Successful treatment with ivabradine for haemodynamically unstable junctional ectopic tachycardia occurring early after ST-elevation myocardial infarction.

Junctional ectopic tachycardia (JET) is a relatively uncommon arrhythmia predominantly observed in infancy, often occurring after congenital heart surgery. Although JET is rare in adults, it can occur in the presence of myocardial ischaemia. We describe a woman in her early 70s who presented with multivessel ST-segment elevation myocardial infarction and underwent percutaneous coronary intervention on left anterior descending artery and right coronary artery. She developed JET on the second day, resulting in haemodynamic compromise. Despite initial treatment attempts including amiodarone and beta-blocking agents proving insufficient in controlling JET, we successfully managed by administering ivabradine. Subsequently, she was discharged with recovered cardiac function without recurrence of JET. JET often proves refractory to multiple antiarrhythmic agents and can lead to unfavourable outcomes. Several case reports have demonstrated the effectiveness of ivabradine in treating JET during infancy, which can also be an effective therapeutic option for adult without adversely affecting haemodynamics.

Influence of the Hypoxia-Activated Prodrug Evofosfamide (TH-302) on Glycolytic Metabolism of Canine Glioma: A Potential Improvement in Cancer Metabolism.

The transcription factor hypoxia-inducible factor 1α (HIF-1α) drives metabolic reprogramming in gliomas (GLs) under hypoxic conditions, promoting glycolysis for tumor development. Evofosfamide (EVO) releases a DNA-alkylating agent within hypoxic regions, indicating that it may serve as a hypoxia-targeted therapy. The aim of this study was to investigate the glycolytic metabolism and antitumor effects of EVO in a canine GL model. Our clinical data showed that overall survival was significantly decreased in GL dog patients with higher HIF-1α expression compared to that of those with lower HIF-1α expression, and there was a positive correlation between HIF-1α and pyruvate dehydrogenase kinase 1 (PDK1) expression, suggesting that glycolytic activity under hypoxia conditions may contribute to poor outcomes in canine GL. Our glycolysis assay tests showed that the glycolytic ATP level was higher than the mitochondrial ATP level in three types of canine GL cell lines by activating the HIF-1 signal pathway under hypoxia conditions, resulting in an overall increase in total cellular ATP production. However, treatment with EVO inhibited the glycolytic ATP level in the GL cell lines under hypoxia conditions by targeting HIF-1α-positive cells, leading to decrease in total cellular ATP production. Our in vivo tests showed that EVO significantly reduced tumor development compared to controls and temozolomide in murine GL models. A metabolic analysis demonstrated that EVO effectively suppressed glycolytic metabolism by eliminating HIF-1α-positive cells, suggesting that it may restore metabolism in canine GLs. The evidence presented here supports the favorable preclinical evaluation of EVO as a potential improvement in cancer metabolism.

Successful treatment of sclerosing encapsulating peritonitis in a cat using bioresorbable hyaluronate-carboxymethylcellulose membrane after surgical adhesiolysis and long-term prednisolone.

Case summary: An 8-year-old neutered male domestic shorthair indoor cat was presented with an 8-week history of intermittent vomiting, anorexia and weight loss that had been unresponsive to supportive treatment. Abdominal ultrasound revealed plication of the small intestine and fluid accumulation proximal to the lesion, and a linear foreign body was suspected. An exploratory celiotomy showed cocoon-like encapsulation of the entire intestine. Surgical adhesiolysis and full-thickness biopsy were performed, and histopathologic examination revealed mild thickening of the visceral peritoneum with fibrin deposition, as well as mild neutrophil and lymphocyte infiltration. These findings were compatible with sclerosing encapsulating peritonitis (SEP). The cat recovered well postoperatively and was discharged the next day. Prednisolone was administered for 7 weeks to prevent recurrence of SEP. Five months after surgery, the cat was re-presented with anorexia and chronic vomiting. Based on the clinical examination findings, recurrent SEP was suspected. At the second surgery, surgical adhesiolysis was repeated and a bioresorbable hyaluronate-carboxymethylcellulose membrane was used to cover the serosal surface and thus prevent adhesion formation. Histopathologic findings of the peritoneal biopsy specimen confirmed SEP. Long-term prednisolone treatment (1 mg/kg for the first dose and 0.5 mg/kg every 48 h for maintenance) was administered postoperatively. The cat survived for more than 1239 days without recurrence. Relevance and novel information: To our knowledge, this is the first report of SEP in a cat with long-term survival. The use of a bioresorbable hyaluronate-carboxymethylcellulose membrane and long-term prednisolone treatment may have prevented short-term and long-term recurrence, respectively, in this case.

