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CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth, Genital anomalies and Ear abnormalities) syndrome is a disorder caused by mutations in the gene encoding CHD7, an ATP dependent chromatin remodelling factor, and is characterised by a diverse array of congenital anomalies. These include a range of neuroanatomical comorbidities which likely underlie the varied neurodevelopmental disorders associated with CHARGE syndrome, which include intellectual disability, motor coordination deficits, executive dysfunction, and autism spectrum disorder. Cranial imaging studies are challenging in CHARGE syndrome patients, but high-throughput magnetic resonance imaging (MRI) techniques in mouse models allow for the unbiased identification of neuroanatomical defects. Here, we present a comprehensive neuroanatomical survey of a Chd7 haploinsufficient mouse model of CHARGE syndrome. Our study uncovered widespread brain hypoplasia and reductions in white matter volume across the brain. The severity of hypoplasia appeared more pronounced in posterior areas of the neocortex compared to anterior regions. We also perform the first assessment of white matter tract integrity in this model through diffusion tensor imaging (DTI) to assess the potential functional consequences of widespread reductions in myelin, which suggested the presence of white matter integrity defects. To determine if white matter alterations correspond to cellular changes, we quantified oligodendrocyte lineage cells in the postnatal corpus callosum, uncovering reduced numbers of mature oligodendrocytes. Together, these results present a range of promising avenues of focus for future cranial imaging studies in CHARGE syndrome patients., (© 2023 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)

Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), occurs in 1 in 800 live births and is the most common human aneuploidy. DS results in multiple phenotypes, including craniofacial dysmorphology, which is characterised by midfacial hypoplasia, brachycephaly and micrognathia. The genetic and developmental causes of this are poorly understood. Using morphometric analysis of the Dp1Tyb mouse model of DS and an associated mouse genetic mapping panel, we demonstrate that four Hsa21-orthologous regions of mouse chromosome 16 contain dosage-sensitive genes that cause the DS craniofacial phenotype, and identify one of these causative genes as Dyrk1a. We show that the earliest and most severe defects in Dp1Tyb skulls are in bones of neural crest (NC) origin, and that mineralisation of the Dp1Tyb skull base synchondroses is aberrant. Furthermore, we show that increased dosage of Dyrk1a results in decreased NC cell proliferation and a decrease in size and cellularity of the NC-derived frontal bone primordia. Thus, DS craniofacial dysmorphology is caused by an increased dosage of Dyrk1a and at least three other genes., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

The interplay among different cells in a tissue is essential for maintaining homeostasis. Although disease states have been traditionally attributed to individual cell types, increasing evidence and new therapeutic options have demonstrated the primary role of multicellular functions to understand health and disease, opening new avenues to understand pathogenesis and develop new treatment strategies. We recently described the cellular composition and dynamics of the human oral mucosa; however, the spatial arrangement of cells is needed to better understand a morphologically complex tissue. Here, we link single-cell RNA sequencing, spatial transcriptomics, and high-resolution multiplex fluorescence in situ hybridisation to characterise human oral mucosa in health and oral chronic inflammatory disease. We deconvolved expression for resolution enhancement of spatial transcriptomic data and defined highly specialised epithelial and stromal compartments describing location-specific immune programs. Furthermore, we spatially mapped a rare pathogenic fibroblast population localised in a highly immunogenic region, responsible for lymphocyte recruitment through CXCL8 and CXCL10 and with a possible role in pathological angiogenesis through ALOX5AP . Collectively, our study provides a comprehensive reference for the study of oral chronic disease pathogenesis., Competing Interests: AC, YR, FK, PD, SK, RN, AV, LN, VB, PS No competing interests declared, ED is an employee of Unilever Plc. The authors state no conflict of interest, (© 2023, Caetano et al.)

Telocytes (TCs) or interstitial cells are characterised in vivo by their long projections that contact other cell types. Although telocytes can be found in many different tissues including the heart, lung, and intestine, their tissue-specific roles are poorly understood. Here we identify a specific cell signalling role for telocytes in the periodontium whereby telocytes regulate macrophage activity. We performed scRNA-seq and lineage tracing to identify telocytes and macrophages in mouse periodontium in homeostasis and periodontitis and carried out hepatocyte growth factor (HGF) signalling inhibition experiments using tivantinib. We show that telocytes are quiescent in homeostasis; however, they proliferate and serve as a major source of HGF in periodontitis. Macrophages receive telocyte-derived HGF signals and shift from an M1 to an M1/M2 state. Our results reveal the source of HGF signals in periodontal tissue and provide new insights into the function of telocytes in regulating macrophage behaviour in periodontitis through HGF/Met cell signalling, which may provide a novel approach in periodontitis treatment., Competing Interests: JZ, AB, MA, YR, JO, PS No competing interests declared, (© 2022, Zhao et al.)

Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease. However, additional de-regulated genes and the resulting pathophysiology is unknown. Therefore, we have generated mouse models of this disease. In addition to exhibiting loss of Mmachc, metabolic perturbations, and developmental defects previously observed in cblC, we uncovered reduced expression of target genes that encode ribosome protein subunits. We also identified specific phenotypes that we ascribe to deregulation of ribosome biogenesis impacting normal translation during development. These findings identify HCFC1/RONIN as transcriptional regulators of ribosome biogenesis during development and their mutation results in complex syndromes exhibiting aspects of both cblC and ribosomopathies., (© 2022. The Author(s).)

