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This study aimed to investigate the development of the kidneys and adrenal glands in rabbits using histological, histochemical, and biochemical techniques. The experiment was conducted on 28 kidney and adrenal gland samples at different ages (one day, seven days, fourteen days, and ninety days). Histological findings revealed that the kidney was covered by a small amount of collagen and reticular fibers and had a thin capsule that thickened with age. The renal corpuscle increased in diameter as the age progressed. The proximal convoluted tubules were the longest, surrounded by cuboidal epithelial tissue, and had a brush border. The adrenal glands were encased in a well-developed capsule, and the cortex was divided into the glomerular, fasciculate, and reticular zones. The medulla was composed of large, pale-staining hexagonal cells arranged in small anastomosing strands held together by reticular fibers and separated by sinusoids. Norepinephrine cells were smaller. Histochemical studies showed that the brush border in the kidney responded positively to PAS, AB, and PAS-AB stains. PAS staining revealed that the basement membranes of the glomerulus and renal tubules were fully developed. Biochemical tests showed significant age-related differences in uric acid levels and each enzyme. As the urea burden increased, more urine was needed because the kidneys' ability to filter urea was limited. The kidneys underwent postnatal developmental changes, reaching maturity three months after birth when the normal adult nephron structure was observed. This indicated that the structure of the kidney and adrenal glands developed after birth with age progression. [ABSTRACT FROM AUTHOR]

The thymus gland is the primary lymphoid organ that undergoes postnatal growth followed by gradual atrophies and functional decline with age progress. The thymus gland has similar morphology across species, with a thoracic portion in the cranial mediastinum and a cervical portion along the trachea. Histologically, the thymus consists of an outer cortex populated with darkly stained T lymphocytes and a pale inner medulla. The medulla contains thymic Hassall's corpuscles (THC), which may function as sites for T cell maturation or as communication points between T cells and antigen-presenting cells. The thymus gland in camels has yet to be well studied, with limited research on its macroscopic and microscopic anatomy. In this study, the thymus glands of camel calves were examined. The thoracic portion was triangular and located in the cranioventral part of the mediastinum. The cervical portion extends cranially to the level of the thyroid gland and, in some cases, to the larynx. Histologically, the camel thymus had a fibrous capsule and connective tissue trabeculae, dividing the gland into incomplete lobules. The cortex was heavily populated with thymocytes, while the medulla contained epithelial reticular cells. A perivascular space (PVS) consisting of mature T lymphocytes surrounding blood vessels was also identified. THCs were present in the medulla, with variable shapes and forms ranging from small-sized to very large-sized with degenerative changes. Further research is needed to fully understand the role of the thymus gland in camels and its implications for vaccination programs and immune health.

We present a 3D discrete‐continuum model to simulate blood pressure in large microvascular tissues in the absence of known capillary network architecture. Our hybrid approach combines a 1D Poiseuille flow description for large, discrete arteriolar and venular networks coupled to a continuum‐based Darcy model, point sources of flux, for transport in the capillary bed. We evaluate our hybrid approach using a vascular network imaged from the mouse brain medulla/pons using multi‐fluorescence high‐resolution episcopic microscopy (MF‐HREM). We use the fully‐resolved vascular network to predict the hydraulic conductivity of the capillary network and generate a fully‐discrete pressure solution to benchmark against. Our results demonstrate that the discrete‐continuum methodology is a computationally feasible and effective tool for predicting blood pressure in real‐world microvascular tissues when capillary microvessels are poorly defined. [ABSTRACT FROM AUTHOR]

Mylodon darwinii is an extinct terrestrial species of sloth with a wide fossil record in South America, the record of the skin and hairs found from "La Cueva del Milodón", Chile. More than a century after the first studies on its hair, we aimed to redescribe the morphological characteristics of the hairs of M. darwinii by applying modern protocols of trichology and microscopy. Hair patterns were also compared with those of two other extinct species of sloths available in the literature. Hairs from mummified specimen housed in Museo de La Plata (Argentina) were analyzed through light and scanning electron microscopy to identify their cuticular and medullary patterns. Guard hairs lack medulla and have a wavy cuticle with irregular scale orientation, while underhairs have an amorphous cuticle pattern and no medulla. Hence, the former ones help in the diagnosis of the hair morphology of the species, while the latter ones do not. Differences found in the final product of each microscopy technique are discussed and should be considered in future research. The outcomes presented herein are a step further toward the understanding of evolutionary processes within Xenarthra, providing important data for such a poorly studied group that has only been recorded in Central and South America. [ABSTRACT FROM AUTHOR]

Simple Summary: Feathers are remarkable skin appendages that serve various ecological functions due to their complex structure and composition. This study focuses on frizzling feathers, which are known for their unique curling patterns. By examining frizzle chickens, both those with two copies of the frizzling gene and those with one, we analyzed how soft and stiff keratin materials are distributed in the shafts of their flight feathers. Our findings show that the way these keratins are arranged affects the internal structure and biomechanics of the feathers, causing them to curl naturally. Specifically, we discovered that a reduction in soft keratin in the core of the feather shaft changes the internal stresses and leads to frizzling. This research enhances our understanding of how curl feather structures develop and adapt to different ecological needs, providing valuable insights into the diversity of feather forms in nature. The morphological and compositional complexities of keratinized components make feathers ingenious skin appendages adapted to diverse ecological needs. Frizzling feathers, characterized by their distinct curling phenotypes, offer a unique model to explore the intricate morphogenesis in developing a keratin-based bioarchitecture over a wide range of morphospace. Here, we investigated the heterogeneous allocation of α- and β-keratins in flight feather shafts of homozygous and heterozygous frizzle chickens by analyzing the medulla–cortex integrations using quantitative morphology characterizations across scales. Our results reveal the intriguing construction of the frizzling feather shaft through the modified medulla development, leading to a perturbed balance of the internal biomechanics and, therefore, introducing the inherent natural frizzling compared to those from wild-type chickens. We elucidate how the localized developmental suppression of the α-keratin in the medulla interferes with the growth of the hierarchical keratin organization by changing the internal stress in the frizzling feather shaft. This research not only offers insights into the morphogenetic origin of the inherent bending of frizzling feathers but also facilitates our in-depth understanding of the developmental strategies toward the diverse integuments adapted for ecological needs. [ABSTRACT FROM AUTHOR]