Safety and clinical efficacy of an anti-PD-L1 antibody (c4G12) in dogs with advanced malignant tumours.

Immune checkpoint inhibitors (ICIs) have been developed for canine tumour treatment, and pilot clinical studies have demonstrated their antitumour efficacy in dogs with oral malignant melanoma (OMM). Although ICIs have been approved for various human malignancies, their clinical benefits in other tumour types remain to be elucidated in dogs. Here, we conducted a clinical study of c4G12, a canine chimeric anti-PD-L1 antibody, to assess its safety and efficacy in dogs with various advanced malignant tumours (n = 12) at the Veterinary Teaching Hospital of Hokkaido University from 2018 to 2023. Dogs with digit or foot pad malignant melanoma (n = 4), osteosarcoma (n = 2), hemangiosarcoma (n = 1), transitional cell carcinoma (n = 1), nasal adenocarcinoma (n = 1), B-cell lymphoma (n = 1), or undifferentiated sarcoma (n = 2) were treated with 2 or 5 mg/kg c4G12 every 2 weeks. Treatment-related adverse events of any grade were observed in eight dogs (66.7%), including elevated aspartate aminotransferase (grade 3) in one dog (8.3%) and thrombocytopenia (grade 4) in another dog (8.3%). Among dogs with target disease at baseline (n = 8), as defined by the response evaluation criteria for solid tumours in dogs (cRECIST), one dog with nasal adenocarcinoma and another with osteosarcoma experienced a partial response (PR), with an objective response rate of 25.0% (2 PR out of 8 dogs; 95% confidence interval: 3.2-65.1%). These results suggest that c4G12 is safe and tolerable and shows antitumor effects in dogs with malignant tumours other than OMM. Further clinical studies are warranted to identify the tumour types that are most likely to benefit from c4G12 treatment.

An inflammatory bowel disease-associated SNP increases local thyroglobulin expression to develop inflammation in miniature dachshunds.

Inflammatory colorectal polyp (ICRP) in miniature dachshunds (MDs) is a chronic inflammatory bowel disease (IBD) characterized by granulomatous inflammation that consists of neutrophil infiltration and goblet cell hyperplasia in the colon. Recently, we identified five MD-associated single-nucleotide polymorphisms (SNPs), namely PLG, TCOF1, TG, COL9A2, and COL4A4, by whole-exome sequencing. Here, we investigated whether TG c.4567C>T (p.R1523W) is associated with the ICRP pathology. We found that the frequency of the T/T SNP risk allele was significantly increased in MDs with ICRP. In vitro experiments showed that TG expression in non-immune cells was increased by inducing the IL-6 amplifier with IL-6 and TNF-α. On the other hand, a deficiency of TG suppressed the IL-6 amplifier. Moreover, recombinant TG treatment enhanced the activation of the IL-6 amplifier, suggesting that TG is both a positive regulator and a target of the IL-6 amplifier. We also found that TG expression together with two NF-κB targets, IL6 and CCL2, was increased in colon samples isolated from MDs with the T/T risk allele compared to those with the C/C non-risk allele, but serum TG was not increased. Cumulatively, these results suggest that the T/T SNP is an expression quantitative trait locus (eQTL) of TG mRNA in the colon, and local TG expression triggered by this SNP increases the risk of ICRP in MDs via the IL-6 amplifier. Therefore, TG c.4567C>T is a diagnostic target for ICRP in MDs, and TG-mediated IL-6 amplifier activation in the colon is a possible therapeutic target for ICRP.