Amyotrophic lateral sclerosis and frontotemporal dementia are overlapping diseases in which MRI reveals brain structural changes in advance of symptom onset. Recapitulating these changes in preclinical models would help to improve our understanding of the molecular causes underlying regionally selective brain atrophy in early disease. We therefore investigated the translational potential of the TDP-43 Q331K knock-in mouse model of amyotrophic lateral sclerosis-frontotemporal dementia using MRI. We performed in vivo MRI of TDP-43 Q331K knock-in mice. Regions of significant volume change were chosen for post-mortem brain tissue analyses. Ex vivo computed tomography was performed to investigate skull shape. Parvalbumin neuron density was quantified in post-mortem amyotrophic lateral sclerosis frontal cortex. Adult mutants demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of amyotrophic lateral sclerosis-frontotemporal dementia. Subcortical, cerebellar and brain stem regions were also affected in line with observations in pre-symptomatic carriers of mutations in C9orf72 , the commonest genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Volume loss was also observed in the dentate gyrus of the hippocampus, along with ventricular enlargement. Immunohistochemistry revealed reduced parvalbumin interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia was in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the dentate gyrus, indicative of impaired adult neurogenesis, while a paucity of parvalbumin interneurons in P14 mutant mice suggests that TDP-43 Q331K disrupts neurodevelopment. Computerized tomography imaging showed altered skull morphology in mutants, further suggesting a role for TDP-43 Q331K in development. Finally, analysis of human post-mortem brains confirmed a paucity of parvalbumin interneurons in the prefrontal cortex in sporadic amyotrophic lateral sclerosis and amyotrophic lateral sclerosis linked to C9orf72 mutations. Regional brain MRI changes seen in human amyotrophic lateral sclerosis-frontotemporal dementia are recapitulated in TDP-43 Q331K knock-in mice. By marrying in vivo imaging with targeted histology, we can unravel cellular and molecular processes underlying selective brain vulnerability in human disease. As well as helping to understand the earliest causes of disease, our MRI and histological markers will be valuable in assessing the efficacy of putative therapeutics in TDP-43 Q331K knock-in mice., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Characterising phenotypes often requires quantification of anatomical shape. Quantitative shape comparison (morphometrics) traditionally uses manually located landmarks and is limited by landmark number and operator accuracy. Here, we apply a landmark-free method to characterise the craniofacial skeletal phenotype of the Dp1Tyb mouse model of Down syndrome and a population of the Diversity Outbred (DO) mouse model, comparing it with a landmark-based approach. We identified cranial dysmorphologies in Dp1Tyb mice, especially smaller size and brachycephaly (front-back shortening), homologous to the human phenotype. Shape variation in the DO mice was partly attributable to allometry (size-dependent shape variation) and sexual dimorphism. The landmark-free method performed as well as, or better than, the landmark-based method but was less labour-intensive, required less user training and, uniquely, enabled fine mapping of local differences as planar expansion or shrinkage. Its higher resolution pinpointed reductions in interior mid-snout structures and occipital bones in both the models that were not otherwise apparent. We propose that this landmark-free pipeline could make morphometrics widely accessible beyond its traditional niches in zoology and palaeontology, especially in characterising developmental mutant phenotypes., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Mutations in FUS are causative for amyotrophic lateral sclerosis with a dominant mode of inheritance. In trying to model FUS-amyotrophic lateral sclerosis (ALS) in mouse it is clear that FUS is dosage-sensitive and effects arise from overexpression per se in transgenic strains. Novel models are required that maintain physiological levels of FUS expression and that recapitulate the human disease-with progressive loss of motor neurons in heterozygous animals. Here, we describe a new humanized FUS-ALS mouse with a frameshift mutation, which fulfils both criteria: the FUS Delta14 mouse. Heterozygous animals express mutant humanized FUS protein at physiological levels and have adult onset progressive motor neuron loss and denervation of neuromuscular junctions. Additionally, we generated a novel antibody to the unique human frameshift peptide epitope, allowing specific identification of mutant FUS only. Using our new FUSDelta14 ALS mouse-antibody system we show that neurodegeneration occurs in the absence of FUS protein aggregation. FUS mislocalization increases as disease progresses, and mutant FUS accumulates at the rough endoplasmic reticulum. Further, transcriptomic analyses show progressive changes in ribosomal protein levels and mitochondrial function as early disease stages are initiated. Thus, our new physiological mouse model has provided novel insight into the early pathogenesis of FUS-ALS., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Telocytes are CD34+ interstitial cells that have long cytoplasmic projections (called telopodes), and have been detected in several organs, including those of the male reproductive system. In this brief review we evaluate the role of telocytes in tissue organization of the different organs of the male reproductive system in which these cells were studied. In general terms, telocytes act in the tissue organization through networks of telopodes that separate the epithelia from the stroma, as well as dividing the stroma into different compartments. In addition to this contribution to the structural integrity, there is direct and indirect evidence that such "walls" formed by telocytes also compartmentalize paracrine factors that they or other cells produce, which have a direct impact on morphogenesis and the maintenance of organ cell differentiation, as well as on their normal physiology. Moreover, alterations in telocytes and telopode networks are correlated with pathological conditions in the male reproductive system, in response to profound changes in structural organization of the organs, in inflammation, hyperplasia and cancer. Further studies are necessary to evaluate the molecular pathways telocytes employ in different contexts of physiology and disease. [ABSTRACT FROM AUTHOR]

DYRK1A syndrome results from a reduction in copy number of the DYRK1A gene, which resides on human chromosome 21 (Hsa21). DYRK1A has been implicated in the development of cognitive phenotypes associated with many genetic disorders, including Down syndrome (DS) and Alzheimer's disease (AD). Additionally, overexpression of DYRK1A in DS has been implicated in the development of abnormal skeletal phenotypes in these individuals. Analyses of mouse models with Dyrk1a dosage imbalance (overexpression and underexpression) show skeletal deficits and abnormalities. Normalization of Dyrk1a copy number in an otherwise trisomic animal rescues some skeletal health parameters, and reduction of Dyrk1a copy number in an otherwise euploid (control) animal results in altered skeletal health measurements, including reduced bone mineral density (BMD) in the femur, mandible, and skull. However, little research has been conducted thus far on the implications of DYRK1A reduction on human skeletal health, specifically in individuals with DYRK1A syndrome. This review highlights the skeletal phenotypes of individuals with DYRK1A syndrome, as well as in murine models with reduced Dyrk1a copy number, and provides potential pathways altered by a reduction of DYRK1A copy number, which may impact skeletal health and phenotypes in these individuals. Understanding how decreased expression of DYRK1A in individuals with DYRK1A syndrome impacts bone health may increase awareness of skeletal traits and assist in the development of therapies to improve quality of life for these individuals. [ABSTRACT FROM AUTHOR]

This article explores the activities of those British travellers and settlers who carried out open field research in the Andean northwest of Río de la Plata during the 1820s. The focus is set upon Doctor Joseph Redhead, who became a regional expert on questions of mountain altitudes and natural portents such as giant fossil bones and large masses of native iron. Redhead was at the centre of a network of British doctors, entrepreneurs, adventurers and civil servants who crisscrossed the territory attracted by new mining ventures and the opening of trade, and driven by the need for geographical surveys implicit in the logic of empire. James Paroissien, Woodbine Parish, Joseph Pentland and others managed to combine research on the natural environment while engaged in their commercial, diplomatic or military missions. Particular attention is paid to the interactions of Redhead and his fellow countrymen with Humboldt and the kind of science cultivated by him, as well as to issues of scientific authority at the time of deciding on the cause of unexplained natural phenomena. [ABSTRACT FROM AUTHOR]

