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Fused in sarcoma (FUS), coded by FUS, is a heterogeneous nuclear ribonucleoprotein (hnRNP). FUS mutations are among the major mutations in familial amyotrophic lateral sclerosis (ALS-FUS: ALS6). The pathological hallmarks of ALS-FUS are FUS-positive neuronal cytoplasmic inclusions (NCI). We examined various hnRNPs in FUS NCIs in the hippocampus in ALS-FUS cases with different FUS mutations (Case 1, H517P; Case 2, R521C). We also examined TDP43-positive NCIs in sporadic ALS hippocampi. Immunohistochemistry was performed using primary antibodies against FUS, p-TDP43, TDP43, hnRNPA1, hnRNPD, PCBP1, PCBP2, and p62. Numerous FUS inclusions were found in the hippocampal granule and pyramidal cell layers. Double immunofluorescence revealed colocalization of FUS and p-TDP43, and FUS and PCBP2 (p-TDP43/FUS: 64.3%, PCBP2/FUS: 23.9%). Colocalization of FUS and PCBP1, however, was rare (PCBP1/FUS: 7.6%). In the hippocampi of patients with sporadic ALS, no colocalization was observed between TDP43-positive inclusions and other hnRNPs. This is the first study to show that FUS inclusions colocalize with other hnRNPs, such as TDP43, PCBP2, and PCBP1. These findings suggest that in ALS-FUS, FUS inclusions are the initiators, followed by alterations of multiple other hnRNPs, resulting in impaired RNA metabolism.

Knowledge of aging-related tau astrogliopathy (ARTAG) in healthy elderly individuals remains incomplete and studies to date have not focused on the olfactory nerve, which is a vulnerable site of various neurodegenerative disease pathologies. We performed a semiquantitative evaluation of ARTAG in 110 autopsies in the Japanese general population (Hisayama study). Our analysis focused on Alzheimer disease (AD) and cognitive healthy cases (HC), including primary age-related tauopathy. Among the various diseased and nondiseased brains, ARTAG was frequently observed in the amygdala. The ARTAG of HC was exclusively limited to the amygdala whereas gray matter ARTAG in AD cases was prominent in the putamen and middle frontal gyrus following the amygdala. ARTAG of the olfactory nerve mainly consists of subpial pathology that was milder in the amygdala. A logistic regression analysis revealed that age at death and neurofibrillary tangle Braak stage significantly affected the ARTAG of HC. In AD, age at death and male gender had significant effects on ARTAG. In addition, the Thal phase significantly affected the presence of white matter ARTAG. In conclusion, our research revealed differences in the distribution of ARTAG and affected variables across AD and HC individuals.

Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by inflammatory responses and fibrotic scar formation leading to cholestasis. Ductular reaction and liver fibrosis are typical liver changes seen in human PSC and cholestasis patients. The current study aimed to clarify the role of liver-specific microRNA-34a in the cholestasis-associated ductular reaction and liver fibrosis. We demonstrated that miR-34a expression was significantly increased in human PSC livers along with the enhanced ductular reaction, cellular senescence, and liver fibrosis. A liver-specific miR-34a knockout mouse was established by crossing floxed miR-34a mice with albumin-promoter-driven Cre mice. Bile duct ligation (BDL) induced liver injury characterized by necrosis, fibrosis, and immune cell infiltration. In contrast, liver-specific miR-34a knockout in BDL mice resulted in decreased biliary ductular pathology associated with the reduced cholangiocyte senescence and fibrotic responses. The miR-34a-mediated ductular reactions may be functioning through Sirt-1-mediated senescence and fibrosis. The hepatocyte-derived conditioned medium promoted LPS-induced fibrotic responses and senescence in cholangiocytes, and miR-34a inhibitor suppressed these effects, further supporting the involvement of paracrine regulation. In conclusion, we demonstrated that liver-specific miR-34a plays an important role in ductular reaction and fibrotic responses in a BDL mouse model of cholestatic liver disease.