Chronic intermittent hypoxia (CIH) is a prevalent condition characterized by recurrent episodes of oxygen deprivation, linked to respiratory and neurological disorders. Prolonged CIH is known to have adverse effects, including endothelial dysfunction, chronic inflammation, oxidative stress, and impaired neuronal function. These factors can contribute to serious comorbidities, including metabolic disorders and cardiovascular diseases. To investigate the molecular impact of CIH, we examined male C57BL/6J mice exposed to CIH for 21 days, comparing with normoxic controls. We used single-nucleus RNA sequencing to comprehensively examine the transcriptomic impact of CIH on key cell classes within the brainstem, specifically excitatory neurons, inhibitory neurons, and oligodendrocytes. These cell classes regulate essential physiological functions, including autonomic tone, cardiovascular control, and respiration. Through analysis of 10,995 nuclei isolated from pontine-medullary tissue, we identified seven major cell classes, further subdivided into 24 clusters. Our findings among these cell classes, revealed significant differential gene expression, underscoring their distinct responses to CIH. Notably, neurons exhibited transcriptional dysregulation of genes associated with synaptic transmission, and structural remodeling. In addition, we found dysregulated genes encoding ion channels and inflammatory response. Concurrently, oligodendrocytes exhibited dysregulated genes associated with oxidative phosphorylation and oxidative stress. Utilizing CellChat network analysis, we uncovered CIH-dependent altered patterns of diffusible intercellular signaling. These insights offer a comprehensive transcriptomic cellular atlas of the pons-medulla and provide a fundamental resource for the analysis of molecular adaptations triggered by CIH. NEW & NOTEWORTHY This study on chronic intermittent hypoxia (CIH) from pons-medulla provides initial insights into the molecular effects on excitatory neurons, inhibitory neurons, and oligodendrocytes, highlighting our unbiased approach, in comparison with earlier studies focusing on single target genes. Our findings reveal that CIH affects cell classes distinctly, and the dysregulated genes in distinct cell classes are associated with synaptic transmission, ion channels, inflammation, oxidative stress, and intercellular signaling, advancing our understanding of CIH-induced molecular responses. [ABSTRACT FROM AUTHOR]

Hair is important to our appearance as well as to protect our heads. Human hair mainly consists of proteins (80-85%), melanin pigments (0- 5%), water (10-13%), and lipids (1-6%). The physicochemical properties of hair have been studied for over 100 years. However, they are not yet thoroughly understood. In this review, recent progress and the latest findings are summarized from the following three perspectives: structural characteristics, delivery and distribution of active ingredients, and hair as a template. The structural characteristics of hair have been mainly investigated by microscopic and/or spectroscopic techniques such as atomic force microscopy integrated with infrared spectroscopy (AFM-IR) and rheological measurements. The distribution of active ingredients has been generally evaluated through techniques such as nanoscale secondary ion mass spectrometry (NanoSIMS). And finally, attempts to explore the potential of hair to be used as a substrate for flexible device fabrication will be introduced. [ABSTRACT FROM AUTHOR]

Haemangioblastomas are benign, highly vascular tumours containing neoplastic stromal cells with characteristic immunohistochemical features. They are slow-growing tumours with a solid or cystic pattern of unknown origin and are classified as Grade-I benign tumours. They mostly arise in the cerebellum, medulla and spinal cord and are histologically similar to the vascular lesions in the retina. Haemangioblastomas are the most frequent manifestations of an autosomal-dominant inherited syndrome, von Hippel-Lindau (VHL) disease but can also occur as sporadic non hereditary tumours. Hereby, the current case report is on a 53-year-old male who presented to the tertiary care hospital with a persistent headache for six weeks. Based on just the clinical history and examination, the patient was given a probable diagnosis of either cerebellar haemangioblastoma or cerebellar tumour. Magnetic Resonance Imaging (MRI) was performed, which suggested that the lesion could be a glioma or metastatic deposits from a different tumour. In view of these differentials, the patient underwent tumour excision and decompression via suboccipital craniectomy, and an extraventricular drainage was placed for ease of Cerebrospinal Fluid (CSF) drainage. With the help of histopathological diagnosis, the patient was diagnosed with an apparent sporadic type of cerebellar haemangioblastoma, but this can be confirmed only after detailed genetic screening.

Visual circuit development is characterized by subdivision of neuropils into layers that house distinct sets of synaptic connections. We find that, in the Drosophila medulla, this layered organization depends on the axon guidance regulator Plexin A. In Plexin A null mutants, synaptic layers of the medulla neuropil and arborizations of individual neurons are wider and less distinct than in controls. Analysis of semaphorin function indicates that Semaphorin 1a, acting in a subset of medulla neurons, is the primary partner for Plexin A in medulla lamination. Removal of the cytoplasmic domain of endogenous Plexin A has little effect on the formation of medulla layers; however, both null and cytoplasmic domain deletion mutations of Plexin A result in an altered overall shape of the medulla neuropil. These data suggest that Plexin A acts as a receptor to mediate morphogenesis of the medulla neuropil, and as a ligand for Semaphorin 1a to subdivide it into layers. Its two independent functions illustrate how a few guidance molecules can organize complex brain structures by each playing multiple roles. [ABSTRACT FROM AUTHOR]