The current investigation aims to study the embryonic dermis formed in the early stages of development and identify the initial interstitial components of the dermis that serve as biological and structural scaffolds for the development of the dermal tissue. To investigate the dermal structure, the current study used morphological and immunological techniques. TCs identified by TEM. They had a cell body and unique podomeres and podoms. They formed a 3D network spread throughout the dermis. Homocellular contact established between them, as well as heterocellular contacts with other cells. Immunohistochemical techniques using specific markers for TCss CD34, CD117, and VEGF confirmed TC identification. TCs represent the major interstitial component in the dermal tissue. They established a 3D network, enclosing other cells and structures. Expression of VEGF by TC promotes angiogenesis. TCs establish cellular contact with sprouting endothelial cells. At the site of cell junction with TCs, cytoskeletal filaments identified and observed to form the pseudopodium core that projects from endothelial cells. TCs had proteolytic properties that expressed MMP-9, CD68, and CD21. Proteolytic activity aids in the removal of components of the extracellular matrix and the phagocytosis of degraded remnants to create spaces to facilitate the development of new dermal structures. In conclusion, TCs organized the scaffold for the development of future dermal structures, including fibrous components and skin appendages. Studying dermal TCs would be interested in the possibility of developing therapeutic strategies for treating different skin disorders and diseases. [ABSTRACT FROM AUTHOR]

Ants are crucial ecosystem engineers, and their ecological success is facilitated by a division of labour among sterile "workers". In some ant lineages, workers have undergone further morphological differentiation, resulting in differences in body size, shape, or both. Distinguishing between changes in size and shape is not trivial. Traditional approaches based on allometry reduce complex 3D shapes into simple linear, areal, or volume metrics; modern approaches using geometric morphometrics typically rely on landmarks, introducing observer bias and a trade‐off between effort and accuracy. Here, we use a landmark‐free method based on large deformation diffeomorphic metric mapping (LDDMM) to assess the co‐variation of size and 3D shape in the mandibles and head capsules of Atta vollenweideri leaf‐cutter ants, a species exhibiting extreme worker size‐variation. Body mass varied by more than two orders of magnitude, but a shape atlas created via LDDMM on μ‐CT‐derived 3D mesh files revealed only two distinct head capsule and mandibles shapes—one for the minims (body mass < 1 mg) and one for all other workers. We discuss the functional significance of the identified 3D shape variation, and its implications for the evolution of extreme polymorphism in Atta. [ABSTRACT FROM AUTHOR]

Turner Syndrome (TS) is a rare genetic disorder that affects females when one of the X chromosomes is partially or completely missing. Due to high genetic and phenotypic variability, TS diagnosis is challenging and is often delayed until adolescence, resulting in poor clinical management. Numerous oral, dental and craniofacial anomalies have been associated with TS, yet a comprehensive description is still lacking. This study addresses this gap through a detailed analysis of oral health and craniofacial characteristics in a cohort of 15 females with TS and their first-degree relatives. Subjects with TS ranged from 3 to 48 years old, none showed evidence of periodontal disease and only the youngest was in mixed dentition. Using the Multifunction System, we identified an aggregation of multiple signs and symptoms in each TS subject, including tooth anomalies (supernumerary molars, agenesis, microdontia, enamel defects, alterations in eruption patterns -advanced and delayed for chronological age-, crowding, rotations and transpositions), malocclusion (class II/1 and II/2) and Class II facial profile, while relatives exhibited fewer manifestations. The early detection of these signs and symptoms is crucial for appropriate referral and the optimal clinical management of TS, especially during the critical period of 9 to 10 years when congenital dental anomalies appear. The use of an established taxonomy to describe these phenotypic features is essential for early detection. Multidisciplinary teams are required to ensure holistic care management in rare diseases like TS. [ABSTRACT FROM AUTHOR]

Periodontitis is an inflammatory disease that eventually destroys tooth-supporting tissue. Yunnan Baiyao (YNBY), a traditional Chinese medicine compound with haemostatic and anti-inflammatory properties has shown therapeutic potential in several diseases. Our previous study revealed that YNBY suppressed osteoclast differentiation in periodontitis. The purpose of this study is to investigate the influences of YNBY on osteoblasts and explore its potential mechanisms. Materials and Methods: A rat periodontitis model was established by ligation of maxillary second molars. After the end of modelling, histopathological observation by hematoxylin-eosin (HE) staining and Masson trichrome staining, detection of bone resorption by Micro-CT scanning, detection of osteoclasts by tartrate-resistant acid phosphatase (TRAP) staining, expression of osteocalcin (OCN) and microtubule-associated protein 1 light chain 3 (LC3) by immunohistochemistry. Lipopolysaccharides was used to irritate MC3T3-E1 osteoblastic cells and ex vivo calvarial organ as an in vitro model of inflammation. CCK-8 assay was performed to examine the toxicity of YNBY to MC3T3-E1 osteoblastic cells. Osteogenesis was assessed with alizarin red staining, immunofluorescence staining, Western blot and immunohistochemical staining. Transmission electron microscopy, fluorescent double staining, Western blot and immunohistochemical staining were employed to detect autophagy. Results: Histological and micro-CT analyses revealed that YNBY gavage reduced bone loss caused by experimental periodontitis and upregulated osteogenic proteins in vivo. YNBY attenuated the production of autophagy-related proteins in periodontitis rats. Additionally, YNBY promoted osteogenesis by inhibiting inflammation-induced autophagy in vitro. Furthermore, YNBY suppressed LPS-mediated bone resorption and promoted the production of osteoblast-related proteins in inflamed calvarial tissues ex vivo. Conclusion: This study demonstrated, through in vivo, in vitro and ex vivo experiments, that YNBY promoted osteoblast differentiation by suppressing autophagy, which markedly alleviated bone destruction caused by periodontitis. [ABSTRACT FROM AUTHOR]

Tissue-specific mechanisms regulate neutrophil immunity at the oral barrier, which plays a key role in periodontitis. Although it has been proposed that fibroblasts emit a powerful neutrophil chemotactic signal, how this chemotactic signal is driven has not been clear. The objective of this study was to investigate the site-specific regulatory mechanisms by which fibroblasts drive powerful neutrophil chemotactic signals within the oral barrier, with particular emphasis on the role of the IL-36 family. The present study found that IL-36γ, agonist of IL-36R, could promote neutrophil chemotaxis via fibroblast. Single-cell RNA sequencing data disclosed that IL36G is primarily expressed in human and mouse gingival epithelial cells and mouse neutrophils. Notably, there was a substantial increase in IL-36γ levels during periodontitis. In vitro experiments demonstrated that IL-36γ specifically activates gingival fibroblasts, leading to chemotaxis of neutrophils. In vivo experiments revealed that IL-36Ra inhibited the infiltration of neutrophils and bone resorption, while IL-36γ promoted their progression in the ligature-induced periodontitis mouse model. In summary, these data elucidate the function of the site-enriched IL-36γ in regulating neutrophil immunity and bone resorption at the oral barrier. These findings provide new insights into the tissue-specific pathophysiology of periodontitis and offer a promising avenue for prevention and treatment through targeted intervention of the IL-36 family. [ABSTRACT FROM AUTHOR]

