sen-Fang
Published: July 2024

The translocase of the outer membrane (TOM) complex serves as the main gate for preproteins entering mitochondria and thus plays a pivotal role in sustaining mitochondrial stability. Precursor proteins, featuring amino-terminal targeting signals (presequences) or internal targeting signals, are recognized by the TOM complex receptors Tom20, Tom22, and Tom70, and then translocated into mitochondria through Tom40. By using chemical cross-linking to stabilize Tom20 in the TOM complex, this study unveils the structure of the human TOM holo complex, encompassing the intact Tom20 component, at a resolution of approximately 6 Å by cryo-electron microscopy. Our structure shows the TOM holo complex containing only one Tom20 subunit, which is located right at the center of the complex and stabilized by extensive interactions with Tom22, Tom40, and Tom6. Based on the structure, we proposed a possible translocation mode of TOM complex, by which different receptors could work simultaneously to ensure that the preproteins recognized by them are all efficiently translocated into the mitochondria.
Singular effect of linkage on long-term genetic gain in Fisher’s infinitesimal model
Authors: Tourrette Elise , Martin Olivier C
Published: July 2024

During the founding of the field of quantitative genetics, Fisher formulated in 1918 his “infinitesimal model” that provided a novel mathematical framework to describe the Mendelian transmission of quantitative traits. If the infinitely many genes in that model are assumed to segregate independently during reproduction, corresponding to having no linkage, directional selection asymptotically leads to a constant genetic gain at each generation. In reality, genes are subject to strong linkage because they lie on chromosomes and thus segregate in a correlated way. Various approximations have been used in the past to study that more realistic case of the infinitesimal model with the expectation that the asymptotic gain per generation is modestly decreased. To treat this system even in the strong linkage limit, we take the genes to lie on continuous chromosomes. Surprisingly, the consequences of genetic linkage are in fact rather singular, changing the nature of the long-term gain per generation: the asymptotic gain vanishes rather than being simply decreased. Nevertheless, the per-generation gain tends to zero sufficiently slowly for the total gain, accumulated over generations, to be unbounded.
Granulomatosis with polyangiitis with and without antineutrophil cytoplasmic antibodies: a case-control study
Authors: Casal Moura Marta , Falde Sam , Sethi Sanjeev , Fervenza Fernando C , Specks Ulrich , Baqir Misbah
Published: July 2024

Objective

ANCA-negative granulomatosis with polyangiitis (GPA) remains a diagnosis of exclusion. Clinical differences between patients with ANCA-negative vs ANCA-positive GPA have not been analysed in sizable case-control studies, and the effects of ANCA-seroconversion from negative to positive are not well documented.

Methods

A single-centre, sex and age matched case-control study evaluated ANCA-negative vs ANCA-positive GPA from 1 January 1996 to 31 December 2015. Patients who experienced seroconversion were the subject of a case-crossover study. Clinical data and outcomes were retrieved from electronic medical records.

Results

ANCA-negative GPA was identified in 110 patients; 65% were female; median age was 55 (IQR 39–65) years at time of diagnosis. Disease severity was milder in ANCA-negative GPA (BVAS/WG = 2 vs 6, P < 0.001). Mucous membranous/eye manifestations were more frequent in ANCA-negative GPA. General symptoms, pulmonary and renal involvement were more frequent in ANCA-positive GPA. Patients with ANCA-positive GPA relapsed more over 60 months (21.8% vs. 9.1%, P = 0.009) compared with ANCA-negative GPA and had shorter time to event (P = 0.043). Patients with general manifestations, BMI > 30kg/m2 and necrotizing granulomatous inflammation were more likely to relapse. The 16 patients who seroconverted into ANCA-positive during follow-up had higher mean BVAS/WG at time of diagnosis (P < 0.001) and increased incidence of relapses (P = 0.004) after seroconversion. Necrotizing granulomatous inflammation on biopsy in ANCA-negative GPA patients was identified as a risk factor for subsequent seroconversion to ANCA-positivity.