Diverse genome-wide DNA methylation alterations in canine hepatocellular tumours.

BACKGROUND: Canine hepatocellular tumours (HCTs) are common primary liver tumours. However, the exact mechanisms of tumourigenesis remain unclear. Although some genetic mutations have been reported, DNA methylation alterations in canine HCT have not been well studied. OBJECTIVES: In this study, we aimed to analyse the DNA methylation status of canine HCT. METHODS: Tissues from 33 hepatocellular carcinomas, 3 hepatocellular adenomas, 1 nodular hyperplasia, 21 non-tumour livers from the patients and normal livers from 5 healthy dogs were used. We analysed the DNA methylation levels of 72,367 cytosine-guanine dinucleotides (CpG sites) in all 63 samples. RESULTS AND CONCLUSIONS: Although a large fraction of CpG sites that were highly methylated in the normal liver became hypomethylated in tumours from most patients, we also found some patients with less remarkable change or no change in DNA methylation. Hierarchical clustering analysis revealed that 32 of 37 tumour samples differed from normal livers, although the remaining 5 tumour livers fell into the same cluster as normal livers. In addition, the number of hypermethylated genes in tumour livers varied among tumour cases, suggesting various DNA methylation patterns in different tumour groups. However, patient and clinical parameters, such as age, were not associated with DNA methylation status. In conclusion, we found that HCTs undergo aberrant and diverse patterns of genome-wide DNA methylation compared with normal liver tissue, suggesting a complex epigenetic mechanism in canine HCT.

Investigation of the therapeutic effects, predictors, and complications of long-term immunosuppressive therapy in dogs with precursor-targeted immune-mediated anemia.

Dogs with precursor-targeted immune-mediated anemia (PIMA) are commonly treated with immunosuppressive therapy, but information on predictors of treatment response and response time is limited. Therefore, we retrospectively investigated predictive factors that influenced the treatment response and duration required to observe a response in dogs with PIMA receiving continuous immunosuppressive therapies for more than 105 days. Of 50 client-owned dogs that developed PIMA, 27 were included in this study, of which 18 were responders and 9 were non-responders to immunosuppressive therapies. Sixteen of the 18 responders responded to treatment within 60 days and the remaining 2 responded at 93 and 126 days, respectively. We found that an erythroid-maturation ratio of <0.17 may be a useful predictor for treatment response. In addition, complications of immunosuppressive therapies were investigated further in 50 dogs. Pancreatitis (n=4) and pneumonia (3) occurred over the entire treatment period, and infections such as abscesses (3) tended to be more common in dogs on an extended period of immunosuppressive therapy. These findings may be helpful when planning for the initial treatment and may provide evidence for informed consent about potential comorbidities throughout the treatment course.

Effectiveness of 2-dimensional shear wave elastography for noninvasive and reliable estimation of right atrial pressure in dogs with induced volume overload.

BACKGROUND: Two-dimensional shear wave elastography (2D-SWE) provides information on hepatic elastic modulus as shear wave velocity (SWV). HYPOTHESIS/OBJECTIVES: To assess SWV using 2D-SWE in dogs with induced volume overload, investigate the relationship between this information and right atrial pressure (RAP) measured by invasive right heart catheterization, and also evaluate the difference in SWV before and after diuretic administration. ANIMALS: Six healthy beagles. METHODS: Prospective experimental study. Right heart catheterization and 2D-SWE were performed in 6 anesthetized beagles at baseline and after the induction of volume overload. Volume overload was induced by IV hydroxyethyl starch 70/0.5 infusion (100 mL/kg/h). Furosemide (4-6 mg/kg, IV) was administered, and the SWVs were measured. RESULTS: Shear wave velocity showed a significant gradual increase during acute volume overload compared to baseline. SWV was significantly positively correlated with RAP (P < .0001, ρ = 0.9729). The area under the curve of SWV to predict RAP at >10, >15, and >20 mm Hg was 0.9896 (95% confidence interval [95% CI], 0.9690-1.000), 0.9907 (95% CI, 0.9701-1.000), and 0.9722 (95% CI, 0.9280-1.000), respectively. The SWV after diuretic use decreased significantly. CONCLUSIONS AND CLINICAL IMPORTANCE: Two-dimensional shear wave elastography might be useful for noninvasive and reliable estimation of RAP in dogs with acute volume overload and has potential as a quantitative biomarker for evaluating therapeutic response in dogs with right sided congestive heart failure.