GPI anchorless prion diseases (GPIALPs) show numerous coarse prion protein (PrP) deposits in the CNS but neuropil spongiform changes are mild and the incidence of dementia is low. Here, we examined differences in resident microglial phenotypes between GPIALP (D178fs25) and the other prion diseases Gerstmann-Sträussler-Scheinker (GSS) disease and sporadic Creutzfeldt-Jakob disease (sCJD) with respect to homeostasis and activation. Immunohistochemistry was performed on 2 GPIALP (D178fs25), 4 GSS (P102L), and 4 sCJD cases. Homeostatic microglia expressing TMEM119 and P2RY12 were preserved in GPIALP compared to GSS and sCJD. Microglia/macrophage activation in GSS and sCJD was associated with the extent of spongiform change. Immunoelectron microscopy revealed TMEM119 and P2RY12 in PrP plaque cores. Activated microglia/macrophages expressing HLA-DR and CD68 were predominant in GSS and sCJD whereas in GPIALP, homeostatic microglia were retained and activated microglia/macrophages were rarely observed. These data suggest that PrP deposition in GPIALP is less toxic and that microglia may be immune-tolerant to PrP deposition. This may be associated with milder tissue damage and a low incidence of dementia. Whereas microglia/macrophage activation is considered to be a reaction to tissue injury, this study shows that the degree of microglia/macrophage activity might influence the extent of tissue damage.

The differential effects of sporadic Creutzfeldt-Jakob disease (sCJD) on the hippocampus and other neocortical areas are poorly understood. We aimed to reveal the histological patterns of cellular prion protein (PrPC) and abnormal prion protein (PrPSc) in hippocampi of sCJD patients and normal controls (NCs). Our study examined 18 postmortem sCJD patients (MM1, 14 cases; MM1 + 2c, 3 cases; MM1 + 2t, 1 case) and 12 NCs. Immunohistochemistry was conducted using 4 primary antibodies, of which 3 targeted the N-terminus of the prion protein (PrP), and 1 (EP1802Y) targeted the C-terminal domain. PrPC expression was abundant in the hippocampus of NCs, and the distribution of PrPC at CA3/4 was reminiscent of synaptic complexes. In sCJD cases with a disease history of2 years, antibodies against the N-terminus could not detect synapse-like PrP expression at CA4; however, EP1802Y could characterize the synapse-like expression. PrPSc accumulation and spongiform changes became evident after 2 years of illness, when PrPSc deposits were more noticeably detected by N-terminal-specific antibodies. Our findings highlighted the chronology of histopathological alterations in the CA4 region in sCJD patients.

TMEM119 and purinergic receptor P2Y12 (P2RY12), which are not expressed by recruited peripheral blood macrophages, are proposed to discriminate microglia from macrophages. Therefore, we investigated the distribution patterns of microglia and macrophages in 10 concentric lesions from four autopsied Baló's disease cases and one neuromyelitis optica spectrum disorder (NMOSD) case, using quantitative immunohistochemistry for the markers TMEM119, P2RY12, CD68, CD163 and GLUT5. Three cases with Baló's disease had distal oligodendrogliopathy (DO) showing preferential loss of myelin-associated glycoprotein and early active demyelination in the outermost demyelinating layer (termed DMY-MO). In DMY-MO with DO, TMEM119-positive activated microglia expressing upregulated GLUT5 but markedly downregulated P2RY12 were significantly increased. These activated microglia expressed inducible nitric oxide synthase. Oligodendrocytes and their precursors showed apoptotic-like nuclear condensation in DMY-MO. TMEM119-negative and CD68/CD163-positive macrophages were distributed throughout the lesion center of DMY-MO with DO and these cells demonstrated foamy morphology only in the inner portion but not in the outer portion. In concentric demyelinating lesions from another Baló's case and lamellar demyelinating lesions in an NMOSD case, which had late active demyelination without DO, the densities of TMEM119-, GLUT5- and P2RY12-positive microglia with ramified morphology were significantly increased in myelinated layers but not in demyelinating layers. In particular, in the NMOSD case, TMEM119-positive microglia were confined to the outer portion of the myelinated layers. CD68-positive macrophages with foamy morphology also expressing CD163 accumulated in myelinated as well as in demyelinated layers. These findings suggest that activated microglia expressing TMEM119 and GLUT5, but not P2RY12, are associated with apoptosis of oligodendrocytes in the leading edge of Baló's concentric lesions with DO, whereas TMEM119-, GLUT5- and P2RY12-positive microglia with ramified morphology are associated with myelin preservation in concentric lesions without DO in Baló's disease and NMOSD. These two types of microglia appear to play distinct roles in the formation of concentric lesions.

