Therefore, Hsp60 is a novel regulator of mitochondrial permeability transition, contributing to a cytoprotective chaperone network that antagonizes CypD-dependent cell death in tumors. Cancer Res; 70(22); 8988-93.

(C) 2010 AACR.”
“Cytidine deaminase (EC 3.5.4.5, CDA), an enzyme of the pyrimidine salvage pathways, is responsible for the degradation and inactivation of several cytidine-based antitumor drugs such as cytarabine, gemcitabine, decitabine, and check details azacytidine. Thus, CDA inhibitors are highly sought after as compounds to be co-administered with said drugs to improve their effectiveness. Alternatively, the design of antitumor drugs not susceptible to the action of CDA is also regarded as an attractive solution. Herein we describe a virtual screen for CDA ligands based on chemical Sotrastaurin similarity and molecular docking. The campaign led to the identification of three novel inhibitors and one novel substrate, with a 19% hit rate, and allowed a significant extension of the structure-activity relationships, also in light of the compounds that resulted inactive. The most active compound identified through the screen is the inhibitor pseudoisocytidine, which has the potential to serve as a lead for highly stable compounds. The study also delineated the detrimental effect of 5-aza and 6-aza

substitutions, the incompatibility of the presence of an amino group at the 3′-position, as well as the presence of very strict steric requirements around the 2′-arabino position and, even more, the N4-position. Importantly, https://www.selleckchem.com/products/ly2090314.html these features can be exploited for the design of novel antineoplastic agents resistant to the action of CDA.”
“White matter lesions, commonly seen on, MRIs of elderly people, are related to various geriatric disorders, including cerebrovascular diseases, cardiovascular diseases, dementia, and psychiatric disorders. Currently, white matter lesions are divided into periventricular

white matter lesions and deep white matter lesions. Although the meaning of these terms varies by study and this dichotomization itself is still in debate, a possible dissimilarity in pathogenic mechanisms between periventricular white matter lesions and deep white matter lesions are providing some clues for understanding pathophysiology of many geriatric syndromes associated with white matter lesions. We have reviewed the distinctions between periventricular white matter lesions and deep white matter lesions in terms of etiology, histopathology, functional correlates, and imaging methodologies. We suggest a new subclassification of white matter lesions that might have better etiological and functional relevance than the current simple dichotomization. The new categories are juxtaventricular, periventricular, deep white, and juxtacortical. This new classification scheme might contribute to reducing the heterogeneity of white matter lesion findings in future research.

The results showed a large number of genes belonging to subsystems within the axon guidance signaling pathway, macrophages/immune system, glutamate system, and others. We divided the data and discussion of these results into 2 papers, and this is the first paper, which deals with the axon guidance signaling and macrophage/immune system. Other systems will be described in the next paper. Many components of subsystems within the axon guidance signaling Selleck LY3023414 underwent changes in gene expression from 3 M to 6 M so

that the synapse/dendritic spine number would decrease at 6 M. Thus, axon guidance signaling probably contributes to the decrease in synapse/dendritic spine number at 6 M, the phenomenon that fits the overshoot-type synaptic formation in primates. Microglial activity (evaluated by quantifying AIF1 expression) and gene expression of molecules that modulate microglia, decreased at 6 M, just like the synapse/dendritic spine number. Thus, although microglial activity

is believed to be related to phagocytosis of synapses/dendritic spines, microglial activity alone cannot explain how pruning was accelerated in the pruning phase. On the other hand, expression of molecules that tag synapses/dendritic spines as a target of phagocytosis by microglia (e.g., complement components) increased at 6 M, suggesting that these tagging proteins may be involved in the acceleration of pruning during NU7026 solubility dmso the pruning phase. (C) 2014 Elsevier Inc. All rights reserved.”
“This study was performed to understand the anatomical substrates of amygdaloid modulation of feeding-related peptides-containing