Zoobiquity experiments show the importance of the local MMP9-plasminogen axis in inflammatory bowel diseases in both dogs and patients.

Using a zoobiquity concept, we directly connect animal phenotypes to a human disease mechanism: the reduction of local plasminogen levels caused by matrix metalloproteinase-9 (MMP9) activity is associated with the development of inflammation in the intestines of dogs and patients with inflammatory bowel disease. We first investigated inflammatory colorectal polyps (ICRPs), which are a canine gastrointestinal disease characterized by the presence of idiopathic chronic inflammation, in Miniature Dachshund (MD) and found 31 missense disease-associated SNPs by whole-exome sequencing. We sequenced them in 10 other dog breeds and found five, PLG, TCOF1, TG, COL9A2 and COL4A4, only in MD. We then investigated two rare and breed-specific missense SNPs (T/T SNPs), PLG: c.477G > T and c.478A>T, and found that ICRPs with the T/T SNP risk alleles showed less intact plasminogen and plasmin activity in the lesions compared to ICRPs without the risk alleles but no differences in serum. Moreover, we show that MMP9, which is an NF-κB target, caused the plasminogen reduction and that intestinal epithelial cells expressing plasminogen molecules were co-localized with epithelial cells expressing MMP9 in normal colons with the risk alleles. Importantly, MMP9 expression in patients with ulcerous colitis or Crohn's disease also co-localized with epithelial cells showing enhanced NF-κB activation and less plasminogen expression. Overall, our zoobiquity experiments showed that MMP9 induces the plasminogen reduction in the intestine, contributing to the development of local inflammation and suggesting the local MMP9-plasminogen axis is a therapeutic target in both dogs and patients. Therefore, zoobiquity-type experiments could bring new perspectives for biomarkers and therapeutic targets.

Generation of functional oocytes from male mice in vitro.

Sex chromosome disorders severely compromise gametogenesis in both males and females. In oogenesis, the presence of an additional Y chromosome or the loss of an X chromosome disturbs the robust production of oocytes1-5. Here we efficiently converted the XY chromosome set to XX without an additional Y chromosome in mouse pluripotent stem (PS) cells. In addition, this chromosomal alteration successfully eradicated trisomy 16, a model of Down's syndrome, in PS cells. Artificially produced euploid XX PS cells differentiated into mature oocytes in culture with similar efficiency to native XX PS cells. Using this method, we differentiated induced pluripotent stem cells from the tail of a sexually mature male mouse into fully potent oocytes, which gave rise to offspring after fertilization. This study provides insights that could ameliorate infertility caused by sex chromosome or autosomal disorders, and opens the possibility of bipaternal reproduction.

Molecular characterization of feline immune checkpoint molecules and establishment of PD-L1 immunohistochemistry for feline tumors.