ImportanceSudden smell loss is a specific early symptom of COVID-19, with an estimated prevalence of ~40% to 75%. Smell impairment affects physical and mental health, and dietary behavior. Thus, it is critical to understand the rate and time course of smell recovery.ObjectiveTo characterize smell function and recovery up to 11 months post COVID-19 infection.Settings, ParticipantsThis longitudinal survey of individuals suffering COVID-19-related smell loss assessed disease symptoms and gustatory and olfactory function. Participants (n=12,313) who completed an initial respiratory symptoms, chemosensory function and COVID-19 diagnosis survey (S1) between April and September 2020 and completed a follow-up survey (S2) between September 2020 and February 2021; 27.5% participants responded (n=3,386), with 1,468 being diagnosed with COVID-19 and suffering co-occurring smell and taste loss at the beginning of their illness.Main Outcomes & MeasuresPrimary outcomes are ratings of smell and taste function on a visual analog scale, and self-report of parosmia (smell distortions) and phantosmia (unexplained smells). Secondary outcomes include a checklist of other COVID-19 symptoms.ResultsOn follow-up (median time since COVID-19 onset ~200 days), ~60% of women and ~48% of men reported less than 80% of their pre-illness smell ability. Taste typically recovered faster than smell, and taste loss rarely persisted if smell recovered. Prevalence of parosmia and phantosmia was ~10% of participants in S1 and increased substantially in S2: ~47% for parosmia and ~25% for phantosmia. Persistent smell impairment was associated with more symptoms overall, suggesting it may be a key marker of long-COVID. During COVID-19 illness, the ability to smell was slightly lower among those who did not recover their pre-illness ability to smell at S2.Conclusions and RelevanceWhile smell loss improves for many individuals who lost it due to COVID-19, the prevalence of parosmia and phantosmia increases substantially over time. Olfactory dysfunction is also associated with wider COVID-19 symptoms and may persist for many months after COVID-19 onset. Taste loss in the absence of smell loss is rare. Persistent qualitative smell symptoms are emerging as common long term sequelae; more research into treatment options is strongly warranted given that conservative estimates suggest millions of individuals may experience parosmia following COVID-19. Healthcare providers worldwide need to be prepared to treat post COVID-19 secondary effects on physical and mental health.Trial registrationThis project was pre-registered at OSF: https://osf.io/3e6zc.Graphical abstractKey PointsQuestionWhat are the characteristics of smell and taste recovery of COVID-19 patients?FindingsIn this preregistered observational study of 1,468 participants, smell loss is associated with a higher number of COVID-19 symptoms, and may persist for at least 11 months following disease onset. While a majority of participants report quantitative improvement in their ability to smell, the prevalence of parosmia and phantosmia increases substantially at follow-up. Taste recovers faster than smell, suggesting taste and smell recover separately and can be distinguished by the respondents.MeaningOlfactory dysfunction appears to be a component of long-COVID, with parosmia as a prominent symptom in almost half of those with smell loss. More research into treatment is needed, especially given that olfactory dysfunction is associated with depression and loss of appetite. Health professionals should be aware of these common and long lasting effects.

