Dynamic changes in mitochondrial localization in human neocortical basal radial glial cells during cell cycle.

Mitochondria play critical roles in neural stem/progenitor cell proliferation and fate decisions. The subcellular localization of mitochondria in neural stem/progenitor cells during mitosis potentially influences the distribution of mitochondria to the daughter cells and thus their fates. Therefore, understanding the spatial dynamics of mitochondria provides important knowledge about brain development. In this study, we analyzed the subcellular localization of mitochondria in the fetal human neocortex with a particular focus on the basal radial glial cells (bRGCs), a neural stem/progenitor cell subtype attributed to the evolutionary expansion of the human neocortex. During interphase, bRGCs exhibit a polarized localization of mitochondria that is localized at the base of the process or the proximal part of the process. Thereafter, mitochondria in bRGCs at metaphase show unpolarized distribution in which the mitochondria are randomly localized in the cytoplasm. During anaphase and telophase, mitochondria are still localized evenly, but mainly in the periphery of the cytoplasm. Mitochondria start to accumulate at the cleavage furrow during cytokinesis. These results suggest that the mitochondrial localization in bRGCs is tightly regulated during the cell cycle, which may ensure the proper distribution of mitochondria to the daughter cells and, thus in turn, influence their fates.

Collagen 17A1 in the Urothelium Regulates Epithelial Cell Integrity and Local Immunologic Responses in Obstructive Uropathy.

Collagen 17A1 (COL17A1), an epidermal hemidesmosome component, is ectopically induced in the urothelium of mouse and human renal pelvis (RP) in parallel with urinary tract-associated lymphoid structure development. Here, we found that COL17A1 was induced in obstructive uropathy-prone ureter of humans and cats. To ascertain its function, murine urinary organs with unilateral ureteral obstruction (UUO) were analyzed during 1 week after surgery. One day after UUO, COL17A1 expression increased in urothelial cells of RP and ureter, and was positively correlated with renal tubulointerstitial lesions. A portion of RP where the smooth muscle layer from the ureter was interrupted was sensitive to urothelium deciduation and COL17A1 induction, showing urine leaked from the RP lumen into the parenchyma. After urine stimulation, cultured immune cells expressed Cxcl2, also up-regulated in CD11b+ cells following COL17A1 stimulation. One day after UUO, CXCL2+ CD11b+ cells infiltrated the urothelium-disrupted area; however, these numbers were significantly lower in Col17a1-deficient mice. COL17A1+ urothelial cells partially co-expressed cytokeratin-14, a progenitor cell marker for urothelium, whereas Col17a1-deficient mice had lower numbers of cytokeratin-14+ cells. Gene Ontology analysis revealed that expression of epithelial- and immune-associated genes was up-regulated and down-regulated, respectively, in the ureter of Col17a1-deficient mice 4 days after UUO. Thus, COL17A1 maintains urothelium integrity by regulating urothelial cell adhesion, proliferation, and differentiation, and activates local immune responses during obstructive uropathy in mammals.

Phenotypes of streptozotocin-induced gestational diabetes mellitus in mice.

Gestational diabetes mellitus (GDM) in human patients disrupts glucose metabolism post-pregnancy, affecting fetal development. Although obesity and genetic factors increase GDM risk, a lack of suitable models impedes a comprehensive understanding of its pathology. To address this, we administered streptozotocin (STZ, 75 mg/kg) to C57BL/6N mice for two days before pregnancy, establishing a convenient GDM model. Pregnant mice exposed to STZ (STZ-pregnant) were compared with STZ-injected virgin mice (STZ-virgin), citrate buffer-injected virgin mice (CB-virgin), and pregnant mice injected with citrate buffer (CB-pregnant). STZ-pregnant non-obese mice exhibited elevated blood glucose levels on gestational day 15.5 and impaired glucose tolerance. They also showed fewer normal fetuses compared to CB-pregnant mice. Additionally, STZ-pregnant mice had the highest plasma C-peptide levels, with decreased pancreatic islets or increased alpha cells compared to CB-pregnant mice. Kidneys isolated from STZ-pregnant mice did not display histological alterations or changes in gene expression for the principal glucose transporters (GLUT2 and SGLT2) and renal injury-associated markers. Notably, STZ-pregnant mice displayed decreased gene expression of insulin-receiving molecules (ISNR and IGFR1), indicating heightened insulin resistance. Liver histology in STZ-pregnant mice remained unchanged except for a pregnancy-related increase in lipid droplets within hepatocytes. Furthermore, the duodenum of STZ-pregnant mice exhibited increased gene expression of ligand-degradable IGFR2 and decreased expression of GLUT5 and GLUT12 (fructose and glucose transporters, respectively) compared to STZ-virgin mice. Thus, STZ-pregnant mice displayed GDM-like symptoms, including fetal abnormalities, while organs adapted to impaired glucose metabolism by altering glucose transport and insulin reception without histopathological changes. STZ-pregnant mice offer a novel model for studying mild onset non-obese GDM and species-specific differences in GDM features between humans and animals.

Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase.

Glutamine synthetase (GS), encoded by GLUL, catalyzes the conversion of glutamate to glutamine. GS is pivotal for the generation of the neurotransmitters glutamate and gamma-aminobutyric acid and is the primary mechanism of ammonia detoxification in the brain. GS levels are regulated post-translationally by an N-terminal degron that enables the ubiquitin-mediated degradation of GS in a glutamine-induced manner. GS deficiency in humans is known to lead to neurological defects and death in infancy, yet how dysregulation of the degron-mediated control of GS levels might affect neurodevelopment is unknown. We ascertained nine individuals with severe developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry with de novo variants in GLUL. Seven out of nine were start-loss variants and two out of nine disrupted 5' UTR splicing resulting in splice exclusion of the initiation codon. Using transfection-based expression systems and mass spectrometry, these variants were shown to lead to translation initiation of GS from methionine 18, downstream of the N-terminal degron motif, resulting in a protein that is stable and enzymatically competent but insensitive to negative feedback by glutamine. Analysis of human single-cell transcriptomes demonstrated that GLUL is widely expressed in neuro- and glial-progenitor cells and mature astrocytes but not in post-mitotic neurons. One individual with a start-loss GLUL variant demonstrated periventricular nodular heterotopia, a neuronal migration disorder, yet overexpression of stabilized GS in mice using in utero electroporation demonstrated no migratory deficits. These findings underline the importance of tight regulation of glutamine metabolism during neurodevelopment in humans.

Functional synergy of a human-specific and an ape-specific metabolic regulator in human neocortex development.

Metabolism has recently emerged as a major target of genes implicated in the evolutionary expansion of human neocortex. One such gene is the human-specific gene ARHGAP11B. During human neocortex development, ARHGAP11B increases the abundance of basal radial glia, key progenitors for neocortex expansion, by stimulating glutaminolysis (glutamine-to-glutamate-to-alpha-ketoglutarate) in mitochondria. Here we show that the ape-specific protein GLUD2 (glutamate dehydrogenase 2), which also operates in mitochondria and converts glutamate-to-αKG, enhances ARHGAP11B's ability to increase basal radial glia abundance. ARHGAP11B + GLUD2 double-transgenic bRG show increased production of aspartate, a metabolite essential for cell proliferation, from glutamate via alpha-ketoglutarate and the TCA cycle. Hence, during human evolution, a human-specific gene exploited the existence of another gene that emerged during ape evolution, to increase, via concerted changes in metabolism, progenitor abundance and neocortex size.

Systemic autoimmune abnormalities alter the morphology of mucosa-associated lymphoid tissues in the rectum of MRL/MpJ-Faslpr/lpr mice.

