Elucidating distinct molecular signatures of Lewy body dementias.

Dementia with Lewy bodies and Parkinson's disease dementia are common neurodegenerative diseases that share similar neuropathological profiles and spectra of clinical symptoms but are primarily differentiated by the order in which symptoms manifest. The question of whether a distinct molecular pathological profile could distinguish these disorders is yet to be answered. However, in recent years, studies have begun to investigate genomic, epigenomic, transcriptomic and proteomic differences that may differentiate these disorders, providing novel insights in to disease etiology. In this review, we present an overview of the clinical and pathological hallmarks of Lewy body dementias before summarizing relevant research into genetic, epigenetic, transcriptional and protein signatures in these diseases, with a particular interest in those resolving "omic" level changes. We conclude by suggesting future research directions to address current gaps and questions present within the field.

Induced Pluripotent Stem Cells for Inherited Optic Neuropathies-Disease Modeling and Therapeutic Development.

BACKGROUND: Inherited optic neuropathies (IONs) cause progressive irreversible visual loss in children and young adults. There are limited disease-modifying treatments, and most patients progress to become severely visually impaired, fulfilling the legal criteria for blind registration. The seminal discovery of the technique for reprogramming somatic nondividing cells into induced pluripotent stem cells (iPSCs) has opened several exciting opportunities in the field of ION research and treatment. EVIDENCE ACQUISITION: A systematic review of the literature was conducted with PubMed using the following search terms: autosomal dominant optic atrophy, ADOA, dominant optic atrophy, DOA, Leber hereditary optic neuropathy, LHON, optic atrophy, induced pluripotent stem cell, iPSC, iPSC derived, iPS, stem cell, retinal ganglion cell, and RGC. Clinical trials were identified on the ClinicalTrials.gov website. RESULTS: This review article is focused on disease modeling and the therapeutic strategies being explored with iPSC technologies for the 2 most common IONs, namely, dominant optic atrophy and Leber hereditary optic neuropathy. The rationale and translational advances for cell-based and gene-based therapies are explored, as well as opportunities for neuroprotection and drug screening. CONCLUSIONS: iPSCs offer an elegant, patient-focused solution to the investigation of the genetic defects and disease mechanisms underpinning IONs. Furthermore, this group of disorders is uniquely amenable to both the disease modeling capability and the therapeutic potential that iPSCs offer. This fast-moving area will remain at the forefront of both basic and translational ION research in the coming years, with the potential to accelerate the development of effective therapies for patients affected with these blinding diseases.

Absence of Decussation in Optic Pathway Inflammation in Neuromyelitis Optica and Its Implications for Astrocyte Localization.

ABSTRACT: A 39-year-old woman presented with acute visual loss in her right eye. Brain and orbit MRI demonstrated T2 hyperintensity along a long section of her right optic nerve, chiasm, and tract with no evidence of decussation of the inflammation. Subsequent seropositivity for the aquaporin 4 antibody confirmed a diagnosis of neuromyelitis optica. Posterior pathway involvement is typical in neuromyelitis optica and supports the hypothesis that the condition is an astrocytopathy. Furthermore, the absence of decussation in the condition may be a function of astrocyte localization within the chiasm.

Differential stoichiometric homeostasis and growth in two native and two invasive C3 grasses.

Global changes interact with plant invasions by differentially impacting native and invasive species. For example, invasive plants often benefit from eutrophication to a greater degree than native plants. While this is well-documented, a broad, trait-based explanation for this phenomenon is lacking. Recent research shows that stoichiometric homeostasis predicts plant species responses to eutrophication and drought, but this research has not been extended into an invasion ecology paradigm. We tested the hypotheses that stoichiometric homeostasis would differ between native and invasive plants, that expressed levels of stoichiometric homeostasis would respond to water availability, and that differences in stoichiometric homeostasis would match differences in growth. In a nutrient and water manipulation study, we found that stoichiometric homeostasis differed between native grasses (Elymus canadensis and Pascopyrum smithii) and invasive grasses (Agropyron cristatum and Bromus inermis), that differences in stoichiometric homeostasis matched differences in growth in well-watered grasses, and that expressed levels of stoichiometric homeostasis were stable across the water supply treatments. These results suggest that invasive plants maintain growth advantages over native plants in eutrophic conditions because of differential homeostatic requirements. We argue that stoichiometric homeostasis is therefore a useful functional trait to explain and predict differential native and invasive plant responses to global change.