BACKGROUND The year 2020 was the year of the global COVID-19 pandemic. The severity of the situation has become so substantial that many or even most of the patients with mild to moderate symptoms had to self-isolate without specific medical treatments or even without being tested for COVID-19. Many patients joined internet membership groups to exchange information and support each other. OBJECTIVE Our goal is to determine the benefits and limits of using social media to understand the symptoms of patients with suspected COVID-19 with mild to moderate symptoms and, in particular, their symptoms of anosmia (loss of the sense of smell) and ageusia (loss of the sense of taste). The voluntary reports on an internet website of a membership group will be the platform of the analyses. METHODS Posts and comments of members of an internet group known as COVID-19 Smell and Taste Loss, founded on March 24, 2020, to support patients with suspected COVID-19 were collected and analyzed daily. Demographic data were collected using the software mechanism called Group Insights on the membership group website. RESULTS Membership groups on social media have become rare sources of support for patients with suspected COVID-19 with mild to moderate symptoms. These groups provided mental support to their members and became resources for information on COVID-19 tests and medicines or supplements. However, the membership was voluntary, and often the members leave without notification. It is hard to be precise from the free voluntary reports. The number of women in the group (6995/9227, 75.38% as of October 12, 2020) was about three times more than men (2272/9227, 24.62% as of October 12, 2020), and the peak age of members was between 20-40 years in both men and women. Patients who were asymptomatic other than the senses comprised 14.93% (53/355) of the total patients. Recovery of the senses was higher in the patients who were asymptomatic besides having anosmia and ageusia. Most (112/123, 91.06%) patients experienced other symptoms first and then lost their senses, on average, 4.2 days later. Patients without other symptoms tended to recover earlier (P=.02). Patients with anosmia and ageusia occasionally reported distorted smell and taste (parosmia and dysgeusia) as well as experiencing or perceiving the smell and taste without the sources of the smell or taste (phantosmia and phantogeusia). CONCLUSIONS Our analysis of the social media database of suspected COVID-19 patients’ voices demonstrated that, although accurate diagnosis of patients is not always obtained with social media–based analyses, it may be a useful tool to collect a large amount of data on symptoms and the clinical course of worldwide rapidly growing infectious diseases.

Background The year 2020 was the year of the global COVID-19 pandemic. The severity of the situation has become so substantial that many or even most of the patients with mild to moderate symptoms had to self-isolate without specific medical treatments or even without being tested for COVID-19. Many patients joined internet membership groups to exchange information and support each other. Objective Our goal is to determine the benefits and limits of using social media to understand the symptoms of patients with suspected COVID-19 with mild to moderate symptoms and, in particular, their symptoms of anosmia (loss of the sense of smell) and ageusia (loss of the sense of taste). The voluntary reports on an internet website of a membership group will be the platform of the analyses. Methods Posts and comments of members of an internet group known as COVID-19 Smell and Taste Loss, founded on March 24, 2020, to support patients with suspected COVID-19 were collected and analyzed daily. Demographic data were collected using the software mechanism called Group Insights on the membership group website. Results Membership groups on social media have become rare sources of support for patients with suspected COVID-19 with mild to moderate symptoms. These groups provided mental support to their members and became resources for information on COVID-19 tests and medicines or supplements. However, the membership was voluntary, and often the members leave without notification. It is hard to be precise from the free voluntary reports. The number of women in the group (6995/9227, 75.38% as of October 12, 2020) was about three times more than men (2272/9227, 24.62% as of October 12, 2020), and the peak age of members was between 20-40 years in both men and women. Patients who were asymptomatic other than the senses comprised 14.93% (53/355) of the total patients. Recovery of the senses was higher in the patients who were asymptomatic besides having anosmia and ageusia. Most (112/123, 91.06%) patients experienced other symptoms first and then lost their senses, on average, 4.2 days later. Patients without other symptoms tended to recover earlier (P=.02). Patients with anosmia and ageusia occasionally reported distorted smell and taste (parosmia and dysgeusia) as well as experiencing or perceiving the smell and taste without the sources of the smell or taste (phantosmia and phantogeusia). Conclusions Our analysis of the social media database of suspected COVID-19 patients’ voices demonstrated that, although accurate diagnosis of patients is not always obtained with social media–based analyses, it may be a useful tool to collect a large amount of data on symptoms and the clinical course of worldwide rapidly growing infectious diseases.

Understanding how genes and experiences work in concert to generate phenotypic variability will provide a better understanding of individuality. Here, we considered this in the context of the main olfactory epithelium, a chemosensory structure with over a thousand distinct cell-types, in mice. We identified a subpopulation of at least three types of olfactory sensory neurons, defined by receptor expression, whose abundances were sexually dimorphic. This subpopulation of olfactory sensory neurons was over-represented in sex-separated female mice and responded robustly to the male-specific semiochemicals 2-sec-butyl-4,5-dihydrothaizole and (methylthio)methanethiol. Sex-combined housing led to a robust attenuation of the female over-representation. Testing of Bax null mice revealed a Bax-dependence in generating the sexual dimorphism in sex-separated mice. Altogether, our results suggest a profound role of experience in influencing homeostatic neural lifespan mechanisms to generate a robust sexually dimorphic phenotype in the main olfactory epithelium.