The human oral mucosa contains one of the most complex cellular systems that are essential for normal physiology and defense against a wide variety of local pathogens. Evolving techniques and experimental systems have helped refine our understanding of this complex cellular network. Current single-cell RNA sequencing methods can resolve subtle differences between cell types and states, thus providing a great tool for studying the molecular and cellular repertoire of the oral mucosa in health and disease. However, it requires the dissociation of tissue samples, which means that the interrelationships between cells are lost. Spatial transcriptomic methods bypass tissue dissociation and retain this spatial information, thereby allowing gene expression to be assessed across thousands of cells within the context of tissue structural organization. Here, we discuss the contribution of spatial technologies in shaping our understanding of this complex system. We consider the impact on identifying disease cellular neighborhoods and how space defines cell state. We also discuss the limitations and future directions of spatial sequencing technologies with recent advances in machine learning. Finally, we offer a perspective on open questions about mucosal homeostasis that these technologies are well placed to address. [ABSTRACT FROM AUTHOR]

Vitamin B12 (VitB12) is a micronutrient and acts as a cofactor for fundamental biochemical reactions: the synthesis of succinyl-CoA from methylmalonyl-CoA and biotin, and the synthesis of methionine from folic acid and homocysteine. VitB12 deficiency can determine a wide range of diseases, including nervous system impairments. Although clinical evidence shows a direct role of VitB12 in neuronal homeostasis, the molecular mechanisms are yet to be characterized in depth. Earlier investigations focused on exploring the biochemical shifts resulting from a deficiency in the function of VitB12 as a coenzyme, while more recent studies propose a broader mechanism, encompassing changes at the molecular/cellular levels. Here, we explore existing study models employed to investigate the role of VitB12 in the nervous system, including the challenges inherent in replicating deficiency/supplementation in experimental settings. Moreover, we discuss the potential biochemical alterations and ensuing mechanisms that might be modified at the molecular/cellular level (such as epigenetic modifications or changes in lysosomal activity). We also address the role of VitB12 deficiency in initiating processes that contribute to nervous system deterioration, including ROS accumulation, inflammation, and demyelination. Consequently, a complex biological landscape emerges, requiring further investigative efforts to grasp the intricacies involved and identify potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Vacuolar protein sorting 35 (VPS35), a critical component of the retromer complex, plays a pivotal role in the pathogenesis of neurodegenerative diseases (NDs). It is involved in protein transmembrane sorting, facilitating the transport from endosomes to the trans-Golgi network (TGN) and plasma membrane. Recent investigations have compellingly associated mutations in the VPS35 gene with neurodegenerative disorders such as Parkinson's and Alzheimer's disease. These genetic alterations are implicated in protein misfolding, disrupted autophagic processes, mitochondrial dysregulation, and synaptic impairment. Furthermore, VPS35 exerts a notable impact on neurogenesis by influencing neuronal functionality, protein conveyance, and synaptic performance. Dysregulation or mutation of VPS35 may escalate the progression of neurodegenerative conditions, underscoring its pivotal role in safeguarding neuronal integrity. This review comprehensively discusses the role of VPS35 and its functional impairments in NDs. Furthermore, we provide an overview of the impact of VPS35 on neurogenesis and further explore the intricate relationship between neurogenesis and NDs. These research advancements offer novel perspectives and valuable insights for identifying potential therapeutic targets in the treatment of NDs., (© 2024 International Society for Neurochemistry.)

Neutrophils play a critical role in the immune response to infection and tissue injury. However, recent studies have shown that neutrophils are a heterogeneous population with distinct subtypes that differ in their functional properties. Moreover, aging can alter neutrophil function and exacerbate immune dysregulation. In this review, we discuss the concept of neutrophil heterogeneity and how it may be affected by aging. We then examine the implications of neutrophil heterogeneity and aging for COVID-19 pathogenesis and wound healing. Specifically, we summarize the evidence for neutrophil involvement in COVID-19 and the potential mechanisms underlying neutrophil recruitment and activation in this disease. We also review the literature on the role of neutrophils in the wound healing process and how aging and neutrophil heterogeneity may impact wound healing outcomes. Finally, we discuss the potential for neutrophil-targeted therapies to improve clinical outcomes in COVID-19 and wound healing. [ABSTRACT FROM AUTHOR]

This article explores the potential effects of exercise on intelligence, happiness, and the number of neurons in the brain from a hormetic perspective. It discusses the role of adult hippocampal neurogenesis (AHN) in the positive effects of exercise on cognition and mood, but acknowledges a lack of evidence regarding the specific agents responsible for these effects. The article emphasizes the importance of understanding the biphasic dose response to exercise and the molecular mechanisms involved, and highlights the need for further research in this area. The text also discusses the concept of hormesis and proposes that AHN serves as a physiological basis for the hormetic responses induced by exercise, with growth factors like IGF1 and BDNF potentially mediating this response pattern. [Extracted from the article]

The proper functioning of diverse biological systems depends on the spatial organization of their cells, a critical factor for biological processes like shaping intricate tissue functions and precisely determining cell fate. Nonetheless, conventional bulk or single-cell RNA sequencing methods were incapable of simultaneously capturing both gene expression profiles and the spatial locations of cells. Hence, a multitude of spatially resolved technologies have emerged, offering a novel dimension for investigating regional gene expression, spatial domains, and interactions between cells. Spatial transcriptomics (ST) is a method that maps gene expression in tissue while preserving spatial information. It can reveal cellular heterogeneity, spatial organization and functional interactions in complex biological systems. ST can also complement and integrate with other omics methods to provide a more comprehensive and holistic view of biological systems at multiple levels of resolution. Since the advent of ST, new methods offering higher throughput and resolution have become available, holding significant potential to expedite fresh insights into comprehending biological complexity. Consequently, a rapid increase in associated research has occurred, using these technologies to unravel the spatial complexity during developmental processes or disease conditions. In this review, we summarize the recent advancement of ST in historical, technical, and application contexts. We compare different types of ST methods based on their principles and workflows, and present the bioinformatics tools for analyzing and integrating ST data with other modalities. We also highlight the applications of ST in various domains of biomedical research, especially development and diseases. Finally, we discuss the current limitations and challenges in the field, and propose the future directions of ST. [ABSTRACT FROM AUTHOR]