Conclusion

Patients with ANCA-negative GPA have milder disease and a lower frequency of relapse than those with ANCA-positive GPA. ANCA appearance portended higher disease severity and an increased frequency of relapses.
Submandibular gland tissue RNAseq and spatial transcriptome analyses in IgG4-related disease
Authors: Yamamoto Motohisa , Kamekura Ryuta , Uehara Masaaki , Ichii Yuta , Tanaka Tomonao , Aochi Satsuki , Takano Ken-ichi
Published: July 2024

Objective

To identify genes that could provide clues leading to the discovery of drugs to treat IgG4-related disease (IgG4-RD).

Methods

Submandibular gland tissue bulk RNAseq analysis of 45 cases with a definite diagnosis of IgG4-RD was integrated with Visium spatial transcriptome analysis of two cases to identify pathogenic genes expressed in tertiary lymphoid tissues.

Results

Bulk RNAseq and pathway analyses showed upregulation of cell cycle and T cell-related signals in IgG4-RD. Spatial transcriptome analysis identified the cluster corresponding to germinal centres and the top 38 common genes that showed significant variations in expression compared with other clusters. The top 20 genes were extracted by comparing the bulk RNAseq data. Network analysis identified CDK1 as the gene most strongly associated of the top 20 genes.

Conclusion

The CDK1 gene may be a regulator of the pathogenesis of IgG4-RD and provide clues for drug discovery.
Copper-mediated neurotoxicity and genetic vulnerability in the background of neurodegenerative diseases in C. elegans
Authors: Weishaupt Ann-Kathrin , Ruecker Lysann , Meiners Torben , Schwerdtle Tanja , Silva Avila Daiana , Aschner Michael , Bornhorst Julia
Published: July 2024

The mechanisms associated with neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), have yet to be fully characterized, and genetic as well as environmental factors in their disease etiology are underappreciated. Although mutations in genes such as PARKIN and LRRK2 have been linked to PD, the idiopathic component of the disease suggests a contribution of environmental risk factors, including metals, such as copper (Cu). Cu overexposure has been reported to cause oxidative stress and neurotoxicity, but its role in neurodegenerative diseases is rarely studied. Using Caenorhabditis elegans (C. elegans) as a model organism for neurotoxicity, we assessed the effects of Cu oversupply in AD and PD models. Our findings reveal that although copper treatment did not induce neurodegeneration in wild-type worms or the AD model, it significantly exacerbated neurodegeneration in the PD-associated mutants PARKIN and LRRK2. These results suggest that genetic predisposition for PD enhances the sensitivity to copper toxicity, highlighting the multifactorial nature of neurodegenerative diseases. Furthermore, our study provides insight into the mechanisms underlying Cu-induced neurotoxicity in PD models, including disruptions in dopamine levels, altered dopamine-dependent behavior and degraded dopaminergic neurons. Overall, our novel findings contribute to a better understanding of the complex interactions between genetic susceptibility, environmental factors, and neurodegenerative disease pathogenesis, emphasizing the importance of a tightly regulated Cu homeostasis in the etiology of PD.

Copper oversupply exacerbated neurodegeneration in Caenorhabditis elegans models of Parkinson’s disease, highlighting the genetic susceptibility and emphasizing the crucial role of tightly regulated copper homeostasis in Parkinson’s disease pathogenesis.
Formaldehyde and the transient receptor potential ankyrin-1 contribute to electronic cigarette aerosol-induced endothelial dysfunction in mice
Authors: Jin Lexiao , Richardson Andre , Lynch Jordan , Lorkiewicz Pawel , Srivastava Shweta , Fryar Laura , Miller Alexis , Theis Whitney , Shirk Gregg , Bhatnagar Aruni , Srivastava Sanjay , Riggs Daniel W , Conklin Daniel J
Published: July 2024