The history of using essential oils is extremely long but the scientific studies at the chemical compound level are still in need. Essential oils have been used in three different ways: using diffusers, which will use the olfactory system primarily; drinking, which will use primarily the digestive system; and topical application, which will enter primarily through the skin. Various effects of essential oils have been reported so far. These diversity in the influences of essential oils could be due to 1) different chemical compounds or combination of different chemical compounds used, or 2) the differences in the routes (olfactory, skin, gut-intestine) the same essential oil activated, which suggest that different routes activate different receptors and thus different chemical signaling pathways. We need to consider these different routes as well as the differences in the chemical compounds in studying the influences of essential oils. It is also very important to conduct studies at the chemical compound level rather than using the whole essential oil in order to know which chemical compound affects. Using chemical compounds will enable precise control of the concentration in studying the effects as well.

The year 2020 became the year of the outbreak of coronavirus, SARS-CoV-2, which escalated into a worldwide pandemic and continued into 2021. One of the unique symptoms of the SARS-CoV-2 disease, COVID-19, is the loss of chemical senses, i.e., smell and taste. Smell training is one of the methods used in facilitating recovery of the olfactory sense, and it uses essential oils of lemon, rose, clove, and eucalyptus. These essential oils were not selected based on their chemical constituents. Although scientific studies have shown that they improve recovery, there may be better combinations for facilitating recovery. Many phytochemicals have bioactive properties with anti-inflammatory and anti-viral effects. In this review, we describe the chemical compounds with anti- inflammatory and anti-viral effects, and we list the plants that contain these chemical compounds. We expand the review from terpenes to the less volatile flavonoids in order to propose a combination of essential oils and diets that can be used to develop a new taste training method, as there has been no taste training so far. Finally, we discuss the possible use of these in clinical settings.

Over 60% of all patients with dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) have been diagnosed in Japan. The incubation period has ranged from 1 to 30 years and the age at onset from 15 to 80 years. Here, we report a 77-year-old male Japanese autopsied dCJD case with the longest incubation period so far in Japan. He received a cadaveric dural graft at the right cranial convexity following a craniotomy for meningioma at the age of 46. At 30 years post-dural graft placement, disorientation was observed as an initial symptom of dCJD. He rapidly began to present with inconsistent speech, cognitive impairment and tremor of the left upper extremity. Occasional myoclonic jerks were predominantly observed on the left side. Brain MRI presented hyperintense signals on diffusion-weighted and T2-weighted images, at the right cerebral cortex. The most hyperintense lesion was located at the right parietal lobe, where the dura mater graft had been transplanted. Single-photon emission CT scan showed markedly decreased cerebral blood flow at the right parietal lobe. EEG revealed diffuse and slow activities with periodic sharp-wave complex discharges seen in the right parietal, temporal and occipital lobes. He died of pneumonia 9 months after onset. Brain pathology revealed non-plaque-type dCJD. Laterality of neuropathological changes, including spongiform change, neuronal loss, gliosis or PrP deposits, was not evident. Western blot analysis showed type 1 PrPCJD . Alzheimer-type pathology and PSP-like pathology were also observed.

We investigated the trends in dementia over the past 29 years in the town of Hisayama, Japan using 1266 autopsy specimens. The Hisayama study is a prospective cohort study of lifestyle-related diseases that was started in 1961. Clinical examination of dementia was started in 1985 with five detailed cross-sectional assessments conducted in 1985, 1992, 1998, 2005 and 2012. To examine the trends in dementia, we divided the 1266 autopsy samples into five groups according to the year of death: I (1986-1991, 257 cases), II (1992-1997, 268 cases), III (1998-2004, 318 cases), IV (2005-2011, 296 cases) and V (2012-2014, 127 cases). The prevalence of all-cause dementia significantly increased over time (28.4% in group I, 22.4% in group II, 32.1% in group III, 30.1% in group IV, 51.2% in group V; P for trend