Geometric morphometrics (GM) enable the quantification of morphological variation on various scales. Recent technical advances allow analyzing complex three‐dimensional shapes also in cases where landmark‐based approaches are not appropriate. Pelvic girdle bones (basipterygia) of Sulawesi ricefishes are 3D structures that challenge traditional morphometrics. We hypothesize that the pelvic girdle of ricefishes experienced sex‐biased selection pressures in species where females provide brood care by carrying fertilized eggs supported by elongated pelvic fins ("pelvic brooding"). We test this by comparing pelvic bone shapes of both sexes in species exhibiting pelvic brooding and the more common reproductive strategy "transfer brooding," by using landmark‐free 2D and 3D GM, as well as qualitative shape descriptions. Both landmark‐free approaches revealed significant interspecific pelvic bone variation in the lateral process, medial facing side of the pelvic bone, and overall external and internal wing shape. Within pelvic brooders, the three analyzed species are clearly distinct, while pelvic bones of the genus Adrianichthys are more similar to transfer brooding Oryzias. Female pelvic brooding Oryzias exhibit prominent, medially pointing tips extending from the internal wing and basipterygial plate that are reduced or absent in conspecific males, Adrianichthys and transfer brooding Oryzias, supporting our hypothesis that selection pressures affecting pelvic girdle shape are sex‐biased in Sulawesi ricefishes. Furthermore, both sexes of pelvic brooding Oryzias have overall larger pelvic bones than other investigated ricefishes. Based on these differences, we characterized two reproductive strategy‐ and sex‐dependent pelvic girdle types for Sulawesi ricefishes. Morphological differences between the investigated pelvic brooding genera Adrianichthys and Oryzias provide additional evidence for two independent origins of pelvic brooding. Overall, our findings add to a better understanding on traits related to pelvic brooding in ricefishes and provide a basis for upcoming studies on pelvic girdle function and morphology. [ABSTRACT FROM AUTHOR]

Objective: This narrative review illuminates on the application of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) in periodontitis and highlights the probability of relating cell population and gene signatures to the pathogenesis of the disease for a better diagnosis., Methods: An electronic search of the literature in the PubMed database for the keywords, "single cell sequencing" OR "spatial transcriptomics" and "periodontitis" OR "gingiva" OR "oral mucosa" yielded 486 research articles and reviews. After filtering duplicates and careful curation, 22 papers conducted in humans were retained., Results: The molecular mechanisms underlying periodontitis are complex and involve the interaction of multiple cells and various gene expressions. Most residing cells in periodontal tissues participate in maintaining homeostasis and health, while in addition to infiltrating immune cells contribute to the fight against the bacterial insult., Conclusion: scRNA-seq and ST have provided new insights into the cellular and molecular changes associated with periodontitis for a better diagnosis and clinical outcome. New functions of cells and genes are revealed with these techniques; however, no cells or gene signatures are attributed to periodontitis so far., (© 2023 Wiley Periodicals LLC.)

Introduction: Fibroblasts are the dominant stromal cells in the gingival lamina propria with a well-established relevance in regulation of inflammation, and in innate immunity. This is exemplified by their hypersecretion of CXCL8, enhancing leukocyte infiltration in chronic and sustained inflammatory conditions. We have previously shown adenosine to be a key metabolic nucleoside that regulates stromal inflammation, but the underlying mechanisms linking adenosine to the metabolic status of fibroblasts and to the resultant inflammatory response are unclear. This study examined, by seahorse real-time cell metabolic analysis, the bioenergetics of the stromal fibroblast response to extracellular adenosine and IL-1β, focusing on CXCL8 secretion by primary human gingival fibroblasts (HGF). Methods: Markers of the glycolytic pathway and mitochondrial biogenesis were tracked through immunoblot. Further, the influence of adenosine on mitochondrial accumulation was measured by uptake of MitoTracker Red fluorescent probe and assessment of the role of FCCP (a mitochondrial uncoupler) in CXCL8 secretion and mitochondrial accumulation. Results: Our results show that the anti-inflammatory response of HGF to extracellular adenosine, typified by reduced CXCL8 secretion, is mediated by mitochondrial oxidative phosphorylation, reflected in higher oxygen consumption rate (OCR). In the presence of IL-1β, adenosine-treated cells induced higher ATP production, basal respiration and proton leak compared to IL-1β without adenosine. Surprisingly, adenosine had no additional effect on the IL-1β-induced higher glycolysis rate demonstrated by the extracellular acidification rate (ECAR). In addition, the higher OCR in adenosine-stimulated cells was not due to the mitochondrial fuel dependency or capacity, but due to an increase in mitochondrial biogenesis and accumulation in the cells with concomitant decrease in mitophagy-required p-PINK1 marker. We detected the accumulation of functional mitochondria with increased activation of the AMPK/SIRT1/PGC-1α pathway. The adenosine-induced uptake of MitoTracker was abrogated by PGC-1α inhibition with SR-12898. In addition, the adenosine effects on reduced CXCL8 were ablated by treatment with FCCP, a potent uncoupler of mitochondrial oxidative phosphorylation. Conclusion: Our findings reveal a key role for mitochondrial bioenergetics in regulation of CXCL8-mediated inflammation by HGF through the adenosine/AMPK/SIRT1/PGC-1α axis. Therapeutically targeting this pathway in gingival fibroblasts might be a promising future strategy to modulate stromal-mediated sustained hyper-inflammatory responses. [ABSTRACT FROM AUTHOR]

Simple Summary: Landmarks are commonly used to investigate how objects vary in form. However, many objects present few identifiable landmarks. To remedy this, several approaches have been developed to densely match points between surfaces lacking readily identifiable landmarks. These matched points are termed semilandmarks. The investigator has to make choices about which approach to use and the eventual locations and density of semilandmarks. In studies of growth or evolution of biological material, landmarks represent points that, from prior knowledge, are equivalent in each individual at each stage of developmental or evolutionary transformation. Their differences in relative location over time describe the transformation. However, semilandmarks are located on specimens using algorithms that do not pay regard to development or evolution, and so the consequences of using semilandmarks on resulting analyses of developmental or evolutionary differences in form are unclear. In this study, we compare results among analyses based on landmarks and semilandmarks with each other and with analyses based only on landmarks. We find that while there is some consistency among findings from different semilandmarking approaches, there are also some differences, and that results from such analyses should be considered as approximations of reality that require cautious interpretation. Often, few landmarks can be reliably identified in analyses of form variation and covariation. Thus, 'semilandmarking' algorithms have increasingly been applied to surfaces and curves. However, the locations of semilandmarks depend on the investigator's choice of algorithm and their density. In consequence, to the extent that different semilandmarking approaches and densities result in different locations of semilandmarks, they can be expected to yield different results concerning patterns of variation and co-variation. The extent of such differences due to methodology is, as yet, unclear and often ignored. In this study, the performance of three landmark-driven semilandmarking approaches is assessed, using two different surface mesh datasets (ape crania and human heads) with different degrees of variation and complexity, by comparing the results of morphometric analyses. These approaches produce different semilandmark locations, which, in turn, lead to differences in statistical results, although the non-rigid semilandmarking approaches are consistent. Morphometric analyses using semilandmarks must be interpreted with due caution, recognising that error is inevitable and that results are approximations. Further work is needed to investigate the effects of using different landmark and semilandmark templates and to understand the limitations and advantages of different semilandmarking approaches. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive and selective degeneration of motor neurons in the motor cortex of brain and spinal cord. Ferroptosis is a newly discovered form of cell death and reported to mediate selective motor neuron death in the mouse model of ALS. The growing awareness of ferroptosis and iron metabolism dysfunction in ALS prompted us to investigate the expression pattern of ferroptosis and iron metabolism-related genes (FIRGs) in ALS. Here, we performed a conjoint analysis of bulk-RNA sequence and single-nucleus RNA sequence data using the datasets from Gene Expression Omnibus (GEO) to reveal the role of FIRGs in ALS, especially in selective motor neuron death of ALS. We first investigated the differentially expressed genes (DEGs) between ALS and non-neurological controls. Weighted gene co-expression network analysis constructed the gene co-expression network and identified three modules closely associated with ALS. Fifteen FIRGs was identified as target genes based on least absolute shrinkage and selection operator regression analysis as follows: ACSL4, ANO6, ATP6V0E1, B2M, CD44, CHMP5, CYBB, CYBRD1, HIF1A, MOSPD1, NCF2, SDCBP, STEAP2, TMEM14C, ULK1. These genes could differentiate ALS patients from non-neurological controls (p < 2.2e16) and had a valid value in predicting and diagnosing ALS (AUC = 0.881 in primary dataset and AUC = 0.768 in validation dataset). Then we performed the functional enrichment analysis of DEGs between ALS cases, the most significantly influenced by target genes, and non-neurological controls. The result indicated that the most significantly influenced functions in ALS pathogenesis by these identified FIRGs are synapse pathways, calcium signaling pathway, cAMP signaling pathway, and phagosome and several immune pathways. At last, the analysis of single- nuclear seq found that CHMP5, one of the 15 FIRGs identified by bulk single-nucleus RNA-seq data, was expressed significantly higher in ALS than pathologically normal (PN), specifically in excitatory neuron populations with layer 2 and layer 3 markers (Ex L2_L3), layer 3 and layer 5 markers (Ex L3_L5). Taken together, our study indicates the positive correlation between FIRGs and ALS, presents potential markers for ALS diagnosis and provides new research directions of CHMP5 function in selective motor neuron death in ALS. [ABSTRACT FROM AUTHOR]

