Overview of a novel osmotin abolishes abnormal metabolic-associated adiponectin mechanism in Alzheimer's disease: Peripheral and CNS insights.

Alzheimer's disease (AD) is a degenerative brain disease that affects millions of people worldwide. It is caused by abnormalities in cholinergic neurons, oxidative stress, and inflammatory cascades. The illness is accompanied by personality changes, memory issues, and dementia. Metabolic signaling pathways help with fundamental processes like DNA replication and RNA transcription. Being adaptable is essential for both surviving and treating illness. The body's metabolic signaling depends on adipokines, including adiponectin (APN) and other adipokines secreted by adipose tissues. Energy homeostasis is balanced by adipokines, and nutrients. Overconsumption of nutrients messes with irregular signaling of adipokines, such as APN in both peripheral and brain which leads to neurodegeneration, such as AD. Despite the failure of traditional treatments like memantine and cholinesterase inhibitors, natural plant bioactive substances like Osmotin (OSM) have been given a focus as potential therapeutics due to their antioxidant properties, better blood brain barrier (BBB) permeability, excellent cell viability, and especially nanoparticle approaches. The review highlights the published preclinical literature regarding the role of OSM in AD pathology while there is a need for more research to investigate the hidden therapeutic potential of OSM which may open a new gateway and further strengthen its healing role in the pathogenesis of neurodegeneration, especially AD.

Trajectory of brain-derived amyloid beta in Alzheimer's disease: where is it coming from and where is it going?

Alzheimer's disease (AD) is a progressive neurological disorder that primarily impacts cognitive function. Currently there are no disease-modifying treatments to stop or slow its progression. Recent studies have found that several peripheral and systemic abnormalities are associated with AD, and our understanding of how these alterations contribute to AD is becoming more apparent. In this review, we focuse on amyloid­beta (Aß), a major hallmark of AD, summarizing recent findings on the source of brain-derived Aß and discussing where and how the brain-derived Aß is cleared in vivo. Based on these findings, we propose future strategies for AD prevention and treatment, from a novel perspective on Aß metabolism.

Attracting medical school graduates to residency programs in remotely located hospitals: the challenge lies beyond financial incentives.

BACKGROUND: Recruitment to residency programs in hospitals located in other than major hubs ("remotely located") is a challenge in many countries. In 2011, the Israeli Ministry of Health launched a 10-year financial incentive to encourage physicians to enroll in residency programs in such hospitals. Nearly 1 billion New Israeli Shekels (260 million US$) were invested in that program which had only limited success. As a new physician association's collective agreement is impending, we aimed to measure the effectiveness of selected incentives in attracting medical school graduates to residencies in remotely located hospitals. METHODS: This study included Israeli medical students in their final year of medical school. We used an online questionnaire with multiple-choice demographic questions and a 5-point Likert scale to gauge the effect of various incentives on their preference for residency location. RESULTS: Between July and November 2022, 522 students responded (405 studied in Israeli medical schools [out of 705 students] and 117 in foreign medical schools [out of 1936 students]). Forty-two percent had at least one clerkship in a remotely located hospital, and 24% had included at least one remotely located hospital among their top five choices for internship. Only 13% reported that they prefer a residency program in those institutions. The incentive selected by students as most persuasive was government assistance in acceptance to and financial support for a fellowship abroad, followed by a financial grant and fewer on-call hours. Only 7% of the students indicated that no incentive would influence them to choose a remotely located hospital for their residency training. Medical education in a remotely located university and the choice of at least one remotely located hospital among the top five choices for internship were significantly associated with positive incentive receptivity, whereas male sex and older age were associated with negative receptivity. CONCLUSION: This study on the attitudes of Israeli medical school graduates toward incentives aimed at attracting them to residencies in remotely located institutions revealed that career development opportunities and assistance in obtaining fellowships might influence their choice.

Spatially limited pathogen pollution in an invasive tick and host system.