neurons in the lateral hypothalamic area (LHA). After biotinylated dextranamine (BDA) injection into the central amygdaloid nucleus (CeA) and immunostaining of melanin-concentrating hormone (MCH)- or orexin (ORX)-containing hypothalamic neurons in the mouse, the prominent overlap of the distribution field of the BDA-labeled fibers and that of the MCH-immunoreactive (ir) or ORX-ir neurons was found in the dorsolateral part of the LHA, and the labeled axon terminals made symmetrical synaptic contacts with somata Selleck Compound C and dendrites of the MCH-ir or ORX-ir neurons. It was further revealed that nearly all the BDA-labeled axon terminals in the dorsolateral part of LHA were immunoreactive for glutamic acid decarboxylase, an enzyme for conversion of glutamic acid to gamma-aminobutyric acid (GABA). The present data suggest that the CeA is involved in the regulation of feeding behavior by exerting its GABAergic inhibitory action upon the MCH- and ORX-containing LHA neurons. (C) 2009 Elsevier BV. All rights reserved.”
“Homomeric alpha 7 nicotinic acetylcholine receptors represent an important and complex pharmaceutical target.

Despite the important roles of cationic amino acid transporters

for normal brain functioning and various brain diseases there is currently only fragmentary knowledge about their cellular and regional distribution patterns in the human brain. We mapped the immunohistochemical localization of human cationic amino acid transporters 1, 2 and 3 (hCAT1, 2, and 3) throughout five adult human brains and found a wide but uneven distribution of these transporters. All three MLN2238 manufacturer hCAT1s were mainly localized in neurons, but were also found in numerous astrocytes, oligodendrocytes, plexus choroideus epithelial cells, and small blood vessels. The highest density of hCAT expressing neurons was observed in the hypothalamus, in some areas of the cerebral cortex, the thalamic reticular nucleus and the caudate nucleus, whereas weak to moderate expression was detected in the hippocampus,

the prefrontal cortex (hCAT1 only), pons, brain stem and cerebellum. In contrast to what has been found in rodent brain, we detected hCAT2 and hCAT3 also in astrocytes. Overall, each hCAT has its characteristic, individual cerebral expression patterns, which, however, overlap with the others.”
“Nanocomposite films were prepared successfully by simple solution casting method from plasticized starch/functionalized multiwalled carbon nanotubes (PS/f-MWCNTs). The interaction of starch with functionalized multiwalled carbon nanotube (f-MWCNT) was evidenced by PCI-34051 ultraviolet-visible (UV-vis) spectroscopy and Fourier transforms infrared (FTIR) spectroscopy. The morphological and thermal properties of the composite films were investigated using scanning electron microscope (SEM), high resolution transmission electron microscope (HRTEM), X-ray diffraction (XRD) and thermo gravimetric analysis (TGA). The electrical conductivity of the composites was increased significantly by sixteen times, from 0.1 x 10(-9) to 1.6 x 10(-9) S/cm. This reveals better dispersion of f-MWCNT with low concentration of f-MWCNT. The oxygen permeability of the composites was

reduced by half as compared to virgin PS. This indicates better dispersion of f-MWCNT in PS matrix due to formation of strong hydrogen bonding with PS matrix. (C) 2013 Elsevier Ltd. All rights reserved.”
“OBJECTIVES: To examine the effects of calorie this website labeling on food selection and intake in dieters and non-dieters, and to explore whether expectations about food healthfulness moderate these effects.\n\nMETHODS: Participants were presented with a menu containing two items, a salad and a pasta dish. The menu had (a) no calorie information, (b) information that the salad was low in calories and the pasta was high in calories, (c) information that the salad was high in calories and the pasta was low in calories or (d) information that both were high in calories (study 2 only).