Purpose: Despite the usefulness of blood oxygenation level-dependent (BOLD) MRI in assessing glomerulonephritis activity, its relationship with histological findings remains unclear. Because glomerulonephritis presents multiple complex injury patterns, analysis of each pattern is essential. We aimed to elucidate the relationship between the histological findings of the kidney and BOLD MRI findings in mesangial proliferative glomerulonephritis. Methods: Children under 16 years of age diagnosed with mesangial proliferative glomerulonephritis by kidney biopsy at our university hospital between January 2013 and September 2022 were included in this study. Cortical andmedullary spin relaxation rate (R2*) values weremeasured using BOLDMRI at 3T within two weeks before and after the kidney biopsy. The R2* values, including the fluctuations with low-dose oxygen administration, were retrospectively examined in relation to the cortical (mesangial proliferation, endothelial cell proliferation, crescent, sclerosis, and fibrosis) and medullary findings (fibrosis). Results: Sixteen times kidney biopsies were performed for glomerulonephritis during the study period, and one patient was excluded because of comorbidities; the remaining 14 patients included six boys with a mean age of 11.9 ± 3.5 years at the BOLD examination. None of the patients had medullary fibrosis. Among the kidney tissue parameters, only sclerosis showed a significant correlation with R2* values: medulla with R2* values under atmospheric pressure (r = 0.53, P < 0.05) and cortex with the rate of change in R2* values with low-dose oxygen administration (r = -0.57, P < 0.03). In the multiple regression analysis, only sclerosis was an independent contributor to the change in R2* values with oxygen administration in the cortex (regression coefficient -0.109, P < 0.05). Conclusion: Since the R2* values reflect histological changes in the kidney, BOLD MRI may facilitate the evaluation of mesangial proliferative glomerulonephritis, potentially reducing the patient burden. [ABSTRACT FROM AUTHOR]

The rhombicbrain (rhombencephalon or intermediate sector) is the vertebrate central nervous system part between the forebrain-midbrain (rostral sector) and spinal cord (caudal sector), and it has three main divisions: pons, cerebellum, and medulla. Using a data-driven approach, here we examine intrinsic rhombicbrain (intrarhombicbrain) network architecture that in rat consists of 52,670 possible axonal connections between 230 gray matter regions (115 bilaterally symmetrical pairs). Our analysis indicates that only 8,089 (15.4%) of these connections exist. Multiresolution consensus cluster analysis yields a nested hierarchy model of rhombicbrain subsystems that at the top level are associated with 1) the cerebellum and vestibular nuclei, 2) orofacial-pharyngeal-visceral integration, and 3) auditory connections; the bottom level has 68 clusters, ranging in size from 2 to 11 regions. The model provides a basis for functional hypothesis development and interrogation. More granular network analyses performed on the intrinsic connectivity of individual and combined main rhombicbrain divisions (pons, cerebellum, medulla, pons + cerebellum, and pons + medulla) demonstrate the mutability of network architecture in response to the addition or subtraction of connections. Clear differences between the structure-function network architecture of the rhombicbrain and forebrain-midbrain are discussed, with a stark comparison provided by the subsystem and small-world organization of the cerebellar cortex and cerebral cortex. Future analysis of the connections within and between the forebrain-midbrain and rhombicbrain will provide a model of brain neural network architecture in a mammal. [ABSTRACT FROM AUTHOR]

Using scanning electron microscopy (SEM), the external and internal structure of the hairs of an adult Pleistocene Don hare Lepus tanaiticus were studied, a frozen mummy of which was first found in Yakutia. Similar to other representatives of the genera Lepus and Oryctolagus, the structure of the guard hairs of the Don hare is unique: it is characterized by a hair shaft striation, specific columnar medulla, and a chevron-resembling cuticle ornament. The hair structure varies in different areas of the pelage and is adapted to the habitation of this species in the extreme conditions of the Arctic; in particular, these are long fur, strongly developed hair medulla and its corrugated septum, and peculiar hair on the soles of paws. The hair of the Don hare and mountain hare (Holocene, Chukotka) were compared, revealing a great similarity between these two species, as well as the pairs of the species: extinct and modern species of hares, hares and pikas, hares and a number of other mammalian species. The features of the hair structure in the hare and some other mammals are discussed in terms of species identification and adaptive traits. [ABSTRACT FROM AUTHOR]

The morphological and compositional complexities of keratinized components make feathers ingenious skin appendages adapted to diverse ecological needs. Frizzling feathers, characterized by their distinct curling phenotypes, offer a unique model to explore the intricate morphogenesis in developing a keratin-based bioarchitecture over a wide range of morphospace. Here, we investigated the heterogeneous allocation of α- and β-keratins in flight feather shafts of homozygous and heterozygous frizzle chickens by analyzing the medulla–cortex integrations using quantitative morphology characterizations across scales. Our results reveal the intriguing construction of the frizzling feather shaft through the modified medulla development, leading to a perturbed balance of the internal biomechanics and, therefore, introducing the inherent natural frizzling compared to those from wild-type chickens. We elucidate how the localized developmental suppression of the α-keratin in the medulla interferes with the growth of the hierarchical keratin organization by changing the internal stress in the frizzling feather shaft. This research not only offers insights into the morphogenetic origin of the inherent bending of frizzling feathers but also facilitates our in-depth understanding of the developmental strategies toward the diverse integuments adapted for ecological needs.