Systemic autoimmune diseases (ADs) might affect the morphology and function of gut-associated lymphoid tissue (LTs) indirectly; however, their exact relationship remains unclear. Therefore, we investigated mouse LTs in the anorectal canal and morphologically compared them between MRL/MpJ-Fas+/+ and MRL/MpJ-Faslpr/lpr mice. LT aggregations, also known as rectal mucosa-associated lymphoid tissues (RMALTs), were exclusively seen in the lamina propria and submucosa of the rectum. The mean size and number of the LT aggregations both significantly increased in MRL/MpJ-Faslpr/lpr mice compared to those in MRL/MpJ-Fas+/+ mice. The distance from the anorectal junction to the first LT aggregate was significantly shorter in MRL/MpJ-Faslpr/lpr mice than that in MRL/MpJ-Fas+/+ mice. Immunostaining revealed that the RMALTs included CD3+,CD4+, and CD8+ T cells; B220+ B cells; IBA1+ macrophages; Ki67+ proliferative cells; and PNAd+ high-endothelial venules (HEVs). The numbers of macrophages, proliferative cells, CD4+ T cells, CD8+ T cells, and HEVs were significantly increased in MRL/MpJ-Faslpr/lpr mice compared to those in MRL/MpJ mice. Furthermore, the gene expression levels of chemokines (Cxcl9 and Cxcl13) and their corresponding receptors (Cxcr3 and Cxcr5) were significantly higher in MRL/MpJ-Faslpr/lpr mice than those in MRL/MpJ-Fas+/+ mice. Although the morphology of rectal epithelium was comparable between the strains, M cell number was significantly higher in MRL/MpJ-Faslpr/lpr mice than in MRL/MpJ-Fas+/+ mice. Thus, ADs could alter RMALT morphology, and quantitative changes in T-cell subsets, proliferative cells, macrophages, HEVs, chemokine expression, and M cells could affect their cell composition and development.

Neocortical neurogenesis in development and evolution-Human-specific features.

In this review, we focus on human-specific features of neocortical neurogenesis in development and evolution. Two distinct topics will be addressed. In the first section, we discuss the expansion of the neocortex during human evolution and concentrate on the human-specific gene ARHGAP11B. We review the ability of ARHGAP11B to amplify basal progenitors and to expand a primate neocortex. We discuss the contribution of ARHGAP11B to neocortex expansion during human evolution and its potential implications for neurodevelopmental disorders and brain tumors. We then review the action of ARHGAP11B in mitochondria as a regulator of basal progenitor metabolism, and how it promotes glutaminolysis and basal progenitor proliferation. Finally, we discuss the increase in cognitive performance due to the ARHGAP11B-induced neocortical expansion. In the second section, we focus on neocortical development in modern humans versus Neanderthals. Specifically, we discuss two recent findings pointing to differences in neocortical neurogenesis between these two hominins that are due to a small number of amino acid substitutions in certain key proteins. One set of such proteins are the kinetochore-associated proteins KIF18a and KNL1, where three modern human-specific amino acid substitutions underlie the prolongation of metaphase during apical progenitor mitosis. This prolongation in turn is associated with an increased fidelity of chromosome segregation to the apical progenitor progeny during modern human neocortical development, with implications for the proper formation of radial units. Another such key protein is transketolase-like 1 (TKTL1), where a single modern human-specific amino acid substitution endows TKTL1 with the ability to amplify basal radial glia, resulting in an increase in upper-layer neuron generation. TKTL1's ability is based on its action in the pentose phosphate pathway, resulting in increased fatty acid synthesis. The data imply greater neurogenesis during neocortical development in modern humans than Neanderthals due to TKTL1, in particular in the developing frontal lobe.

Structural Features of Connective Tissue Formed around Resin Implants Subcutaneously Embedded in Dairy Cows.

Foreign body reactions (FBRs) are inadvertently observed in invading or artificially embedded materials, triggering inflammation and subsequent fibrotic processes to occur in situ. Here, we assessed the spatiotemporal formation of connective tissue around implanted materials to establish a technique using connective tissue formed by FBRs as xenografts. An acrylic resin implant, comprising a columnar inner rod and a tubular outer cylinder (OC) with several slits, was embedded in adult dairy cows. Tissues formed in the inner rod and OC groups were histologically analyzed at weeks 2, 4, 8, and 12. Edematous tissues with non-collagenous fibers formed for 2 weeks and showed increased cellularity after 4 weeks. The weight, thickness, amounts of total protein, collagen, DNA, and quantitative scores of α-smooth muscle actin-positive myofibroblasts or elastic fibers notably increased after 8 weeks, with condensed collagen fibers showing orientation. Inflammatory cells were primarily localized in tissues close to the OC, and their numbers increased, with the count of CD204+ cells peaking at 8 weeks and declining at 12 weeks. The count of Ki67+ proliferating cells slightly increased in tissues close to the OC; however, the number and lumen of CD31+ vessels increased. These results may help understand FBR-related tissue remodeling.