Expansion of global commerce has facilitated pathogen pollution via the transportation and translocation of invasive species and their associated parasites and pathogens. In Florida, imported cane toads (Rhinella horribilis) were accidentally and intentionally released on multiple occasions. Early populations were found to be infested with the invasive tick, Amblyomma rotundatum, yet it is unknown if these ticks dispersed with their hosts as cane toads spread throughout much of the state. The objectives of our investigation were to (1) determine if there are fewer tick infestations on toads at the periphery than at the core of their distribution as predicted by founder effect events, and (2) identify if ticks were infected with exotic pathogens. We captured toads from 10 populations across Florida. We collected ticks, vent tissue, and tick attachment site tissue from each toad, then tested samples for bacteria in the genus, Rickettsia. We found that 3/10 populations had toads that were infested with A. rotundatum, and infested individuals were in the earliest introduced populations at the core of their distribution. Pathogen testing confirmed Rickettisa bellii in ticks, but not in toad tissues. Haplotype networks could not clearly distinguish if R. bellii in Florida was more closely related to North or South American strains, but host-tick associations suggest that the pathogen was exotic to Florida. Our investigation demonstrated that an invasive species facilitated the introduction of parasites and pathogens into Florida, yet the invasive tick species encountered limitations to dispersal on this host species. Supplementary Information: The online version contains supplementary material available at 10.1007/s10530-024-03291-9.

Optical coherence tomography imaging of the peripheral retina.

This review critically assesses the applicability of retinal periphery imaging technology, scrutinizing its practical limitations and potential advancements within ophthalmology. It underscores the significant costs and the need to evaluate the clinical utility of optical coherence tomography (OCT) and OCT angiography devices. It emphasizes how clinicians should consider their practice-specific use-cases while investing in devices with capabilities like ultra-widefield OCT, autofluorescence imaging, and angiography. The paper also highlights the challenges associated with image acquisition, such as artifact management and patient cooperation for extended fixation periods. This review outlines the utility of these modalities in various retinal pathologies, as well as their contribution to telemedicine and personalized care, facilitated by artificial intelligence for improved image processing, quantification, and interpretation. These techniques potentially offer a more comprehensive understanding of peripheral retinal conditions and associated pathologies, thus influencing clinical decision-making, particularly in remote regions with limited specialist access.

PP2A-B55 phosphatase counteracts Ki-67-dependent chromosome individualization during mitosis.

Cell cycle progression is regulated by the orderly balance between kinase and phosphatase activities. PP2A phosphatase holoenzymes containing the B55 family of regulatory B subunits function as major CDK1-counteracting phosphatases during mitotic exit in mammals. However, the identification of the specific mitotic roles of these PP2A-B55 complexes has been hindered by the existence of multiple B55 isoforms. Here, through the generation of loss-of-function genetic mouse models for the two ubiquitous B55 isoforms (B55α and B55δ), we report that PP2A-B55α and PP2A-B55δ complexes display overlapping roles in controlling the dynamics of proper chromosome individualization and clustering during mitosis. In the absence of PP2A-B55 activity, mitotic cells display increased chromosome individualization in the presence of enhanced phosphorylation and perichromosomal loading of Ki-67. These data provide experimental evidence for a regulatory mechanism by which the balance between kinase and PP2A-B55 phosphatase activity controls the Ki-67-mediated spatial organization of the mass of chromosomes during mitosis.

Drosophila HCN mediates gustatory homeostasis by preserving sensillar transepithelial potential in sweet environments.

Establishing transepithelial ion disparities is crucial for sensory functions in animals. In insect sensory organs called sensilla, a transepithelial potential, known as the sensillum potential (SP), arises through active ion transport across accessory cells, sensitizing receptor neurons such as mechanoreceptors and chemoreceptors. Because multiple receptor neurons are often co-housed in a sensillum and share SP, niche-prevalent overstimulation of single sensory neurons can compromise neighboring receptors by depleting SP. However, how such potential depletion is prevented to maintain sensory homeostasis remains unknown. Here, we find that the Ih-encoded hyperpolarization-activated cyclic nucleotide-gated (HCN) channel bolsters the activity of bitter-sensing gustatory receptor neurons (bGRNs), albeit acting in sweet-sensing GRNs (sGRNs). For this task, HCN maintains SP despite prolonged sGRN stimulation induced by the diet mimicking their sweet feeding niche, such as overripe fruit. We present evidence that Ih-dependent demarcation of sGRN excitability is implemented to throttle SP consumption, which may have facilitated adaptation to a sweetness-dominated environment. Thus, HCN expressed in sGRNs serves as a key component of a simple yet versatile peripheral coding that regulates bitterness for optimal food intake in two contrasting ways: sweet-resilient preservation of bitter aversion and the previously reported sweet-dependent suppression of bitter taste.

