Advancements in massively parallel short-read sequencing technologies and the associated decreasing costs have led to large and diverse variant discovery efforts across species. However, processing high-throughput short-read sequencing data can be challenging with potential pitfalls and bioinformatics bottlenecks in generating reproducible results. Although a number of pipelines exist that address these challenges, these are often geared toward human or traditional model organism species and can be difficult to configure across institutions. Whole Animal Genome Sequencing (WAGS) is an open-source set of user-friendly, containerized pipelines designed to simplify the process of identifying germline short (SNP and indel) and structural variants (SVs) geared toward the veterinary community but adaptable to any species with a suitable reference genome. We present a description of the pipelines [adapted from the best practices of the Genome Analysis Toolkit (GATK)], along with benchmarking data from both the preprocessing and joint genotyping steps, consistent with a typical user workflow. High-throughput sequencing (HTS) has revolutionized the field of genetics and helped usher in today's modern genomic era. Continued advances in sequencing technologies coupled with decreased costs have empowered researchers to generate massive amounts of short-read sequencing data, particularly for whole genome sequencing (WGS) studies. WGS projects may range from single individuals with a phenotype of interest to entire cohorts, broadening our ability to answer biological questions at population-level scales. In addition to large efforts in human medicine ], analysis pipelines, and best practices geared for human WGS projects . Reconfihttps://github.com/jonahcullen/wags). These pipelines, which are meant to be run on a high-performance Linux-based cluster, employ best practices championed by GATK developers while lowering barriers often faced by animal researchers seeking to analyze WGS data. WAGS consists of 3 pipelines. The first pipeline processes raw FASTQ files into genomic variant call format (GVCF) files and is capable of processing samples split across flow cells or lanes. The second pipeline takes multiple GVCF files as inputs and performs joint genotype calling and variant annotation. And the third pipeline compares variants in a specific sample to variants in a larger variant call file (VCF) database to enable the identification of unique variants in a particular animal.To address these hurdles, we developed scalable, adaptable, open-source, containerized, Snakemake-based pipelines tailored for the veterinary community under the umbrella term Whole Animal Genome Sequencing (WAGS)  with future plans to include additional schedulers .WAGS consists of 3 pipelines for (1) processing raw short-read FASTQ files into GVCF files OneWAG, , (2) joike-based ) can be https://github.com/jonahcullen/wags).To process WGS data from a single sample, a plain text file containing the sample name, the breed , and the prefix of paired-end FASTQ data files is required. This text file is used to generate the pipeline inputs as well as a job script to be submitted to the scheduler. The meta file may contain 1 or more samples to process with 1 sample per row, producing pipeline inputs and submission scripts organized by breed and sample name. There are no limitations on the number of FASTQ files associated with a given sample (e.g. sequenced across multiple lanes or separate flowcells) as long as they share a common portion of the FASTQ file names. Required arguments and various options are described in the documentation . This enables the attachment of user-defined metadata (e.g. sample name) or metadata parsed from the FASTQ identifier  as part of the initial setup. Adapters are then marked (MarkIlluminaAdapters) prior to converting the uBAM back to FASTQ, and alignment to a reference genome is performed with BWA (view from SAMtools (MergeBamAlignment), retaining the added metadata. The next steps include marking duplicate reads (MarkDuplicates), sorting (SortSam), adding tags (SetNmMdAndUqTags), and generating a BAM index file. Optionally, indels may be left aligned (LeftAlignIndels). Depending on the availability of known variant (SNP and indel) positions for the species, base quality score recalibration (BQSR) may be performed. For select species, known variant position files are included within the container and may be utilized. Users may also supply their own known variant position files if desired. BQSR is conducted in parallel using chromosome- or contig-scale intervals by building a recalibration model per interval , combining recalibration reports across intervals (GatherBQSRReports), and adjusting the quality score for each base using the combined recalibration report per interval (ApplyBQSR). The recalibrated BAM files are gathered across intervals to create a final analysis-ready BAM and index. If BQSR is not desired, the BAM produced following marking duplicates, sorting, and adding tags is considered the final BAM for downstream analysis. Whether or not a recalibration step is included, a compressed BAM (CRAM) and index are generated to minimize data storage requirements (PrintReads).The data processing steps implemented in idelines  and relya FastQC  and convwith BWA ; these sScatterIntervalsByNs; Picard tools, http://broadinstitute.github.io/picard/). The initial interval list is then split into sets  of approximately equal size  over which variants are called in parallel , producing a GVCF for each set. GVCF files for each interval set are then gathered (MergeVcfs), resulting in a sample-level GVCF and index, ready for joint genotyping by ManyWAGS.SNPs and indels are called in parallel by first creating an interval list by splitting the reference at stretches of missing base calls (Ns) (tunable with default of maximum 50 Ns tolerated before splitting) . Due to the difficulty in identifying SVs from short-read sequencing data and the variability between SV calling algorithms, s: DELLY , Smoove OneWAG also provides output from SAMtools’ flagstat . Species- or reference-specific configuration files needed for joint genotyping are first generated (config_joint.py). Similar to OneWAG, all pipeline inputs and a job script are generated to initiate joint genotyping adapted from GATK Best Practice guidelines (To joint genotype GVCF files generated from the idelines .OneWAG pipeline), while the other utilizes midpoints of intergenic regions, thus requiring a reference annotation file such as a gene transfer format (GTF) file. This second option may be particularly useful for nearly complete (i.e. few missing bases) reference genomes. Regardless of the interval boundary method, the resulting intervals are collapsed into larger intervals of an ideal maximum length (default 10 million). This value can be modified; however, this default setting was chosen to balance efficient parallel processing with the number of submissions to the cluster simultaneously . GVCF files are then combined into GenomicsDB workspaces via GenomicsDBImport, genotyped (GenotypeGVCFs), filtered (VariantFiltration) by excess heterozygosity, and converted to sites-only VCFs (MakeSitesOnlyVcf) for each of the collapsed intervals in parallel. If variant quality score recalibration (VQSR) is enabled, which is strongly encouraged by GATK developers, the sites-only VCFs are combined (GatherVcfsCloud), sorted (SortVcf), and used as inputs to generate recalibration models for SNPs and indels separately . User-supplied files of known SNP and indel positions are required for this step unless they are already stored within the container. ApplyVQSR then filters the collapsed interval VCFs in parallel, where each site is marked as PASS or binned based on user-defined tranche sensitivity. The recalibrated VCFs are combined (GatherVcfsCloud) into a complete VCF and indexed (IndexFeatureFile). If VQSR is not possible or desired (e.g. lack of known SNP and/or indel sites), hard filtering of SNPs and/or indels may be conducted with default thresholds that may be adjusted. Finally, the complete VCF is annotated with the Ensembl Variant Effect Predictor (VEP)  .stats and GATK's CollectVariantCallingMetrics. Per-interval VEP summaries are also collected, enabling the examination of variant classes and consequences, along with other standard metrics. MultiQC aggregates all QC data and plots into a single, user-friendly report.Summary statistics are collected on the final VCF using both BCFtools’ OnlyWAG pipeline was designed to identify private or rare variants in a single individual compared to variants in a population of interest generated by ManyWAGS or any other VCF. The OneWAG pipeline yields an individual GVCF , which is genotyped using the ManyWAGS pipeline to produce a single-sample VCF. The single-sample VCF is compared to the population VCF using GATK's SelectVariants, and 2 specific outputs are produced: (1) a VCF containing variants that are unique to the single-sample VCF and (2) a VCF containing variants in the single sample that are rare  in the population VCF. BCFtools’ +split-vep is used to create delimited tables of the unique and rare VCFs, which are then parsed and output as Excel sheets for downstream analysis and easy visualization by end users.The OneWAG  using 100 canine WGS samples as well as ManyWAGS for joint genotyping of various cohort sizes.WAGS has been utilized and validated for processing and genotyping large cohorts of horses, dogs, and tigers. For example, we have cataloged genetic variants from WGS data of nearly 700 dogs across more than 50 breeds, using 2 canine reference genomes  cohorts of 1, 5, 10, 25, and 50 dogs and ran Abundant resources and pipelines tailored for WGS processing and variant discovery are available for humans; however, this is not typically the case for many veterinary species. WAGS was developed in an effort to close this gap and empower veterinary researchers to analyze WGS data in a user-friendly and reproducible manner. As a Snakemake-based, containerized pipeline, FASTQ files may be processed with little user input and configuration, yielding GVCF files with relatively short runtimes. Similarly, genotyping and annotation of moderate-to-large cohorts, a potentially error-prone endeavor, may be accomplished without substantial bioinformatics knowledge. WAGS is open source and open access. We expect that the majority of users will be researchers in veterinary medicine interested in identifying variants associated with a disease or trait of interest in cohorts of public and private WGS data.jkad117_Supplementary_DataClick here for additional data file.