Spinal cord injury is a devastating condition that haunts human lives. Typically, patients experience referred phantom sensations on the hand when they are touched on the face. In adult monkeys, massive deafferentations such as chronic dorsal column lesions at higher cervical levels result in the large-scale expansion of face inputs into the deafferented hand cortex of area 3b. However, adult rats with thoracic dorsal column lesions do not demonstrate such large-scale reorganization. The large-scale face expansion in area 3b of monkeys is driven by the reorganization of the cuneate nucleus in the medulla. The sprouting of afferents from the trigeminal nucleus to the adjacent deafferented cuneate nucleus is facilitated by close proximity and compactness of the medulla in primates. Previously, in adult rats with thoracic lesions, the cuneate nucleus was not deafferented and its functional organization was not explored. The extent of the deafferentation and the duration of the recovery period are two major factors that determine the extent of reorganization. Hence, higher cervical (C3-C4) dorsal column lesions were performed, which cause massive deafferentations, and physiological maps were obtained after prolonged recovery periods (3 weeks −18 months). In spite of the above, the expansion of the intact face inputs was not observed in the deafferented zones of the primary somatosensory cortex (SI) and medulla of adult rats. The deafferented forelimb and hindlimb representations in SI were unresponsive to cutaneous stimulation of any part of the body. The cuneate and gracile nuclei in rats with complete dorsal column lesions remained mostly inactive except for a few sites which responded to stimulation of the spared upper arm. Hence, dorsal column lesions have different effects on the adult primate and rodent somatosensory systems. Appreciating this inter-species difference can aid in identifying the underlying neural substrates and restrict maladaptive reorganizations to cure phantom sensations.

Purpose: To evaluate renal cortical and medullary stiffness using 2D Shear-wave elastography (SWE) in healthy children. Methods: In this IRB approved prospective study, we measured the stiffness of cortex and medulla of children (4 months-17 years) at the upper pole, mid pole, and lower pole in bilateral kidneys. Results: The median (IQR) values of renal cortex in <1 year age group was 8.7 (5.7–11.7) kPa for right and 8.7 (4.2–14.1) kPa for the left side. For 1–5 years age group, it was 7.3 (5.3–10) kPa for the right and 8.9 (6–12.3) kPa for the left side. For >5 years, it was 7.4 (5.3–11.2) kPa for the right and 9.6 (6.2–12.7) kPa for the left side. The median (IQR) values of renal medulla in <1 year age group was 7.1 (5.1–12.5) kPa for right and 6.8 (4–10.6) kPa for the left side. For 1–5 years age group, it was 7.2 (4.9–9.7) kPa for the right and 6.9 (5.6–9.9) kPa for the left side. For >5 years, it was 6.8 (5.1–9.6) kPa for the right and 7 (5–10.2) kPa for the left side. The differences in the elasticity values amongst these groups were statistically insignificant (p>0.05). There was a significant correlation between SWE values of cortex and medulla of right kidney (ρ=0.64) and of left kidney (ρ=0.61), respectively. Conclusion: SWE values of renal cortical and medullary stiffness in healthy children do not correlate with age. There is a significant correlation between SWE values of cortex and medulla of the kidneys in healthy children. [ABSTRACT FROM AUTHOR]

Animal hair examination may provide valuable information on forensic investigations. However, there are limited data on the hair histology of Indonesian mammals for serving as a database for identification. The present study provides histological analyses of the dorsal guard hairs of the Indonesian Suidae species Sus scrofa, S. barbatus, S. verrucosus and S. celebensis, which were examined from the collections of Museum Zoologicum Bogoriense, National Research and Innovation Agency. Comparative analysis was performed by light and scanning electron microscope. Different features of each animal species' hair were identified based on the morphology, cuticle scale pattern, type of medulla, pigmentation and cross-section characteristics. The results show that the cuticle scale pattern is an irregular wave in all species. The cuticle scale margin is rippled, and the distance between scales is close. The hair medulla is amorphous in all species. The hair pigmentation is yellowish-reddish in all species, but no pigmentation of hair is found in S. verrucosus. The cross-section shape of the hair shaft is different in all Indonesian Suidae species, which can be used for identifying the species of Indonesian Suidae. [ABSTRACT FROM AUTHOR]

We describe prenatal diagnosis of Poland-Möbius syndrome using a combination of ultrasound and MRI. Poland syndrome was diagnosed based on absence of the pectoralis muscles associated with dextroposition of the fetal heart and elevation of the left diaphragm. Associated brain anomalies that led to the diagnosis of Poland-Möbius syndrome, included ventriculomegaly, hypoplastic cerebellum, tectal beaking, and a peculiar flattening of the posterior aspect of the pons and medulla oblongata, which has been reported by postnatal diffusion tensor imaging studies as a reliable neuroimaging marker for Möbius syndrome. Since abnormalities of cranial nerves VI and VII may be difficult to detect prenatally, careful attention to the appearance of the brain stem as illustrated in the current report may aid in the prenatal diagnosis of Möbius syndrome. [ABSTRACT FROM AUTHOR]

We report an uncommon, infratentorial localization of adult H3 K27M-altered diffuse midline glioma arising in a particularly rare site (medulla oblongata). In addition to this unusual presentation, the lesion exhibited a substantial contrast enhancement and size decrease after dexamethasone, generating diagnostic dilemmas. Histology, molecular details, advanced Magnetic Resonance imaging features and differential diagnoses are here described and discussed, as well as common misconceptions about steroid-sensitive mass lesions, and practical difficulties for clinicians involved in the process of making diagnosis.