Investigating the crowding effect on letters and symbols in deaf adults.

Reading requires the transformation of a complex array of visual features into sounds and meaning. For deaf signers who experience changes in visual attention and have little or no access to the sounds of the language they read, understanding the visual constraints underlying reading is crucial. This study aims to explore a fundamental aspect of visual perception intertwined with reading: the crowding effect. This effect manifests as the struggle to distinguish a target letter when surrounded by flanker letters. Through a two-alternative forced choice task, we assessed the recognition of letters and symbols presented in isolation or flanked by two or four characters, positioned either to the left or right of fixation. Our findings reveal that while deaf individuals exhibit higher accuracy in processing letters compared to symbols, their performance falls short of that of their hearing counterparts. Interestingly, despite their proficiency with letters, deaf individuals didn't demonstrate quicker letter identification, particularly in the most challenging scenario where letters were flanked by four characters. These outcomes imply the development of a specialized letter processing system among deaf individuals, albeit one that may subtly diverge from that of their hearing counterparts.

A nuclear architecture screen in Drosophila identifies Stonewall as a link between chromatin position at the nuclear periphery and germline stem cell fate.

The association of genomic loci to the nuclear periphery is proposed to facilitate cell type-specific gene repression and influence cell fate decisions. However, the interplay between gene position and expression remains incompletely understood, in part because the proteins that position genomic loci at the nuclear periphery remain unidentified. Here, we used an Oligopaint-based HiDRO screen targeting ∼1000 genes to discover novel regulators of nuclear architecture in Drosophila cells. We identified the heterochromatin-associated protein Stonewall (Stwl) as a factor promoting perinuclear chromatin positioning. In female germline stem cells (GSCs), Stwl binds and positions chromatin loci, including GSC differentiation genes, at the nuclear periphery. Strikingly, Stwl-dependent perinuclear positioning is associated with transcriptional repression, highlighting a likely mechanism for Stwl's known role in GSC maintenance and ovary homeostasis. Thus, our study identifies perinuclear anchors in Drosophila and demonstrates the importance of gene repression at the nuclear periphery for cell fate.

Positive and negative facial valence perception are modulated differently by eccentricity in the parafovea: Replication from KDEF to NimStim.

While perceiving the emotional state of others may be crucial for our behavior even when this information is present outside of central vision, emotion perception studies typically focus on central visual field. We have recently investigated emotional valence (pleasantness) perception across the parafovea (≤ 4°) and found that for briefly presented (200 ms) emotional face images (from the established KDEF image-set), positive (happy) valence was the least affected by eccentricity (distance from the central visual field) and negative (fearful) valence the most. Furthermore, we found that performance at 2° predicted performance at 4°. Here we tested (n = 37) whether these effects replicate with face stimuli of different identities from a different well-established image-set (NimStim). All our prior findings replicated and eccentricity-based modulation magnitude was smaller with NimStim (~ 16.6% accuracy reduction at 4°) than with KDEF stimuli (~ 27.3% reduction). Our current investigations support our earlier findings that for briefly presented parafoveal stimuli, positive and negative valence perception are differently affected by eccentricity and may be dissociated. Furthermore, our results highlight the importance of investigating emotions beyond central vision and demonstrate commonalities and differences across different image sets in the parafovea, emphasizing the contribution of replication studies to substantiate our knowledge about perceptual mechanisms.

Peripheral preprocessing in Drosophila facilitates odor classification.