Ants are abundant, diverse, and occupy nearly all habitats and regions of the world. Previous work has demonstrated that ant diversification coincided with the rise of the angiosperms, and that several plant traits evolved as ants began to expand their nesting and foraging habits. In this study, we investigate whether associations with plants enabled niche expansion and are linked to climatic niche evolution in ants. Our analysis of over 1,400 ant species reveals that ancestral expansion from forest floors into the canopy and out into non-forested habitats closely followed evolutionary innovations in angiosperms. Several Paleogene-Neogene ant lineages independently diversified in non-forested habitats on multiple continents, tracking the evolution and expansion of elaiosome-bearing and arid-adapted angiosperms. The evolution of arboreal nesting tracked shifts in angiosperm physiology associated with the onset of everwet tropical rainforests, and climatic optima and rates of climatic niche evolution were linked to nesting location, with arboreally nesting groups having warmer and less seasonal climatic optima, and lower rates of climatic niche evolution. Our work further underscores the varied paths by which niche diversification occurred in ants, and how angiosperms influenced the ecological and evolutionary trajectories of interacting lineages. Shifts in vegetation may be driven by climate change and by evolutionary innovations. Such turnover in vegetation may drive feedbacks that modify climate or facilitate the expansion of other lineages dependent on these plants via the climates the plants help engender . Ants arWhile non-forested biomes pre-date the Early Cretaceous origin of ants , their rEuphorbia species  can provide important food sources for ants , and the species , 2014. S species , and couThe confluence of the expanding open-canopy angiosperm-dominated ecosystems, the evolution of physiological adaptations in angiosperms, and the evolution of novel angiosperm-derived food sources for ants thus highlights the Paleogene-Neogene as an important period for the potential colonization of open-canopy habitats by ants. A Paleogene expansion of ants into non-forested habitats—tracking the angiosperm invasion of these habitats—has been hypothesized , but hasIn addition to the outward expansion from forested habitats, ants also moved upward from the ground and evolved to nest arboreally. Nesting space is one of the most important resources for ants; it is where the queen is sheltered, the brood is reared, and food is stored and exchanged . While aLike most modern ants, the earliest ants were ground-nesting, with the evolution of arboreal nesting proceeding in Late Cretaceous-Paleogene . One expOur overarching goal is to study the ecological diversification of ants in the context of angiosperm and biome evolution. More specifically, we seek to understand: (1) whether ants began to rely extensively on, and to diversify in, non-forested habitats during the Paleogene-Neogene; and (2) whether ant nesting location modulates the evolution of climatic occupation. Our results strengthen our understanding of the diverse and complex ways by which ants evolved to occupy disparate habitats, and how angiosperms likely shaped their evolution.To characterize the climatic niche of extant ants and model its evolution, we first obtained occurrence data with geographic coordinates that enabled us to extract climatic and biome data for individual occurrences. Occurrence records for ant species in the 2017 Bolton checklist of valid species  were obt3, CaSO4, ESP, ECE) variables from various sources  or closed (forested) . Biome tTo assess how climatic niche occupancy evolved in ants, we fit several models of evolution to median estimates of six climatic variables: annual mean temperature (BIO1), temperature seasonality (BIO4), minimum temperature of the coldest month (BIO6), temperature annual range (BIO7), mean temperature of the coldest quarter (BIO11), and annual precipitation (BIO12) for 1417 species that had environmental data and nesting location (see below). These variables were selected as they represent different measures of temperature, seasonality, and water limitation, which play strong roles in structuring ant distributions .2 (V) . Here, we emphasize that our definition of optima is based on known occurrences and coarse-grained estimates of temperature, and is regarded as an evolutionary optimum, rather than fine-scaled estimates and experimentally validated tolerances and physiological optima (We fit Brownian motion (BM) and Ornstein-Uhlenbeck (OU) models, and then tested whether the rate and model of evolution of climatic niche occupancy was linked to nesting position. We used OUwie  to fit tl optima . If the 0) was estimated in all analyses except the BMS model. As fitting some models can be especially problematic, we performed diagnostic analyses, and checked that all eigenvalues in the Hessian matrix were greater than 0. AICc values and weights were then compared to identify the best-fit model. In the case of OU models, we calculated the phylogenetic half-life (ln(2)/α), which represents the time required for trait value to move halfway from the ancestral value to the optimum (2/(2α)), which represents the equilibrium variance under a stationary optimum (θ). For each trait, we then performed parametric bootstrapping by simulating 50 datasets under the best-fit model and the estimated parameter values, fit this model to the data, and calculated 95% confidence intervals for each parameter.Nesting position was derived from  and modi optimum , and theAncestral state reconstruction of the root node yielded ambiguous results for whether the ancestor of extant ants occupied forested or non-forested habitats . Our wor2]) model was recovered as the best fit (2) than those of ground nesting lineages. In addition, the optimum for the precipitation variable investigated (BIO12) was significantly wetter for arboreal nesting groups. Stationary variance for arboreal-nesting groups was significantly lower for all variables except BIO12, for which their distributions overlapped. Despite OUMVA always being the best-fit, selection strength (α) and the phylogenetic half-lives (ln(2)/α) did not vary significantly among nesting groups. It was not immediately clear why the more complex model (OUMVA) was favored over OUMV, when parametric bootstrapping did not reveal a significant difference among state-dependent selection strengths.For all six climatic variables , the OUMbest fit . The OUMbest fit . ArboreaWhile non-forested habitats, such as deserts, have always been available for ants to occupy, our analyses suggest many of the earliest ant lineages were likely restricted to forested habitats during the Cretaceous , as prevPogonomyrmex ants  with a North American distribution (Dorylus) lineage with an African distribution and center of diversity  that occurs throughout South America (Polyrhachis spp.) in Australia (Banksia species (Polyrhachis may yield dates more in line with grass fossil data or new fossil data may yield a slightly older age for Australian open-habitat grasses. Future work including more taxa, outgroups, fossil data, and ancestral ranges may resolve ambiguities across the phylogeny and in the root state.By contrast, our analyses demonstrate that ants did not extensively diversify in non-forested habitats until the middle-late Paleogene-early Neogene . This wamex ants , and to ribution  (Figure ribution . Similarribution  and earlribution , respectiversity  (Figure iversity . Open-haiversity ; this is America  (Figure  America . Finally America ; this isustralia , but pos species . RefinedCephalotes and Tetramorium (We demonstrate that while early ants likely occupied forested habitats, they constructed their nests in the ground instead of the surrounding trees. The subsequent Late Cretaceous-early Paleogene shifts to arboreal nesting increased the stratification of communities, while likely reducing interspecific competition and facilitating species coexistence in greater numbers. These convergent transitions to arboreal nesting were geographically widespread, as indicated by independent biogeographic reconstructions of lineages such as ramorium .Our analyses also demonstrate that the evolutionary trajectories of climatic occupancy are linked to nesting location. For instance, climatic optima of arboreally nesting lineages were wetter, warmer and experienced reduced thermal variability than those of ground-nesting lineages. These transitions to arboreal nesting broadly coincided with major physiological changes in angiosperm leaf hydraulics that increased leaf gas exchange capacity and, thus, water loss—ultimately increasing the abundance and reliability of precipitation while reducing seasonality in the tropics . Thus, tThis study furthers our understanding of how ants convergently evolved to occupy similar climatic regimes and habitat types in geographically disparate regions, that were likely facilitated by physiological and anatomical innovations in angiosperms. Ant diversification in non-forested habitats broadly coincided with the evolution of photosynthetic pathways enabling angiosperms to invade these habitats, and the evolution of plant-derived food sources for ants. Arboreally nesting lineages occupy warmer, wetter and less seasonal climates than ground-nesting lineages, and diversified as angiosperms facilitated the evolution of these climates and complex arboreal communities. Together, this work further illustrates the complex and diverse means by which angiosperms likely enabled the ecological diversification of ants .qrad008_suppl_Supplementary_MaterialClick here for additional data file.qrad008_suppl_Supplementary_Table_S4Click here for additional data file.