Ameliorated Renal Pathological Feature in MRL/MpJ-Faslpr/lpr Background Interleukin-36 Receptor-Deficient Mice.

Systemic autoimmune diseases frequently induce lupus nephritis, causing altered balance and expression of interleukin 36 receptor (IL-36R) ligands, including agonists (IL-36α, ß, γ) and antagonists (IL-36Ra, IL-38), in kidneys. Here, we established and analyzed a mouse model of lupus nephritis, MRL/MpJ-Faslpr/lpr with IL-36R-knockout (KO), compared to wild-type (WT) mice. In both genotypes, indices for immune abnormalities and renal functions were comparable, although female WT mice showed higher serum autoantibody levels than males. IL-36R ligand expression did not differ significantly between genotypes at the mRNA level or in IL-36α and IL-38 scores. However, glomerular lesions, especially mesangial matrix expansion, were significantly ameliorated in both sexes of IL-36R-KO mice compared to WT mice. Cell infiltration into the tubulointerstitium with the development of tertiary lymphoid structures was comparable between genotypes. However, the positive correlation with the IL-36α score in WT mice was not evident in IL-36R-KO mice. Fibrosis was less in female IL-36R-KO mice than in WT mice. Importantly, some IL-36α+ nuclei co-localized with acetylated lysine and GCN5 histone acetyltransferase, in both genotypes. Therefore, IL-36R ligands, especially IL-36α, contribute to the progression of renal pathology in lupus nephritis via IL-36R-dependent and IL-36R-independent pathways.

Effects of autoimmune abnormalities on skeletal muscle regeneration after needle puncture in mice.

Regeneration of injured skeletal muscles is supported by the activation of satellite cells, and excessive traumatic injuries may trigger abnormal processes, such as fibrosis. Because the participation of immune cells is crucial during skeletal muscle repair, systemic autoimmune diseases impair their regeneration. This study focused on a traumatic injury by injection and investigated the effect of autoimmune diseases on skeletal muscle regeneration. Male mice of MRL/MpJ-Faslpr/lpr and MRL/MpJ (6-7 months old) were used for autoimmune disease and healthy groups. The abdominal walls punctured by a needle were histologically analyzed at 1, 3, and 8 days postinjection. In both groups, injured skeletal muscle tissues showed necrosis and inflammatory cell infiltrations on day 1, increased cell density at 3 days, and regenerative myotubes with central nuclei without fibrosis at 8 days. Gr-1+ neutrophils at injured skeletal muscle were abundant at 1 day, and then substantially decreased starting from 3 days in both groups. The number of CD3+ T cells was remarkably higher in MRL/MpJ-Faslpr/lpr than that in MRL/MpJ at 1 day, and a similar tendency was observed in B220+ B cells. The numbers of IBA1+ macrophages and bromodeoxyuridine-incorporating cells tended to be higher at 3 days, and those of the latter, mainly proliferating paired-box-7+ satellite cells, showed significance at other time points and negatively correlated with the autoimmune disease indices, such as spleen weights or serum autoantibody level. Thus, this result suggested that injured skeletal muscle by minor trauma is normally regenerated regardless of the effects of autoimmune diseases, although lymphocyte infiltrations during these processes were more severe in MRL/MpJ-Faslpr/lpr.

Transcriptome and proteome analysis of dogs with precursor targeted immune-mediated anemia treated with splenectomy.

Precursor-targeted immune-mediated anemia (PIMA) in dogs is characterized by persistent non-regenerative anemia and ineffective erythropoiesis, and it is suspected to be an immune-mediated disease. Most affected dogs respond to immunosuppressive therapies; however, some are resistant. In this study, we carried out splenectomy as an alternative therapy for refractory PIMA in dogs, and analyzed gene expression levels in the spleen of dogs with or without PIMA and in serum before and after splenectomy. A total of 1,385 genes were found to express differentially in the spleens from dogs with PIMA compared with healthy dogs by transcriptome analysis, of which 707 genes were up-regulated, including S100A12, S100A8, and S100A9 that are linked directly to the innate immune system and have been characterized as endogenous damage-associated molecular patterns. Furthermore, immunohistochemistry confirmed that S100A8/A9 protein expression levels were significantly higher in dogs with PIMA compared with those in healthy dogs. A total of 22 proteins were found to express differentially between the serum samples collected before and after splenectomy by proteome analysis, of which 12 proteins were up-regulated in the samples before. The lectin pathway of complement activation was identified by pathway analysis in pre-splenectomy samples. We speculated that S100A8/9 expression may be increased in the spleen of dogs with PIMA, resulting in activation of the lectin pathway before splenectomy. These findings further our understanding of the pathology and mechanisms of splenectomy for PIMA.