The mammalian brain implements sophisticated sensory processing algorithms along multilayered ("deep") neural networks. Strategies that insects use to meet similar computational demands, while relying on smaller nervous systems with shallow architectures, remain elusive. Using Drosophila as a model, we uncover the algorithmic role of odor preprocessing by a shallow network of compartmentalized olfactory receptor neurons. Each compartment operates as a ratiometric unit for specific odor-mixtures. This computation arises from a simple mechanism: electrical coupling between two differently sized neurons. We demonstrate that downstream synaptic connectivity is shaped to optimally leverage amplification of a hedonic value signal in the periphery. Furthermore, peripheral preprocessing is shown to markedly improve novel odor classification in a higher brain center. Together, our work highlights a far-reaching functional role of the sensory periphery for downstream processing. By elucidating the implementation of powerful computations by a shallow network, we provide insights into general principles of efficient sensory processing algorithms.

Critical complex network structures in animal gastrointestinal tract microbiomes.

BACKGROUND: Living things from microbes to their hosts (plants, animals and humans) interact with each other, and their relationships may be described with complex network models. The present study focuses on the critical network structures, specifically the core/periphery nodes and backbones (paths of high-salience skeletons) in animal gastrointestinal microbiomes (AGMs) networks. The core/periphery network (CPN) mirrors nearly ubiquitous nestedness in ecological communities, particularly dividing the network as densely interconnected core-species and periphery-species that only sparsely linked to the core. Complementarily, the high-salience skeleton network (HSN) mirrors the pervasive asymmetrical species interactions (strictly microbial species correlations), particularly forming heterogenous pathways in AGM networks with both "backbones" and "rural roads" (regular or weak links). While the cores and backbones can act as critical functional structures, the periphery nodes and weak links may stabilize network functionalities through redundancy. RESULTS: Here, we build and analyze 36 pairs of CPN/HSN for the AGMs based on 4903 gastrointestinal-microbiome samples containing 473,359 microbial species collected from 318 animal species covering all vertebrate and four major invertebrate classes. The network analyses were performed at host species, order, class, phylum, kingdom scales and diet types with selected and comparative taxon pairs. Besides diet types, the influence of host phylogeny, measured with phylogenetic (evolutionary) timeline or "age", were integrated into the analyses. For example, it was found that the evolutionary trends of three primary microbial phyla (Bacteroidetes/Firmicutes/Proteobacteria) and their pairwise abundance-ratios in animals do not mirror the patterns in modern humans phylogenetically, although they are consistent in terms of diet types. CONCLUSIONS: Overall, the critical network structures of AGMs are qualitatively and structurally similar to those of the human gut microbiomes. Nevertheless, it appears that the critical composition (the three phyla of Bacteroidetes, Firmicutes, and Proteobacteria) in human gut microbiomes has broken the evolutionary trend from animals to humans, possibly attributable to the Anthropocene epoch and reflecting the far-reaching influences of agriculture and industrial revolution on the human gut microbiomes. The influences may have led to the deviations between modern humans and our hunter-gather ancestors and animals.

Correlative cryo-microscopy pipelines for in situ cellular studies.

Correlative cryo-microscopy pipelines combining light and electron microscopy and tomography in cryogenic conditions (cryoCLEM) on the same sample are powerful methods for investigating the structure of specific cellular targets identified by a fluorescent tag within their unperturbed cellular environment. CryoCLEM approaches circumvent one of the inherent limitations of cryo EM, and specifically cryo electron tomography (cryoET), of identifying the imaged structures in the crowded 3D environment of cells. Whereas several cryoCLEM approaches are based on thinning the sample by cryo FIB milling, here we present detailed protocols of two alternative cryoCLEM approaches for in situ studies of adherent cells at the single-cell level without the need for such cryo-thinning. The first approach is a complete cryogenic pipeline in which both fluorescence and electronic imaging are performed on frozen-hydrated samples, the second is a hybrid cryoCLEM approach in which fluorescence imaging is performed at room temperature, followed by rapid freezing and subsequent cryoEM imaging. We provide a detailed description of the two methods we have employed for imaging fluorescently labeled cellular structures with thickness below 350-500nm, such as cell protrusions and organelles located in the peripheral areas of the cells.

Repertoire of timescales in uni - and transmodal regions mediate working memory capacity.