The immune system plays a crucial role during tissue repair and wound healing processes. Biomaterials have been leveraged to assist in this in situ tissue regeneration process to dampen the foreign body response by evading or suppressing the immune system. An emerging paradigm within regenerative medicine is to use biomaterials to influence the immune system and create a pro-reparative microenvironment to instigate endogenously driven tissue repair. In this review, we discuss recent studies that focus on immunomodulation of innate and adaptive immune cells for tissue engineering applications through four biomaterial-based mechanisms of action: biophysical cues, chemical modifications, drug delivery, and sequestration. These materials enable augmented regeneration in various contexts, including vascularization, bone repair, wound healing, and autoimmune regulation. While further understanding of immune-material interactions is needed to design the next generation of immunomodulatory biomaterials, these materials have already demonstrated great promise for regenerative medicine.The immune system plays an important role in tissue repair. Many biomaterial strategies have been used to promote tissue repair, and recent work in this area has looked into the possibility of doing repair by tuning. Thus, we examined the literature for recent works showcasing the efficacy of these approaches in animal models of injuries. In these studies, we found that biomaterials successfully tuned the immune response and improved the repair of various tissues. This highlights the promise of immune-modulating material strategies to improve tissue repair.  Regeneration and repair have been the long-term goals of the field of tissue engineering . As the It has been long known that biomaterials interact with the immune system, notably in the resulting host reaction from implanted materials, leading to a foreign body response . Many stIn this review, we will provide a brief overview of immune cell populations and how material cues have been used to control their responses. We will then examine studies exploring tissue engineering applications with immunomodulatory biomaterials from the last 5 years, where we identify four mechanisms of action utilized in the design of these materials: biophysical cues, chemical modifications, drug delivery, and sequestration of endogenous factors Fig. . We discFollowing tissue injury, damaged tissue undergoes four stages of repair in canonical wound healing: hemostasis, inflammation, proliferation, and remodeling . ThroughMacrophages play a key role in the innate immune system’s response to wounds, to inflammatory cues, clearing pathogens, and cellular debris, and mediating the downstream remodeling process through cellular cross-talk. In response to local stimuli, macrophages activate to perform different subsets of functions. These activation states exist on a multi-axial spectrum, where different signals induce specific transcriptional responses . Early wNeutrophils are one of the first innate immune cells to respond to infection and inflammation, responding to stimulation to undergo one of three different functions: degranulation, apoptosis, and the formation of neutrophil extracellular traps (NETosis). All these functions can result in increased levels of neutrophil-derived antibacterial proteins and proteases, which can cause further inflammation and recruitment of other immune cells in the tissue . The bioother innate immune cells include dendritic cells, natural killer cells, basophils, eosinophils, and mast cells. These cell populations play roles in wound healing by aiding in the resolution of inflammation and beginning repair processes in the proliferation phase –53. Dend+ helper cells or CD8+ cytotoxic cells and exhibit a variety of subsets, each with their own functions. While high levels of CD8+ cytotoxic T cells have been shown to impede wound repair, different subsets of CD4+ helper T cells are beneficial for specific immune responses [+ helper T cell subsets, CD4+ regulatory T cells (Tregs) can encourage immunosuppression that leads to homeostasis and improved wound healing. It has been shown that biomaterials that skew T cell responses towards a protective Th2 response promote a regenerative phenotype, reiterating the importance of rational material selection for regenerative engineering applications [The adaptive immune system plays a key role in reparative processes, exerting effects most prominently in the proliferation and remodeling phases. T cells respond to a host of cues from the innate immune system, making them central to the adaptive immune response as they produce cytokines and regulate the immune system. They can broadly be categorized as either CD4esponses , 58. In ications . Furtherications , 61. Topications . Many maications –66. Beyoications .B cells play a key role in the adaptive immune system through their production of antibodies in response to antigens, as well as their secretion of cytokines. To this end, however, the role of B cells in the context of repair has been much less studied , as bothBiomaterials can interface with the local microenvironment to influence the immune system through a variety of methods. Here, we describe recent advancements in tissue engineering applications within the field of immunomodulatory biomaterials through the biomaterial’s mechanisms of action, including: biophysical cues, chemical modifications, drug delivery, and sequestration Table .Table 1SThe inherent material properties of a platform can influence the local innate and adaptive immune response. This can include mechanical characteristics of the biomaterial such as the shape, dimensionality, micro- and nano-topography, and stiffness. Several reviews have covered the effect of these material cues on various cell functions such as migration, adhesion, proliferation, and differentiation in a variety of biological contexts , 74. TheThe effect of biomaterial topography on the innate immune system is of great interest, as changes in topography can alter macrophage shape, and therefore downstream macrophage polarization. Zhu et al. recently found that by modifying the scale of honeycomb structures in titanium dioxide they could control the level of macrophage polarization. Smaller structures resulted in M2 polarization and helped drive integration of bone implants . For ele+ macrophage recruitment to the site of injury 3 and 10 days postinjury, compared to control groups. This was reflected in H&E staining that showed lower levels of fibrosis and adipogenesis as compared to controls. Mice with the 3D lymph node ECM implant had improved gait analysis, indicating improved muscle function and coordination  provide native architecture to help guide tissue repair following injury. Compositionally, the network of proteins and glycosaminoglycans provides physical and chemical cues for mediation of cellular phenotypes. Furthermore, native ECM also can both release embedded cytokines and sequester endogenous cytokines to dictate regeneration within the local microenvironment . Ultimation Fig. .Fig. 2BiWhile decellularized ECM alone can promote an anti-inflammatory response, this can be enhanced in the presence of injected cytokines to drive local immune modulation. In the context of cartilage regeneration, decellularized cartilage matrix polarized macrophages towards a reparative phenotype, which in turn drove mesenchymal stem cell infiltration and chondrogenic differentiation in vitro. When injected into osteochondral defects in mice, the scaffold itself was able to increase the number of M2-like macrophages in the articular space. This value increased when the scaffold was delivered in combination with injections of IL-4, a pro-chondrogenic cytokine, leading to cartilage regeneration 4 and 8 weeks postinjury .Beyond the initial innate immune response, native acellular ECM can drive downstream adaptive immune modulation as well. Anderson et al. designed an acellular adipose ECM for soft tissue reconstruction. Processing of the ECM was designed to retain biophysical cues while clearing lipids that can induce inflammation in the site of implantation. This ECM instigated an IL-4 driven M2-like phenotype, as well as elevated levels of eosinophil and helper T cell infiltration in a mouse model of muscle loss . NotablyQuantum dots (QDs) have been traditionally used as bio-imaging agents; however, their high surface-to-volume ratio and surface-bound reactive groups make them attractive candidates for applications in drug delivery, tissue engineering, and regenerative medicine. To this effect, titanium carbide MXene quantum dots were shown to downregulate effector T cells and promote the expansion of regulatory T cells in vitro . PrelimiChemical modifications to biomaterials can enhance the base biomaterial’s tissue engineering properties through two main mechanisms. The first is changes to the fabrication process to chemically alter the structure of the biomaterial in order to promote a specific immune response. Additionally, chemical modifications can also encompass adding metal ions and biologics to the surface through different physicochemical reactions, such as layer-by-layer deposition or chemical conjugation to the scaffold . These sVariation in biomaterial fabrication methods can enhance the biomaterial’s effect on the immune system and at driving regeneration. Witherel et al. created a collagen scaffold cross-linked with various chemicals to identify which chemical modifications induced anti-inflammatory versus inflammatory phenotypes . They foSurface chemical modifications have been leveraged to mediate macrophage behavior for improved bone repair –89. The Various labs have looked at how chemical modifications of biomaterial building blocks during fabrication can drive divergent regeneration responses in the adaptive immune system. The Segura lab has previously established and tested the use of microporous annealed particles (MAPs) as an injectable scaffold to encourage wound healing and tissue regeneration. By synthesizing a hydrogel made up of discrete microgel building blocks, the bulk lattice allows for efficient cell infiltration and tissue integration . FurtherSurface modifications of biomaterials can enable localized presentation of biologics that otherwise have short half-lives and deleterious off-target effects when administered systemically. To this effect, PD-L1 checkpoint inhibitors were conjugated to PEG microgels to regulate the immune response after island graft transplantation . These g+ T cells in vitro. In mouse and preclinical canine models of periodontis, the authors injected regulatory T-cell membrane-coated nanoparticles into the site of inflammation and observed decreased levels of inflammatory cytokines and regulatory T cells  (PLGA) wraps for