Introduction: Debilitating Long-Covid symptoms occur frequently after SARSCOVID- 19 infection. Methods: Functional MRI was acquired in 10 Long Covid (LCov) and 13 healthy controls (HC) with a 7 Tesla scanner during a cognitive (Stroop color-word) task. BOLD time series were computed for 7 salience and 4 default-mode network hubs, 2 hippocampus and 7 brainstem regions (ROIs). Connectivity was characterized by the correlation coefficient between each pair of ROI BOLD time series. We tested for HC versus LCov differences in connectivity between each pair of the 20 regions (ROI-to- ROI) and between each ROI and the rest of the brain (ROI-to-voxel). For LCov, we also performed regressions of ROI-to-ROI connectivity with clinical scores. Results: Two ROI-to-ROI connectivities differed between HC and LCov. Both involved the brainstem rostral medulla, one connection to the midbrain, another to a DM network hub. Both were stronger in LCov than HC. ROI-to-voxel analysis detected multiple other regions where LCov connectivity differed from HC located in all major lobes. Most, but not all connections, were weaker in LCov than HC. LCov, but not HC connectivity, was correlated with clinical scores for disability and autonomic function and involved brainstem ROI. Discussion: Multiple connectivity differences and clinical correlations involved brainstem ROIs. Stronger connectivity in LCov between the medulla and midbrain may reflect a compensatory response. This brainstem circuit regulates cortical arousal, autonomic function and the sleep-wake cycle. In contrast, this circuit exhibited weaker connectivity in ME/CFS. LCov connectivity regressions with disability and autonomic scores were consistent with altered brainstem connectivity in LCov. [ABSTRACT FROM AUTHOR]

Laminins are the major water-soluble glycoproteins in the basement membrane of epithelial tissue. The laminin content of the renal parenchyma was studied in rats that were fed a 60-h alternative water diet with either excessive water intake or a complete lack of drinking water. It was shown that osmotic concentration of the urine, which develops due to water deprivation, is accompanied by a quantitative change in the laminin composition. It was found that the level of the laminin β chain increases in the renal medulla, but not in the renal cortex, of dehydrated rats. This effect occurs only in WAG rats with a normally expressed vasopressin gene and is absent in mutant Brattleboro rats unable to synthesize this hormone. Based on the initial and new data, it is assumed that laminin, as a key regulatory element in the basement membrane of the tubular epithelium, is involved in the adaptive response of the renal urine concentrating system to prolonged dehydration. Hyperhydration does not affect laminin levels in the renal parenchyma. [ABSTRACT FROM AUTHOR]

γδT cells are produced in the thymus throughout life and provide immunity at epithelial‐rich sites. Unlike conventional αβT cells, γδT‐cell development involves intrathymic acquisition of effector function, with priming for either IL17 or IFN‐γ production occurring during embryonic or adult life, respectively. How the thymus controls effector‐primed γδT‐cell generation in adulthood is poorly understood. Here, we distinguished de novo γδT cells from those undergoing thymus recirculation and/or retention using Rag2GFP mice alongside markers of maturation/effector priming including CD24, CD25, CD73, and IFN‐γ, the latter by crossing with IFN‐γYFP GREAT mice. We categorize newly developing γδT‐cells into an ordered sequence where CD25+CD73−IFN‐γYFP− precursors are followed sequentially by CD25−CD73+IFN‐γYFP− intermediates and CD25−CD73+IFN‐γYFP+ effectors. To determine intrathymic requirements controlling this sequence, we examined γδT‐cell development in Relb−/− thymus grafts that lack medullary microenvironments. Interestingly, medulla deficiency did not alter CD25+ γδT‐cell precursor generation, but significantly impaired development of effector primed stages. This impact on γδT‐cell priming was mirrored in plt/plt mice lacking the medullary chemoattractants CCL19 and CCL21, and also Ccl21a−/− but not Ccl19−/− mice. Collectively, we identify the medulla as an important site for effector priming during adult γδT‐cell development and demonstrate a specific role for the medullary epithelial product CCL21 in this process. [ABSTRACT FROM AUTHOR]

Abstract Background The classification of thymomas is based on the morphology of epithelial tumor cells and the proportion of lymphocytes. Type A thymomas are composed of the spindle or oval tumor epithelial cells. Tumor cells of B thymomas are epithelioid-shaped with increasing atypia. Type AB thymomas have the features of epithelial tumor cells of A and B thymomas. The diagnosis can be difficult because of the complex morphology. Some novel thymic epithelial markers have been reported in several preclinical studies, but they have not been applied to clinical practice. Here, we investigated the expression of 3 cortical and 3 medullary markers, which are thymoproteasome-specific subunit β5t (β5t), thymus-specific serine protease 16 (PRSS16), cathepsin V, autoimmune regulator (AIRE), CD40 and claudin-4. Methods Immunohistochemistry was used to analyze 53 cases of thymomas and thymic squamous cell carcinomas (TSCC), aiming to explore the expression of cortical and medullary epithelial markers and their correlation with histological classification, Masaoka-Koga stage, and prognosis. Results Our results found that for cortical epithelial markers the expression of β5t, PRSS16, and cathepsin V was higher in type AB and B thymomas than in micronodular thymoma with lymphoid stroma (MNT), and we observed a dramatic increase of β5t and PRSS16 expression in type AB compared to type A thymomas. In medullary epithelial markers, the expression of AIRE was higher in type A than in B3 thymomas. CD40 and β5t expression were associated with the Masaoka-Koga stage. High cathepsin V expression was related to a good prognosis and a longer progression-free survival. Conclusion This is the first comprehensive analysis of the role of thymic cortical and medullary epithelial markers as biomarkers for differential diagnosis and prognosis in thymic tumors. Thymic medullary epithelial immunophenotype was found to exhibit in type A, MNT, and TSCC. Type B thymomas primarily exhibited a cortical epithelial immunophenotype. Type AB thymomas showed cortical, medullary, or mixed corticomedullary epithelial immunophenotype. Our results demonstrated that thymic cortical and medullary epithelial markers including β5t, PRSS16, cathepsin V, and AIRE could be used as ancillary markers in the diagnosis and prognosis of thymic epithelial tumors.