Spontaneous tumors are a major cause of death in cats. Treatment of human tumors has progressed dramatically in the past decade, partly due to the success of immunotherapies using immune checkpoint inhibitors, such as anti-programmed death 1 (PD-1) and anti-PD-ligand 1 (PD-L1) antibodies. However, little is known about the PD-1 pathway and its association with tumor disease in cats. This study investigated the applicability of anti-PD-1/PD-L1 therapy in feline tumors. We first determined the complete coding sequence of feline PD-L1 and PD-L2, and found that the deduced amino acid sequences of feline PD-L1/PD-L2 share high sequence identities (66-83%) with orthologs in other mammalian species. We prepared recombinant feline PD-1, PD-L1, and PD-L2 proteins and confirmed receptor-ligand binding between PD-1 and PD-L1/PD-L2 using flow cytometry. Next, we established an anti-feline PD-L1 monoclonal antibody (clone CL1Mab-7) to analyze the expression of PD-L1. Flow cytometry using CL1Mab-7 revealed the cell surface expression of PD-L1 in a feline macrophage (Fcwf-4) and five mammary adenocarcinoma cell lines (FKNp, FMCm, FYMp, FONp, and FONm), and showed that PD-L1 expression was upregulated by interferon-γ stimulation. Finally, immunohistochemistry using CL1Mab-7 also showed PD-L1 expression in feline squamous cell carcinoma (5/5, 100%), mammary adenocarcinoma (4/5, 80%), fibrosarcoma (5/5, 100%), and renal cell carcinoma (2/2, 100%) tissues. Our results strongly encourage further investigations of the PD-1/PD-L1 pathway as a potential therapeutic target for feline tumors.

The effects of pregnancy discrimination on postpartum depressive symptoms: a follow-up study.

BACKGROUND: Pregnancy discrimination in the workplace is prevalent worldwide. However, few studies have examined the effects of pregnancy discrimination on mothers' perinatal mental health. We aimed to investigate the association between pregnancy discrimination and postpartum depressive symptoms, and the mediation effects of prenatal depressive symptoms on this association. METHODS: Our sample consisted of 285 Japanese women employed during pregnancy who completed a baseline online survey in May 2020 and a follow-up mail survey two months postpartum. Pregnancy discrimination was defined as exposure to any of 16 forms of disadvantageous treatment or harassment related to pregnancy, prohibited by national guidelines. Prenatal (assessed at baseline) and postpartum (assessed at follow-up) depressive symptoms were measured using the Edinburgh Postnatal Depression Scale. Multiple linear regression and mediation analyses were performed overall and stratified by regular (permanent) and non-regular (precarious) employees. RESULTS: Overall, 23.9% of participants experienced pregnancy discrimination during pregnancy. After adjusting for potential confounders, pregnancy discrimination was significantly associated with postpartum depressive symptoms (coefficient 1.76, 95% confidence interval [CI] 0.65-2.88). When stratified by employment type, these effects were observable among non-regular employees (coefficient 2.51, 95% CI 0.45-4.57) but not regular employees. Mediation analysis showed that prenatal depressive symptoms mediated 57.1% (95% CI 20.1-94.1%) of the association between pregnancy discrimination and postpartum depressive symptoms among all participants, with a greater effect among non-regular employees (64.1% [95% CI 18.5-109.8%]). CONCLUSIONS: Pregnancy discrimination has adverse effects on postpartum depressive symptoms, partially through prenatal depressive symptoms, especially among non-regular employees. To prevent perinatal depression in female workers, employers should comply with legislation and take preventive measures against pregnancy discrimination, while considering vulnerable employees.

Ex vivo reconstitution of fetal oocyte development in humans and cynomolgus monkeys.

In vitro oogenesis is key to elucidating the mechanism of human female germ-cell development and its anomalies. Accordingly, pluripotent stem cells have been induced into primordial germ cell-like cells and into oogonia with epigenetic reprogramming, yet further reconstitutions remain a challenge. Here, we demonstrate ex vivo reconstitution of fetal oocyte development in both humans and cynomolgus monkeys (Macaca fascicularis). With an optimized culture of fetal ovary reaggregates over three months, human and monkey oogonia enter and complete the first meiotic prophase to differentiate into diplotene oocytes that form primordial follicles, the source for oogenesis in adults. The cytological and transcriptomic progressions of fetal oocyte development in vitro closely recapitulate those in vivo. A comparison of single-cell transcriptomes among humans, monkeys, and mice unravels primate-specific and conserved programs driving fetal oocyte development, the former including a distinct transcriptomic transformation upon oogonia-to-oocyte transition and the latter including two active X chromosomes with little X-chromosome upregulation. Our study provides a critical step forward for realizing human in vitro oogenesis and uncovers salient characteristics of fetal oocyte development in primates.