unidirectional release of the anti-inflammatory lipid mediator Resolvin D1. Localized application of wraps at the site of the graft attenuated neointimal hyperplasia and reduced macrophage infiltration into the neointima in rabbit models . ImportaThe usage of exosomes has also gained popularity in recent years, with exosomes derived from mesenchymal stem cells demonstrating immunomodulatory effects on a variety of cells , 106. XiBiomaterials can also augment drug delivery in traditionally hard-to-target areas, such as the brain. A hyaluronic acid hydrogel containing vascular endothelial growth factor (VEGF) injected into the stroke cavity promoted neural differentiation and re-vascularization . MicroglDelivery of cytokines or cytokine inhibitors in biomaterial scaffolds have shown to be an effective approach to affect T cell populations, extending the survival of engraftment treatments , 109. ThIn addition to the delivery of cytokines, other therapeutics have been explored for immunomodulatory drug delivery. Nanoparticle-based delivery of bilirubin extended the circulation time of bilirubin and suppressed type 2 inflammation through reduction of associated T cell populations, attenuating asthma symptoms and inflammation . Co-deliWhile many immunomodulatory therapies drive anti-inflammatory responses and quiescence of aberrant inflammation, biomaterial strategies to promote inflammatory responses are still relevant in specific circumstances. Inflammatory cytokines play a key role in mediating the resolution of inflammation, driving a variety of cells to produce anti-inflammatory signals . One sucIn lieu of loading and releasing exogenous therapeutic molecules, biomaterials can also be designed to sequester and retain endogenous repair factors produced by the body. Such scaffolds can provide some additional biomimicry of the extracellular matrix, providing structure for cellular adhesion and migration while also presenting reparative factors. Creating this “sink” of growth factors and chemokines can be achieved through various approaches discussed in depth elsewhere , 115, inVascularization has posed a large challenge in advancing the field of tissue engineering to provide conduits for nutrient transport and circulating cells to injured tissue. Modulation of macrophage phenotypes has shown that many different activation states contribute to vascularization, each producing different growth factors . CrucialInterleukin-2 (IL-2) is a key cytokine for the activation and proliferation of T cells . SelectiThe immune system plays a critical role in the reparative processes following injury and disease, and thus presents a clear target for tissue engineering strategies. Material-based strategies have demonstrated the ability to modulate the immune system towards favorable responses, and we have now seen application of these strategies to promote regenerative outcomes. Through the rational design of biomaterial-based systems, an increasing number of biomaterial approaches have presented a variety of mechanisms to deliver immunomodulatory cues in a localized manner. These platforms modulate local immune populations through innate material properties, bioactive surface modifications, drug delivery, and sequestration of endogenous factors, creating favorable microenvironments for repair.Ultimately, to accomplish the goals of tissue engineering within this paradigm, immunomodulatory biomaterials must be translatable to the clinic. Very few biomaterial-based therapies have made it to clinical trials thus far, and even fewer with immunomodulatory components. To this extent, there are still many considerations that must be better understood. The long-term compatibility of these immunomodulatory biomaterials must be further assessed, as prolonged immune altering effects beyond repair may lead to disruption of homeostasis. Patient-to-patient immune system variability is especially important to understand for treatment effectiveness , as are We are still faced with many of the same questions described half a decade ago in understanding the complexity of interactions surrounding immune-mediated repair . Our undRecent work in several fields of science has identified a bias in citation practices such that papers from women and other minorities are under-cited relative to the number of such papers in the field –136. Her


Flywheel resistance training was initially designed and implemented to mitigate the negative effects in the absence of gravity on astronauts during space travels . Later oResearch that clarifies the state-of-the-art technology can be decisive for the optimal implementation of flywheel resistance exercises into training protocols, which is currently limited compared to traditional resistance training . TherefoMartín-Rivera et al.; Weng et al.; Maroto-Izquierdo et al.), two opinion piece articles , and two brief research reports .This Research Topic, “The Science of Flywheel Training: Exercise Physiology and Practical Applications”, contains seven original manuscripts that met the editorial criteria, including three original research articles . Specifically, the authors investigated the relationship between inertial load and mean concentric linear velocity during the flywheel squat exercise in a wide spectrum of moments of inertia. In addition, they compared mean concentric linear velocity and subjective rating of perceived exertion after each load. This article reported that the monitoring of mean concentric linear velocity can be proposed as a valid method to quantify load and to individualize the prescription of flywheel training. Moreover, rating of perceived exertion was a valid and reliable alternative to control flywheel training.Weng et al. studied the effect of accentuated eccentric loading during flywheel training on the running economy of young male well-trained distance runners . The authors found that, firstly, this training program improved the muscles’ explosive strength and other neuromuscular functions, as well as improved the athlete’s running economy under 65%, 75%, and 85% peak oxygen consumption (VO2peak), which can potentially increase endurance performance; secondly, flywheel resistance training can improve the height, rate of force development, the eccentric utilization ratio in jumps, and other lower limb elastic potential energy indicators of young male well-trained distance runners.Maroto-Izquierdo et al. investigated the effects of submaximal and supramaximal accentuated eccentric training on changes in lean mass, anabolic hormonal responses, and muscle function . The authors recruited a sample of physically active university students (n = 27), who were randomly assigned to two training groups. Participants performed isotonic training for 10 weeks, with eccentric loads set at 90%  or 120%  of the concentric one-repetition maximum (1-RM), and a concentric load of 30% of the 1-RM. Supramaximal training was found to be more favorable than submaximal training for increasing 1-RM (effect size = 0.77). However, similar effects on maximal isometric voluntary contraction, local muscle endurance, mechanical power, lean mass, and anabolic hormonal responses (IGF-1 and IL6) were demonstrated after 10 weeks of training with both submaximal and supramaximal eccentric loads. Therefore, although supramaximal loading might be superior for increasing 1-RM, the use of this approach does not appear to be necessary in healthy active individuals.Beato et al. published an opinion article with the aim to provide methodological bases for the periodization in team sports to practitioners. This paper was structured into four sections: 1) rationale and benefits of flywheel exercise; 2) strength training periodization in team sports; 3) flywheel training periodization in teams ports; and 4) limitations and future directions of flywheel training periodization .Maroto-Izquierdo et al. authored an opinion article that aimed to provide the methodological bases for load quantification and testing using flywheel devices in sports. This paper was structured into three sections: 1) load quantification during flywheel exercise; 2) the use of flywheel devices for testing; and 3) limitations and future directions of load monitoring and testing using flywheel devices. , de Keijzer et al., wrote a brief research report that investigated, firstly, the effect of different flywheel moment of inertia on concentric and eccentric peak power and eccentric:concentric peak power ratio during unilateral flywheel leg curl and hip extension exercises. Secondly, the inter-session reliability of peak power in both exercises . These authors found that a variety of moments of inertia can elicit high eccentric knee flexor demands during unilateral leg curls, whereas higher moments of inertia are needed to achieve an eccentric-overload in peak power during hip extensions. Different exercises may have different inertia-power relationships. Finally, concentric and eccentric peak power measures can be used by practitioners to inform training, while the eccentric: concentric ratio should not be used because of its low reliability.de Keijzer et al. wrote another brief research report that described the current application and perception of flywheel resistance training amongst therapists working in sport . The authors recorded the opinions of 52 therapists using an electronic questionnaire and they found that, firstly, most therapists either used or intended to use flywheel training with their athletes. Secondly, more than half suggested they were confident flywheel training could enhance strength and muscular pre-habilitation outcomes. Thirdly, it appeared that therapists would mostly include flywheel training within pre-habilitation or during the later stages of rehabilitation. Although therapists would prescribe most exercises, the squat, rotational exercise, and unilateral leg curl would be the most selected. Finally, the authors reported that the biggest perceived barriers to flywheel training implementation were equipment cost/space, scientific evidence, and scheduling.Collectively, these studies contribute to a better understanding of flywheel resistance training, including valuable information about quantification, individualization, effects on performance and muscle function, and its potential application in sport and rehabilitation settings.This Research Topic aimed to better understand the motivations of some adaptive responses and to elucidate how to better implement such technology into the field of strength training.The seven articles included gave evidence and opinions around training load monitoring, periodization, exercise selection, and so on, which may facilitate the implementation of flywheel resistance technologies into research and applied settings, may improve the coaches’ practice, and may foster new research ideas.