Telocytes (TCs) are CD34-positive interstitial cells that have long cytoplasmic projections, called telopodes; they have been identified in several organs and in various species. These cells establish a complex communication network between different stromal and epithelial cell types, and there is growing evidence that they play a key role in physiology and pathology. In many tissues, TC network impairment has been implicated in the onset and progression of pathological conditions, which makes the study of TCs of great interest for the development of novel therapies. In this review, we summarise the main methods involved in the characterisation of these cells as well as their inherent difficulties and then discuss the functional assays that are used to uncover the role of TCs in normal and pathological conditions, from the most traditional to the most recent. Furthermore, we provide future perspectives in the study of TCs, especially regarding the establishment of more precise markers, commercial lineages and means for drug delivery and genetic editing that directly target TCs., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The gingiva is a key oral barrier that protects oral tissues from various stimuli. A loss of gingival tissue homeostasis causes periodontitis, one of the most prevalent inflammatory diseases in humans. The human gingiva exists as a complex cell network comprising specialized structures. To understand the tissue-specific pathophysiology of the gingiva, we applied a recently developed spatial enhanced resolution omics-sequencing (Stereo-seq) technique to obtain a spatial transcriptome (ST) atlas of the gingiva in healthy individuals and periodontitis patients. By utilizing Stereo-seq, we identified the major cell types present in the gingiva, which included epithelial cells, fibroblasts, endothelial cells, and immune cells, as well as subgroups of epithelial cells and immune cells. We further observed that inflammation-related signalling pathways, such as the JAK-STAT and NF-κB signalling pathways, were significantly upregulated in the endothelial cells of the gingiva of periodontitis patients compared with those of healthy individuals. Additionally, we characterized the spatial distribution of periodontitis risk genes in the gingiva and found that the expression of IFI16 was significantly increased in endothelial cells of inflamed gingiva. In conclusion, our Stereo-seq findings may facilitate the development of innovative therapeutic strategies for periodontitis by mapping periodontitis-relevant genes and pathways and effector cells., (© 2023. Science China Press.)

Neurogenesis is a complex process by which neural progenitor cells (NPCs)/neural stem cells (NSCs) proliferate and differentiate into new neurons and other brain cells. In adulthood, the hippocampus is one of the areas with more neurogenesis activity, which is involved in the modulation of both emotional and cognitive hippocampal functions. This complex process is affected by many intrinsic and extrinsic factors, including nutrition. In this regard, preclinical studies performed in rats and mice demonstrate that high fats and/or sugars diets have a negative effect on adult hippocampal neurogenesis (AHN). In contrast, diets enriched with bioactive compounds, such as polyunsaturated fatty acids and polyphenols, as well as intermittent fasting or caloric restriction, can induce AHN. Interestingly, there is also growing evidence demonstrating that offspring AHN can be affected by maternal nutrition in the perinatal period. Therefore, nutritional interventions from early stages and throughout life are a promising perspective to alleviate neurodegenerative diseases by stimulating neurogenesis. The underlying mechanisms by which nutrients and dietary factors affect AHN are still being studied. Interestingly, recent evidence suggests that additional peripheral mediators may be involved. In this sense, the microbiota-gut-brain axis mediates bidirectional communication between the gut and the brain and could act as a link between nutritional factors and AHN. The aim of this mini-review is to summarize, the most recent findings related to the influence of nutrition and diet in the modulation of AHN. The importance of maternal nutrition in the AHN of the offspring and the role of the microbiota-gut-brain axis in the nutrition-neurogenesis relationship have also been included. [ABSTRACT FROM AUTHOR]

Background: The early craniofacial development is a highly coordinated process involving neural crest cell migration, proliferation, epithelial apoptosis, and epithelial-mesenchymal transition (EMT). Both genetic defects and environmental factors can affect these processes and result in orofacial clefts. Mutations in MID1 gene cause X-linked Opitz Syndrome (OS), which is a congenital malformation characterized by craniofacial defects including cleft lip/palate (CLP). Previous studies demonstrated impaired neurological structure and function in Mid1 knockout mice, while no CLP was observed. However, given the highly variable severities of the facial manifestations observed in OS patients within the same family carrying identical genetic defects, subtle craniofacial malformations in Mid1 knockout mice could be overlooked in these studies. Therefore, we propose that a detailed morphometric analysis should be necessary to reveal mild craniofacial dysmorphologies that reflect the similar developmental defects seen in OS patients. Results: In this research, morphometric study of the P0 male Mid1-cKO mice were performed using Procrustes superimposition as well as EMDA analysis of the size-adjusted three-dimensional coordinates of 105 skull landmarks, which were collected on the bone surface reconstructed using microcomputed tomographic images. Our results revealed the craniofacial deformation such as the increased dimension of the frontal and nasal bone in Mid1-cKO mice, in line with the most prominent facial features such as hypertelorism, prominent forehead, broad and/or high nasal bridge seen in OS patients. Conclusion: While been extensively used in evolutionary biology and anthropology in the last decades, geometric morphometric analysis was much less used in developmental biology. Given the high interspecies variances in facial anatomy, the work presented in this research suggested the advantages of morphometric analysis in characterizing animal models of craniofacial developmental defects to reveal phenotypic variations and the underlining pathogenesis. [ABSTRACT FROM AUTHOR]