Objective Immunoglobulin (Ig)G4-related disease is a major cause of hypertrophic pachymeningitis (HP), presenting as a progressive thickening of the dura mater. HP lacks an animal model to determine its underlying mechanisms. We developed a suitable animal model for the treatment of HP. Methods We longitudinally evaluated dura in mice with a mutation (Y136F) in the linker for activation of T cells (LAT), which induced type 2 T helper (Th2) cell proliferation and IgG1 (IgG4 human equivalent) overexpression. Mice were therapeutically administered daily oral irbesartan from 3 to 6 weeks of age. Human IgG4-related, anti-neutrophil cytoplasmic antibody-related, and idiopathic HP dura were also immunohistochemically examined. Results LATY136F mice showing dural gadolinium enhancement on magnetic resonance imaging had massive infiltration of B220(+) B cells, IgG1(+) cells, CD138(+) plasma cells, CD3(+) T cells, F4/80(+) macrophages, and polymorphonuclear leukocytes in the dura at 3 weeks of age, followed by marked fibrotic thickening. In dural lesions, transforming growth factor (TGF)-beta 1 was produced preferentially in B cells and macrophages while TGF-beta receptor I (TGF-beta RI) was markedly upregulated on fibroblasts. Quantitative western blotting revealed significant upregulation of TGF-beta 1, TGF-beta RI, and phosphorylated SMAD2/SMAD3 in dura of LATY136F mice aged 13 weeks. A similar upregulation of TGF-beta RI, SMAD2/SMAD3, and phosphorylated SMAD2/SMAD3 was present in autopsied dura of all three types of human HP. Irbesartan abolished dural inflammatory cell infiltration and fibrotic thickening in all treated LATY136F mice with reduced TGF-beta 1 and nonphosphorylated and phosphorylated SMAD2/SMAD3. Interpretation TGF-beta 1/SMAD2/SMAD3 pathway is critical in HP and is a potential novel therapeutic target.

Maintenance of specialized epidermis requires signals from the underlying mesenchyme; however, the specific pathways involved remain to be identified. By recombining cells from the ventral skin of the K14-PTHrP transgenic mice [which overexpress parathyroid hormone-related protein (PTHrP) in their developing epidermis and mammary glands] with those from wild type, we show that transgenic stroma is sufficient to reprogram wild-type keratinocytes into nipple-like epidermis. To identify candidate nipple-specific signaling factors, we compared gene expression signatures of sorted Pdgfrα-positive ventral K14-PTHrP and wild-type fibroblasts, identifying differentially expressed transcripts that are involved in WNT, HGF, TGFβ, IGF, BMP, FGF and estrogen signaling. Considering that some of the growth factor pathways are targets for estrogen regulation, we examined the upstream role of this hormone in maintaining the nipple. Ablation of estrogen signaling through ovariectomy produced nipples with abnormally thin epidermis, and we identified TGFβ as a negatively regulated target of estrogen signaling. Estrogen treatment represses Tgfβ1 at the transcript and protein levels in K14-PTHrP fibroblasts in vitro, while ovariectomy increases Tgfb1 levels in K14-PTHrP ventral skin. Moreover, ectopic delivery of Tgfβ1 protein into nipple connective tissue reduced epidermal proliferation. Taken together, these results show that specialized nipple epidermis is maintained by estrogen-induced repression of TGFβ signaling in the local fibroblasts.