Electronic nicotine delivery systems (ENDS) aerosol exposures can induce endothelial dysfunction (ED) in healthy young humans and animals. Thermal degradation of ENDS solvents, propylene glycol, and vegetable glycerin (PG: VG), generates abundant formaldehyde (FA) and other carbonyls. Because FA can activate the transient receptor potential ankyrin-1 (TRPA1) sensor, we hypothesized that FA in ENDS aerosols provokes TRPA1-mediated changes that include ED and “respiratory braking”—biomarkers of harm. To test this, wild-type (WT) and TRPA1-null mice were exposed by inhalation to either filtered air, PG: VG-derived aerosol, or FA (5 ppm). Short-term exposures to PG: VG and FA-induced ED in female WT but not in female TRPA1-null mice. Moreover, acute exposures to PG: VG and FA stimulated respiratory braking in WT but not in TRPA1-null female mice. Urinary metabolites of FA (ie, N-1,3-thiazolidine-4-carboxylic acid, TCA; N-1,3-thiazolidine-4-carbonyl glycine, TCG) and monoamines were measured by LC-MS/MS. PG: VG and FA exposures significantly increased urinary excretion of both TCA and TCG in both WT and TRPA1-null mice. To confirm that inhaled FA directly contributed to urinary TCA, mice were exposed to isotopic 13C-FA gas (1 ppm, 6 h). 13C-FA exposure significantly increased the urine level of 13C-TCA in the early collection (0 to 3 h) supporting a direct relationship between inhaled FA and TCA. Collectively, these data suggest that ENDS use may increase CVD risk dependent on FA, TRPA1, and catecholamines, yet independently of either nicotine or flavorants. This study supports that levels of FA in ENDS-derived aerosols should be lowered to mitigate CVD risk in people who use ENDS.
Genetic Analysis of Stripe Rust Resistance in the Chinese Wheat Cultivar Luomai 163
Authors: Li Zimeng , Yuan Chan , Li Shunda , Zhang Yu , Bai Bin , Yang Fangping , Liu Pengpeng , Sang Wei , Ren Yong , Singh Ravi , Liao Pingan , Lan Caixia
Published: July 2024

Stripe or yellow rust (YR) caused by Puccinia striiformis tritici (Pst) is an important foliar disease affecting wheat production globally. Resistant varieties are the most economically and environmentally effective way to manage this disease. The common winter wheat (Triticum aestivum L.) cultivar Luomai 163 exhibited resistance to the Pst races CYR32 and CYR33 at the seedling stage and showed a high level of adult plant resistance in the field. To understand the genetic basis of YR resistance in this cultivar, 142 F5 recombinant inbred lines (RILs) derived from cross Apav#1 × LM163 and both parents were genotyped with the 16K SNP array and bulked segregant analysis sequencing. The analysis detected a major gene, YrLM163, at the seedling stage associated with the 1BL.1RS translocation. Additionally, three genes for resistance at the adult plant stage were detected on chromosome arms 1BL (Lr46/Yr29/Pm39/Sr58), 6BS, and 6BL in Luomai 163, whereas Apav#1 contributed resistance at a quantitative trait locus (QTL) on 2BL. These QTL explained YR disease severity variations ranging from 6.9 to 54.8%. The kompetitive allele-specific PCR (KASP) markers KASP-2BL, KASP-6BS, and KASP-6BL for the three novel loci QYr.hzau-2BL, QYr.hzau-6BS, and QYr.hzau-6BL were developed and validated. QYr.hzau-1BL, QYr.hzau-2BL, and QYr.hzau-6BS showed varying degrees of resistance to YR when present individually or in combination based on genotype and phenotype analysis of a panel of 570 wheat accessions. Six RILs combining resistance alleles of all QTL, showing higher resistance to YR in the field than Luomai 163 with disease severities of 10.7 to 16.0%, are important germplasm resources for breeding programs to develop YR-resistant wheat varieties with good agronomic traits.
Unstable Transgene Expression Affects Long-Term Efficacy of the Arabidopsis Immune Receptor EFR to Confer Quantitative Resistance to Citrus Canker Under Field Conditions
Authors: Jain Mukesh , Minsavage Gerald V. , Thapa Naweena , Horvath Diana M. , Zipfel Cyril , Moore Gloria A. , Fisher Latanya C. , Orbović Vladimir , Jones Jeffrey B.
Published: July 2024