Analysis of gene expression in poultry red mite, Dermanyssus gallinae, by RNAscope in situ hybridization.

The poultry red mite (PRM; Dermanyssus gallinae) is a hematophagous ectoparasite that mainly infests chickens, and its infestation causes significant economic losses to the poultry industry. In this study, we examined the use of RNAscope-based in situ hybridization (ISH) to characterize gene expression in PRM. We analyzed the mRNA expression of Dermanyssus gallinae cathepsin D-1 (Dg-CatD-1) and Dermanyssus gallinae cystatin (Dg-Cys). RNAscope ISH analysis revealed that mRNA expression of Dg-CatD-1 was observed in the digestive tract, and Dg-Cystatin mRNA was expressed in the ovaries in addition to the digestive tract. RNAscope ISH could be applicable for the analysis of gene expression in each tissue of PRM and is an effective method to investigate the characteristics of target genes.

Morphological Characteristics of Genital Organ-Associated Lymphoid Tissue in the Vaginal Vestibule of Goats and Pigs.

Mucosa-associated lymphoid tissue (MALT) is a specialized form of peripheral lymphoid tissue (LT), which is found on mucosal surfaces exposed to the environment. However, morphological data of these tissues in farm animals are scarce. This study investigated the gross anatomical and histological features of genital organ-associated lymphoid tissues (GOALTs) in the vaginal vestibule (VV) of healthy, non-pregnant, adult goats and pigs. Their VVs were composed of stratified squamous, non-keratinized epithelium, and various-sized dark-blue hematoxylin-positive spots were observed in whole-mount specimens, which were diffusely distributed throughout the mucosal surfaces. These spots were histologically identified as LTs and consisted of lymphatic nodules (LNs) or diffuse lymphoid tissue (DLTs). Both LNs and DLTs contained B cells, T cells, macrophages, dendritic cells, plasma cells, and high endothelial venules. Only the numbers of B cells were significantly higher in both the LNs and DLTs of pigs compared to goats. Furthermore, the surface of the VV epithelium covering the LTs was partially disrupted with a large intercellular space containing abundant connective tissue fibers with numerous lymphocytes. In conclusion, GOALTs in the VV appear to be common local immunological barriers in both examined animals. This knowledge is crucial for understanding the structures and disorders of female reproductive organs in farm animals.

Glutaminolysis and the Control of Neural Progenitors in Neocortical Development and Evolution.

Multiple types of neural progenitor cells (NPCs) contribute to the development of the neocortex, a brain region responsible for our higher cognitive abilities. Proliferative capacity of NPCs varies among NPC types, developmental stages, and species. The higher proliferative capacity of NPCs in the developing human neocortex is thought to be a major contributing factor why humans have the most expanded neocortex within primates. Recent studies have shed light on the importance of cell metabolism in the neocortical NPC proliferative capacity. Specifically, glutaminolysis, a metabolic pathway that converts glutamine to glutamate and then to α-ketoglutarate, has been shown to play a critical role in human NPCs, both in apical and basal progenitors. In this review, we summarize our current knowledge of NPC metabolism, focusing especially on glutaminolysis, and discuss the role of NPC metabolism in neocortical development, evolution, and neurodevelopmental disorders, providing a broader perspective on a newly emerging research field.

Embryonic mouse medial neocortex as a model system for studying the radial glial scaffold in fetal human neocortex.