Purpose: Russel described a rare clinical entity known as diencephalic syndrome (DS) in 1951, which was traditionally caused by a neoplasm in the hypothalamic–optic chiasmatic region. DS is characterized by severe emaciation despite adequate or slightly reduced caloric intake, locomotor hyperactivity, euphoria and other minor features. Current evidence suggests that a rare population of children with a similar phenotype may have their tumor located in the posterior fossa instead, defining the DS-like presentation, a rare entity with few cases reported in the literature. Methods: A thorough search of three databases (PubMed, Ovid Medline, and Ovid Embase) was conducted to identify relevant papers reporting children with DS associated with brainstem tumors. To our knowledge, only seven cases have been documented in the literature. Moreover, we present four of our own cases, focusing on the unusual clinical presentation, the diagnosis process, and the lag time between the initial symptoms and the definitive diagnosis. Results: In this review, the mean lag time between the onset of symptoms and diagnosis was 20.9 months (median: 16 months; range: 1.5–72 months), whereas in our series of cases, the time was 32.5 months (median: 33 months; range: 7–57 months). Conclusion: Despite recent significant advances in neuro-oncology diagnostic tools, this mean lag time did not improve when compared with the previous literature review from 1976. Throughout these data, we aim to raise awareness in the hopes of detecting intracranial neoplasms earlier in cases of children with profound emaciation of unknown cause. [ABSTRACT FROM AUTHOR]

Opioid medications are the mainstay of pain management but present substantial side-effects such as respiratory depression which can be lethal with overdose. Most opioid drugs, such as fentanyl, act on opioid receptors such as the G-protein-coupled μ-opioid receptors (MOR). G-protein-coupled receptors activate pertussis toxin-sensitive G-proteins to inhibit neuronal activity. Binding of opioid ligands to MOR and subsequent activation G proteins βγ is modulated by regulator of G-protein signaling (RGS). The roles of G-proteins βγ and RGS in MOR-mediated inhibition of the respiratory network are not known. Using rodent models to pharmacologically modulate G-protein signaling, we aim to determine the roles of βγ G-proteins and RGS4. We showed that inhibition of βγ G-proteins using gallein perfused in the brainstem circuits regulating respiratory depression by opioid drugs results in complete reversal of respiratory depression. Blocking of RGS4 using CCG55014 did not change the respiratory depression induced by MOR activation despite co-expression of RGS4 and MORs in the brainstem. Our results suggest that neuronal inhibition by opioid drugs is mediated by G-proteins, but not by RGS4, which supports the concept that βγ G-proteins could be molecular targets to develop opioid overdose antidotes without the risks of re-narcotization often found with highly potent opioid drugs. On the other hand, RGS4 mediates opioid analgesia, but not respiratory depression, and RGS4 may be molecular targets to develop pain therapies without respiratory liability. [ABSTRACT FROM AUTHOR]

The parabrachial nucleus (PBN) integrates interoceptive and exteroceptive information to control various behavioral and physiological processes including breathing, emotion, and sleep/wake regulation through the neural circuits that connect to the forebrain and the brainstem. However, the precise identity and function of distinct PBN subpopulations are still largely unknown. Here, we leveraged molecular characterization, retrograde tracing, optogenetics, chemogenetics, and electrocortical recording approaches to identify a small subpopulation of neurotensin-expressing neurons in the PBN that largely project to the emotional control regions in the forebrain, rather than the medulla. Their activation induces freezing and anxiety-like behaviors, which in turn result in tachypnea. In addition, optogenetic and chemogenetic manipulations of these neurons revealed their function in promoting wakefulness and maintaining sleep architecture. We propose that these neurons comprise a PBN subpopulation with specific gene expression, connectivity, and function, which play essential roles in behavioral and physiological regulation. [ABSTRACT FROM AUTHOR]

IntroductionDebilitating Long-Covid symptoms occur frequently after SARS-COVID-19 infection.MethodsFunctional MRI was acquired in 10 Long Covid (LCov) and 13 healthy controls (HC) with a 7 Tesla scanner during a cognitive (Stroop color-word) task. BOLD time series were computed for 7 salience and 4 default-mode network hubs, 2 hippocampus and 7 brainstem regions (ROIs). Connectivity was characterized by the correlation coefficient between each pair of ROI BOLD time series. We tested for HC versus LCov differences in connectivity between each pair of the 20 regions (ROI-to-ROI) and between each ROI and the rest of the brain (ROI-to-voxel). For LCov, we also performed regressions of ROI-to-ROI connectivity with clinical scores.ResultsTwo ROI-to-ROI connectivities differed between HC and LCov. Both involved the brainstem rostral medulla, one connection to the midbrain, another to a DM network hub. Both were stronger in LCov than HC. ROI-to-voxel analysis detected multiple other regions where LCov connectivity differed from HC located in all major lobes. Most, but not all connections, were weaker in LCov than HC. LCov, but not HC connectivity, was correlated with clinical scores for disability and autonomic function and involved brainstem ROI.DiscussionMultiple connectivity differences and clinical correlations involved brainstem ROIs. Stronger connectivity in LCov between the medulla and midbrain may reflect a compensatory response. This brainstem circuit regulates cortical arousal, autonomic function and the sleep–wake cycle. In contrast, this circuit exhibited weaker connectivity in ME/CFS. LCov connectivity regressions with disability and autonomic scores were consistent with altered brainstem connectivity in LCov.