The Arabidopsis thaliana pattern recognition ELONGATION FACTOR-TU RECEPTOR (EFR) recognizes and binds the bacterial pathogen-associated molecular pattern (PAMP) elongation factor thermo unstable (EF-Tu) and its highly conserved derived peptide elf18. Previous work revealed that the transgenic expression of EFR (and chimeric EFR:: XA21) in several heterologous plant species, including in members of Solanaceae and in sweet orange, confers broad-spectrum bacterial disease resistance. In this study, stable sweet orange ( Citrus × sinensis) and grapefruit ( Citrus × paradisi) transformants expressing EFR or EFR:: XA21 were generated in an attempt to confer broad spectrum resistance to Xanthomonas citri subsp. citri ( Xcc), the causal agent of citrus canker, a serious disease of commercial citriculture. The transgene expression was confirmed via real-time quantitative reverse transcriptase PCR (RT-qPCR). Juvenile transgenic trees were challenged with Xcc (spray and pinprick inoculation) and evaluated for canker susceptibility and disease progression. Three independently transformed transgenic events (out of 19 total) displayed partial resistance to canker when spray-inoculated, and one line showed resistance when wound-inoculated. Surprisingly, when two mature transgenic lines were evaluated under field conditions and exposure to natural infection, both were found to be as susceptible as the wild-type under prevalent pathogen load. RT-qPCR data indicated a gradual decline and significant spatial variability in EFR expression in leaves excised from different branches of the same tree. The data presented here call for a need for evaluating different promoters for stable and long-term EFR expression in woody perennial species.

[Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Microinvasive intrascleral double continuous suture repair surgery for cyclodialysis clefts
Authors: Xu Cen-Bo , Huang Gong-Yu , Pan Qin-Tuo , Li Yong-Jian , Xu Bo-Lun , Wu Qi , Zhang Zong-Duan
Published: July 2024

Background:

The traditional suturing method for cyclodialysis cleft usually requires an incision in the sclera for direct suturing, resulting in greater damage and a high risk of postoperative complications. The purpose of this work is to propose a newly intrascleral double continuous suture repair technique for the treatment of cyclodialysis clefts.

Methods:

Seven patients with cyclodialysis cleft underwent microinvasive intrascleral double continuous suture repair surgery to restore the attachment of the detached ciliary body to the sclera without scleral incision. All operations were performed by the same surgeon. Preoperative and postoperative visual acuity (VA), intraocular pressure (IOP), slit lamp and corneal examination results, ultrasound biomicroscopy (UBM) and optical coherence tomography (OCT) results were recorded.

Results:

Closure of the cyclodialysis cleft was achieved in 7 eyes and no obvious complications occurred after the operation. Intraocular pressure increased from preoperatively 6.8 ± 1.35 mmHg (range: 4.8–8.0 mmHg) to postoperatively 12.5 ± 4.0 mmHg (range: 8.0–20.0 mmHg) (paired sample T test, P < 0.01). Best-corrected Snellen visual acuity improved from preoperatively range 20/2000-20/63 to range 20/200-20/25 at final follow-up.

Conclusion:

In short, intrascleral double continuous suture repair surgical is safe and effective in treating cyclodialysis cleft, with minimal surgical trauma.
Simple Modification of a DSAEK Carrier Enables Graft Insertion by Injection Without Compromising Endothelial Cell Viability
Authors: Straiko Megan M.W. , Letchworth Emma V. , Dye Philip K. , Galloway Joshua D. , Tran Khoa D.
Published: July 2024

Purpose:

We evaluate the quality and feasibility of preloading Descemet stripping automated endothelial keratoplasty (DSAEK) grafts into a modified EndoGlide Ultrathin system for graft injection.

Methods:

DSAEK grafts were prepared by experienced processing technicians at 2 separate locations, loaded into a modified EndoGlide Ultrathin, and placed in storage media. Grafts processed at one location were shipped cross-country overnight to the other location and were examined on arrival for positioning within the modified EndoGlide Ultrathin. All grafts were ejected and analyzed for endothelial cell loss (ECL) with calcein acetoxymethyl staining and FIJI segmentation. A subset of grafts was measured by optical coherence tomography for graft thickness 1 hour after cut, 1 hour after loading, and 1 day after loading.