With increasing age, NHE1 TG mice exhibited increased myocyte apoptosis, developed left ventricular contractile dysfunction, underwent cardiac remodelling and died prematurely. Our findings indicate that: (1) Cardiac-specific NHE1 over-expression induces the ER stress response in mouse myrocardium, which may afford protection against ischemia/reperfusion-induced injury despite increased NHE activity; (2) Ageing NHE1 TG mice exhibit myocyte apoptosis, cardiac remodelling and failure, likely as a result of Sustained ER stress; (3) The pluripotent effects of the ER stress response may confound studies that are based on the chronic over-expression of complex

proteins in myrocardium. (C) 2008 Elsevier Inc. Stem Cell Compound Library All rights reserved.”
“Recruitment of the growth factor receptor-bound protein 2 (Grb2) by the plasma membrane-associated adapter protein downstream of kinase 3 (Dok-3) attenuates signals transduced by the B cell antigen receptor (BCR). Here we describe molecular details of Dok-3/Grb2 signal integration and function, showing that the Lyn-dependent

activation of the BCR transducer kinase Syk is attenuated by Dok-3/Grb2 in a site-specific manner. This process is associated with the SH3 domain-dependent translocation of Dok-3/ Grb2 complexes into BCR microsignalosomes and augmented phosphorylation of the inhibitory Lyn target HSP990 in vitro SH2 domain-containing inositol 5′ phosphatase. Hence, our findings imply that Dok-3/ Grb2 modulates the balance between activatory and inhibitory Lyn functions selleck chemicals llc with the aim to adjust BCR signaling efficiency.”
“Background: Retroviral integrase catalyzes integration of viral DNA into the host genome. Integrase interactor (INI) 1/hSNF5 is a host factor that binds to HIV-1 IN within the context of Gag-Pol and is specifically incorporated into HIV-1 virions during assembly. Previous studies have indicated that INI1/hSNF5 is required for late events in vivo and for integration in vitro. To determine the effects of disrupting the IN-INI1 interaction

on the assembly and infectivity of HIV-1 particles, we isolated mutants of IN that are defective for binding to INI1/hSNF5 and tested their effects on HIV-1 replication.\n\nResults: A reverse yeast two-hybrid system was used to identify INI1-interaction defective IN mutants (IID-IN). Since protein-protein interactions depend on the surface residues, the IID-IN mutants that showed high surface accessibility on IN crystal structures (K71R, K111E, Q137R, D202G, and S147G) were selected for further study. In vitro interaction studies demonstrated that IID-IN mutants exhibit variable degrees of interaction with INI1. The mutations were engineered into HIV-1(NL4-3) and HIV-Luc viruses and tested for their effects on virus replication.

Methods and results: Moderate-intensity ExT was administrated

to young normotensive Wistar-Kyoto (WKY) and selleck compound SHR rats for 16 weeks. SHR rats had a significant increase in mean arterial pressure and cardiac hypertrophy. SHR rats also had higher levels of glutamate, norepinephrine (NE), phosphorylated IKK beta, NF-kappa B p65 activity, NAD(P) H oxidase subunit gp91(phox), PICs and the monocyte chemokine protein-1 (MCP-1), and lower levels of gamma-aminobutyric acid (GABA) and interleukin-10 (IL-10) in the PVN. These SHR rats also exhibited higher renal sympathetic nerve activity (RSNA), and higher plasma levels of PICs, and lower plasma IL-10. However, ExT ameliorates all these changes in SHR rats. Conclusion: These findings suggest that there are the imbalances between excitatory and inhibitory neurotransmitters and between pro-and anti-inflammatory cytokines in the