Essential oils have been used in multiple ways, i.e., inhaling, topically applying on the skin, and drinking. Thus, there are three major routes of intake or application involved: the olfactory system, the skin, and the gastro-intestinal system. Understanding these routes is important for clarifying the mechanisms of action of essential oils. Here we summarize the three systems involved, and the effects of essential oils and their constituents at the cellular and systems level. Many factors affect the rate of uptake of each chemical constituent included in essential oils. It is important to determine how much of each constituent is included in an essential oil and to use single chemical compounds to precisely test their effects. Studies have shown synergistic influences of the constituents, which affect the mechanisms of action of the essential oil constituents. For the skin and digestive system, the chemical components of essential oils can directly activate gamma aminobutyric acid (GABA) receptors and transient receptor potential channels (TRP) channels, whereas in the olfactory system, chemical components activate olfactory receptors. Here, GABA receptors and TRP channels could play a role, mostly when the signals are transferred to the olfactory bulb and the brain.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motor neurons and appearance of skein-like inclusions. The inclusions are composed of trans-activation response (TAR) DNA-binding protein 43 (TDP-43), a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family. hnRNPA1 and hnRNPA2/B1 are hnRNPs that interact with the C-terminus of TDP-43. Using immunohistochemistry, we investigated the association between TDP-43 and hnRNPA1 in ALS spinal motor neurons. We examined spinal cords of seven ALS cases and six muscular dystrophy cases (used as controls) for the presence of TDP-43 and hnRNPA1 protein. In the control cases, hnRNPA1 immunoreactivity in motor neurons was intense in the nucleus and weak in the cytoplasm where it showed a fine granular appearance. In the ALS cases, hnRNPA1 immunoreactivity in motor neurons was reduced in the nuclei of neurons with skein-like inclusions but was not detected in the skein-like inclusions. The marked loss of hnRNPA1 in motor neurons with concomitant cytoplasmic aggregation of TDP-43 may represent a severe disturbance of mRNA processing, suggesting a key role in progressive neuronal death in ALS.

Enhancement of adult neurogenesis in female mice was previously demonstrated through exposure to soiled bedding from males, although the identity of relevant chemosignals has remained unknown. The farnesenes and SBT (2-sec-butyl-4,5-dihydrothiazole) are male murine pheromones that dominant males secrete at higher levels. Previous studies have shown that they induce oestrus in female mice. We have recently shown that these pheromones strongly increase cell proliferation in the SVZ (subventricular zone) of adult female mice. In addition, we found that a female murine pheromone, 2,5-dimethylpyrazine, facilitates similar changes in males. 2,5-dimethylpyrazine is a female pheromone that is secreted when females are housed in large groups and it was originally found to suppress oestrus in females. We found that it does not have suppressive effect on the cell proliferation in the SVZ of females. Similarly, male murine pheromones, SBT and the farnesenes, do not show a suppressive effect on the cell proliferation in the SVZ of males. Our results demonstrated that pheromonal communication between males and females has strong stimulatory effect on both the reproductive physiology and brain cell proliferation, but intrasex pheromonal exchanges do not reduce progenitor proliferation in these brain regions.

Having glands that secrete milk to nourish neonatal offspring characterizes all mammals. We provide a brief overview of the development and anatomy of nipples and mammary glands in monotremes, marsupials, and marine mammals, and focus on the nipples and mammary glands in terrestrial eutherian species. We first classify eutherians into three groups: the altricial, precocial, and arboreal types based on their rearing system. We then summarize the physiology of lactation and the cell biology of nipples with specific focus on comparing these in the mouse, cow, and human, which represent the three different groups. Finally we propose that the nipple is an example of specialized epidermis. As specialized epidermis, it is dependent the underlying stroma for development and maintenance in adult life. The development of the nipple and signaling pathways that regulate its formation are described.

Background The Hisayama study is a prospective cohort study of lifestyle-related diseases that commenced in 1961. Through it, a significant increasing trend in the prevalence of Alzheimer's disease has been observed over the past 18 years. Objectives We sought to investigate the increases in brain pathology related to Alzheimer's disease using automated MATLAB morphometric analyses for quantifying tau pathology. Methods We examined a series of autopsied cases from Hisayama residents obtained between 1998 and 2003 (group A: 203 cases), and between 2009 and 2014 (group B: 232 cases). We developed custom software in MATLAB to analyze abnormal tau deposits quantitatively. Specimens were immunostained with both anti-amyloid-β-protein and anti-phosphorylated tau antibodies. Results Both the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria for senile plaques and Braak stage for NFT were higher in group B. Morphometric analyses of the hippocampi also revealed a trend toward increased tau pathology in both men and women over 80 years of age in group B. The increases were also significant when the subjects were examined independently according to high or low CERAD scores and in all levels of AD neuropathologic change according to the National Institute on Aging-Alzheimer's Association guidelines (2012). Conclusion We revealed a recent trend of increased tauopathy in the older people, which is partly independent of amyloid-β pathology.

