Publications by authors named "Tomoko Kobayashi"

190 Publications

GABA receptor signaling in the caudate putamen is involved in binge-like consumption during a high fat diet in mice.

Sci Rep 2021 Sep 29;11(1):19296. Epub 2021 Sep 29.

Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan.

Previous studies suggest that signaling by the gamma-aminobutyric acid (GABA) type B receptor (GABAR) is involved in the regulation of binge eating, a disorder which might contribute to the development of obesity. Here, we show that intermittent access to a high fat diet (HFD) induced binge-like eating behavior with activation of dopamine receptor d1 (drd1)-expressing neurons in the caudate putamen (CPu) and nucleus accumbens (NAc) in wild-type (WT) mice. The activation of drd1-expressing neurons during binge-like eating was substantially increased in the CPu, but not in the NAc, in corticostriatal neuron-specific GABAR-deficient knockout (KO) mice compared to WT mice. Treatment with the GABAR agonist, baclofen, suppressed binge-like eating behavior in WT mice, but not in KO mice, as reported previously. Baclofen also suppressed the activation of drd1-expressing neurons in the CPu, but not in the NAc, during binge-like eating in WT mice. Thus, our data suggest that GABAR signaling in CPu neurons expressing drd1 suppresses binge-like consumption during a HFD in mice.
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http://dx.doi.org/10.1038/s41598-021-98590-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481241PMC
September 2021

Neonatal streptozotocin treatment rapidly causes different subtype of hepatocellular carcinoma without persistent hyperglycemia in 4CS mice fed on a normal diet.

Pathol Res Pract 2021 Sep 21;225:153559. Epub 2021 Jul 21.

Department of Pathology and Laboratory Medicine and Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503, Japan; Molecular Pathology and Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503, Japan. Electronic address:

Although diabetes mellitus (DM) is a well-known risk factor for hepatocellular carcinoma (HCC), the underlying mechanisms have not yet to be defined. We previously reported that DIAR mice fed with standard murine diet developed type 1 diabetes and HCC at age of 16 weeks old with a neonatal streptozotocin treatment (n-STZ). Because DIAR mice did not manifest obesity nor develop steatohepatitis, hyperglycemia with streptozotocin trigger or streptozotocin alone might turn on the hepato-carcinogenesis. An insulin-recruitment to DIAR-nSTZ mice showed an increased frequency of HCC during the first 12 weeks of age, although the diabetic indications notably improved. To elucidate the role of hyperglycemia in hepato-carcinogenesis, we performed a head-to-head comparative study by using 4CS mice and DIAR mice with n-STZ treatment. Newborn 4CS mice and DIAR mice were divided into STZ treated group and control group. The blood glucose levels of DIAR-nSTZ mice increased at age of eight weeks, while that of 4CS-nSTZ mice were maintained in the normal range. At eight weeks old, three out of five DIAR-nSTZ mice (60%) and one out of ten 4CS-nSTZ mice (10%) developed multiple liver tumors. At age of 12 weeks old, all eight of DIAR-nSTZ mice (100%) and two of 10 4CS-nSTZ mice (20%) developed multiple liver tumors. At 16 weeks old, all animals of DIAR-nSTZ and 4CS-nSTZ mice occurred liver tumors. DIAR-nSTZ showed hyperglycemia and HCC, and 4CS-nSTZ developed HCC without hyperglycemia. These results were interpreted that the onset of HCC maybe not related to the presence or absence of hyperglycemia but nSTZ treatment. On the other hand, since the carcinogenesis of 4CS-nSTZ is delayed compared to DIAR-nSTZ, hyperglycemia may play a role in the progression of carcinogenesis. Histologically, the liver tumor appeared irregularly trabecular arrangements of hepatocytes with various degrees of nuclear atypia. By immunohistochemical analyses, all liver tumors showed positive staining of glutamine synthetase (GS), an established human HCC marker. The expression pattern of GS was divided into a strong diffuse pattern and weak patchy pattern, respectively. The liver tumor showing the weak GS-patchy pattern expressed biliary/stem markers, EpCAM, and SALL4, partially. Because 4CS-nSTZ mice did not show any metabolic complications such as gaining body weight or high blood glucose level, it is a unique animal model with a simple condition to investigate hepatic carcinogenesis by excluding other factors.
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http://dx.doi.org/10.1016/j.prp.2021.153559DOI Listing
September 2021

Adult-onset autoimmune diabetes identified by glutamic acid decarboxylase autoantibodies: a retrospective cohort study.

Diabetologia 2021 Oct 15;64(10):2183-2192. Epub 2021 Jul 15.

Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Aims/hypothesis: Patients with GAD antibodies (GADAb) showing clinical features of type 2 diabetes typically exhibit progression to an insulin-dependent state in several months or years. This condition is diagnosed as slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) or latent autoimmune diabetes in adults, a subtype of adult-onset autoimmune diabetes. However, some patients diagnosed with adult-onset autoimmune diabetes do not progress to an insulin-dependent state. We conducted a retrospective cohort study to identify patients with non-insulin-dependent diabetes among those diagnosed with adult-onset autoimmune diabetes using measurable indicators in routine clinical practice.

Methods: We surveyed data from the electronic medical records of all patients with GADAb from eight medical centres in Japan for selecting and analysing patients who matched the diagnostic criteria of SPIDDM.

Results: Overall, 345 patients were analysed; of these, 162 initiated insulin therapy (insulin therapy group), whereas 183 did not (non-insulin therapy group) during the follow-up period (median 3.0 years). Patients in the non-insulin therapy group were more likely to be male and presented a later diabetes onset, shorter duration of diabetes, higher BMI, higher blood pressure levels, lower HbA levels, lower GADAb levels and lesser antidiabetic agent use than those in the insulin therapy group when GADAb was first identified as positive. A Cox proportional hazards model showed that BMI, HbA levels and GADAb levels were independent factors for progression to insulin therapy. Kaplan-Meier analyses revealed that 86.0% of the patients with diabetes having GADAb who presented all three factors (BMI ≥ 22 kg/m, HbA < 75 mmol/mol [9.0%] and GADAb <10.0 U/ml) did not require insulin therapy for 4 years.