Results:

No grafts were displaced from the modified carrier over 3 shipping events (n = 9), and all grafts (n = 18) were successfully ejected. Grafts loaded into the modified carrier and ejected exhibited no more cell loss than grafts loaded into the standard carrier and removed by pull-through (14.0% ± 2.8% vs. 12.2% ± 3.4%, respectively, P = 0.24). Carrier modification skills can be successfully transferred as grafts loaded by a processing technician new to carrier modification were within the acceptable limit of 25% ECL for transplant DSAEK grafts. Graft thickness increased significantly (P < 0.05) between the postcut and 1-hour postload measurement and the postcut and 24-hour postload measurement.

Conclusions:

The EndoGlide Ultrathin can be modified to enable its use for graft injection while not compromising the ability to use the pull-through method for graft delivery. Preloaded DSAEK grafts swell significantly during the 24-hour storage period, and patterns of ECL may be linked to swelling.
CAR-T Therapy in HIV: Pioneering Advances and Navigating Challenges
Authors: Wang Xiao , Liu Jianyang , Hao Feike , Ajavavarakula Tatchapon , Shi Xuanling
Published: July 2024

Chimeric antigen receptor T (CAR-T) cell therapy, renowned for its successes in cancer treatment, is now entering the field of human immunodeficiency virus (HIV) therapy, presenting both opportunities and challenges. With the emergence of broadly neutralizing antibodies, multi-target CARs, and T cell receptor–like antibodies aimed at increasing specificity in targeting HIV reservoirs, CAR-T therapy is synergizing with other cutting-edge treatments, including gene-editing technologies, therapeutic vaccines, and latency-reversing agents, in pursuit of a potential functional cure. In this review, we delve into the role of CAR-T therapy in HIV treatment, highlighting its potential to overcome clinical obstacles. We discuss advancements in targeting strategies within CAR constructs and the intricate regulation of T cell proliferation and chemotaxis. Moreover, we explore the use of diverse immune cells, such as gamma-delta T cells and natural killer cells. We review advanced biotechnologies, manufacturing innovations, viral mechanisms, and immune microenvironments. We also discuss the current research landscape and potential future applications of CAR-T therapy against HIV, which remains a critical global health challenge.
Meeting the Health Needs of Society Through Curricular Innovation in Physical Therapist Education: Examples From 3 Entry-Level Programs
Authors: Magnusson Dawn M. , Judd Dana L. , Ambler Steven B. , Magee Julian , Collins Prisca , Kuba Elizabeth , Bilyeu Catherine
Published: July 2024

Background and Purpose.

Entry-level physical therapist (PT) education programs play a critical role in inspiring future leaders to become moral change agents, capable of understanding and addressing evolving societal health needs. Social reconstructionism represents an educational philosophy focused on alleviating pervasive inequities and improving the health of society; however, its application in PT education is not well understood. The purpose of this article is to describe the approach 3 entry-level PT programs used to manifest social reconstructionism within their curricula to foster social consciousness and strengthen moral agency.

Method/Model Description and Evaluation.

The Framework for Educating Health Professionals to Address the Social Determinants of Health informed the development of a conceptual framework that illustrates the role of PT education programs in creating transformative learning environments and preparing learners to meet societal health needs. Concepts within this framework were operationalized according to 5 domains put forth by Jensen et al. and related competencies put forth by the Association of American Medical Colleges.

Outcomes.

Narratives from each program demonstrate how the design and implementation of curricula, grounded in social reconstructionism, can be accomplished through 1) ongoing modifications, 2) thoughtful reconstruction, and 3) initial design. Sample learning activities, objectives, and assessment strategies are provided.

Discussion and Conclusion.