Sleep disturbances are common in various neurological pathologies, including amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), hereditary ataxias, Huntington’s disease (HD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB). This article reviews the prevalence and characteristics of sleep disorders in these conditions, highlighting their impact on patients’ quality of life and disease progression. Sleep-related breathing disorders, insomnia, restless legs syndrome (RLS), periodic limb movement syndrome (PLMS), and rapid eye movement sleep behavior disorder (RBD) are among the common sleep disturbances reported. Both pharmacological and non-pharmacological interventions play crucial roles in managing sleep disturbances and enhancing overall patient care. Neurodegenerative diseases, a group of chronic and progressive disorders affecting the nervous system, pose a significant global health challenge. These conditions, including Alzheimer’s disease, dementia with Lewy bodies disease, Huntington’s disease, and others, are characterized by the gradual deterioration of nerve cells, leading to a decline in cognitive, motor, and functional abilities . While tSleep is a fundamental physiological process that plays a critical role in maintaining overall health and well-being. It serves as a time for restorative processes, memory consolidation, and the regulation of various bodily functions. However, individuals with neurodegenerative diseases frequently experience disrupted sleep patterns, such as insomnia , excessiThe bidirectional relationship between sleep and neurodegeneration is a topic of growing interest and importance in both clinical and research settings. On one hand, the neurodegenerative processes themselves can directly affect the brain regions responsible for regulating sleep–wake cycles and sleep-related processes. On the other hand, sleep disturbances may accelerate or exacerbate neurodegeneration through mechanisms involving oxidative stress, inflammation, and impaired protein clearance . UnderstThis review aims to provide a comprehensive overview of the intricate relationship between sleep disorders and neurodegenerative diseases. By examining the current literature, exploring underlying mechanisms, and discussing potential implications, we seek to shed light on how sleep disturbances contribute to the pathophysiology of neurodegeneration and vice versa. Furthermore, we will explore the relevance of sleep-related interventions as a novel approach to managing and potentially slowing the progression of neurodegenerative diseases. In doing so, this review underscores the significance of recognizing sleep as a crucial factor in the holistic understanding and management of neurodegenerative disorders.The regulation of sleep and its underlying mechanisms are regulated by specific regions within the brain. In terms of microanatomy, it is commonly observed that the cell bodies of neurons responsible for synthesizing neurotransmitters involved in sleep mechanisms are typically concentrated in a specific region, while the terminal ends of their axons extend to other areas . The celThe hypothalamus is situated within the cerebral hemisphere, in close proximity to the pituitary gland. The hypothalamus is comprised of numerous nerve cell bodies known as the suprachiasmatic nuclei (SCN), which receive sensory input regarding light exposure in order to regulate the sleep and arousal cycle . The pinThe neurons comprising the reticular activating system play a pivotal role in the regulation of wakefulness. The brain stem components, namely the midbrain, pons, and medulla oblongata, establish neural connections with the hypothalamus in order to regulate the circadian rhythm governing wakefulness and sleep. The midbrain is implicated in various physiological functions, including visual and auditory processing, motor coordination, regulation of sleep–wake cycles, maintenance of alertness, and control of body temperature. The pons and medulla oblongata exhibit specific associations with descending neural pathways responsible for the regulation of muscle activity, body posture, and limb movements during periods of relaxation. The brainstem nuclei implicated in the processing of sleep encompass the cholinergic nuclei situated at the junction of the pons and midbrain, the raphe nuclei, tuberomammillary nuclei, and locus coeruleus . The thaThe concept of sleep is a multifaceted process that is intricately connected to neurological functioning. The central sleep and circadian regulation centers are situated in the intracranial region and encompass the anterior hypothalamus, reticular activating system, suprachiasmatic nucleus (SCN), and pineal gland. The regulation of sleep is commonly acknowledged to be influenced by the interplay between circadian and homeostatic mechanisms. The homeostatic mechanism of sleep pertains to the concept of “sleep drive,” which denotes the phenomenon where the inclination to sleep intensifies as the duration since the previous sleep period increases and diminishes as more time is spent accumulating sleep . Sleep dThe longer we are awake, the stronger the sleep drive becomes. This drive to sleep gradually builds up as wakefulness continues, reflecting the body’s need for rest and recovery. It is part of the body’s way of maintaining a balance between wakefulness and sleep, ensuring that we obtain the rest we need to function optimally.Sleep drive is regulated by several factors, including the body’s internal circadian rhythm ; the amount of adenosine, a neurotransmitter that builds up during wakefulness and promotes sleep; and other complex biological mechanisms . When slThe circadian timing system is responsible for the temporal organization of various neurobehavioral and physiologic processes, such as body temperature regulation, melatonin synthesis, and the 24 h sleep–wake cycle . The supThe process of sleep involves the activation and deactivation of specific brain structures during different stages of sleep . TypicalThe relationship between sleep and mental disorders is complex and multifaceted. Sleep disturbances, such as insomnia, hypersomnia, nightmares, and circadian rhythm disorders, frequently co-occur with various mental health conditions. Diagnostic criteria, as outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), aid clinicians in identifying sleep disorders within the broader context of mental health evaluations. However, it is vital to recognize the bidirectional nature of this relationship, as untreated sleep disorders can exacerbate mental health symptoms and vice versa.Alzheimer’s disease (AD) is widely recognized as the prevailing neurodegenerative disorder, distinguished by the destruction of neurons and the accumulation of b-amyloid in neurofibrillary tangles within the hippocampus and cortex. These pathological changes ultimately result in cognitive impairment .Both insufficient sleep duration and obstructive sleep apnea (OSA) have been identified as risk factors for Alzheimer’s disease (AD). The APOE-4 allele has been identified as a significant risk factor for both Alzheimer’s disease (AD) and obstructive sleep apnea (OSA) .The relationship between Alzheimer’s disease (AD) and sleep difficulties is reciprocal. The condition leads to significant sleep deprivation and disruptions due to the degeneration of the suprachiasmatic and cholinergic nuclei. These abnormalities may potentially impact cognition by potentially impairing the brain’s ability to eliminate β-amyloid.Sleep disturbances are prevalent, affecting around 45% of individuals, and have a substantial influence on both patients and their caretakers . Sleep pOne prevalent sleep issue is an amplified inclination to advance sleep phases, which is distinguished by frequent daytime somnolence, challenges in initiating sleep at night, fragmented sleep throughout the night, and rising early in the morning .The observed pattern in question has similarities to that reported in older individuals, but with greater severity. It is plausible that this pattern is largely attributable to the degradation of the suprachiasmatic nucleus, which subsequently leads to disturbances in the rhythm of melatonin production.In some instances, individuals may display sundowning syndrome, which is distinguished by the manifestation of restlessness, cognitive impairment, and aggressive behavior throughout the evening and night-time hours. Patients may exhibit confusional arousals, sleepwalking, and agitation during nocturnal periods .The results of polysomnography indicate a reduction in the overall duration of sleep and the effectiveness of sleep, an increase in the time it takes to fall asleep and the duration of wakefulness after falling asleep, a decrease in the duration of both deep sleep and REM sleep, and an increase in the duration of light sleep. Sleep recording in advanced instances presents challenges owing to the lack of the alpha rhythm while awake and the absence of sleep spindles and K complexes. The occurrence of rapid eye movement (REM) sleep disturbances is infrequent, as shown by research findings .The prevalence of restless legs syndrome (RLS) does not seem to be noteworthy, maybe due to the underestimation of its frequency. This underestimation may arise from the diagnostic need for patients to articulate the sensations experienced in their legs. Dementia-specific criteria for restless legs syndrome (RLS) have been established .The incidence of obstructive sleep apnea (OSA) is substantial, impacting a significant proportion of persons, ranging from 40% to 70%. Moreover, it has been shown that OSA might exacerbate cognitive impairment in patients with Alzheimer’s disease.The treatment of sleep problems is founded upon cognitive–behavioral methods, sleep hygiene practices, and the use of bright light therapy .During the first phases, the use of acetylcholinesterase inhibitors has shown the potential to ameliorate sleep disturbances and enhance cognitive function. Continuous positive airway pressure (CPAP) therapy is recommended for the treatment of obstructive sleep apnea (OSA) .Despite the limited availability of compelling scientific data, many drugs are often used to enhance sleep quality. These include melatonin, benzodiazepines, sedative antidepressants, and atypical antipsychotics, such as quetiapine .Dementia with Lewy bodies (DLB) is the second most prevalent kind of dementia, behind Alzheimer’s disease. It is distinguished by a combination of symptoms, including cognitive decline, parkinsonism, motor irregularities, and visual hallucinations. The neuropathological alterations include the manifestation of Lewy bodies throughout the brainstem, limbic system, and cortical regions.Sleep disturbances are prevalent in almost 80% of individuals diagnosed with dementia with Lewy bodies (DLB), surpassing the occurrence rate seen in Alzheimer’s disease (AD) .Insomnia, a circadian rhythm disorder characterized by early morning waking, is often accompanied with excessive daytime sleepiness (EDS) resulting from frequent napping. Additionally, individuals with this condition may have nocturnal hallucinations and confusional arousals accompanied by sleepwalking, which are often-seen symptoms.Episodes of confusional arousals often manifest during the non-rapid eye movement (non-REM) sleep phases.There is no evidence to suggest that DLB patients have a higher prevalence of obstructive sleep apnea (OSA), periodic limb movement disorder (PLMD), and restless legs syndrome (RLS) compared to those of a comparable age in the general community .Individuals diagnosed with idiopathic rapid eye movement sleep behavior disorder (RBD) may exhibit a range of