Conclusions/interpretation: Higher BMI (≥22 kg/m), lower HbA (<75 mmol/mol [9.0%]) and lower GADAb levels (<10.0 U/ml) can predict a non-insulin-dependent state for at least several years in Japanese patients with diabetes having GADAb.
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http://dx.doi.org/10.1007/s00125-021-05516-1DOI Listing
October 2021

Assessment of myocardial performance index in late-onset fetal growth restriction.

Nagoya J Med Sci 2021 May;83(2):259-268

Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

The aim of this study is to determine whether the myocardial performance index (MPI) is increased in fetal growth restriction (FGR) fetuses and if increased MPI is related to adverse outcomes of FGR. This is a prospective cross-sectional study. Seventy-three late-onset FGR fetuses and 97 gestational-age matched control fetuses were enrolled in this study. Fetal blood flow parameters including MPI values were measured and compared between the two groups. For the effect of severity of growth restriction on MPI value, they were also compared with < 3 and 3 - 10 centile groups. FGR fetuses were divided into two groups by favorable and adverse outcome and ultrasound parameters were compared between these two groups. Moreover, significant factors related to adverse outcomes by univariate analysis were analyzed by multivariate logistic regression analysis. Pulsatility index of umbilical arterial flow (UA-PI), MPI and amniotic fluid index in the FGR were significantly different from the control fetuses. However, no significant difference between < 3 and 3 - 10 centile groups was detected in MPI and UA-PI. The increased levels of MPI and UA-PI were independently related with adverse outcome of late-onset FGR pregnancy. In conclusion, MPI values were increased in late-onset FGR pregnancy, and the higher level of MPI could predict adverse outcome as well as the measurement of UA-PI. Clinicians should consider cardiac dysfunction in FGR through increased MPI.
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http://dx.doi.org/10.18999/nagjms.83.2.259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236689PMC
May 2021

The return of individual genomic results to research participants: design and pilot study of Tohoku Medical Megabank Project.

J Hum Genet 2021 Jul 8. Epub 2021 Jul 8.

Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Miyagi, Japan.

Certain large genome cohort studies attempt to return the individual genomic results to the participants; however, the implementation process and psychosocial impacts remain largely unknown. The Tohoku Medical Megabank Project has conducted large genome cohort studies of general residents. To implement the disclosure of individual genomic results, we extracted the potential challenges and obstacles. Major challenges include the determination of genes/disorders based on the current medical system in Japan, the storage of results, prevention of misunderstanding, and collaboration of medical professionals. To overcome these challenges, we plan to conduct multilayer pilot studies, which deal with different disorders/genes. We finally chose familial hypercholesterolemia (FH) as a target disease for the first pilot study. Of the 665 eligible candidates, 33.5% were interested in the pilot study and provided consent after an educational "genetics workshop" on the basic genetics and medical facts of FH. The genetics professionals disclosed the results to the participants. All positive participants were referred to medical care, and a serial questionnaire revealed no significant psychosocial distress after the disclosure. Return of genomic results to research participants was implemented using a well-prepared protocol. To further elucidate the impact of different disorders, we will perform multilayer pilot studies with different disorders, including actionable pharmacogenomics and hereditary tumor syndromes.
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http://dx.doi.org/10.1038/s10038-021-00952-8DOI Listing
July 2021

Different cholinergic cell groups in the basal forebrain regulate social interaction and social recognition memory.

Sci Rep 2021 06 30;11(1):13589. Epub 2021 Jun 30.

Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan.

Social behaviour is a complex construct that is reported to include several components of social approach, interaction and recognition memory. Alzheimer's disease (AD) is mainly characterized by progressive dementia and is accompanied by cognitive impairments, including a decline in social ability. The cholinergic system is a potential constituent for the neural mechanisms underlying social behaviour, and impaired social ability in AD may have a cholinergic basis. However, the involvement of cholinergic function in social behaviour has not yet been fully understood. Here, we performed a selective elimination of cholinergic cell groups in the basal forebrain in mice to examine the role of cholinergic function in social interaction and social recognition memory by using the three-chamber test. Elimination of cholinergic neurons in the medial septum (MS) and vertical diagonal band of Broca (vDB) caused impairment in social interaction, whereas ablating cholinergic neurons in the nucleus basalis magnocellularis (NBM) impaired social recognition memory. These impairments were restored by treatment with cholinesterase inhibitors, leading to cholinergic system activation. Our findings indicate distinct roles of MS/vDB and NBM cholinergic neurons in social interaction and social recognition memory, suggesting that cholinergic dysfunction may explain social ability deficits associated with AD symptoms.
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http://dx.doi.org/10.1038/s41598-021-93045-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245640PMC
June 2021

Glucocorticoid receptor signaling in ventral tegmental area neurons increases the rewarding value of a high-fat diet in mice.

Sci Rep 2021 06 18;11(1):12873. Epub 2021 Jun 18.

Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Turumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan.

The reward system, which consists of dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens and caudate-putamen in the striatum, has an important role in the pathogenesis of not only drug addiction but also diet-induced obesity. In the present study, we examined whether signaling through glucocorticoid receptors (GRs) in the reward system affects the rewarding value of a high-fat diet (HFD). To do so, we generated mice that lack functional GRs specifically in dopaminergic neurons (D-KO mice) or corticostriatal neurons (CS-KO mice), subjected the mice to caloric restriction stress conditions, and evaluated the rewarding value of a HFD by conditioned place preference (CPP) test. Caloric restriction induced increases in serum corticosterone to similar levels in all genotypes. While CS-KO as well as WT mice exhibited a significant preference for HFD in the CPP test, D-KO mice exhibited no such preference. There were no differences between WT and D-KO mice in consumption of HFD after fasting or cognitive function evaluated by a novel object recognition test. These data suggest that glucocorticoid signaling in the VTA increases the rewarding value of a HFD under restricted caloric stress.
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http://dx.doi.org/10.1038/s41598-021-92386-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213822PMC
June 2021

Necroptosis protects against exacerbation of acute pancreatitis.