Treatment strategies for Leber hereditary optic neuropathy.

PURPOSE OF REVIEW: Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) disorder in the population and it carries a poor visual prognosis. In this article, we review the development of treatment strategies for LHON, the evidence base and the areas of unmet clinical need. RECENT FINDINGS: There is accumulating evidence that increasing mitochondrial biogenesis could be an effective strategy for protecting retinal ganglion cells in LHON. A number of clinical trials are currently investigating the efficacy of viral-based gene therapy for patients harbouring the m.11778G>A mtDNA mutation. For female LHON carriers of childbearing age, mitochondrial replacement therapy is being offered to prevent the maternal transmission of pathogenic mtDNA mutations. SUMMARY: Although disease-modifying treatment options remain limited, a better understanding of the underlying disease mechanisms in LHON is paving the way for complementary neuroprotective and gene therapeutic strategies for this mitochondrial optic nerve disorder.

The Neon Fruit Illusion: A Fresh Recipe for Colour Science Demonstrations.

At this year's European Conference on Visual Perception, we debuted a novel colour science demonstration-and visual illusion-for the Un mare di illusioni exhibition. Under carefully curated lighting conditions, cycling through different illuminant spectra, certain fruits and vegetables appear to glow and dim in an unchanging environment. Encouraged by the positive reactions it received, and the numerous and specific questions from conference delegates, we here describe what this illusion is, why we believe it may work, and how this particular low-cost setup may be assembled and demonstrated for the amazement of your friends, students, and members of the public.

Hand-Foot Coupling: An Advantage for Crossed Legs.

It is difficult to perform distinct, simultaneous motor actions with the ipsilateral hand and foot; for example, clockwise circles with the right hand and counter-clockwise circles with the right foot. By chance, we discovered that this hand-foot coupling task is easier when seated with legs crossed. We consider various explanations. First, that there are reduced demands on the contralateral hemisphere when the motor programme of the right foot is executed on the left side of the body. Second, that the legs-crossed scenario is easier because movements are symmetrical with respect to body midline. By considering related motor actions, we conclude that neither of these explanations provides a full account. Thus, we suggest a third explanation, which is that coupling effects are reduced by virtue of increased postural stability and reduced anticipatory postural adjustments.

Bow-shaped caustics from conical prisms: a 13th-century account of rainbow formation from Robert Grosseteste's De iride.

The rainbow has been the subject of discussion across a variety of historical periods and cultures, and numerous optical explanations have been suggested. Here, we further explore the scientific treatise De iride [On the Rainbow] written by Robert Grosseteste in the 13th century. Attempting to account for the shape of the rainbow, Grosseteste bases his explanation on the optical properties of transparent cones, which he claims can give rise to arc-shaped projections through refraction. By stating that atmospheric phenomena are reducible to the geometric optics of a conical prism, the De iride lays out a coherent and testable hypothesis. Through both physical experiment and physics-based simulation, we present a novel characterization of cone-light interactions, demonstrating that transparent cones do indeed give rise to bow-shaped caustics-a nonintuitive phenomenon that suggests Grosseteste's theory of the rainbow is likely to have been grounded in observation.

Improving Pulse Rate Measurements during Random Motion Using a Wearable Multichannel Reflectance Photoplethysmograph.

Photoplethysmographic (PPG) waveforms are used to acquire pulse rate (PR) measurements from pulsatile arterial blood volume. PPG waveforms are highly susceptible to motion artifacts (MA), limiting the implementation of PR measurements in mobile physiological monitoring devices. Previous studies have shown that multichannel photoplethysmograms can successfully acquire diverse signal information during simple, repetitive motion, leading to differences in motion tolerance across channels. In this paper, we investigate the performance of a custom-built multichannel forehead-mounted photoplethysmographic sensor under a variety of intense motion artifacts. We introduce an advanced multichannel template-matching algorithm that chooses the channel with the least motion artifact to calculate PR for each time instant. We show that for a wide variety of random motion, channels respond differently to motion artifacts, and the multichannel estimate outperforms single-channel estimates in terms of motion tolerance, signal quality, and PR errors. We have acquired 31 data sets consisting of PPG waveforms corrupted by random motion and show that the accuracy of PR measurements achieved was increased by up to 2.7 bpm when the multichannel-switching algorithm was compared to individual channels. The percentage of PR measurements with error ≤ 5 bpm during motion increased by 18.9% when the multichannel switching algorithm was compared to the mean PR from all channels. Moreover, our algorithm enables automatic selection of the best signal fidelity channel at each time point among the multichannel PPG data.

Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial.

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to rapid and severe bilateral vision loss. Idebenone has been shown to be effective in stabilizing and restoring vision in patients treated within 1 year of onset of vision loss. The open-label, international, multicenter, natural history-controlled LEROS study (ClinicalTrials.gov NCT02774005) assesses the efficacy and safety of idebenone treatment (900 mg/day) in patients with LHON up to 5 years after symptom onset (N = 199) and over a treatment period of 24 months, compared to an external natural history control cohort (N = 372), matched by time since symptom onset. LEROS meets its primary endpoint and confirms the long-term efficacy of idebenone in the subacute/dynamic and chronic phases; the treatment effect varies depending on disease phase and the causative mtDNA mutation. The findings of the LEROS study will help guide the clinical management of patients with LHON.

Sensory perception: lessons from synesthesia: using synesthesia to inform the understanding of sensory perception.

Synesthesia, the conscious, idiosyncratic, repeatable, and involuntary sensation of one sensory modality in response to another, is a condition that has puzzled both researchers and philosophers for centuries. Much time has been spent proving the condition's existence as well as investigating its etiology, but what can be learned from synesthesia remains a poorly discussed topic. Here, synaesthesia is presented as a possible answer rather than a question to the current gaps in our understanding of sensory perception. By first appreciating the similarities between normal sensory perception and synesthesia, one can use what is known about synaesthesia, from behavioral and imaging studies, to inform our understanding of "normal" sensory perception. In particular, in considering synesthesia, one can better understand how and where the different sensory modalities interact in the brain, how different sensory modalities can interact without confusion - the binding problem - as well as how sensory perception develops.

Thermotolerance of tomato plants grafted onto wild relative rootstocks.

Heat stress is a major environmental constraint limiting tomato production. Tomato wild relatives Solanum pennellii and S. peruvianum are known for their drought tolerance but their heat stress responses have been less investigated, especially when used as rootstocks for grafting. This study aimed to evaluate the physiological and biochemical heat stress responses of tomato seedlings grafted onto a commercial 'Maxifort' and wild relative S. pennellii and S. peruvianum rootstocks. 'Celebrity' and 'Arkansas Traveler' tomato scion cultivars, previously characterized as heat-tolerant and heat-sensitive, respectively, were grafted onto the rootstocks or self-grafted as controls. Grafted seedlings were transplanted into 10-cm pots and placed in growth chambers set at high (38/30°C, day/night) and optimal (26/19°C) temperatures for 21 days during the vegetative stage. Under heat stress, S. peruvianum-grafted tomato seedlings had an increased leaf proline content and total non-enzymatic antioxidant capacity in both leaves and roots. Additionally, S. peruvianum-grafted plants showed more heat-tolerant responses, evidenced by their increase in multiple leaf antioxidant enzyme activities (superoxide dismutase, catalase and peroxidase) compared to self-grafted and 'Maxifort'-grafted plants. S. pennellii-grafted plants had similar or higher activities in all antioxidant enzymes than other treatments at optimal temperature conditions but significantly lower activities under heat stress conditions, an indication of heat sensitivity. Both S. pennellii and S. peruvianum-grafted plants had higher leaf chlorophyll content, chlorophyll fluorescence and net photosynthetic rate under heat stress, while their plant growth was significantly lower than self-grafted and 'Maxifort'-grafted plants possibly from graft incompatibility. Root abscisic acid (ABA) contents were higher in 'Maxifort' and S. peruvianum rootstocks, but no ABA-induced antioxidant activities were detected in either leaves or roots. In conclusion, the wild relative rootstock S. peruvianum was effective in enhancing the thermotolerance of scion tomato seedlings, showing potential as a breeding material for the introgression of heat-tolerant traits in interspecific tomato rootstocks.

Mitochondria and the eye-manifestations of mitochondrial diseases and their management.

