Sex chromosomes generally evolve from a homomorphic to heteromorphic state. Once a heteromorphic system is established, the sex chromosome system may remain stable for an extended period. Here, we ...show the opposite case of sex chromosome evolution from a heteromorphic to a homomorphic system in the Japanese frog
Glandirana rugosa.
One geographic group, Neo-ZW, has ZZ-ZW type heteromorphic sex chromosomes. We found that its western edge populations, which are geographically close to another West-Japan group with homomorphic sex chromosomes of XX-XY type, showed homozygous genotypes of sex-linked genes in both sexes. Karyologically, no heteromorphic sex chromosomes were identified. Sex-reversal experiments revealed that the males were heterogametic in sex determination. In addition, we identified another similar population around at the southwestern edge of the Neo-ZW group in the Kii Peninsula: the frogs had homomorphic sex chromosomes under male heterogamety, while shared mitochondrial haplotypes with the XY group, which is located in the east and bears heteromorphic sex chromosomes. In conclusion, our study revealed that the heteromorphic sex chromosome systems independently reversed back to or turned over to a homomorphic system around each of the western and southwestern edges of the Neo-ZW group through hybridization with the West-Japan group bearing homomorphic sex chromosomes.
This article is part of the theme issue ‘Challenging the paradigm in sex chromosome evolution: empirical and theoretical insights with a focus on vertebrates (Part II)’.
Objective It has been established that stroke occurrence is influenced by seasonality. Stroke is divided into three subtypes: cerebral hemorrhage (CH), cerebral infarction (CI), and subarachnoid ...hemorrhage (SAH). The purpose of this paper was to analyze stroke events by subtype and month, in order to clarify the biggest factors that affect seasonal differences and thereby gain insight into stroke prevention. Methods Initial stroke events in the Akita Stroke Registry from 1991 to 2010 (58,684 cases; male 30,549, female 28,135) were classified by subtype and the month of onset, and correlations were estimated based on 115 healthy volunteers' monthly mean resting blood pressure (BP) at home and outdoor temperature measured by the Akita Meteorological Observatory in 2001. Results Systolic BP showed monthly variation in both morning and evening measurements. BP and outdoor temperature showed significant correlations with hemorrhagic stroke events by month (CH: r=0.87, r=-0.82; SAH: r=0.68, r=-0.82). Among the stroke subtypes, seasonal differences were the greatest in CH. Systolic BP was the most important factor for monthly and seasonal variation in stroke events. By comparing monthly BP variations with CH incidence throughout the year, we concluded that a decrease in home BP of 5 mmHg can reduce the risk of CH by 35%. Conclusion Our findings suggest that lowering BP would be the best strategy for CH prevention. Simple daily actions may be affected by cold stress. As physicians, we must strive to help patients lower their BP throughout the year not only with medication but with lifestyle guidance, especially in winter.
The pandemic influenza 2009 (A(H1N1)pdm09) virus currently causes seasonal and annual epidemic outbreaks. The widespread use of anti-influenza drugs such as neuraminidase and matrix protein 2 (M2) ...channel inhibitors has resulted in the emergence of drug-resistant influenza viruses. In this study, we aimed to determine the anti-influenza A(H1N1)pdm09 virus activity of azithromycin, a re-positioned macrolide antibiotic with potential as a new anti-influenza candidate, and to elucidate its underlying mechanisms of action. We performed in vitro and in vivo studies to address this. Our in vitro approaches indicated that progeny virus replication was remarkably inhibited by treating viruses with azithromycin before infection; however, azithromycin administration after infection did not affect this process. We next investigated the steps inhibited by azithromycin during virus invasion. Azithromycin did not affect attachment of viruses onto the cell surface, but blocked internalization into host cells during the early phase of infection. We further demonstrated that azithromycin targeted newly budded progeny virus from the host cells and inactivated their endocytic activity. This unique inhibitory mechanism has not been observed for other anti-influenza drugs, indicating the potential activity of azithromycin before and after influenza virus infection. Considering these in vitro observations, we administered azithromycin intranasally to mice infected with A(H1N1)pdm09 virus. Single intranasal azithromycin treatment successfully reduced viral load in the lungs and relieved hypothermia, which was induced by infection. Our findings indicate the possibility that azithromycin could be an effective macrolide for the treatment of human influenza.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Arsenic round the world: a review Mandal, Badal Kumar; Suzuki, Kazuo T