Cell Death Dis 2021 06 10;12(6):601. Epub 2021 Jun 10.

Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Tokushima, Japan.

The sensing of various extrinsic stimuli triggers the receptor-interacting protein kinase-3 (RIPK3)-mediated signaling pathway, which leads to mixed-lineage kinase-like (MLKL) phosphorylation followed by necroptosis. Although necroptosis is a form of cell death and is involved in inflammatory conditions, the roles of necroptosis in acute pancreatitis (AP) remain unclear. In the current study, we administered caerulein to Ripk3- or Mlkl-deficient mice (Ripk3 or Mlkl mice, respectively) and assessed the roles of necroptosis in AP. We found that Ripk3 mice had significantly more severe pancreatic edema and inflammation associated with macrophage and neutrophil infiltration than control mice. Consistently, Mlkl mice were more susceptible to caerulein-induced AP, which occurred in a time- and dose-dependent manner, than control mice. Mlkl mice exhibit weight loss, edematous pancreatitis, necrotizing pancreatitis, and acinar cell dedifferentiation in response to tissue damage. Genetic deletion of Mlkl resulted in downregulation of the antiapoptotic genes Bclxl and Cflar in association with increases in the numbers of apoptotic cells, as detected by TUNEL assay. These findings suggest that RIPK3 and MLKL-mediated necroptosis exerts protective effects in AP and caution against the use of necroptosis inhibitors for AP treatment.
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http://dx.doi.org/10.1038/s41419-021-03847-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192754PMC
June 2021

Applying Probe Electrospray Ionization Mass Spectrometry to Cytological Diagnosis: A Preliminary Study by Using Cultured Lung Cancer Cells.

Acta Cytol 2021 7;65(5):430-439. Epub 2021 Jun 7.

Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan,

Objectives: Cytology and histology are 2 indispensable diagnostic tools for cancer diagnosis, which are rapidly increasing in importance with aging populations. We applied mass spectrometry (MS) as a rapid approach for swiftly acquiring nonmorphological information of interested cells. Conventional MS, which primarily rely on promoting ionization by pre-applying a matrix to cells, has the drawback of time-consuming both on data acquisition and analysis. As an emerging method, probe electrospray ionization-MS (PESI-MS) with a dedicated probe is capable to pierce sample and measure specimen in small amounts, either liquid or solid, without the requirement for sample pretreatment. Furthermore, PESI-MS is timesaving compared to the conventional MS. Herein, we investigated the capability of PESI-MS to characterize the cell types derived from the respiratory tract of human tissues.

Study Design: PESI-MS analyses with DPiMS-2020 were performed on various type of cultured cells including 5 lung squamous cell carcinomas, 5 lung adenocarcinomas, 5 small-cell carcinomas, 4 malignant mesotheliomas, and 2 normal controls.

Results: Several characteristic peaks were detected at around m/z 200 and 800 that were common in all samples. As expected, partial least squares-discriminant analysis of PESI-MS data distinguished the cancer cell types from normal control cells. Moreover, distinct clusters divided squamous cell carcinoma from adenocarcinoma.

Conclusion: PESI-MS presented a promising potential as a novel diagnostic modality for swiftly acquiring specific cytological information.
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http://dx.doi.org/10.1159/000516639DOI Listing
September 2021

Hypertension and dyslipidemia are risk factors for herpes zoster in patients with rheumatoid arthritis: a retrospective analysis using a medical information database.

Rheumatol Int 2021 Sep 6;41(9):1633-1639. Epub 2021 Jun 6.

Department of Epidemiology and Preventive Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.

This study used data from a large-scale multicenter medical information database in Japan to estimate the incidence rate of herpes zoster (HZ) and to examine the relationship between hypertension, dyslipidemia, and diabetes mellitus (DM), and the risk of HZ among patients with rheumatoid arthritis (RA). The research dataset consisted of 221,196 records of potential target patients with RA extracted between April 1, 2008 and August 31, 2017 from the Medical Data Vision database. To assess the association between hypertension, dyslipidemia, and DM and the risk of HZ, a case-control study was set up. Records of 101,498 study subjects met the inclusion criteria. During the observation period, 2566 patients developed HZ and the overall incidence rate was 5.2 (95% confidence interval: 5.0-5.4 per 1000 patient-years). Hypertension, dyslipidemia, and DM were significantly associated with an increased risk of HZ after adjustment for sex, age, hospital size, and use of anti-rheumatic drugs. When mutual adjustment was made for hypertension, dyslipidemia, and DM, the positive associations between hypertension and dyslipidemia and the risk of HZ remained significant; however, the positive association with DM completely disappeared. RA patients with hypertension or dyslipidemia may be at higher risk of HZ.
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http://dx.doi.org/10.1007/s00296-021-04889-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316192PMC
September 2021

Anti-pituitary antibodies and susceptible human leukocyte antigen alleles as predictive biomarkers for pituitary dysfunction induced by immune checkpoint inhibitors.

J Immunother Cancer 2021 05;9(5)

Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan

Background: Pituitary dysfunction is a life-threatening immune-related adverse event (irAE) induced by immune checkpoint inhibitors (ICIs). To date, it is not possible to identify patients who may develop pituitary irAEs prior to ICI treatment. The aim of this study was to characterize the predisposition for ICI-induced pituitary irAEs by analyzing anti-pituitary antibodies (APAs) and human leukocyte antigens (HLAs).

Methods: In this case-control study, APAs and HLA alleles were analyzed in 62 patients (17 who developed ICI-induced isolated adrenocorticotropic hormone deficiency (ICI-IAD), 5 who developed ICI-induced hypophysitis (ICI-H) and 40 who did not develop pituitary irAEs) treated with ICIs between November 2, 2015, and March 31, 2020, at Nagoya University Hospital. The main outcome measures in this study were the association between the development of pituitary irAEs with APAs at baseline and after treatment and HLA alleles.