This article discusses the implications of µ-opioid receptor expression in the brainstem for respiratory control. The rise in opioid use has led to a significant increase in fatal opioid overdoses, which has become a public health crisis. Opioid-induced respiratory depression (OIRD) is a global issue that requires coordinated efforts in public health policy, medical education, and patient safety initiatives. The article explores the expression of µ-opioid receptors in specific brainstem areas involved in respiratory control and related behaviors. Understanding the neural control of breathing and the impact of opioids at various levels is crucial for developing interventions and improving patient outcomes. [Extracted from the article]

Opioid medications are the mainstay of pain management but present substantial side-effects such as respiratory depression which can be lethal with overdose. Most opioid drugs, such as fentanyl, act on opioid receptors such as the G-protein-coupled µ-opioid receptors (MOR). G-protein-coupled receptors activate pertussis toxin-sensitive G-proteins to inhibit neuronal activity. Binding of opioid ligands to MOR and subsequent activation G proteins βγ is modulated by regulator of G-protein signaling (RGS). The roles of G-proteins βγ and RGS in MOR-mediated inhibition of the respiratory network are not known. Using rodent models to pharmacologically modulate G-protein signaling, we aim to determine the roles of βγ G-proteins and RGS4. We showed that inhibition of βγ G-proteins using gallein perfused in the brainstem circuits regulating respiratory depression by opioid drugs results in complete reversal of respiratory depression. Blocking of RGS4 using CCG55014 did not change the respiratory depression induced by MOR activation despite co-expression of RGS4 and MORs in the brainstem. Our results suggest that neuronal inhibition by opioid drugs is mediated by G-proteins, but not by RGS4, which supports the concept that βγ G-proteins could be molecular targets to develop opioid overdose antidotes without the risks of re-narcotization often found with highly potent opioid drugs. On the other hand, RGS4 mediates opioid analgesia, but not respiratory depression, and RGS4 may be molecular targets to develop pain therapies without respiratory liability.

Background: The classification of thymomas is based on the morphology of epithelial tumor cells and the proportion of lymphocytes. Type A thymomas are composed of the spindle or oval tumor epithelial cells. Tumor cells of B thymomas are epithelioid-shaped with increasing atypia. Type AB thymomas have the features of epithelial tumor cells of A and B thymomas. The diagnosis can be difficult because of the complex morphology. Some novel thymic epithelial markers have been reported in several preclinical studies, but they have not been applied to clinical practice. Here, we investigated the expression of 3 cortical and 3 medullary markers, which are thymoproteasome-specific subunit β5t (β5t), thymus-specific serine protease 16 (PRSS16), cathepsin V, autoimmune regulator (AIRE), CD40 and claudin-4. Methods: Immunohistochemistry was used to analyze 53 cases of thymomas and thymic squamous cell carcinomas (TSCC), aiming to explore the expression of cortical and medullary epithelial markers and their correlation with histological classification, Masaoka-Koga stage, and prognosis. Results: Our results found that for cortical epithelial markers the expression of β5t, PRSS16, and cathepsin V was higher in type AB and B thymomas than in micronodular thymoma with lymphoid stroma (MNT), and we observed a dramatic increase of β5t and PRSS16 expression in type AB compared to type A thymomas. In medullary epithelial markers, the expression of AIRE was higher in type A than in B3 thymomas. CD40 and β5t expression were associated with the Masaoka-Koga stage. High cathepsin V expression was related to a good prognosis and a longer progression-free survival. Conclusion: This is the first comprehensive analysis of the role of thymic cortical and medullary epithelial markers as biomarkers for differential diagnosis and prognosis in thymic tumors. Thymic medullary epithelial immunophenotype was found to exhibit in type A, MNT, and TSCC. Type B thymomas primarily exhibited a cortical epithelial immunophenotype. Type AB thymomas showed cortical, medullary, or mixed corticomedullary epithelial immunophenotype. Our results demonstrated that thymic cortical and medullary epithelial markers including β5t, PRSS16, cathepsin V, and AIRE could be used as ancillary markers in the diagnosis and prognosis of thymic epithelial tumors. [ABSTRACT FROM AUTHOR]

Serotonin is not only a neurotransmitter but also an important humoral regulator of various physiological processes outside the central nervous system. In the last decade, the concept of local serotonergic systems in peripheral organs, where serotonin realizes its effects via autocrine/paracrine mechanisms, has been under development. Such local systems have already been described in the pancreas, thymus, mammary gland, and bone marrow. We consider that a similar local serotonergic system is also characteristic of the adrenal glands. These paired organs are a key component of the mammalian endocrine system, providing a complex physiological response to stress. The adrenal glands consist of two parts distinct in origin and function—the cortex and medulla—while serotonin plays an important role in regulating hormone secretion in both of these structures. This review is aimed at analyzing the structure of the local serotonergic system in the adrenal gland as well as its role both in the regulation of adrenal functions in adult animals and in the formation of adrenals in embryogenesis. Analysis of the available data suggests that local serotonergic systems makes an organ susceptible to fluctuations in the level of serotonin circulating in the blood at all stages of ontogenesis. Thus, local sensitivity to serotonin provides the possibility of systemic humoral coordination of the development and functioning of the adrenal glands and other peripheral organs. From this perspective, the importance of local serotoninergic systems for developmental biology and medicine becomes clear. [ABSTRACT FROM AUTHOR]

We report a patient with spontaneous upbeat nystagmus (UBN) due to an ischemic lesion involving the paramedian tract (PMT) in the medulla. Eye movement recordings, using an infrared video-oculography (VOG) system, showed that the slow phase of the nystagmus was initially velocity-decreasing but gradually became velocity-increasing. Simulation of the nystagmus with a mathematical model supports a role for the PMT in relaying premotor signals for vertical gaze holding to the cerebellum. Our model shows that the disruption in cerebellar input from PMT can lead to the velocity-increasing waveform of the nystagmus, whereas the velocity-decreasing waveform could be related to a mismatch between the innervational commands to the ocular muscles (the pulse and step) needed to hold gaze steady. [ABSTRACT FROM AUTHOR]