Neocortex is the evolutionarily newest region in the brain, and is a structure with diversified size and morphology among mammalian species. Humans have the biggest neocortex compared to the body size, and their neocortex has many foldings, that is, gyri and sulci. Despite the recent methodological advances in in vitro models such as cerebral organoids, mice have been continuously used as a model system for studying human neocortical development because of the accessibility and practicality of in vivo gene manipulation. The commonly studied neocortical region, the lateral neocortex, generally recapitulates the developmental process of the human neocortex, however, there are several important factors missing in the lateral neocortex. First, basal (outer) radial glia (bRG), which are the main cell type providing the radial scaffold to the migrating neurons in the fetal human neocortex, are very few in the mouse lateral neocortex, thus the radial glial scaffold is different from the fetal human neocortex. Second, as a consequence of the difference in the radial glial scaffold, migrating neurons might exhibit different migratory behavior and thus distribution. To overcome those problems, we propose the mouse medial neocortex, where we have earlier revealed an abundance of bRG similar to the fetal human neocortex, as an alternative model system. We found that similar to the fetal human neocortex, the radial glial scaffold, neuronal migration and neuronal distribution are tangentially scattered in the mouse medial neocortex. Taken together, the embryonic mouse medial neocortex could be a suitable and accessible in vivo model system to study human neocortical development and its pathogenesis.

Expression of Indian hedgehog signaling in murine oviductal infundibulum and its relationship with epithelial homeostasis.

Homeostasis of the oviductal infundibulum epithelium is continuously regulated by signaling pathways under physiological and pathological conditions. Herein, we investigated the expression of hedgehog (Hh) signaling-related components in the murine oviductal infundibulum, which is known to maintain homeostasis in the adult epithelium. Additionally, using autoimmune disease-prone MRL/MpJ-Faslpr/lpr (MRL/lpr) mice showing abnormal morphofunction of the ciliated epithelium of the infundibulum related to the oviductal inflammation, we examined the relationship between Hh signaling and pathology of the infundibulum. The expression and localization of Pax8, a marker for progenitor cells in the oviductal epithelium, and Foxj1, a marker for ciliogenesis, were examined in the infundibulum. The results showed that Pax8 was downregulated and Foxj1 was upregulated with aging, suggesting that homeostasis of the infundibulum epithelium of MRL/lpr mice was disturbed at 6 months of age. In all mice, the motile cilia of ciliated epithelial cells in the infundibulum harbored Hh signaling pathway-related molecules: patched (Ptch), smoothened (Smo), and epithelial cells harbor Gli. In contrast, Ptch, Smo, and Gli2 were significantly downregulated in the infundibulum of MRL/lpr mice at 6 months of age. The expression levels of Pax8 and Foxj1 were significantly positively correlated with those of Ptch1, Smo, and Gli2. Hh signaling is thought to be involved in homeostasis of the ciliated epithelium in the infundibulum. In MRL/lpr mice, which show exacerbated severe systemic autoimmune abnormalities, molecular alterations in Hh signaling-related components are considered to interact with local inflammation in the infundibulum, leading to disturbances in epithelial homeostasis and reproductive function.

Human-specific ARHGAP11B ensures human-like basal progenitor levels in hominid cerebral organoids.

The human-specific gene ARHGAP11B has been implicated in human neocortex expansion. However, the extent of ARHGAP11B's contribution to this expansion during hominid evolution is unknown. Here we address this issue by genetic manipulation of ARHGAP11B levels and function in chimpanzee and human cerebral organoids. ARHGAP11B expression in chimpanzee cerebral organoids doubles basal progenitor levels, the class of cortical progenitors with a key role in neocortex expansion. Conversely, interference with ARHGAP11B's function in human cerebral organoids decreases basal progenitors down to the chimpanzee level. Moreover, ARHGAP11A or ARHGAP11B rescue experiments in ARHGAP11A plus ARHGAP11B double-knockout human forebrain organoids indicate that lack of ARHGAP11B, but not of ARHGAP11A, decreases the abundance of basal radial glia-the basal progenitor type thought to be of particular relevance for neocortex expansion. Taken together, our findings demonstrate that ARHGAP11B is necessary and sufficient to ensure the elevated basal progenitor levels that characterize the fetal human neocortex, suggesting that this human-specific gene was a major contributor to neocortex expansion during human evolution.

Human TKTL1 implies greater neurogenesis in frontal neocortex of modern humans than Neanderthals.