The methods of geometric morphometrics are commonly used to quantify morphology in a broad range of biological sciences. The application of these methods to large datasets is constrained by manual landmark placement limiting the number of landmarks and introducing observer bias. To move the field forward, we need to automate morphological phenotyping in ways that capture comprehensive representations of morphological variation with minimal observer bias. Here, we present Morphological Variation Quantifier (morphVQ), a shape analysis pipeline for quantifying, analyzing, and exploring shape variation in the functional domain. morphVQ uses descriptor learning to estimate the functional correspondence between whole triangular meshes in lieu of landmark configurations. With functional maps between pairs of specimens in a dataset we can analyze and explore shape variation. morphVQ uses Consistent ZoomOut refinement to improve these functional maps and produce a new representation of shape variation, area-based and conformal (angular) latent shape space differences (LSSDs). We compare this new representation of shape variation to shape variables obtained via manual digitization and auto3DGM, an existing approach to automated morphological phenotyping. We find that LSSDs compare favorably to modern 3DGM and auto3DGM while being more computationally efficient. By characterizing whole surfaces, our method incorporates more morphological detail in shape analysis. We can classify known biological groupings, such as Genus affiliation with comparable accuracy. The shape spaces produced by our method are similar to those produced by modern 3DGM and to auto3DGM, and distinctiveness functions derived from LSSDs show us how shape variation differs between groups. morphVQ can capture shape in an automated fashion while avoiding the limitations of manually digitized landmarks, and thus represents a novel and computationally efficient addition to the geometric morphometrics toolkit. Author summary: The quantification of biological shape variation has relied on expert placement of relatively small subsets of landmarks and their analysis using tools of geometric morphometrics (GM). This paper introduces morphVQ, a novel, automated, learning-based approach to shape analysis that approximates the non-rigid correspondence between surface models of bone. With accurate functional correspondence between bones, we can characterize the shape variation within a dataset. Our results demonstrate that morphVQ performs similarly to manual digitization and to an existing automated phenotyping approach, auto3DGM. morphVQ has the advantages of greater computational efficiency and while capturing shape variation directly from surface model representations of bone. We can classify biological shapes to the Genus level with comparable accuracy to previous approaches, and we can demonstrate which aspects of bone shape differ most between groups. The ability to provide comparable accuracy in a Genus level classification with features extracted from morphVQ further guarantees the validity of this approach. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests synaptic dysfunction is a central and possibly triggering factor in Amyotrophic Lateral Sclerosis (ALS). Despite this, we still know very little about the molecular profile of an ALS synapse. To address this gap, we designed a synaptic proteomics experiment to perform an unbiased assessment of the synaptic proteome in the ALS brain. We isolated synaptoneurosomes from fresh-frozen post-mortem human cortex (11 controls and 18 ALS) and stratified the ALS group based on cognitive profile (Edinburgh Cognitive and Behavioural ALS Screen (ECAS score)) and presence of a C9ORF72 hexanucleotide repeat expansion (C9ORF72-RE). This allowed us to assess regional differences and the impact of phenotype and genotype on the synaptic proteome, using Tandem Mass Tagging-based proteomics. We identified over 6000 proteins in our synaptoneurosomes and using robust bioinformatics analysis we validated the strong enrichment of synapses. We found more than 30 ALS-associated proteins in synaptoneurosomes, including TDP-43, FUS, SOD1 and C9ORF72. We identified almost 500 proteins with altered expression levels in ALS, with region-specific changes highlighting proteins and pathways with intriguing links to neurophysiology and pathology. Stratifying the ALS cohort by cognitive status revealed almost 150 specific alterations in cognitively impaired ALS synaptic preparations. Stratifying by C9ORF72-RE status revealed 330 protein alterations in the C9ORF72-RE +ve group, with KEGG pathway analysis highlighting strong enrichment for postsynaptic dysfunction, related to glutamatergic receptor signalling. We have validated some of these changes by western blot and at a single synapse level using array tomography imaging. In summary, we have generated the first unbiased map of the human ALS synaptic proteome, revealing novel insight into this key compartment in ALS pathophysiology and highlighting the influence of cognitive decline and C9ORF72-RE on synaptic composition. [ABSTRACT FROM AUTHOR]

Altered skeletal development in Down syndrome (DS) results in a brachycephalic skull, flattened face, shorter mandibular ramus, shorter limbs, and reduced bone mineral density (BMD). Our previous study showed that low doses of green tea extract enriched in epigallocatechin-3-gallate (GTE-EGCG), administered continuously from embryonic day 9 to postnatal day 29, reduced facial dysmorphologies in the Ts65Dn (TS) mouse model of DS, but high doses could exacerbate them. Here, we extended the analyses to other skeletal structures and systematically evaluated the effects of high and low doses of GTE-EGCG treatment over postnatal development in wild-type (WT) and TS mice using in vivo µCT and geometric morphometrics. TS mice developed shorter and wider faces, skulls, and mandibles, together with shorter and narrower humerus and scapula, and reduced BMD dynamically over time. Besides facial morphology, GTE-EGCG did not rescue any other skeletal phenotype in TS treated mice. In WT mice, GTE-EGCG significantly altered the shape of the skull and mandible, reduced the length and width of the long bones, and lowered the BMD. The disparate effects of GTE-EGCG depended on the dose, developmental timepoint, and anatomical structure analyzed, emphasizing the complex nature of DS and the need to further investigate the simultaneous effects of GTE-EGCG supplementation. [ABSTRACT FROM AUTHOR]

The foundations of geometric morphometrics were worked out about 30 years ago and have continually been refined and extended. What has remained as a central thrust and source of debate in the morphometrics community is the shared goal of meaningful biological inference through a tight connection between biological theory, measurement, multivariate biostatistics, and geometry. Here we review the building blocks of modern geometric morphometrics: the representation of organismal geometry by landmarks and semilandmarks, the computation of shape or form variables via superimposition, the visualization of statistical results as actual shapes or forms, the decomposition of shape variation into symmetric and asymmetric components and into different spatial scales, the interpretation of various geometries in shape or form space, and models of the association between shape or form and other variables, such as environmental, genetic, or behavioral data. We focus on recent developments and current methodological challenges, especially those arising from the increasing number of landmarks and semilandmarks, and emphasize the importance of thorough exploratory multivariate analyses rather than single scalar summary statistics. We outline promising directions for further research and for the evaluation of new developments, such as "landmark‐free" approaches. To illustrate these methods, we analyze three‐dimensional human face shape based on data from the Avon Longitudinal Study of Parents and Children (ALSPAC). [ABSTRACT FROM AUTHOR]