Five-sixths nephrectomy is a widely used experimental model of chronic kidney disease (CKD) that is associated with severe mitochondrial dysfunction of the remnant tissue. In this study, we assessed the effect of CKD on mitochondrial respiration separately in the rat kidney cortex and medulla 10 weeks after induction of CKD by subtotal 5/6 nephrectomy (SNX). Mitochondrial oxygen consumption was evaluated on mechanically permeabilized samples of kidney cortex and medulla using high-resolution respirometry and expressed per mg of tissue wet weight or IU citrate synthase (CS) activity. Mitochondrial respiration in the renal cortex of SNX rats was significantly reduced in all measured respiratory states if expressed per unit wet weight and remained lower if recalculated per IU citrate synthase activity, i.e. per mitochondrial mass. In contrast, the profound decrease in the activity of CS in SNX medulla resulted in significantly elevated respiratory states expressing the OXPHOS capacity when Complexes I and II or II only are provided with electrons, LEAK respiration after oligomycin injection, and Complex IV-linked oxygen consumption per unit CS activity suggesting compensatory hypermetabolic state in remaining functional mitochondria that is not sufficient to fully compensate for respiratory deficit expressed per tissue mass. The results document that CKD induced by 5/6 nephrectomy in the rat is likely to cause not only mitochondrial respiratory dysfunction (in the kidney cortex), but also adaptive changes in the medulla that tend to at least partially compensate for mitochondria loss. [ABSTRACT FROM AUTHOR]

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Abstract Background The TRH/TRH-R1 receptor signaling pathway within the neurons of the dorsal vagal complex is an important mediator of the brain-gut axis. Mental health and protection from a variety of neuropathologies, such as autism, Attention Deficit Hyperactivity Disorder, Alzheimer’s and Parkinson’s disease, major depression, migraine and epilepsy are influenced by the gut microbiome and is mediated by the vagus nerve. The antibiotic rifaximin (RF) does not cross the gut-blood barrier. It changes the composition of the gut microbiome resulting in therapeutic benefits for traveler’s diarrhea, hepatic encephalopathy, and prostatitis. TRH and TRH-like peptides, with the structure pGlu-X-Pro-NH2, where “X” can be any amino acid residue, have reproduction-enhancing, caloric-restriction-like, anti-aging, pancreatic-β cell-, cardiovascular-, and neuroprotective effects. TRH and TRH-like peptides occur not only throughout the CNS but also in peripheral tissues. To elucidate the involvement of TRH-like peptides in brain-gut-reproductive system interactions 16 male Sprague–Dawley rats, 203 ± 6 g, were divided into 4 groups (n = 4/group): the control (CON) group remained on ad libitum Purina rodent chow and water for 10 days until decapitation, acute (AC) group receiving 150 mg RF/kg powdered rodent chow for 24 h providing 150 mg RF/kg body weight for 200 g rats, chronic (CHR) animals receiving RF for 10 days; withdrawal (WD) rats receiving RF for 8 days and then normal chow for 2 days. Results Significant changes in the levels of TRH and TRH-like peptides occurred throughout the brain and peripheral tissues in response to RF. The number of significant changes in TRH and TRH-like peptide levels in brain resulting from RF treatment, in descending order were: medulla (16), piriform cortex (8), nucleus accumbens (7), frontal cortex (5), striatum (3), amygdala (3), entorhinal cortex (3), anterior (2), and posterior cingulate (2), hippocampus (1), hypothalamus (0) and cerebellum (0). The corresponding ranking for peripheral tissues were: prostate (6), adrenals (4), pancreas (3), liver (2), testis (1), heart (0). Conclusions The sensitivity of TRH and TRH-like peptide expression to RF treatment, particularly in the medulla oblongata and prostate, is consistent with the participation of these peptides in the therapeutic effects of RF.

Lateral medullary syndrome (LMS) or Wallenberg's syndrome is an uncommon and often underdiagnosed cause of posterior circulation stroke. Thrombosis, embolization, or dissection of vertebral or posterior inferior cerebellar artery (PICA) often results into LMS. The most pathognomonic symptoms of LMS includes pain and temperature deficits on ipsilateral facial side and contralateral side of rest of the body, ipsilateral ataxia, vertigo, nystagmus, dysphagia, hoarseness, hiccups and Horner's syndrome. We report a case of LMS in a 49-year-old Indian female with no known classical risk factors for stroke who presented with chief complaints of debilitating headache. Clinical examination was suggestive of LMS and radiological investigation confirmed the diagnosis. Patient's hospital stay was uneventful and she was discharged to home with gradual improvement in her symptoms.

Stress elicits a variety of autonomic responses, including hyperthermia (stress fever) in humans and animals. In this present study, we investigated the circuit basis for thermogenesis and heat conservation during this response. We first demonstrated the glutamatergic identity of the dorsal hypothalamic area (DHAVglut2) neurons that innervate the raphe pallidus nucleus (RPa) to regulate core temperature (Tc) and mediate stress-induced hyperthermia. Then, using chemogenetic and optogenetic methods to manipulate this hypothalamomedullary circuit, we found that activation of DHAVglut2 neurons potently drove an increase in Tc, but surprisingly, stress-induced hyperthermia was only reduced by about one-third when they were inhibited. Further investigation showed that DHAVglut2 neurons activate brown adipose tissue (BAT) but do not cause vasoconstriction, instead allowing reflex tail artery vasodilation as a response to BAT-induced hyperthermia. Retrograde rabies virus tracing revealed projections from DHAVglut2 neurons to RPaVglut3, but not to RPaGABA neurons, and identified a set of inputs to DHAVglut2 → RPa neurons that are likely to mediate BAT activation. The dissociation of the DHAVglut2 thermogenic pathway from the thermoregulatory vasoconstriction (heat-conserving) pathway may explain stress flushing (skin vasodilation but a feeling of being too hot) during stressful times.