Working memory (WM) describes the dynamic process of maintenance and manipulation of information over a certain time delay. Neuronally, WM recruits a distributed network of cortical regions like the visual and dorsolateral prefrontal cortex as well as the subcortical hippocampus. How the input dynamics and subsequent neural dynamics impact WM remains unclear though. To answer this question, we combined the analysis of behavioral WM capacity with measuring neural dynamics through task-related power spectrum changes, e.g., median frequency (MF) in functional magnetic resonance imaging (fMRI). We show that the processing of the input dynamics, e.g., the task structure's specific timescale, leads to changes in the unimodal visual cortex's corresponding timescale which also relates to working memory capacity. While the more transmodal hippocampus relates to working memory capacity through its balance across multiple timescales or frequencies. In conclusion, we here show the relevance of both input dynamics and different neural timescales for WM capacity in uni - and transmodal regions like visual cortex and hippocampus for the subject's WM performance.

Towards a unified medical microbiome ecology of the OMU for metagenomes and the OTU for microbes.

BACKGROUND: Metagenomic sequencing technologies offered unprecedented opportunities and also challenges to microbiology and microbial ecology particularly. The technology has revolutionized the studies of microbes and enabled the high-profile human microbiome and earth microbiome projects. The terminology-change from microbes to microbiomes signals that our capability to count and classify microbes (microbiomes) has achieved the same or similar level as we can for the biomes (macrobiomes) of plants and animals (macrobes). While the traditional investigations of macrobiomes have usually been conducted through naturalists' (Linnaeus & Darwin) naked eyes, and aerial and satellite images (remote-sensing), the large-scale investigations of microbiomes have been made possible by DNA-sequencing-based metagenomic technologies. Two major types of metagenomic sequencing technologies-amplicon sequencing and whole-genome (shotgun sequencing)-respectively generate two contrastingly different categories of metagenomic reads (data)-OTU (operational taxonomic unit) tables representing microorganisms and OMU (operational metagenomic unit), a new term coined in this article to represent various cluster units of metagenomic genes. RESULTS: The ecological science of microbiomes based on the OTU representing microbes has been unified with the classic ecology of macrobes (macrobiomes), but the unification based on OMU representing metagenomes has been rather limited. In a previous series of studies, we have demonstrated the applications of several classic ecological theories (diversity, composition, heterogeneity, and biogeography) to the studies of metagenomes. Here I push the envelope for the unification of OTU and OMU again by demonstrating the applications of metacommunity assembly and ecological networks to the metagenomes of human gut microbiomes. Specifically, the neutral theory of biodiversity (Sloan's near neutral model), Ning et al.stochasticity framework, core-periphery network, high-salience skeleton network, special trio-motif, and positive-to-negative ratio are applied to analyze the OMU tables from whole-genome sequencing technologies, and demonstrated with seven human gut metagenome datasets from the human microbiome project. CONCLUSIONS: All of the ecological theories demonstrated previously and in this article, including diversity, composition, heterogeneity, stochasticity, and complex network analyses, are equally applicable to OMU metagenomic analyses, just as to OTU analyses. Consequently, I strongly advocate the unification of OTU/OMU (microbiomes) with classic ecology of plants and animals (macrobiomes) in the context of medical ecology.

Extrathymic AIRE-Expressing Cells: A Historical Perspective.

Since its discovery, Aire has been the topic of numerous studies in its role as a transcriptional regulator in the thymus where it promotes the "promiscuous" expression of a large repertoire of tissue-restricted antigens (TRAs) that are normally expressed only in the immune periphery. This process occurs in specialized medullary thymic epithelial cells (mTECs) and mediates the elimination of self-reactive T cells or promotes their conversion to the Foxp3+ regulatory T cell lineage, both of which are required for the prevention of autoimmunity. In recent years, there has been increasing interest in the role of extrathymic Aire expression in peripheral organs. The focus has primarily been on the identification of the cellular source(s) and mechanism(s) by which extrathymic AIRE affects tolerance-related or other physiological processes. A cadre of OMICs tools including single cell RNA sequencing and novel transgenic models to trace Aire expression to perform lineage tracing experiments have shed light on a phenomenon that is more complex than previously thought. In this chapter, we provide a deeper analysis of how extrathymic Aire research has developed and progressed, how cellular sources were identified, and how the function of AIRE was determined. Current data suggests that extrathymic AIRE fulfills a function that differs from what has been observed in the thymus and strongly argues that its main purpose is to regulate transcriptional programs in a cell content-dependent manner. Surprisingly, there is data that also suggests a non-transcriptional role of extrathymic AIRE in the cytoplasm. We have arrived at a potential turning point that will take the field from the classical understanding of AIRE as a transcription factor in control of TRA expression to its role in immunological and non-immunological processes in the periphery.