International audience; Whereas the house mouse (Mus domesticus) has been studied extensively in terms of physiology/behavior and pheromonal attributes, the evolutionarily related mound-building mouse (Mus spicilegus) has received attention only recently due to its divergent behavioral traits related to olfaction. To date, no chemical studies on urinary volatile compounds have been performed on M. spicilegus. The rationale for our investigations was to determine if there are differences in urinary volatiles of intact and castrated M. spicilegus males and to explore further whether this species could utilize the same or structurally similar pheromones as the male house mouse, M. domesticus. The use of capillary gas chromatography/mass spectrometry (GC-MS) together with sorptive stir bar extraction sampling enabled quantitative comparisons between the intact and castrated M. spicilegus urinary profiles. Additionally, through GC-MS and atomic emission (sulfur-selective) detection, we identified qualitative molecular differences between intact M. spicilegus and M. domesticus. A series of volatile and odoriferous lactones and the presence of coumarin were the unique features of M. spicilegus, as was the notable absence of 2-sec-butyl-4,5-dihydrothiazole (a prominent M. domesticus male pheromone) and other sulfur-containing compounds. Castration of M. spicilegus males eliminated several substances, including delta-hexalactone and gamma-octalactone, and substantially decreased additional compounds, suggesting their possible role in chemical communication. Some other M. domesticus pheromone components were also found in M. spicilegus urine. These comparative chemical analyses support the notion of metabolic similarities as well as the uniqueness of some volatiles for M. spicilegus, which may have a distinct physiological function in reproduction and behavior.

We investigated the trends in dementia over the past 29 years in the town of Hisayama, Japan using 1266 autopsy specimens. The Hisayama study is a prospective cohort study of lifestyle-related diseases that was started in 1961. Clinical examination of dementia was started in 1985 with five detailed cross-sectional assessments conducted in 1985, 1992, 1998, 2005 and 2012. To examine the trends in dementia, we divided the 1266 autopsy samples into five groups according to the year of death: I (1986-1991, 257 cases), II (1992-1997, 268 cases), III (1998-2004, 318 cases), IV (2005-2011, 296 cases) and V (2012-2014, 127 cases). The prevalence of all-cause dementia significantly increased over time (28.4% in group I, 22.4% in group II, 32.1% in group III, 30.1% in group IV, 51.2% in group V; P for trend0.001). A similar trend was observed for Alzheimer's disease (AD) (15.2%, 11.9%, 17.3%, 20.6% and 33.1%, respectively; P for trend0.001). A significant increasing trend was observed in both men and women. A rapid increase in senile dementia of the NFT type (SD-NFT) in recent years was notable. Vascular dementia was the most common type of dementia in men prior to 2004; however, its prevalence decreased over time. Our study revealed that tauopathies, including AD and SD-NFT, significantly increased in the aged Japanese population over the course of this study. The neuritic plaque pathology of AD was associated with metabolic disorders such as insulin resistance and abnormal lipid metabolism, whereas the risk factors for tau pathology remain unclear. Although aging is considered one of the important risk factors accelerating tau pathology, there could be other risk factors associated with lifestyle diseases.

The biology of mice has been studied for centuries with the main purpose of pest control. With the advent of scientific approaches to human medical care, mice have become the most popular animal model system because of the many similarities between their physiology and that of humans. More recently, they have been used in an even broader range of scientific studies aimed at manipulating their genome. With the development of olfactory neuroscience from 1990s and sequencing the whole mouse genome at the beginning of 21st century, olfactory communication is now studied at cell and molecular levels. This work requires using various transgenic mice to visualize neuronal connections, cellular responses at the single sensory neuron level to exposure of the animal to odors and/or pheromones, and their neural circuits in the brain. Some of this work has involved genetically altering laboratory strains of mice to produce and secrete less chemical components in their urine compared to wild house mice. Nonetheless mice are still mice, with all, or many of their behavioral characteristics intact and still possessing the communication system typical to mice. The knowledge of mouse biology helps in optimally designing mouse behavioral experiments but also mouse housing conditions and helps to avoid contamination of olfactory signaling factors that may affect the results significantly.