cognitive impairments, including modest deficits in executive functioning, visuospatial abilities, and memory.The temporal duration between moderate cognitive impairment and the initiation of dementia is estimated to be roughly 2 years.Rapid eye movement behavior disorder (RBD) has been seen in around 80% of patients and has been shown to potentially precede the start of dementia in around 70% of cases .The identification of rapid eye movement behavior disorder (RBD) in an individual with dementia is indicative of dementia with Lewy bodies (DLB), since this sleep disorder rarely occurs in alternative types of dementia such as Alzheimer’s disease (AD), frontotemporal dementia, and progressive supranuclear palsy.The current diagnostic criteria for dementia with Lewy bodies (DLB) include idiopathic rapid eye movement sleep behavior disorder (RBD) as an indicative characteristic of the condition.Idiopathic rapid eye movement sleep behavior disorder (RBD) is mostly seen in males within the context of dementia with Lewy bodies (DLB). This condition is characterized by a brief duration of dementia, an early start of parkinsonism, visual hallucinations, and the presence of non-Alzheimer’s pathology upon postmortem examination.Differentiating between confusional arousals and nocturnal visual hallucinations from REM sleep behavior disorder (RBD) merely based on the patient’s clinical history might pose challenges.Individuals diagnosed with advanced dementia who undergo polysomnography may have disturbances in their sleep patterns as a result of the deterioration of neurological systems responsible for regulating sleep .Progressive supranuclear palsy (PSP) is a neurodegenerative disorder that is distinguished by a combination of clinical symptoms, including dementia, parkinsonism, falls, and vertical gaze palsy.Progressive supranuclear palsy (PSP) is a neurological condition characterized by the degeneration of many regions within the brain, including the brainstem, basal ganglia, frontal lobe, and other associated areas .Polysomnographic investigations have shown a decline in overall sleep duration, a fall in the proportion of rapid eye movement (REM) sleep, as well as a reduction in the occurrence of sleep spindles and K complexes.In instances of significant severity, the alpha rhythm is not present, resulting in challenges in distinguishing between wakefulness and sleep phases.Excessive daytime sleepiness (EDS), obstructive sleep apnea syndrome (OSAS), periodic limb movement disorder (PLMD), and restless legs syndrome (RLS) are seldom-seen consequences in progressive supranuclear palsy (PSP).Insomnia is the prevailing sleep disturbance seen in individuals with progressive supranuclear palsy (PSP). It is characterized by challenges in both beginning and sustaining sleep, sometimes accompanied with indications indicative of rapid eye movement sleep behavior disorder (RBD) .In some individuals, symptoms resembling rapid eye movement sleep behavior disorder (RBD) may manifest as episodes of nocturnal roaming and confusional arousals. These manifestations are often seen in patients diagnosed with various forms of dementia.Rapid eye movement sleep behavior disorder (RBD) manifests in roughly 10% to 20% of individuals diagnosed with progressive supranuclear palsy (PSP) and is often characterized by a modest intensity. This condition frequently emerges subsequent to the beginning of dementia.Approximately 20% of patients exhibit the subclinical manifestation of REM sleep behavior disorder (RBD), characterized by the absence of symptoms and the persistence of REM sleep without atonia.Huntington’s disease (HD) is a hereditary condition that follows an autosomal dominant pattern of inheritance. It is distinguished by symptoms such as dementia, chorea, and mental disorders. These symptoms are linked to the presence of enlarged CAG repeats in the Huntington gene .Pathological investigations reveal significant degeneration of the striatum, including the caudate nucleus and putamen, with a comparatively lower impact on the cortex .Sleep difficulties have been shown to impact a significant proportion, specifically up to 87%, of those diagnosed with Huntington’s disease (HD), with a greater prevalence seen in those in late stages of the illness. The incidence of sleep disturbances rises in proportion to the intensity and duration of the ailment.It is often seen among patients that they have suboptimal sleep quality, insomnia, fragmented sleep patterns with many awakenings throughout the night, excessive daytime sleepiness (EDS), and a circadian rhythm disruption defined by an advanced sleep phase leading to early morning waking .Polysomnographic investigations have shown a decrease in sleep efficiency, an increase in wakefulness after sleep initiation, an elevated proportion of light sleep, a lengthening of the time it takes to enter rapid eye movement (REM) sleep, and a reduction in the proportion of deep sleep and REM sleep.Rapid eye movement sleep behavior disorder (RBD) , obstrucIndividuals with the premutation gene have a higher degree of sleep disruption, defined by a fragmented sleep pattern, as compared to control participants.Hereditary ataxias are a class of neurological illnesses that are often transmitted with genetic inheritance, mostly caused by mutations in certain genes .These illnesses have an impact on many brain areas such as the spinocerebellar tracts, cerebellum, and brainstem. Clinically, these individuals have increasing ataxia along with a diverse range of other neurological symptoms and indications, including polyneuropathy and parkinsonism .Hereditary ataxias are not often associated with obstructive sleep apnea syndrome (OSAS) and excessive daytime sleepiness (EDS).The occurrence of nocturnal stridor resulting from vocal cord anomalies has been documented in spinocerebellar ataxias (SCA) 1 and SCA 3 .Rapid eye movement sleep behavior disorder (RBD) has been seen in a significant proportion, around 50%, of individuals diagnosed with spinocerebellar ataxia type 3 . Additionally, patients with spinocerebellar ataxia type 2, although with moderate clinical severity, have also been shown to exhibit RBD. The presence of RBD has not been detected in individuals with spinocerebellar ataxia type 2 (SCA 2).Sleep-related breathing difficulties have been documented in spinocerebellar ataxia type 1 (SCA 1), spinocerebellar ataxia type 2 (SCA 2), spinocerebellar ataxia type 3 (SCA 3), and spinocerebellar ataxia type 6 (SCA 6).Amyotrophic lateral sclerosis (ALS) is distinguished by the degeneration of neurons situated in the cortex, brainstem nuclei, and the ventral horn of the spinal cord .The condition exhibits a constellation of symptoms including rapidly advancing weakness, muscular wasting, involuntary muscle twitches, increased muscle tone, difficulty with speech, difficulty with swallowing, and the inability to breathe properly.Respiratory dysfunction arises as a consequence of the weakening of the pharyngeal, laryngeal, diaphragmatic, and intercostal muscles due to the depletion of motor neurons in the brainstem and spinal cord. Apnea is the most prevalent sleep problem.Sleep-related respiratory disorders occur in 17% to 76% of cases and include nocturnal hypoventilation, obstructive sleep apnea syndrome (OSAS) , laryngeThe incidence of sleep apnea is lower compared to hypoventilation. The majority of apneic occurrences are classified as central in nature due to the presence of diaphragm weakness and paralysis of the accessory respiratory muscles, which contribute to the development of this particular kind of sleep apnea.To manage respiratory compromise in ALS, various interventions are employed. CPAP (continuous positive airway pressure) is commonly used to alleviate obstructive sleep apnea and ensure adequate airflow during sleep . Non-invIn some regions, particularly in Europe, Italy, and East Asian countries, more advanced interventions may be considered. Tracheostomy or tracheostomy-assisted ventilation might be employed for those who require more sustained and invasive respiratory support. Tracheostomy allows for direct access to the airway, enabling long-term mechanical ventilation through a tracheostomy tube .The use of these interventions can significantly impact the sleep quality and overall well-being of ALS patients. While respiratory support measures aim to enhance breathing, they can also influence sleep architecture and potentially cause sleep disturbances. Ensuring patient comfort, optimizing ventilator settings, and offering psychological support are vital aspects of managing sleep-related issues in ALS patients undergoing such interventions.The primary sleep problems are nocturia, muscular cramps, early insomnia, decreased total sleep duration, and excessive daytime sleepiness (EDS) .Rapid eye movement sleep behavior disorder (RBD)  and restMultiple system atrophy (MSA) is a neurological disorder that manifests as a mix of parkinsonism, cerebellar syndrome, and autonomic failure, occurring in diverse combinations. The defining pathological feature of MSA is the presence of alpha-synuclein-positive cytoplasmic inclusions in the glial cells of different brain areas . Sleep iApproximately 50% of individuals have insomnia during sleep onset and interrupted sleep. There are many potential variables that might lead to sleep fragmentation. These include urine incontinence, anxiety, sadness, the difficulty to change body position in bed owing to parkinsonism, and the use of several drugs .Excessive daytime sleepiness (EDS) is seen in around 28% of individuals, but it is often not considered a prevalent condition. Sleep attacks may occur in some people after the treatment of levodopa .The prevalence of restless legs syndrome (RLS) and periodic limb movement syndrome (PLMS) in the general population of a comparable age remains uncertain.Multiple system atrophy (MSA) is found to be ultimately identified in a limited number of individuals who were initially diagnosed with idiopathic rapid eye movement sleep behavior disorder (RBD). It is worth noting that a majority of these individuals are subsequently diagnosed with Parkinson’s disease and dementia with Lewy bodies. This discrepancy in diagnosis rates can be attributed to the relatively lower prevalence of MSA in the general population when compared to Parkinson’s disease and dementia with Lewy bodies.The occurrence of rapid eye movement sleep behavior disorder (RBD) in patients with multiple system atrophy (MSA) ranges from 80% to 100% . The lacThe manifestation of respiratory difficulties in individuals with multiple system atrophy (MSA) may arise from both central and peripheral sources, including obstructive factors. Degeneration of the bulbar respiratory centers is the primary cause of central respiratory disorders. This degeneration results in many aberrant respiratory responses, including hypoxic ventilatory responses, Cheyne–Stokes breathing, irregular breathing, and central sleep apnea .Nocturnal stridor, a high-pitched sound produced with disrupted airflow during sleep, is a common sleep-related issue in MSA patients. Its occurrence can vary depending on the stage of MSA and individual patient factors. It is noteworthy that nocturnal stridor appears to be relatively frequent in MSA patients, and the reported prevalence may vary between different studies and clinical practices .Approximately 20% of patients have nocturnal stridor.The prevalence of the phenomenon discussed in the previous statement may vary depending on the stage of MSA and geographical differences, perhaps exceeding the original estimate provided . Based oStridor is seen throughout all phases of the ailment