Historically, distinct mitochondrial syndromes were recognised clinically by their ocular features. Due to their predilection for metabolically active tissue, mitochondrial diseases frequently involve the eye, resulting in a range of ophthalmic manifestations including progressive external ophthalmoplegia, retinopathy and optic neuropathy, as well as deficiencies of the retrochiasmal visual pathway. With the wider availability of genetic testing in clinical practice, it is now recognised that genotype-phenotype correlations in mitochondrial diseases can be imprecise: many classic syndromes can be associated with multiple genes and genetic variants, and the same genetic variant can have multiple clinical presentations, including subclinical ophthalmic manifestations in individuals who are otherwise asymptomatic. Previously considered rare diseases with no effective treatments, considerable progress has been made in our understanding of mitochondrial diseases with new therapies emerging, in particular, gene therapy for inherited optic neuropathies.

Epigenetic insights into neuropsychiatric and cognitive symptoms in Parkinson's disease: A DNA co-methylation network analysis.

Parkinson's disease is a highly heterogeneous disorder, encompassing a complex spectrum of clinical presentation including motor, sleep, cognitive and neuropsychiatric symptoms. We aimed to investigate genome-wide DNA methylation networks in post-mortem Parkinson's disease brain samples and test for region-specific association with common neuropsychiatric and cognitive symptoms. Of traits tested, we identify a co-methylation module in the substantia nigra with significant correlation to depressive symptoms and with ontological enrichment for terms relevant to neuronal and synaptic processes. Notably, expression of the genes annotated to the methylation loci present within this module are found to be significantly enriched in neuronal subtypes within the substantia nigra. These findings highlight the potential involvement of neuronal-specific changes within the substantia nigra with regard to depressive symptoms in Parkinson's disease.

Progress and harmonization of gene editing to treat human diseases: Proceeding of COST Action CA21113 GenE-HumDi.

The European Cooperation in Science and Technology (COST) is an intergovernmental organization dedicated to funding and coordinating scientific and technological research in Europe, fostering collaboration among researchers and institutions across countries. Recently, COST Action funded the "Genome Editing to treat Human Diseases" (GenE-HumDi) network, uniting various stakeholders such as pharmaceutical companies, academic institutions, regulatory agencies, biotech firms, and patient advocacy groups. GenE-HumDi's primary objective is to expedite the application of genome editing for therapeutic purposes in treating human diseases. To achieve this goal, GenE-HumDi is organized in several working groups, each focusing on specific aspects. These groups aim to enhance genome editing technologies, assess delivery systems, address safety concerns, promote clinical translation, and develop regulatory guidelines. The network seeks to establish standard procedures and guidelines for these areas to standardize scientific practices and facilitate knowledge sharing. Furthermore, GenE-HumDi aims to communicate its findings to the public in accessible yet rigorous language, emphasizing genome editing's potential to revolutionize the treatment of many human diseases. The inaugural GenE-HumDi meeting, held in Granada, Spain, in March 2023, featured presentations from experts in the field, discussing recent breakthroughs in delivery methods, safety measures, clinical translation, and regulatory aspects related to gene editing.

Characterisation of a novel OPA1 splice variant resulting in cryptic splice site activation and mitochondrial dysfunction.

Autosomal dominant optic atrophy (DOA) is an inherited optic neuropathy that results in progressive, bilateral visual acuity loss and field defects. OPA1 is the causative gene in around 60% of cases of DOA. The majority of patients have a pure ocular phenotype, but 20% have extra-ocular features (DOA +). We report on a patient with DOA + manifesting as bilateral optic atrophy, spastic paraparesis, urinary incontinence and white matter changes in the central nervous system associated with a novel heterozygous splice variant NM_015560.2(OPA1):c.2356-1 G > T. Further characterisation, which was performed using fibroblasts obtained from a skin biopsy, demonstrated that this variant altered mRNA splicing of the OPA1 transcript, specifically a 21 base pair deletion at the start of exon 24, NM_015560.2(OPA1):p.Cys786_Lys792del. The majority of variant transcripts were shown to escape nonsense-mediated decay and modelling of the predicted protein structure suggests that the in-frame 7 amino acid deletion may affect OPA1 oligomerisation. Fibroblasts carrying the c.2356-1 G > T variant demonstrated impaired mitochondrial bioenergetics, membrane potential, increased cell death, and disrupted and fragmented mitochondrial networks in comparison to WT cells. This study suggests that the c.2356-1 G > T OPA1 splice site variant leads to a cryptic splice site activation and may manifest in a dominant-negative manner, which could account for the patient's severe syndromic phenotype.