Results: Eleven of 17 (64.7%) patients who developed ICI-IAD had APAs at baseline, whereas APAs were positive only in 1 of 40 (2.5%) control patients. Although APAs were negative at baseline in all patients who developed ICI-H, they had become positive before the onset of ICI-H in 3 of 4 patients several weeks after ipilimumab administration. At the onset of ICI-IAD and ICI-H, APAs were positive in 15 of 17 (88.2%) and 4 of 5 (80%) patients, respectively. The prevalence of HLA-Cw12, HLA-DR15, HLA-DQ7, and HLA-DPw9 was significantly higher in patients with ICI-IAD, whereas that of HLA-Cw12 and HLA-DR15 was significantly higher in patients with ICI-H than in controls.

Conclusions: This study showed distinct and overlapped patterns of APAs and HLA alleles between ICI-IAD and ICI-H. Our findings also showed that positive APAs at baseline and after treatment, together with susceptible HLA alleles, could become predictive biomarkers for ICI-IAD and ICI-H, respectively.

Trial Registration Number: UMIN000019024.
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http://dx.doi.org/10.1136/jitc-2021-002493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137231PMC
May 2021

A CASE OF VAGUS NERVE SCHWANNOMA DIFFICULT TO DISTINGUISH FROM LYMPH NODAL METASTASIS OF ESOPHAGEAL CANCER.

J Med Invest 2021 ;68(1.2):205-208

Department of Thoracic, Endocrine Surgery and Oncology, Tokushima University Graduate School.

In this report, we describe a rare case of vagus nerve schwannoma associated with esophageal cancer. A 70-year-old man visited our hospital complaining of worsening dysphagia. His upper gastrointenstinal endoscopy revealed a mass in the esophagus. A contrast-enhanced chest computed tomography also detected a 15 mm nodule attached to the tracheal membrane. This nodule was diagnosed as a metastatic lymph node. Although the primary tumor reduced after neoadjuvant chemotherapy, the nodule remained intact ; it showed fluorodeoxyglucose accumulation on positron emission tomography. We had a clinical diagnosis of stage III after neoadjuvant chemotherapy and underwent surgery. Intraoperatively, the nodule could not be detached from the right vagus nerve ; therefore, we excised the nodule along with the adjacent vagus nerve. The nodule was pathologically diagnosed as a vagus schwannoma. The nodule was not a regional lymph node metastasis of esophageal cancer. His postoperative course was uneventful, and he is currently undergoing outpatient follow-up without recurrence. J. Med. Invest. 68 : 205-208, February, 2021.
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http://dx.doi.org/10.2152/jmi.68.205DOI Listing
January 2021

CD4 T cells are essential for the development of destructive thyroiditis induced by anti-PD-1 antibody in thyroglobulin-immunized mice.

Sci Transl Med 2021 05;13(593)

Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.

Immune-related adverse events induced by anti-programmed cell death-1 antibodies (PD-1-Ab), including destructive thyroiditis (thyroid-irAE), are thought to be caused by activated T cells. However, the T cell subsets that are directly responsible for damaging self-organs remain unclear. To clarify which T cell subsets are involved in the development of thyroid-irAE, a mouse model of thyroid-irAE was analyzed. PD-1-Ab administration 2.5 months after immunization with thyroglobulin caused destructive thyroiditis. Thyroiditis was completely prevented by previous depletion of CD4 T cells and partially prevented by depleting CD8 T cells. The frequencies of central and effector memory CD4 T cell subsets and the secretion of interferon-γ after stimulation with thyroglobulin were increased in the cervical lymph nodes of mice with thyroid-irAE compared with controls. Histopathological analysis revealed infiltration of CD4 T cells expressing granzyme B in thyroid glands and major histocompatibility complex class II expression on thyrocytes in mice with thyroid-irAE. Adoptive transfer of CD4 T cells from cervical lymph nodes in mice with thyroid-irAE caused destruction of thyroid follicular architecture in the irradiated recipient mice. Flow cytometric analyses showed that the frequencies of central and effector memory CD4 T cells expressing the cytotoxic marker CD27 were higher in peripheral blood mononuclear cells collected from patients with thyroid-irAE induced by PD-1-Ab versus those without. These data suggest a critical role for cytotoxic memory CD4 T cells activated by PD-1-Ab in the pathogenesis of thyroid-irAE.
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http://dx.doi.org/10.1126/scitranslmed.abb7495DOI Listing
May 2021

Clinical Characteristics, Management, and Potential Biomarkers of Endocrine Dysfunction Induced by Immune Checkpoint Inhibitors.

Endocrinol Metab (Seoul) 2021 Apr 27;36(2):312-321. Epub 2021 Apr 27.

Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Immune-related adverse events (irAEs) affecting the endocrine glands are among the most frequent irAEs induced by immune checkpoint inhibitors (ICIs) and include hypopituitarism, primary adrenal insufficiency, thyrotoxicosis, hypothyroidism, hypoparathyroidism, and type 1 diabetes mellitus. Since the incidence and clinical features of endocrine irAEs vary according to the ICI used, it is important to understand the characteristics of these irAEs and to manage each one appropriately. Since some endocrine irAEs, including adrenal crisis and diabetic ketoacidosis, are potentially life-threatening, predicting the risk of endocrine irAEs before their onset is critical. Several autoantibodies have been detected in patients who develop endocrine irAEs, among which anti-thyroid antibodies may be predictive biomarkers of thyroid dysfunction. In this review, we describe the clinical features of each endocrine irAE induced by ICIs and discuss their potential biomarkers, including autoantibodies.
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http://dx.doi.org/10.3803/EnM.2021.1007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090479PMC
April 2021

Efficacies of programmed cell death 1 ligand 1 blockade in non-small cell lung cancer patients with acquired resistance to prior programmed cell death 1 inhibitor and development of diabetic ketoacidosis caused by two different etiologies: a retrospective case series.