and signifies the presence of an airway blockage specifically at the level of the vocal cords inside the larynx. As the condition advances, there is a possibility of experiencing nocturnal stridor during waking as a result of the progressive constriction of the glottis .Individuals diagnosed with multiple system atrophy (MSA), particularly those exhibiting stridor, may encounter characteristic occurrences of obstructive sleep apnea (OSA) accompanied by oxygen desaturations. Additionally, in some instances, they may face subacute bouts of respiratory failure .The occurrence of vocal cord paralysis is often found in a significant proportion of patients who exhibit nocturnal stridor. This observation is made with clinical evaluation of the vocal cords using laryngoscopy when the patients are awake.The occurrence of stridor in multiple system atrophy (MSA) has been shown to be associated with reduced rates of survival and an elevated likelihood of experiencing unexpected death while asleep .The use of continuous positive airway pressure (CPAP) and tracheostomy has been shown to effectively alleviate symptoms of stridor and obstructive apneas in individuals with multiple system atrophy (MSA) .The management of sleep disturbances in neurodegenerative diseases is a complex endeavor, often requiring a tailored approach that considers the underlying disease pathology and the specific sleep-related symptoms experienced by patients. Below, we outline various treatment methods and interventions with their corresponding relevance to different neurodegenerative diseases and pathological conditions.Pharmacological approaches can target specific sleep disturbances commonly associated with neurodegenerative diseases. For instance, patients with Parkinson’s disease experiencing REM sleep behavior disorder (RBD) might benefit from medications that suppress REM sleep, such as Temazepam or melatonin. Individuals with Alzheimer’s disease facing insomnia could be prescribed sedative-hypnotics, although caution is exercised due to potential cognitive side effects .Benzodiazepines: Estazolam, Quazepam, Triazolam, Flurazepam, Temazepam;Non-benzodiazepines: Zaleplon, Zolpidem, Eszopiclone;Sedative Antidepressants: Doxepin;Melatonin Receptor Agonists: Ramelteon;Melatonin.Pharmacological approaches for managing sleep disturbances can vary based on the specific neurological pathology and type of insomnia observed:These pharmacological options can be relevant for patients across different neurodegenerative diseases based on the predominant sleep-related symptoms they experience.Non-pharmacological interventions play a crucial role in managing sleep disturbances, often focusing on improving sleep hygiene and behavioral modifications. Patients across various neurodegenerative diseases can benefit from creating a consistent sleep schedule, optimizing the sleep environment, and engaging in relaxation techniques . CognitiExternal Devices for Assisting Breathing (CPAP—Continuous Positive Airway Pressure): Particularly relevant for patients with sleep-related breathing disorders, such as obstructive sleep apnea, which can occur in various neurodegenerative diseases.Phototherapy: Valuable for conditions like Alzheimer’s disease, where disruptions in circadian rhythms are common and can contribute to sleep disturbances.Cognitive–Behavioral Therapy: Effective in addressing insomnia in neurodegenerative diseases by targeting maladaptive sleep-related behaviors and thoughts.Sleep Hygiene Practices: A general approach that can benefit patients across various neurodegenerative diseases by promoting healthy sleep habits.Non-pharmacological interventions also vary depending on the neurological pathology and type of insomnia:Patients with neurodegenerative diseases that exhibit sleep-related breathing disorders, such as obstructive sleep apnea, might be candidates for CPAP or non-invasive ventilation. This intervention is particularly relevant for conditions like multiple system atrophy (MSA) where nocturnal stridor is frequent, and ALS where respiratory muscle weakness leads to compromised breathing during sleep .Light therapy has shown promise in regulating sleep–wake cycles, particularly in conditions like Alzheimer’s disease where disruptions in circadian rhythms are common. Exposure to bright light during specific times of the day can help re-establish a proper sleep–wake pattern and alleviate sleep disturbances .In cases of REM sleep behavior disorder, where patients physically act out their dreams during REM sleep, safety measures are vital. This may involve creating a safe sleep environment by removing potentially harmful objects from the bedroom .Patients with restless legs syndrome, common in neurodegenerative diseases like Parkinson’s disease, might benefit from iron supplementation and dopamine agonist medications. Treating the underlying condition contributing to RLS can also alleviate its symptoms .It is important to note that treatment approaches should be individualized, considering the patient’s overall health, disease stage, and specific sleep-related symptoms. Multidisciplinary collaboration involving neurologists, sleep specialists, psychologists, and other healthcare professionals is often necessary to optimize treatment strategies for sleep disturbances in the context of neurodegenerative diseases.The present study aimed to investigate the sleep disorders associated with various neurological pathologies, including amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), hereditary ataxias, Huntington’s disease (HD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB) . The finIn ALS, sleep-related breathing disorders, particularly hypoventilation and central sleep apnea, were observed in a significant proportion of patients . These rIn MSA, sleep problems were reported by a substantial number of patients, with insomnia, fragmented sleep, and excessive daytime sleepiness being the most common issues . StridorHereditary ataxias are associated with various sleep disturbances, including insomnia, restless legs syndrome (RLS), and periodic limb movement syndrome (PLMS) . The exaHuntington’s disease is characterized by various sleep issues, such as insomnia at sleep onset and fragmented sleep, which can be influenced by several contributing factors, including anxiety, depression, and medication use. Proper management of these sleep disturbances may improve patients’ overall well-being and potentially delay disease progression .In progressive supranuclear palsy (PSP), sleep disorders, such as rapid eye movement sleep behavior disorder (RBD), are prevalent. RBD emerged as a valuable diagnostic criterion for PSP, as its absence can raise suspicion of other neurodegenerative conditions . Early dDementia with Lewy bodies (DLB) is associated with rapid eye movement sleep behavior disorder (RBD) in a significant number of patients. This finding reinforces the importance of considering RBD as a potential early marker of DLB and highlights its diagnostic significance in differentiating DLB from other forms of dementia .Overall, the findings of this study underscore the importance of recognizing and addressing sleep disorders in various neurological pathologies. Both pharmacological and non-pharmacological interventions play vital roles in managing these sleep disturbances and enhancing patients’ overall quality of life. Further research is warranted to better understand the underlying mechanisms of sleep disturbances in neurological diseases, thus paving the way for more effective and tailored treatment strategies. Integrating sleep assessment and management into the comprehensive care of patients with neurological disorders is crucial to optimize their clinical outcomes and overall well-being.Virtual Reality (VR) and Sleep Therapy: Future developments in virtual reality technology may enable the creation of immersive and interactive sleep therapy experiences. Virtual environments could be tailored to address specific sleep disturbances related to different mental disorders, providing a unique and engaging approach to sleep interventions.Digital Sleep Tracking and Feedback: Advancements in digital sleep tracking and artificial intelligence algorithms could lead to personalized sleep feedback systems. Integrating sleep data from wearable devices and other sources, AI-powered platforms may offer real-time insights and actionable recommendations for optimizing sleep in individuals with mental disorders.Targeting Sleep Circuitry: Emerging research on the neural circuits involved in sleep regulation and their interactions with mental health pathways may open new avenues for therapeutic interventions. Targeted neuromodulation techniques, such as transcranial magnetic stimulation (TMS) or deep brain stimulation (DBS), could be explored to modulate sleep-related brain regions in mental disorders.Chronotherapeutics: Chronotherapy, the strategic timing of treatments based on circadian rhythms, could be investigated as a complementary approach for managing sleep disturbances in mental disorders. Tailoring interventions to align with individual circadian preferences may optimize treatment outcomes.Gut Microbiome and Sleep: The gut–brain axis, a bidirectional communication system between the gut microbiome and the central nervous system, has emerged as a fascinating area of research in sleep and mental health. Studies suggest that gut microbiota may influence sleep patterns through various mechanisms, including the production of neurotransmitters and metabolites that impact sleep regulation. Alterations in the gut microbiome have been associated with sleep disturbances and mental health conditions. Thus, interventions targeting the gut microbiome, such as probiotics or dietary changes, could potentially improve sleep quality and mental health outcomes.Sleep-Inducing Nutraceuticals: Investigating natural sleep-inducing compounds presents a promising avenue for addressing sleep disruptions in mental disorders. Certain foods or herbal supplements rich in melatonin, a hormone that regulates sleep–wake cycles, might have sleep-promoting effects. Incorporating sleep-inducing nutraceuticals into dietary interventions could offer an adjunctive approach to improve sleep quality. However, further research is needed to determine the safety and efficacy of these compounds and their potential interactions with medications used in mental health treatment.AI-Powered Sleep Disorder Prediction: Artificial intelligence algorithms have shown remarkable capabilities in analyzing vast amounts of data. In the context of sleep and mental health, AI-powered platforms may integrate data from wearable devices, electronic health records, genetic information, and behavioral patterns to predict the likelihood of developing mental disorders based on sleep disturbances. Early identification of individuals at risk could facilitate timely interventions, preventive strategies, and personalized treatment plans. AI-driven approaches hold the potential to enhance the accuracy and efficiency of clinical assessments and improve patient outcomes.In summary, the future perspectives for the aspects of sleep in mental disorders are exciting and multi-faceted. Digital health interventions, advances in sleep circuitry targeting, gut–brain axis research, and the integration of artificial intelligence all offer promising opportunities to optimize sleep interventions, enhance mental health care, and improve the well-being of individuals living with mental disorders. As these innovative approaches continue to evolve, the potential for transformational advancements in sleep research and mental health care becomes increasingly tangible.