Local cerebral blood flow assessment using transcranial Doppler ultrasonography in a dog with brain infarction in the right middle cerebral artery territory.

A 12-year-old neutered male Chihuahua was diagnosed with acute brain infarction in the right middle cerebral artery (MCA) territory. Transcranial Doppler ultrasonography (TCD) was performed to assess the local cerebral blood flow at the time of diagnosis and after 4 and 31 hr. Initially, the right MCA retained blood flow but with a lower cerebral blood flow velocity (CBFV; 14.9 cm/sec) than the left MCA (27.9 cm/sec). The TCD vascular resistance variables were higher in the right than in the left MCA. An increase in the CBFV and a decrease in TCD vascular resistance variables were observed, consistent with improvements in neurological symptoms. TCD can be a non-invasive, and easy-to-use modality for bedside monitoring of cerebral edema and infarction.

Optimized protocol to derive germline stem-cell-like cells from mouse pluripotent stem cells.

Male germ-cell development comprises primordial germ-cell (PGC) development, spermatogonium differentiation, and ensuing spermatogenesis. We present a step-by-step protocol for differentiation of mouse pluripotent stem cells (PSCs) into germline stem-cell-like cells (GSCLCs) via PGC-like cell and spermatogonium-like cell intermediates. The differentiation protocol has higher fidelity than our previous protocol. Upon transplantation into testes in vivo or culture for testis transplants, GSCLCs robustly contribute to spermatogenesis, providing a paradigm for PSC-based reconstitution of mammalian male germ-cell development. For complete details on the use and execution of this protocol, please refer to Ishikura et al. (2021).

Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy.

Immune checkpoint inhibitors (ICIs) such as anti-PD-L1 antibodies are widely used to treat human cancers, and growing evidence suggests that ICIs are promising treatments for canine malignancies. However, only some canine oral malignant melanoma (OMM) cases respond to ICIs. To explore biomarkers predictive of survival in dogs with pulmonary metastatic OMM receiving the anti-PD-L1 antibody c4G12 (n = 27), serum concentrations of prostaglandin E2 (PGE2), cytokines, chemokines, and growth factors were measured prior to treatment initiation. Among 12 factors tested, PGE2, interleukin (IL)-12p40, IL-8, monocyte chemotactic protein-1 (MCP-1), and stem cell factor (SCF) were higher in OMM dogs compared to healthy dogs (n = 8). Further, lower baseline serum PGE2, MCP-1, and vascular endothelial growth factor (VEGF)-A concentrations as well as higher IL-2, IL-12, and SCF concentrations predicted prolonged overall survival. These observations suggest that PGE2 confers resistance against anti-PD-L1 therapy through immunosuppression and thus is a candidate target for combination therapy. Indeed, PGE2 suppressed IL-2 and interferon (IFN)-γ production by stimulated canine peripheral blood mononuclear cells (PBMCs), while inhibition of PGE2 biosynthesis using the COX-2 inhibitor meloxicam in combination with c4G12 enhanced Th1 cytokine production by PBMCs. Thus, serum PGE2 may be predictive of c4G12 treatment response, and concomitant use of COX-2 inhibitors may enhance ICI antitumor efficacy.

Successful robotic proximal gastrectomy with side overlap esophagogastrostomy following preoperative chemotherapy: A case report.