Neanderthal brains were similar in size to those of modern humans. We sought to investigate potential differences in neurogenesis during neocortex development. Modern human transketolase-like 1 (TKTL1) differs from Neanderthal TKTL1 by a lysine-to-arginine amino acid substitution. Using overexpression in developing mouse and ferret neocortex, knockout in fetal human neocortical tissue, and genome-edited cerebral organoids, we found that the modern human variant, hTKTL1, but not the Neanderthal variant, increases the abundance of basal radial glia (bRG) but not that of intermediate progenitors (bIPs). bRG generate more neocortical neurons than bIPs. The hTKTL1 effect requires the pentose phosphate pathway and fatty acid synthesis. Inhibition of these metabolic pathways reduces bRG abundance in fetal human neocortical tissue. Our data suggest that neocortical neurogenesis in modern humans differs from that in Neanderthals.

Ureteral morphology and pathology during urolithiasis in cats.

Cats exhibit high susceptibility to urinary organ-related diseases. We investigated the healthy ureter morphologies and compared these with ureters that were surgically resected distal to a urolithiasis obstruction in cats. Healthy ureters (total length 9.88 ± 0.38 cm) developed adventitia composed of collagen fibers (ADCF), containing a longitudinal muscular layer, toward the distal segment. The healthy ureter was the smallest in the middle segment (4.71-6.90 cm from the urinary bladder) with significantly decreased luminal and submucosal areas compared to those in the proximal segment. Diseased cats exhibited a high incidence of calcium oxalate urolithiasis with renal dysfunction, regardless of age, sex, and body size. Diseased ureters showed increased perimeters, inflammation, and decreased nerves in ADCF. Collagen fibers were increased in the submucosal area, intermuscular spaces, and ADCF, particularly near the obstructed lesion. The mean resected ureter length was 5.66 ± 0.49 cm, suggesting a high obstruction risk in the middle segment. The middle segment also increased the cross-sectional area of the ureter and ADCF, regardless of the distance from the obstructed lesion. The ureters in several cases either lacked the transitional epithelium, or exhibited transitional epithelial hyperplasia, and some of these formed the mucosal folds. In conclusion, we demonstrated the following characteristics and histopathological features of cat ureters: decreases in the ureter size, lumen area, and submucosa area from proximal to middle segment in healthy; ADCF changes in urolithiasis, including increased connective tissues with inflammation and decreased nerves. These data are important to understand the pathogenesis of feline ureteral obstruction.

Modified foreign body reaction to silicone imbedded in subcutaneous tissues by different mouse systemic immune conditions.

Foreign body reaction (FBR) causes unexpected adverse effects due to implanted materials in humans and animals. Inflammation and subsequent fibrosis during FBR seems to be affected by recipient immunity, such as the balance of T helper (Th) response that has the potential to regulate FBR-related macrophage function. Here, the immunological effects of FBR on subcutaneously imbedded silicone tubes (ST) at 8 weeks were investigated histologically by comparing Th1-biased C57BL/6N, Th2-biased MRL/MpJ, and autoimmune disease-prone MRL/MpJ-Faslpr/lpr . Tissue surrounding ST (TSS) was analyzed at day (D) 7 and 14 (reaction phase) or D35 (stability phase) after surgery. In all strains, the TSS was composed of a thin layer (TL) containing fibrous tissues and loose connective tissues formed outside the TL. Few lymphocytes and mast cells, several neutrophils, and numerous macrophages infiltrated the TSS. Active vascularization was observed at D14 in all strains. For the examined indices, M1-type macrophage density in the TSS of C57BL/6N mice was significantly higher at D14 compared to other strains. No significant strain difference relating to M2-type macrophages was detected, suggesting the effects of Th1-biased immunity on FBR-related inflammation. Collagen fibers in the TSS increased in density and became stable with age in all strains. In particular, MRL/MpJ-Faslpr/lpr showed progressive fibrotic features. Serum autoantibody levels in MRL/MpJ-Faslpr/lpr mice were inversely correlated with M1-type macrophage density. These data from MRL/MpJ-Faslpr/lpr mice suggested modifications of FBR-related inflammation and fibrosis by autoimmune abnormalities. The results provide crucial insights into the pathological modification of FBR by recipient immunity and emphasize its clinicopathological importance in humans and animals.