Endocr J 2021 May 1;68(5):613-620. Epub 2021 May 1.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

The programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis is vital for immune resistance during tumor development, while PD-L1 inhibitors can also inhibit the PD-L1/B7-1 (CD80) interaction, indicating one of the molecular differences between PD-1 and PD-L1 inhibitors. However, the clinical benefits of PD-L1 inhibitors in patients previously treated with PD-1 inhibitors remain unknown. In this study, we retrospectively analyzed the clinical data of eight patients with non-small cell lung cancer who received the PD-L1 inhibitor atezolizumab and previously treated with the PD-1 inhibitor nivolumab. The median progression-free survival was 2.1 months (1.8-18.7 months), and 4 of 8 patients achieved at least stable disease. In two of these patients, atezolizumab treatment resulted in longer progression-free survival (PFS) compared with that of nivolumab. Conversely, one patient exhibited grade 4 diabetic ketoacidosis (DKA) within 2 weeks after the initial administration of atezolizumab. Another patient had developed type 1 diabetes mellitus (T1DM) during the prior nivolumab treatment and then developed DKA due to an infection after the initiation of atezolizumab. Both of them had high-risk human leukocyte antigen-DR/DQ types relevant to T1DM. These results demonstrate the potential efficacy of PD-L1 inhibitors to some tumors that have acquired resistance to PD-1 inhibitors and suggest that appropriate managements are required for not only a newly onset of T1DM but also blood glucose control after the development of T1DM during a reiteration of the PD-1/PD-L1 blockade.
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http://dx.doi.org/10.1507/endocrj.EJ20-0769DOI Listing
May 2021

Comprehensive Investigation on the Interplay between Feline APOBEC3Z3 Proteins and Feline Immunodeficiency Virus Vif Proteins.

J Virol 2021 06 10;95(13):e0017821. Epub 2021 Jun 10.

Laboratory of Systems Virology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.

As the hosts of lentiviruses, almost 40 species of felids (family ) are distributed around the world, and more than 20 feline species test positive for feline immunodeficiency virus (FIV), a lineage of lentiviruses. These observations suggest that FIVs globally infected a variety of feline species through multiple cross-species transmission events during a million-year history. Cellular restriction factors potentially inhibit lentiviral replication and limit cross-species lentiviral transmission, and cellular APOBEC3 deaminases are known as a potent restriction factor. In contrast, lentiviruses have evolutionary-acquired viral infectivity factor (Vif) to neutralize the APOBEC3-mediated antiviral effect. Because the APOBEC3-Vif interaction is strictly specific for viruses and their hosts, a comprehensive investigation focusing on Vif-APOBEC3 interplay can provide clues that will elucidate the roles of this virus-host interplay on cross-species transmission of lentiviruses. Here, we performed a comprehensive investigation with 144 patterns of a round robin test using 18 feline genes, an antiviral gene in felid, and 8 FIV Vifs and derived a matrix showing the interplay between feline APOBEC3Z3 and FIV Vif. We particularly focused on the interplay between the APOBEC3Z3 of three felids (domestic cat, ocelot, and Asian golden cat) and an FIV Vif (strain Petaluma), and revealed that residues 65 and 66 of the APOBEC3Z3 protein of multiple felids are responsible for the counteraction triggered by FIV Petaluma Vif. Altogether, our findings can be a clue to elucidate not only the scenarios of the cross-species transmissions of FIVs in felids but also the evolutionary interaction between mammals and lentiviruses. Most of the emergences of new virus infections originate from the cross-species transmission of viruses. The fact that some virus infections are strictly specific for the host species indicates that certain "species barriers" in the hosts restrict cross-species jump of viruses, while viruses have evolutionary acquired their own "arms" to overcome/antagonize/neutralize these hurdles. Therefore, understanding of the molecular mechanism leading to successful cross-species viral transmission is crucial for considering the menus of the emergence of novel pathogenic viruses. In the field of retrovirology, APOBEC3-Vif interaction is a well-studied example of the battles between hosts and viruses. Here, we determined the sequences of 11 novel feline genes and demonstrated that all 18 different feline APOBEC3Z3 proteins tested exhibit anti-feline immunodeficiency virus (FIV) activity. Our comprehensive investigation focusing on the interplay between feline APOBEC3 and FIV Vif can be a clue to elucidate the scenarios of the cross-species transmissions of FIVs in felids.
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http://dx.doi.org/10.1128/JVI.00178-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437355PMC
June 2021

Dietary sodium chloride attenuates increased β-cell mass to cause glucose intolerance in mice under a high-fat diet.

PLoS One 2021 17;16(3):e0248065. Epub 2021 Mar 17.

Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.

Excessive sodium salt (NaCl) or fat intake is associated with a variety of increased health risks. However, whether excessive NaCl intake accompanied by a high-fat diet (HFD) affects glucose metabolism has not been elucidated. In this study, C57BL/6J male mice were fed a normal chow diet (NCD), a NCD plus high-NaCl diet (NCD plus NaCl), a HFD, or a HFD plus high-NaCl diet (HFD plus NaCl) for 30 weeks. No significant differences in body weight gain, insulin sensitivity, and glucose tolerance were observed between NCD-fed and NCD plus NaCl-fed mice. In contrast, body and liver weights were decreased, but the weight of epididymal white adipose tissue was increased in HFD plus NaCl-fed compared to HFD-fed mice. HFD plus NaCl-fed mice had lower plasma glucose levels in an insulin tolerance test, and showed higher plasma glucose and lower plasma insulin levels in an intraperitoneal glucose tolerance test compared to HFD-fed mice. The β-cell area and number of islets were decreased in HFD plus NaCl-fed compared to HFD-fed mice. Increased Ki67-positive β-cells, and increased expression levels of Ki67, CyclinB1, and CyclinD1 mRNA in islets were observed in HFD-fed but not HFD plus NaCl-fed mice when compared to NCD-fed mice. Our data suggest that excessive NaCl intake accompanied by a HFD exacerbates glucose intolerance, with impairment in insulin secretion caused by the attenuation of expansion of β-cell mass in the pancreas.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248065PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968668PMC
October 2021

Deficiency of WFS1 leads to the impairment of AVP secretion under dehydration in male mice.