In recent decades, growing rates of mental illness  and soci joining  and a 30 joining . NumbersIn this Research Topic, we present seven articles exploring the therapeutic potential of classic and non-classic psychedelics for SUDs. Recognizing that psychedelic research has been prone to hype  and thatZafar et al. present a wide-ranging review of observational studies and clinical trials investigating the therapeutic effects of classic and non-classic psychedelics in SUDs. They also extensively discuss different translational human neuropsychopharmacology techniques  that should be employed in future work to enhance mechanistic understanding of how psychedelics might treat SUDs.Whinkin et al. explore the treatment potential of ketamine for depression, anxiety, and psychosocial/spiritual distress in patients with SUDs, via a 2-year chart review on 18 patients with problematic substance use receiving ketamine-assisted psychotherapy. Statistically significant reductions in anxiety and depression rating scores were observed, suggesting further investigations in this area are warranted.Goldfine et al. reviewed the human literature on the therapeutic potential of ketamine for alcohol use disorder (AUD), as well as alcohol withdrawal. Their findings regarding AUD included studies reporting reduced cravings, reduced alcohol consumption, and longer abstinence in patients receiving ketamine treatments, with longer periods of abstinence associated with receiving more psychotherapy sessions. The authors also identified literature demonstrating earlier resolution of alcohol withdrawal syndrome (AWS) and delirium tremens with the adjunctive use of ketamine in patients receiving benzodiazepine therapy during severe alcohol withdrawal.Phan and Terry systematically reviewed the human literature on psychedelics, including ketamine, in the treatment of cannabis use disorder (CUD), a condition that has received relatively little attention in psychedelics research thus far. The authors identified one article assessing the open-label use of ketamine in conjunction with motivational enhancement therapy (MET) and mindfulness-based relapse prevention treatments for CUD. Patients in that study had a statistically significant reduction in cannabis use, though there were only eight participants. The authors also identified data from a placebo-controlled study of the serotonin 5-HT2c agonist lorcaserin in non-treatment seeking daily cannabis smokers indicating decreased cannabis use, though data were only reported for less than a week. Lorcaserin is not a psychedelic, though 5-HT2c agonism may play a role in psychedelics' potential anti-addictive properties, since this modulates dopaminergic activity in the ventral tegmental area-nucleus accumbens reward pathway , a condition for which current pharmacological treatments offer little to no efficacy, and discuss the rationale for investigating psilocybin-assisted therapy for this indication. The authors note that since psilocybin-assisted therapy has demonstrated promising findings in clinical trials for AUD and tobacco use disorder, the possibility of transdiagnostic treatment potential justifies exploring its potential in MUD.Rounding out articles on human data, Zhornitsky et al. explore the potential of neuroplasticity as a therapeutic mechanism for psychedelics in patients with SUDs, as well as mental health conditions, by systematically reviewing the effects of psychedelics on markers associated with synaptic density. They found most eligible studies have investigated the non-classic psychedelic ketamine, with mixed findings for synaptic changes in the hippocampus and prefrontal cortex when ketamine is administered in single or repeated doses. Fewer studies have been conducted for other psychedelics, though these data indicate that markers associated with synaptic density can be enhanced under basal conditions and that stress-associated deficits can be reversed. Taken together, these findings suggest that psychedelics' abilities to normalize abnormal levels of synaptic markers in some brain regions could contribute to their treatment potential for SUDs.Black argues for an increased focus on the potential of psychedelic treatments for patients with SUDs. To do this demands that we work toward equitably employing psychedelic therapies, rather than maintaining the status quo in mental healthcare, which would likely see them primarily restricted to use in wellness markets or patients who are commercially insured. Among other points, Black observes that recruitment and training of diverse psychedelic clinicians, collaboration with mutual support groups, and a willingness to provide access to psychedelic treatments to higher-risk individuals in need of complex care will be essential to maximizing the potential societal benefits of psychedelic assisted therapy.Finally, in a compelling perspective piece, In summary, these articles provide a valuable view into the emerging field of psychedelics as potential treatment for SUDs. With growing interest among researchers in exploring this line of inquiry, we expect this Research Topic will prepare readers for deeper future engagement with an area of research that could yield important assistance in humanity's quest to ameliorate the widespread suffering wrought by SUDs.BB: Conceptualization, Writing—original draft. AB: Writing—review and editing. NS: Writing—review and editing. JW: Writing—review and editing.


Adverse nutritional and genetic factors play a significant role in the pathogenesis of non-communicable diseases. Pregnancy represents a critical time window in which maternal metabolic disturbances, such as obesity and hyperglycemia, may result in short- and long-term complications for both the mother and the offspring.There is strong evidence that even pre- and periconceptional parental insults can affect fetal development by activating specific key mechanisms of epigenetic reprogramming. Therefore, the study of trans-generational effects is a very promising field of research, as the knowledge of pathophysiological and clinical mechanisms induced by maternal obesity and hyperglycemia during pregnancy could shed light on the health of the next generation and provide useful preventive tools.This Research Topic aims to provide insight into several facets of the connections between obesity, hyperglycemia, and pregnancy. The Research Topic encompasses four curated contributions, each covering different aspects.Obesity negatively affects female fertility and is associated with infertility, abnormal menstruation, ovulation abnormalities (OA), polycystic ovary syndrome (PCOS), miscarriage, pregnancy complications, and neonatal congenital disabilities.Long-term follow-up studies have shown that sleeve gastrectomy, which is the most commonly performed bariatric procedure worldwide, significantly increases postoperative patient pregnancy, live birth, and vaginal delivery rates and reduces pregnancy complications than women without surgical treatment. However, no research has identified a reliable indicator for predicting OA recovery after bariatric procedure.Liu et al. in a prospective study performed in obese women who underwent sleeve gastrectomy for weight reduction, examined the prognostic usefulness of preoperative the luteinizing hormone (LH) to follicle-stimulating hormone (FSH) ratio (LFR). They found that LFR levels were the only component linked with ovulation abnormalities. Patients with a preoperative LFR of >182, who had a greater incidence of PCOS and more disrupted sex hormone levels, did not seem to regain ovulation despite achieving the same weight reduction 12 months after surgery. These findings underline the potential predictive role of preoperative sexual hormone levels, as expressed by LFR, on the fate of ovulation abnormalities following bariatric procedure.Maternal obesity is also a key predictor for childhood obesity and neurodevelopmental delay in the offspring. This could be due to the shared genetic polymorphism between the obese mother and the child or changes of epigenome in the child. Medicinal plants are considered to be the safe and best option to treat maternal obesity, and at the same time, probiotic consumption during pregnancy provides beneficial effects for both the mother and the child. Current research has shown that Elateriospermum tapos (E. tapos) yoghurt is safe to consume and consists of many bioactive compounds that can exert an anti-obesity effect.Naomi et al. investigated the role of E. tapos yoghurt in mitigating maternal obesity. In an experimental study performed on obese female Sprague Dawley rats in pregnancy, they found that supplementation of highest concentration of E. tapos yoghurt was associated with reduction in body weight and calorie intake and modulation of lipid levels, liver, and renal enzymes to a normal level. Moreover, in histological analysis, E. tapos yoghurt reversed the damage caused by high-fat diet in liver and colon, and the adipocytes’ hypertrophy in retroperitoneal white adipose tissue and visceral fat. This study provides useful insights into considering natural probiotics such as yoghurt as a therapeutic agent to treat maternal obesity.Gestational diabetes mellitus (GDM) is a common endocrine disorder complicating up to 9-26% of pregnancies . GDM is Visiedo et al. investigated the impact of key inflammatory mediators on the regulation of placental fatty acid metabolism from pregnancies complicated by GDM. They showed that women with GDM had elevated serum levels of IL- 6, TNF-a and leptin in the third trimester of pregnancy. These enhanced maternal cytokines levels were associated with an altered placental fatty acid metabolism, including a diminished placental fatty acid b‐oxidation capacity and an excess of free fatty acid accumulation in form of triglycerides. These findings highlight that an exacerbated proinflammatory environment in pregnancy would be closely related to the emergence of inadequate transport of essential lipids to the fetus and, consequently, to the onset of placental lipotoxic damage.GDM is associated with adverse pregnancy outcomes, including increased rate of cesarean section, macrosomic infants, birth trauma and neonatal adverse outcomes . In longPopova et al. aimed to investigate the effect of a mobile-based personalized recommendation system DiaCompanion I on glycaemic levels and pregnancy outcomes in women with GDM. Women with GDM will be randomized to 2 treatment groups: utilizing and not utilizing DiaCompanion I. The app provides women in the intervention group the resulting data-driven prognosis of 1-hour postprandial glucose levels, which are independent predictors of adverse maternal and perinatal outcomes and of T2DM ( of T2DM . MoreoveIn summary, this Research Topic has provided new insights into pathophysiological mechanisms and management strategies of GDM and potential predictors of infertility in women with obesity. This research could shed light on the health of the next generation and give useful preventive tools in the development of non-communicable diseases.EV: Writing – original draft, Writing – review & editing. ES: Writing – original draft, Writing – review & editing.