Acyl-ghrelin (AG) is an orexigenic hormone that has a unique octanoyl modification on its third serine residue. It is often referred to as the "hunger hormone" due to its involvement in stimulating food intake and regulating energy homeostasis. The discovery of the enzyme ghrelin-O-acyltransferase (GOAT), which catalyses ghrelin acylation, provided further insights into the relevance of this lipidation process for the activation of the growth hormone secretagogue receptor (GHS-R) by acyl-ghrelin. Although acyl-ghrelin is predominantly linked with octanoic acid, a range of saturated fatty acids can also bind to ghrelin possibly leading to specific functions. Sources of ghrelin acylation include betaoxidation of longer chain fatty acids, with contributions from fatty acid synthesis, the diet, and the microbiome. In addition, both acyl-ghrelin and unacyl-ghrelin (UAG) have feedback effects on lipid metabolism which in turn modulate their levels. Recently we showed that whilst acyl-ghrelin promotes adult hippocampal neurogenesis and enhances memory function, UAG inhibits these processes. As a result, we postulated that the circulating acylghrelin: unacyl-ghrelin (AG:UAG) ratio might be an important regulator of neurogenesis and cognition. In this review, we discuss emerging evidence behind the relevance of ghrelin acylation in the context of brain physiology and pathology, as well as the current challenges of identifying the provenance of the acyl moiety. [ABSTRACT FROM AUTHOR]

Cortical neuron loss is a pathological hallmark of late-onset Alzheimer's disease (AD). However, it remains unclear which neuronal subtypes beyond broad excitatory and inhibitory classes are most vulnerable. Here, we analyzed cell subtype proportion differences in AD compared to non-AD controls using 1037 post-mortem brain samples from six neocortical regions. We identified the strongest associations of AD with fewer somatostatin (SST) inhibitory neurons (β = −0.48, p bonf = 8.98 × 10–9) and intra-telencephalic (IT) excitatory neurons (β = -0.45, p bonf = 4.32 × 10–7). Replication in three AD case-control single-nucleus RNAseq datasets most strongly supported the bulk tissue association of fewer SST neurons in AD. In depth analyses of cell type proportions with specific AD-related neuropathological and cognitive phenotypes revealed fewer SST neurons with greater brain-wide post-mortem tau and beta amyloid, as well as a faster rate of antemortem cognitive decline. In contrast, greater IT neuron proportions were associated with a slower rate of cognitive decline as well as greater residual cognition–a measure of cognitive resilience–but not canonical AD neuropathology. Our findings implicate somatostatin inhibitory and intra-telencephalic excitatory neuron subclasses in the pathogenesis of AD and in cognitive resilience to AD pathology, respectively. [ABSTRACT FROM AUTHOR]

Copyright of Lilloa is the property of Fundacion Miguel Lillo and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectives: Morphometrics has played essential roles in the comprehension of biological variation and the evolution of morphological phenotypes. This approach usually imposes strict requirements on data, such as rigid alignment of subjects, and the collection and manual preprocessing of data meeting these requirements are often time consuming. Artificial intelligence (AI) technology is developing and it potentially reduces this load, but they usually presuppose the availability of "big data" for successful learning, beyond the empirically plausible amount in biological studies. Here, we propose a deep learning‐based analysis of three‐dimensional data. Materials and Methods: We built a deep learning‐based analysis of three‐dimensional morphological data that does not require strict alignment or an implausible sample size. We benchmarked the proposed method by case studying sex classification of macaques, referring to computed tomography scans of their mandible. Results: The model learned from just 139 mandible specimens of Japanese macaques and successfully generalized the learned classification to previously unseen specimens of the same species and even other species of macaques. Moreover, we visualized those characteristic regions in the data that the model used during sex classification and showed that they were consistent with the criteria used by human experts. Discussion: Our analysis does not require rigidly aligned data, so can effectively use data collected in previous studies with different focus/aims. This proposed AI method can potentially help researchers to discover new morphological features of different species and other biological groups. Implementation of this proposed AI system will be available to other researchers for further investigation. [ABSTRACT FROM AUTHOR]

Copyright of Brazilian Journal of Law & International Relations / Relações Internacionais no Mundo is the property of Relacoes Internacionais no Mundo and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive degeneration of motor neurons leading to skeletal muscle denervation. Earlier studies have shown that motor neuron degeneration begins in motor cortex and descends to the neuromuscular junction (NMJ) in a dying forward fashion. However, accumulating evidences support that ALS is a distal axonopathy where early pathological changes occur at the NMJ, prior to onset of clinical symptoms and propagates towards the motor neuron cell body supporting "dying back" hypothesis. Despite several evidences, series of events triggering NMJ disassembly in ALS are still obscure. Neuromuscular junction is a specialized tripartite chemical synapse which involves a well-coordinated communication among the presynaptic motor neuron, postsynaptic skeletal muscle, and terminal Schwann cells. This review provides comprehensive insight into the role of NMJ in ALS pathogenesis. We have emphasized the molecular alterations in cellular components of NMJ leading to loss of effective neuromuscular transmission in ALS. Further, we provide a preview into research involved in exploring NMJ as potential target for designing effective therapies for ALS. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by degeneration of upper and lower motor neurons and neurons of the prefrontal cortex. The emergence of the C9ORF72 hexanucleotide repeat expansion mutation as the leading genetic cause of ALS and FTD has led to a progressive understanding of the multiple cellular pathways leading to neuronal degeneration. Disturbances in neuronal function represent a major subset of these mechanisms and because such functional perturbations precede degeneration, it is likely that impaired neuronal function in ALS/FTD plays an active role in pathogenesis. This is supported by the fact that ALS/FTD patients consistently present with neurophysiological impairments prior to any apparent degeneration. In this review we summarize how the discovery of the C9ORF72 repeat expansion mutation has contributed to the current understanding of neuronal dysfunction in ALS/FTD. Here, we discuss the impact of the repeat expansion on neuronal function in relation to intrinsic excitability, synaptic, network and ion channel properties, highlighting evidence of conserved and divergent pathophysiological impacts between cortical and motor neurons and the influence of non-neuronal cells. We further highlight the emerging association between these dysfunctional properties with molecular mechanisms of the C9ORF72 mutation that appear to include roles for both, haploinsufficiency of the C9ORF72 protein and aberrantly generated dipeptide repeat protein species. Finally, we suggest that relating key pathological observations in C9ORF72 repeat expansion ALS/FTD patients to the mechanistic impact of the C9ORF72 repeat expansion on neuronal function will lead to an improved understanding of how neurophysiological dysfunction impacts upon pathogenesis. [ABSTRACT FROM AUTHOR]