Talanta,
08/2002, Volume:
58, Issue:
1
Book Review, Journal Article
Peer reviewed
This review deals with environmental origin, occurrence, episodes, and impact on human health of arsenic. Arsenic, a metalloid occurs naturally, being the 20th most abundant element in the earth's ...crust, and is a component of more than 245 minerals. These are mostly ores containing sulfide, along with copper, nickel, lead, cobalt, or other metals. Arsenic and its compounds are mobile in the environment. Weathering of rocks converts arsenic sulfides to arsenic trioxide, which enters the arsenic cycle as dust or by dissolution in rain, rivers, or groundwater. So, groundwater contamination by arsenic is a serious threat to mankind all over the world. It can also enter food chain causing wide spread distribution throughout the plant and animal kingdoms. However, fish, fruits, and vegetables primarily contain organic arsenic, less than 10% of the arsenic in these foods exists in the inorganic form, although the arsenic content of many foods (i.e. milk and dairy products, beef and pork, poultry, and cereals) is mainly inorganic, typically 65–75%. A few recent studies report 85–95% inorganic arsenic in rice and vegetables, which suggest more studies for standardisation. Humans are exposed to this toxic arsenic primarily from air, food, and water. Thousands and thousands of people are suffering from the toxic effects of arsenicals in many countries all over the world due to natural groundwater contamination as well as industrial effluent and drainage problems. Arsenic, being a normal component of human body is transported by the blood to different organs in the body, mainly in the form of MMA after ingestion. It causes a variety of adverse health effects to humans after acute and chronic exposures such as dermal changes (pigmentation, hyperkeratoses, and ulceration), respiratory, pulmonary, cardiovascular, gastrointestinal, hematological, hepatic, renal, neurological, developmental, reproductive, immunologic, genotoxic, mutagenetic, and carcinogenic effects. Key research studies are needed for improving arsenic risk assessment at low exposure levels urgently among all the arsenic research groups.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
A 63-year-old Japanese woman with advanced lung adenocarcinoma developed isolated adrenocorticotropin deficiency caused by immune checkpoint inhibitor (ICI)-related hypophysitis following 8 months of ...nivolumab therapy. Prompt corticosteroid replacement therapy effectively relieved her secondary adrenal insufficiency symptoms and allowed her to pursue nivolumab therapy, which had been effective for the control of lung adenocarcinoma. Human leukocyte antigen (HLA) typing revealed the presence of the DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype, which is associated with susceptibility to autoimmune polyglandular syndrome with pituitary disorder in the Japanese population. This case suggests that genetic factors, such as HLA, contribute to the development of endocrinopathies induced by ICIs.
Inorganic arsenic is converted to methylated metabolites, and most is excreted in urine as dimethylarsinic acid in humans and animals. The present study was conducted to investigate the metabolism of ...arsenic and identify hepatic and renal metabolites of arsenic after an intravenous injection of arsenite (0.5 mg As/kg body weight) in rats. Similar levels of arsenic were found in the soluble (SUP) and nonsoluble sediment (SED) fractions of both organs after 1 h. More than 80% of the SUP arsenic was bound to high molecular weight (HMW) proteins in both organs. Arsenic bound to the HMW and SED proteins were oxidized with H2O2 and released in the pentavalent forms (arsenate, monomethylarsonic, and dimethylarsinic acids). The relative ratios of the three arsenicals changed depending on organ, fraction (HMW and SED), and time. Since the arsenic metabolites/intermediates were liberated from proteins by oxidation with H2O2 and recovered in the pentavalent forms, and only tri- but not pentavalent arsenicals were bound to proteins in vitro, it was deduced that arsenic metabolites bound to proteins during the successive methylation pathway are in the trivalent forms; that is, successive methylation reaction takes place with simultaneous reductive rather than stepwise oxidative methylation. Thus, on the basis of the present observations, it was proposed that inorganic arsenic was successively methylated reductively in the presence of glutathione, rather than a stepwise oxidative methylation, and pentavalent arsenicals (MMAV and DMAV) were present as end products of metabolism, rather than intermediates. We also discussed the in vitro formation of dimethylthioarsenicals after incubating dimethylarsinous acid with liver homogenate.