PVN of SHR rats, which at least partly contributing to sympathoexcitation, hypertension and cardiac AZD8055 hypertrophy; chronic exercise training attenuates hypertension and cardiac hypertrophy by restoring the balances between excitatory and inhibitory neurotransmitters and between pro-and anti-inflammatory cytokines in the PVN; NF-kappa B and oxidative stress in the PVN may be involved in these exercise-induced effects.”
“Objectives: Peripheral blood mononuclear cells (PBMC) are an attractive source for the generation of osteoclasts in vitro, which is an important prerequisite for the examination of resorption and remodeling of biomaterials. In this study, different preparation methods are used to obtain cell populations GDC-0994 ic50 with a rising content of CD14(+) monocytes. We wanted to address the question whether there is a correlation between content of CD14(+) cells in the preparation and functionality of formed osteoclasts. Materials and Methods: PBMC obtained by density gradient centrifugation with and without further purification by plastic adherence or immunomagnetic separation of CD14(+) cells were seeded on both cell culture

polystyrene and a calcium phosphate bone cement (CPC) and cultivated under stimulation with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B ligand (RANKL). Cell cultures were characterized by histological and fluorescent staining of multinucleated cells that were positive for tartrate-resistant acid phosphatase (TRAP) activity and the presence of actin rings, respectively. Furthermore, activities of osteoclast marker enzymes TRAP and carbonic anhydrase II (CA II) were quantified. For osteoclasts cultured on CPC, resorption pits were visualized using scanning electron microscopy (SEM). Results: Monocytes of all preparations were successfully differentiated into multinucleated osteoclasts showing TRAP and CA II activity on both cell culture plastic and CPC.

72).\n\nCONCLUSION:

Sample age is the best predictor of successful mRNA profiling of FFPE material, and miRNA profiling overcomes the limitation of age and copes well with older samples. British Journal of Cancer (2012) 107, 684-694. doi:10.1038/bjc.2012.294 www.bjcancer.com Published online 17 July 2012 (C) 2012 Cancer Research UK”
“Understanding the underlying qualitative features of memory deficits in mild cognitive impairment (MCI) can provide critical information for early detection of Alzheimer’s disease MK-2206 cell line (AD). This study sought to investigate the utility of both learning and retention measures in (a) the diagnosis of MCI, (b) predicting progression to AD, and (c) examining their underlying brain morphometric correlates. A total of 607 participants were assigned to three MCI groups Nocodazole (high learning-low retention; low learning-high retention; low learning-low retention) and one control group (high learning-high retention) based on scores above or below a 1.5 SD cutoff on learning and retention indices of the Rey Auditory Verbal Learning Test. Our results demonstrated that MCI individuals with predominantly a learning deficit showed a widespread pattern of gray matter loss at baseline, whereas individuals with a retention deficit showed more focal gray matter loss. Moreover, either learning or retention measures provided good predictive value for longitudinal clinical outcome over two years, although

impaired learning had modestly better predictive power than impaired retention. As expected, impairments in both measures provided the best predictive power. Thus, the conventional practice of relying solely on the use of delayed recall or retention measures in studies of amnestic MCI misses an important subset of older adults at risk of developing AD. Overall. our results highlight the importance of including learning measures in addition to retention measures when making click here a diagnosis of MCI and for predicting clinical outcome. (C)

2009 Elsevier Ltd. All rights reserved.”
“Background: Neutropenia is a common adverse effect of the treatment of chronic hepatitis C with pegylated interferon and ribavirin. However, the mechanism involved is unknown. The present study aimed to investigate the cause of treatment-induced neutropenia by determining cytokine levels in plasma and in bone marrow smears. Methods: Fifteen patients with chronic hepatitis C were enrolled in this study. Plasma cytokine levels were determined using the Luminex assay before and during treatment. We simultaneously determined the levels of granulocyte colony-stimulating factor (G-CSF), granulocyte- macrophage colony-stimulating factor (GM-CSF), and 7 other cytokines, and performed bone marrow cytology when blood cell counts indicated neutropenia. Results: Only 1 bone marrow smear indicated a low cell proliferation level, whereas active proliferation was observed in the remaining 14 patients.