Pituitary 2021 Aug 5;24(4):582-588. Epub 2021 Mar 5.

Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Wolfram syndrome (WS) is mainly caused by mutations in the WFS1 gene and characterized by diabetes mellitus, optic atrophy, hearing loss, and central diabetes insipidus (CDI). WFS1 is an endoplasmic reticulum (ER)-resident transmembrane protein, and Wfs1 knockout (Wfs1-/-) mice, which have been used as a mouse model for WS, reportedly manifested impairment of glucose tolerance due to pancreatic β-cell loss. In the present study, we examined water balance, arginine vasopressin (AVP) secretion, and ER stress in AVP neurons of the hypothalamus in Wfs1-/- mice. There were no differences in urine volumes between Wfs1-/- and wild-type mice with free access to water. Conversely, when mice were subjected to intermittent water deprivation (WD) for 20 weeks, during which water was unavailable for 2 days a week, urine volumes were larger in Wfs1-/- mice, accompanied by lower urine AVP concentrations and urine osmolality, compared to wild-type mice. The mRNA expression of immunoglobulin heavy chain binding protein, a marker of ER stress, was significantly increased in the supraoptic nucleus and paraventricular nuclei in Wfs1-/- mice compared to wild-type mice after WD. Our results thus showed that Wfs1 knockout leads to a decrease in AVP secretion during dehydration, which could explain in part the mechanisms by which Wfs1 mutations cause CDI in humans.
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http://dx.doi.org/10.1007/s11102-021-01135-6DOI Listing
August 2021

Arginine vasopressin-Venus reporter mice as a tool for studying magnocellular arginine vasopressin neurons.

Peptides 2021 05 26;139:170517. Epub 2021 Feb 26.

Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan. Electronic address:

Arginine vasopressin (AVP) synthesized in the magnocellular neurons of the hypothalamus is transported through their axons and released from the posterior pituitary into the systemic circulation to act as an antidiuretic hormone. AVP synthesis and release are precisely regulated by changes in plasma osmolality. Magnocellular AVP neurons receive innervation from osmosensory and sodium-sensing neurons, but previous studies showed that AVP neurons per se are osmosensitive as well. In the current study, we made AVP-Venus reporter mice and showed that Venus was expressed exclusively in AVP neurons and was upregulated under water deprivation. In hypothalamic organotypic cultures from the AVP-Venus mice, Venus-labeled AVP neurons in the supraoptic and paraventricular nuclei survived for 1 month, and Venus expression was upregulated by forskolin. Furthermore, in dissociated Venus-labeled magnocellular neurons, treatment with NaCl, but not with mannitol, decreased Venus fluorescence in the soma of the AVP neurons. Thus, Venus expression in AVP-Venus transgenic mice, as well as in primary cultures, faithfully showed the properties of intrinsic AVP expression. These findings indicate that AVP-Venus mice as well as the primary hypothalamic cultures could be useful for studying magnocellular AVP neurons.
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http://dx.doi.org/10.1016/j.peptides.2021.170517DOI Listing
May 2021

A target enrichment high throughput sequencing system for characterization of BLV whole genome sequence, integration sites, clonality and host SNP.

Sci Rep 2021 Feb 25;11(1):4521. Epub 2021 Feb 25.

Division of Genomics and Transcriptomics, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-8556, Japan.

Bovine leukemia virus (BLV) is an oncogenic retrovirus which induces malignant lymphoma termed enzootic bovine leukosis (EBL) after a long incubation period. Insertion sites of the BLV proviral genome as well as the associations between disease progression and polymorphisms of the virus and host genome are not fully understood. To characterize the biological coherence between virus and host, we developed a DNA-capture-seq approach, in which DNA probes were used to efficiently enrich target sequence reads from the next-generation sequencing (NGS) library. In addition, enriched reads can also be analyzed for detection of proviral integration sites and clonal expansion of infected cells since the reads include chimeric reads of the host and proviral genomes. To validate this DNA-capture-seq approach, a persistently BLV-infected fetal lamb kidney cell line (FLK-BLV), four EBL tumor samples and four non-EBL blood samples were analyzed to identify BLV integration sites. The results showed efficient enrichment of target sequence reads and oligoclonal integrations of the BLV proviral genome in the FLK-BLV cell line. Moreover, three out of four EBL tumor samples displayed multiple integration sites of the BLV proviral genome, while one sample displayed a single integration site. In this study, we found the evidence for the first time that the integrated provirus defective at the 5' end was present in the persistent lymphocytosis cattle. The efficient and sensitive identification of BLV variability, integration sites and clonal expansion described in this study provide support for use of this innovative tool for understanding the detailed mechanisms of BLV infection during the course of disease progression.
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http://dx.doi.org/10.1038/s41598-021-83909-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907107PMC
February 2021

High-fat Feeding Causes Inflammation and Insulin Resistance in the Ventral Tegmental Area in Mice.

Neuroscience 2021 05 18;461:72-79. Epub 2021 Feb 18.

Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.

The reward system plays an important role in the pathogenesis of not only drug addiction, but also diet-induced obesity. Recent studies have shown that insulin and leptin receptor signaling in the ventral tegmental area (VTA) regulate energy homeostasis and that their dysregulation is responsible for obesity and altered food preferences. Although a high-fat diet (HFD) induces inflammation that leads to insulin and leptin resistance in the brain, it remains unclear whether HFD induces inflammation in the VTA. In the present study, we placed male mice on a chow diet or HFD for 3, 7, and 28 days and evaluated the mRNA expression of inflammatory cytokines and microglial activation markers in the VTA. The HFD group showed significantly elevated mRNA expressions of IL1β at 3 days; tumor necrosis factor-alpha (TNFα), IL1β, IL6, Iba1, and CD11b at 7 days; and TNFα, IL1β, Iba1, and CD11b at 28 days. The changes in TNFα were also confirmed in immunohistochemical analysis. Next, after administration of chow or HFD for 7 days, we selected mice with equal weights in both groups. In experiments using these mice, Akt phosphorylation in the VTA was significantly decreased after intracerebroventricular injection of insulin, whereas no change in STAT3 phosphorylation was found with leptin. Taken together, these results suggest that HFD induces inflammation at least partly associated with microglial activation in the VTA leading to insulin resistance, independently of the energy balance. Our data provide new insight into the pathophysiology of obesity caused by a dysfunctional reward system under HFD conditions.
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http://dx.doi.org/10.1016/j.neuroscience.2021.02.009DOI Listing
May 2021

Vitamin D improves pulmonary function in a rat model for congenital diaphragmatic hernia.