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IJS, KILJ, NUK, PNG, UL, UM
Chronic ingestion of arsenic-contaminated drinking water induces skin lesions and urinary bladder cancer in humans. It is now recognized that thioarsenicals such as dimethylmonothioarsinic acid ...(DMMTAV) are commonly excreted in the urine of humans and animals and that the production of DMMTAV may be a risk factor for the development of the diseases caused by arsenic. The toxicity of DMMTAV was compared with that of related nonthiolated arsenicals with respect to cell viability, uptake ability, generation of reactive oxygen species (ROS), and cell cycle progression of human epidermoid carcinoma A431 cells, arsenate (iAsV), arsenite (iAsIII), dimethylarsinic acid (DMAV), and dimethylarsinous acid (DMAIII) being used as reference nonthiolated arsenicals. DMMTAV (LC50 = 10.7 µM) was shown to be much more cytotoxic than iAsV (LC50 = 571 µM) and DMAV (LC50 = 843 µM), and its potency was shown to be close to that of trivalent arsenicals iAsIII (LC50 = 5.49 µM) and DMAIII (LC50 = 2.16 µM). The greater cytotoxicity of DMMTAV was associated with greater cellular uptake and distribution, and the level of intracellular ROS remarkably increased in A431 cells upon exposure to DMMTAV compared to that after exposure to other trivalent arsenicals at the respective LC50. Exposure of DMMTAV to cells for 24 h induced cell cycle perturbation. Namely, the percentage of cells residing in S and G2/M phases increased from 10.2 and 15.6% to 46.5 and 20.8%, respectively. These results suggest that although DMMTAV is a pentavalent arsenical, it is taken up efficiently by cells and causes various levels of toxicity, in a manner different from that of nonthiolated pentavalent arsenicals, demonstrating that DMMTAV is one of the most toxic arsenic metabolites. The high cytotoxicity of DMMTAV was explained and/or proposed by (1) efficient uptake by cells followed by (2) its transformation to DMAV, (3) producing ROS in the redox equilibrium between DMAV and DMAIII in the presence of glutathione.
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IJS, KILJ, NUK, PNG, UL, UM
The kynurenine pathway (KP) of tryptophan metabolism is linked to antimicrobial activity and modulation of immune responses but its role in stem cell biology is unknown. We show that human and mouse ...mesenchymal and neural stem cells (MSCs and NSCs) express the complete KP, including indoleamine 2,3 dioxygenase 1 (IDO) and IDO2, that it is highly regulated by type I (IFN-β) and II interferons (IFN-γ), and that its transcriptional modulation depends on the type of interferon, cell type and species. IFN-γ inhibited proliferation and altered human and mouse MSC neural, adipocytic and osteocytic differentiation via the activation of IDO. A functional KP present in MSCs, NSCs and perhaps other stem cell types offers novel therapeutic opportunities for optimisation of stem cell proliferation and differentiation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Acute tubulointerstitial nephritis (ATIN) has been increasingly recognized as an important manifestation of kidney injury associated with the use of immune checkpoint inhibitors (anti-PD-1 and ...anti-CTLA-4). While the exact pathophysiology remains unknown, corticosteroids are the mainstay of management.
We describe a 67-year-old man with stage IV non-small-cell lung cancer who developed kidney injury during treatment with the anti-PD-1 antibody nivolumab. A kidney biopsy showed ATIN without granuloma formation. Considering their mechanism of action, immune checkpoint inhibitors can alter immunological tolerance to concomitant drugs that have been safely used for a long time. For more than 4 years before the initiation of nivolumab therapy, the patient had been receiving the proton pump inhibitor lansoprazole, known to cause drug-induced ATIN, without significant adverse events including kidney injury. He showed rapid improvement in kidney function in 3 days (creatinine decreased from 2.74 to 1.82 mg/dl) on discontinuation of lansoprazole. He then received 500 mg intravenous methylprednisolone for 3 days followed by 1 mg/kg/day oral prednisolone and his creatinine levels eventually stabilized around 1.7 mg/dl. Drug-induced lymphocyte stimulation test (DLST) for lansoprazole was positive.
The rapid improvement of kidney function after discontinuation and DLST positivity indicate that lansoprazole contributed to the development of ATIN during nivolumab therapy. Considering the time course, it is plausible that nivolumab altered the long-lasting immunological tolerance against lansoprazole in this patient. To the best of our knowledge, this is the first case report of DLST positivity for a drug that had been used safely before the initiation of an immune checkpoint inhibitor. Although corticosteroid therapy is recommended, the recognition and discontinuation of concomitant drugs, especially those known to induce ATIN, is necessary for the management of kidney injury associated with anti-PD-1 therapy.
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