INTRODUCTION AND IMPORTANCE: Adenocarcinoma of the esophagogastric junction (AEJ) has been on the rise in recent years, but the technical aspects of reconstruction and reflux prevention are unsolved problems. This case report aimed to illustrate the usefulness of preoperative chemotherapy for tumor shrinkage and the advantage of robotic surgery for stable reconstruction with reflux prevention. CASE PRESENTATION: A 69-year-old male patient was diagnosed with AEJ cT3N0M0 cStage IIB. Three courses of doublet chemotherapy with 80 mg/m2/day of S-1 on days 1-14 and 100 mg/m2 of oxaliplatin on day 1 were administered every 3 weeks before surgery. After chemotherapy, the tumor shrunk, and the proximal margin changed from 1.5 cm above the esophagogastric junction (EGJ) to be the gastric side of the EGJ. A radical robotic proximal gastrectomy with D2 lymphadenectomy was performed. Since sufficient length of the esophagus was secured in the hiatus due to tumor shrinkage, reconstruction was performed by the side-overlap esophagogastrostomy (mSOFY) method. The postoperative course was uneventful with no reflux symptoms two months after surgery, even without medication. CLINICAL DISCUSSION: Preoperative chemotherapy is expected to improve the rates of complete resection and survival. In the present case, preoperative treatment with SOX resulted in tumor shrinkage, which enabled reconstruction using the mSOFY method. Robotic surgery may be useful for such complex reconstruction procedures. CONCLUSION: To our knowledge, this is the first report of robotic reconstruction using the mSOFY method after proximal gastrectomy for AEG tumors. This work was reported in line with the SCARE 2020 criteria.

Nucleome programming is required for the foundation of totipotency in mammalian germline development.

Germ cells are unique in engendering totipotency, yet the mechanisms underlying this capacity remain elusive. Here, we perform comprehensive and in-depth nucleome analysis of mouse germ-cell development in vitro, encompassing pluripotent precursors, primordial germ cells (PGCs) before and after epigenetic reprogramming, and spermatogonia/spermatogonial stem cells (SSCs). Although epigenetic reprogramming, including genome-wide DNA de-methylation, creates broadly open chromatin with abundant enhancer-like signatures, the augmented chromatin insulation safeguards transcriptional fidelity. These insulatory constraints are then erased en masse for spermatogonial development. Notably, despite distinguishing epigenetic programming, including global DNA re-methylation, the PGCs-to-spermatogonia/SSCs development entails further euchromatization. This accompanies substantial erasure of lamina-associated domains, generating spermatogonia/SSCs with a minimal peripheral attachment of chromatin except for pericentromeres-an architecture conserved in primates. Accordingly, faulty nucleome maturation, including persistent insulation and improper euchromatization, leads to impaired spermatogenic potential. Given that PGCs after epigenetic reprogramming serve as oogenic progenitors as well, our findings elucidate a principle for the nucleome programming that creates gametogenic progenitors in both sexes, defining a basis for nuclear totipotency.

Characterization of mucin gene expression and goblet cell proportion in inflammatory colorectal polyps in miniature dachshunds.

Hyperplastic goblet cells and abundant mucus are significant characteristics of inflammatory colorectal polyps (ICRPs) in miniature dachshunds. In this study, selected mucin gene expressions and goblet cell proportions were evaluated in miniature dachshunds with ICRPs and in healthy dogs. Mucin 2 (MUC2) gene expression was not significantly different among the groups, whereas mucin 5AC (MUC5AC) gene expression was significantly higher in the polypoid lesions than in healthy colonic mucosa. Although the percentage of goblet cells in the upper crypt regions did not significantly differ between the groups, that in the lower crypt regions was significantly decreased in polypoid lesions. In conclusion, increased MUC5AC gene expression and goblet cell proportion changes may be associated with the pathogenesis of ICRPs.

Design, synthesis and biological evaluation of novel indole derivatives as gut-selective NaPi2b inhibitors.

Intestinal sodium-dependent phosphate transport protein 2b (SLC34A2, NaPi2b) inhibitors are expected to be potential new candidates for anti-hyperphosphatemia drugs. However, a risk of on-target side effects based on the inhibition of NaPi2b in the lung and testis has been reported.In this article, we report on our identification of novel indole derivatives as gut-selective NaPi2b inhibitors with good activity, low systemic exposure and moderate hydrophobicity.In particular, gut-selective compound 27, with even lower bioavailability and lower systemic exposure as compared to previously reported pyridine derivatives, demonstrated excellent phosphate absorption-inhibitory effect in SD rats. Compound 27 has an ideal profile and appears to offer promise as a candidate drug for the treatment of hyperphosphatemia, with minimal risk of side effects due to systemic exposure.