The proposed method was effective in guiding meaningful objectives, learning activities, and assessment strategies grounded in social reconstructionism. Such findings can inform the design of curricula that inspire the next generation of transformative leaders who work to alleviate pervasive inequities and improve the health of society.
Prevalence and Type of HPV Genital Infection in Girls: A Systematic Review and Meta-Analysis
Authors: de Azevedo Bispo Raianne Kívia , Fonseca Marcelo Cunio Machado , de Góis Speck Neila Maria
Published: July 2024

Objectives

This investigation explored the prevalence of human papillomavirus (HPV) infection by subtypes in girls aged up to 12.

Methods

Four indexed databases, PubMed, EMBASE, Cochrane, and LILACS, were evaluated. Twenty-nine observational studies published between 1992 and 2018 were included.

Results

The prevalence of genital condyloma acuminatum or HPV-positive serology due to prior infection among girls with suspected/confirmed sexual abuse was 25%, and without a history or information about abuse, 8%. The analysis indicated that low-risk HPV types were the most prevalent among this group, corresponding to 86.6% of the identified types. Human papillomavirus 6 and 11 were the most prevalent types, followed by HPV 16 and 2. Moreover, the analysis identified limited epidemiological data on genital warts in children up to 12 years. Several studies focused on convenience sampling, sexually abused girls, or failed to separate data by gender.

Conclusion

Findings of our systematic review and prevalence meta-analysis indicate that the occurrence of HPV infection in girls aged 12 or younger is relatively rare, underscoring the significance of understanding the prevalence of HPV in the pediatric population. However, it is essential to be cautious when applying these results to the pediatric population, given cases of girls who are suspected of or have suffered sexual abuse. There is a pressing need for further research to fill the information gap on HPV infection in this vulnerable group.
The Grief Debate, the DSM, and Clinical Practice
Authors: Phillips James
Published: July 2024

There has been an ongoing debate regarding grief, whether it may be at times pathological, and whether it is different from depression. This article addresses those questions by tracking the changing course of the Diagnostic and Statistical Manuals of Mental Disorders (DSMs) since DSM-III and by reviewing the debate concerning grief and depression. At the time when DSM-III was being prepared in the late 1970s (it was published in 1980), there was a concern that normal bereavement (or grief) was being diagnosed as major depression. To address this concern, the editors of DSM-III added a category of “uncomplicated bereavement.” The fourth edition of the DSM (DSM-IV), published in 1994, then followed by a minor change. However, the editors of DSM-5 decided to eliminate the bereavement exclusion entirely. Their concern was simply whether the individual did or did not suffer from major depression. Since an individual might not warrant a diagnosis of major depression but might still be experiencing grief, the DSM discussion leads directly into the question of whether grief—later called prolonged grief disorder—and depression are separate conditions. Advocates for prolonged grief disorder maintained that grief is different from depression but that patients may present with a mix of grief and depressive symptoms that are clinically difficult to distinguish. Advocates of separate conditions have in fact developed an inventory of symptoms that identify prolonged grief disorder. However, inasmuch as a typical grief presentation will include depressive symptoms, the clinical challenge is to distinguish prolonged grief disorder and major depression, as well as to distinguish both from normal grief. Given the temporal limits of an average consultation, this article argues that making the required distinctions is an unrealistic expectation. Finally, researchers have developed specific treatment programs for prolonged grief disorder, but a conflict between the 2 primary researchers involved and the generalities in which the programs are phrased have led to the suggestion of a different approach to treatment that replaces generalities with a person-centered approach.
“What you’re born with, you die with.” Half a Lifetime of Psychiatric Care for a Traumatized Young Woman With Cystic Fibrosis
Authors: Bruxner George
Published: July 2024

This case report describes 19 years of psychiatric care of a young female survivor of childhood sexual and physical abuse and neglect who also had the misfortune of having a life-compromising and life-limiting physical disease, cystic fibrosis. It summarizes ~ 100 therapeutic contacts from age 21 to age 40 and spans her journey through lung transplantation to the end of her life. The nature of cystic fibrosis and its treatment is reviewed and there is a discussion of the therapeutic process. The case is enriched by emails from the young woman describing her struggles to maintain personal integrity as her lung function declined. The case is presented with the young woman’s consent.