Arch Biochem Biophys 2021 03 20;700:108769. Epub 2021 Jan 20.

Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8550, Japan; Centre for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Aichi, 466-8560, Japan. Electronic address:

A congenital diaphragmatic hernia (CDH) is an anomaly caused by defects in the diaphragm; the resulting limited thorax cavity in turn restricts lung growth (pulmonary hypoplasia). This condition is related to pulmonary hypertension. Despite advances in neonatal CDH therapy, the mortality for severe pulmonary hypoplasia remains high. Therefore, it is essential to establish prenatal therapeutic interventions. Vitamin D was reported to have beneficial effects on adult pulmonary hypertension. This study aims to evaluate the efficacy of prenatal vitamin D administration for CDH. First, serum 25-hydroxyvitamin D [25(OH)D] levels in umbilical cord blood were evaluated among CDH newborns. Second, Sprague Dawley rat CDH models were exposed to nitrofen on embryo day 9 (E9). Randomly selected rats in the nitrofen-treated group were infused with calcitriol from E9 to E21. Samples from CDH pups diagnosed after birth were used for lung weight measurements, blood gas analysis, and immunohistochemical analysis. Third, microarray analysis was performed to examine the effect of vitamin D on gene expression profiles in CDH pulmonary arterial tissues. Serum 25(OH)D levels in the umbilical cord blood of newborns who did not survive were significantly lower than those who were successfully discharged. Prenatal vitamin D showed no significant effect on CDH incidence or lung weight but attenuated alveolarization and pulmonary artery remodeling accompanied the improved blood gas parameters. Vitamin D inhibited several gene expression pathways in the pulmonary arteries of CDH rats. Our results suggest that prenatal vitamin D administration attenuates pulmonary vascular remodeling by influencing several gene pathways in CDH.
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http://dx.doi.org/10.1016/j.abb.2021.108769DOI Listing
March 2021

Characterization of dental pulp stem cells isolated from a patient diagnosed with Crouzon syndrome.

J Cell Physiol 2021 07 1;236(7):5317-5324. Epub 2021 Jan 1.

Department of Pharmacology, The Nippon Dental University School of Life Dentistry, Tokyo, Japan.

Stem cells isolated from patients with rare diseases are important to elucidate their pathogeny and mechanisms to enable regenerative therapy. However, the mechanisms underlying tissue regeneration using patient-derived dental pulp stem cells (DPSCs) are unclear. In this study, we investigated the levels of mRNA and protein expression related to cellular differentiation of Crouzon syndrome patient-derived DPSCs (CS-DPSCs) with a Gly338Arg fibroblast growth factor receptor 2 mutation. Multipotency-related gene expression levels were equivalent in both healthy donor DPSCs and CS-DPSCs. CS-DPSCs showed higher osteocalcin (OCN) expression than healthy donor DPSCs. CS-DPSCs showed a lower increase in the rate of OCN expression among phorbol 12-myristate 13-acetate (PMA)-treated cells than healthy donor DPSCs compared with untreated control cells. CS-DPSCs showed a lower phosphorylation rate of p38 and p44/42 in PMA-treated cells than healthy donor DPSCs compared with untreated control cells. These results demonstrate that CS-DPSCs have higher OCN expression and lower PMA stimulation-responsiveness than healthy donor DPSCs.
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http://dx.doi.org/10.1002/jcp.30241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048801PMC
July 2021

Effects of excitation light intensity on parathyroid autofluorescence with a novel near-infrared fluorescence imaging system: two surgical case reports.

Gland Surg 2020 Oct;9(5):1584-1589

Department of Thoracic, Endocrine Surgery, and Oncology, Institute of Health Biosciences, The University of Tokushima, Kuramoto-cho, Tokushima, Japan.

The intraoperative identification and preservation of the parathyroid glands are vital techniques, which are largely dependent on a surgeon's experience. Therefore, a simple and reproducible technique to identify the parathyroid glands during surgery is needed. Parathyroid tissue shows near-infrared (NIR) autofluorescence, which enables the intraoperative identification of the parathyroid gland. We herein present two cases that underwent surgery on the parathyroid glands, which were observed using the NIR fluorescence imaging system LIGHTVISION (Shimazu, Kyoto, Japan). In a case of papillary thyroid carcinoma, the system was adopted to preserve normal parathyroid glands during left hemithyroidectomy. The left lower parathyroid gland was identified using the imaging system under white light; however, its autofluorescence was visualized more clearly with the excitation light of NIR. In a case of primary hyperparathyroidism due to MEN1, the system was adopted to identify and remove all of the parathyroid glands during total parathyroidectomy. The autofluorescence of diseased glands was weaker than that of normal glands, even with the excitation light of NIR. When the parathyroid glands were irradiated with a red laser pointer, the intensity of autofluorescence significantly increased. However, the largest gland, which was pathologically proven to contain strongly proliferating chief cells, did not show autofluorescence. These results suggest that normal or less diseased parathyroid glands, which are generally small and difficult to identify during surgery, showed relatively strong autofluorescence. A stronger excitation light increases the autofluorescence of parathyroid glands, which enhances sensitivity for detecting parathyroid glands during surgery. In conclusion, LIGHTVISION is a useful device to identify parathyroid glands and an additional excitation light of a red laser pointer increases the detection sensitivity.
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http://dx.doi.org/10.21037/gs-20-386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667091PMC
October 2020

Endoplasmic reticulum chaperone BiP/GRP78 knockdown leads to autophagy and cell death of arginine vasopressin neurons in mice.