A grazer's niche edge is associated with increasing diet diversity and poor population performance.

The core-periphery hypothesis predicts niche cores should be associated with greater survivorship, reproductive output and population performance rates than marginal habitats at niche edges. However, there is very little empirical evidence of whether niche centrality influences population trends in animals. Using the Cape mountain zebra (Equus zebra zebra) as a model system, we evaluated whether niche centrality is associated with population trends, resource availability and diet across a core-periphery gradient. Population growth rates and density progressively declined towards niche peripheries. Niche peripheries were resource-poor and Cape mountain zebra consumed more phylogenetically diverse diets dominated by non-grass families. In core habitats they consumed grass-rich diets and female reproductive success was higher. This combination of spatial niche modelling and functional ecology provides a novel evaluation of how bottom-up resource limitation can shape species distributions, population resilience and range change and can guide conservation management.

Creating 'good' hospital to home transfers in the rural north of Sweden: informal workarounds and opportunities for improvement.

Hospital to home transfers for older people require effective communication, coordination and collaboration across multiple service settings. Rural Nursing Theory and the Beyond Periphery model explain why this is particularly difficult in rural areas, but there are few examples of how rural services respond. This paper presents a case study of the district of Tärnaby in the inland north of Sweden. Data are drawn from interviews with health and care staff in Tärnaby, observations, and experiences of the researchers. Data were analyzed thematically, with four main themes emerging - role clarity, communication, geography, and understanding of the rural context. Responses to challenges included increasing opportunities for communication between service providers and improving documentation. The paper concludes that informal "workarounds" run the risk of further disconnecting rural service settings from "the city". Rather, the aim needs to be to improve contextual understanding through formally incorporating "the rural" in service design.

Transient attention does not alter the eccentricity effect in estimation of duration.

Previous research investigating the influence of stimulus eccentricity on perceived duration showed an increasing duration underestimation with increasing eccentricity. Based on studies showing that precueing the stimulus location prolongs perceived duration, one might assume that this eccentricity effect is influenced by spatial attention. In the present study, we assessed the influence of transient covert attention on the eccentricity effect in duration estimation in two experiments, one online and one in a laboratory setting. In a duration estimation task, participants judged whether a comparison stimulus presented near or far from fixation with a varying duration was shorter or longer than a standard stimulus presented foveally with a constant duration. To manipulate transient covert attention, either a transient luminance cue was used (valid cue) to direct attention to the position of the subsequent peripheral comparison stimulus or all positions were marked by luminance (neutral cue). Results of both experiments yielded a greater underestimation of duration for the far than for the near stimulus, replicating the eccentricity effect. Although cueing was effective (i.e., shorter response latencies for validly cued stimuli), cueing did not alter the eccentricity effect on estimation of duration. This indicates that cueing leads to covert attentional shifts but does not account for the eccentricity effect in perceived duration.

How to get rich from inflation.

We seem to have rich experience across our visual field. Yet we are surprisingly poor at tasks involving the periphery and low spatial attention. Recently, Lau and collaborators have argued that a phenomenon known as "subjective inflation" allows us to reconcile these phenomena. I show inflation is consistent with multiple interpretations, with starkly different consequences for richness and for theories of consciousness more broadly. What's more, we have only weak reasons favouring any of these interpretations over the others. I provisionally argue for an interpretation on which subjective experience is genuinely rich, but (in peripheral/unattended areas) unreliable as a guide to the external world. The main challenge for this view is that it appears to imply that experience in the periphery is not just unreliable but unstable. However, I argue that this consequence, while initially appearing unintuitive, is in fact plausible.