Sci Rep 2020 11 12;10(1):19730. Epub 2020 Nov 12.

Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

The immunoglobulin heavy chain binding protein (BiP), also referred to as 78-kDa glucose-regulated protein (GRP78), is a pivotal endoplasmic reticulum (ER) chaperone which modulates the unfolded protein response under ER stress. Our previous studies showed that BiP is expressed in arginine vasopressin (AVP) neurons under non-stress conditions and that BiP expression is upregulated in proportion to the increased AVP expression under dehydration. To clarify the role of BiP in AVP neurons, we used a viral approach in combination with shRNA interference for BiP knockdown in mouse AVP neurons. Injection of a recombinant adeno-associated virus equipped with a mouse AVP promoter and BiP shRNA cassette provided specific BiP knockdown in AVP neurons of the supraoptic (SON) and paraventricular nuclei (PVN) in mice. AVP neuron-specific BiP knockdown led to ER stress and AVP neuronal loss in the SON and PVN, resulting in increased urine volume due to lack of AVP secretion. Immunoelectron microscopy of AVP neurons revealed that autophagy was activated through the process of AVP neuronal loss, whereas no obvious features characteristic of apoptosis were observed. Pharmacological inhibition of autophagy by chloroquine exacerbated the AVP neuronal loss due to BiP knockdown, indicating a protective role of autophagy in AVP neurons under ER stress. In summary, our results demonstrate that BiP is essential for the AVP neuron system.
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http://dx.doi.org/10.1038/s41598-020-76839-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661499PMC
November 2020

Genetic variation in Japanese Holstein cattle for EBL development.

BMC Vet Res 2020 Oct 28;16(1):407. Epub 2020 Oct 28.

Laboratory of Molecular Reproduction, Research Institute of Agriculture, Tokai University, 862-8652, Kumamoto, Japan.

Background: Infection with bovine leukemia virus (BLV), the causative agent for enzootic bovine leukosis (EBL), is increasing in dairy farms of Japan. The tendency of tumor development following BLV infection in certain cow families and bull lines has previously been described. We therefore hypothesized the existence of a genetic component which differentiates cattle susceptibility to the disease.

Results: We analyzed routinely collected large-scale data including postmortem inspection data, which were combined with pedigree information and epidemiological data of BLV infection. A total of 6,022 postmortem inspection records of Holstein cattle, raised on 226 farms served by a regional abattoir over 10 years from 2004 to 2015, were analyzed for associations between sire information and EBL development. We then identified statistically the relative susceptibility to EBL development for the progeny of specific sires and paternal grandsires (PGSs). The heritability of EBL development was calculated as 0.19. Similarly, proviral loads (PVLs) of progeny from identified sires and PGSs were analyzed, but no significant differences were found.

Conclusions: These observations suggest that because EBL development in our Holstein population is, at least in part, influenced by genetic factors independent of PVL levels, genetic improvement for lower incidence of EBL development in cattle notwithstanding BLV infection is possible.
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http://dx.doi.org/10.1186/s12917-020-02625-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594299PMC
October 2020

Degradation of Mutant Protein Aggregates within the Endoplasmic Reticulum of Vasopressin Neurons.

iScience 2020 Oct 7;23(10):101648. Epub 2020 Oct 7.

Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.

Misfolded or unfolded proteins in the ER are said to be degraded only after translocation or isolation from the ER. Here, we describe a mechanism by which mutant proteins are degraded within the ER. Aggregates of mutant arginine vasopressin (AVP) precursor were confined to ER-associated compartments (ERACs) connected to the ER in AVP neurons of a mouse model of familial neurohypophysial diabetes insipidus. The ERACs were enclosed by membranes, an ER chaperone and marker protein of phagophores and autophagosomes were expressed around the aggregates, and lysosomes fused with the ERACs. Moreover, lysosome-related molecules were present within the ERACs, and aggregate degradation within the ERACs was dependent on autophagic-lysosomal activity. Thus, we demonstrate that protein aggregates can be degraded by autophagic-lysosomal machinery within specialized compartments of the ER.
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http://dx.doi.org/10.1016/j.isci.2020.101648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578753PMC
October 2020

Maternal Baseline Characteristics and Perinatal Outcomes: the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

J Epidemiol 2020 Oct 10. Epub 2020 Oct 10.

Tohoku Medical Megabank Organization, Tohoku University.

Background: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study was launched in 2013 to evaluate the complex interactions of genetic and environmental factors in multifactorial diseases. The present study describes the maternal baseline profile and perinatal data of participating mothers and infants.

Methods: Expectant mothers living in Miyagi prefecture were recruited from obstetric facilities or affiliated centers between 2013 and 2017. Three sets of self-administered questionnaires were collected, and the medical records were reviewed to obtain precise information about each antenatal visit and each delivery. Biospecimens, including blood, urine, umbilical cord blood, and breast milk, were collected for the study biobank. The baseline maternal sociodemographic characteristics, results of screening tests, and obstetric outcomes were analyzed according to the maternal age group.

Results: A total of 23 406 pregnancies involving 23 730 fetuses resulted in 23 143 live births. Younger maternal participants had a tendency toward a higher incidence of threatened abortion and threatened premature labor, while older age groups exhibited a significantly higher rate of low lying placenta, placenta previa, gestational diabetes and hypertensive disorders of pregnancy.

Conclusions: The present study clearly shows the distribution of maternal baseline characteristics and the range of perinatal outcomes according to maternal age group. This cohort study can provide strategic information for creating breakthroughs in the pathophysiology of perinatal, developmental, and noncommunicable diseases by collaborative data visiting or sharing.
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http://dx.doi.org/10.2188/jea.JE20200338DOI Listing
October 2020
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