This decrease in ISP probably corresponds to the relatively small scattered ion yield usually observed at low incident ion energies. Theoretically, such a decrease indicates that a He+ ion with a low incident energy can be easily neutralized on the surface when the bandwidth is large.”
“Objective: the aim of this study was to evaluate the influence of consumption of a ketogenic diet supplemented

with triheptanoin, a medium-chain anaplerotic triacylglycerol, on the liver fatty acid profile of Wistar rats. Methods: three groups of male Wistar rats (n=10) were submitted to an AIN-93 control diet, a triheptanoin-based ketogenic diet, or a soybean oil-based ketogenic diet for 60 days. Excised livers were subjected to lipid extraction and methylation to obtain fatty acids methyl esters, CX-6258 datasheet which were subjected to gas chromatography-mass spectrometry. Results and discussion: compared to the rats fed the control diet, those fed ketogenic diets showed a significant reduction in the concentrations of 9-hexadecenoic and 9-octadecenoic BTSA1 acids, whereas those fed triheptanoin showed increased levels of octadecanoic acid. Conclusion: changes in the liver fatty acid profiles of the rats fed a triheptanoin-based or a soybean oil-based ketogenic diet did

not seem to be related to the dietary fat source, but rather to the characteristics of the ketogenic diets themselves.”
“An unequal resource distribution is commonly seen in dominance hierarchies, in which the individual with the higher status is more successful in obtaining the resource. One possible resource is preferred temperature. When situations allow, ectotherms regulate their body temperature by behaviourally selecting different environmental conditions, achieving,

when possible, a preferred temperature. Using a shuttlebox, the preferred temperature for Procambarus clarkii was determined to be Fer-1 nmr 23.9 degrees C with upper and lower voluntary escape temperatures of 25.9 and 21.8 degrees C, respectively. If this preferred temperature zone (21.8-25.9 degrees C) was valued as a resource, given the choice between a preferred temperature and a non-preferred temperature, crayfish should compete over the preferred temperature, with the dominant individual of dyadic pairs achieving the preferred temperature more often than the subordinate. Using a dual-choice experimental tank, competition over a binary temperature choice between rank-established paired crayfish was determined under both warm and cold challenge conditions (warm vs preferred temperature and cold vs preferred temperature, respectively). In naive pairings, similar levels of competition over the preferred temperature occurred in both warm and cold challenge trials, as predicted by game theory. In established pairings, however, dominant crayfish gained significantly greater access to preferred temperature in both warm and cold challenge conditions.

Both GTPCH I activity and BH4 levels were reduced in the aortas and small mesenteric arteries of hph-1 mice. However, the BH(4)-to-7,8-dihydrobiopterin ratio was significantly click here reduced only in hph-1 aortas. Furthermore, superoxide anion and 3-nitrotyrosine production were significantly enhanced in aortas but not in small mesenteric arteries of hph-1 mice. In contrast to the aorta, protein expression of copper-and zinc-containing

superoxide dismutase (CuZnSOD) was significantly increased in small mesenteric arteries of hph-1 mice. Protein expression of catalase was increased in both aortas and small mesenteric arteries of hph-1 mice. Further analysis of endothelial nitric oxide synthase (eNOS)/cyclic guanosine monophosphate (cGMP) signaling demonstrated that protein expression of phosphorylated Ser(1177)-eNOS as well as basal cGMP levels and hydrogen peroxide was increased in hph-1 aortas. Increased production of hydrogen peroxide in hph-1 mice aortas appears to be the most likely mechanism responsible for phosphorylation of eNOS and find more elevation of cGMP. In contrast, up-regulation of CuZnSOD and catalase in resistance arteries is sufficient to protect vascular tissue from increased production of reactive oxygen species generated by uncoupling of eNOS. The results of our study suggest that

anatomical origin determines the ability of vessel wall to cope MI-503 with oxidative stress induced by uncoupling of eNOS.”
“Purpose of review\n\nCancer-associated fibroblasts/myofibroblasts and inflammatory cells produce a vast array of growth factors, chemokines and extracellular matrix (ECM) components that facilitate cancer progression, invasion/metastasis and neovascularization. This review highlights some surprisingly novel mechanisms of this paracrine relationship.\n\nRecent

findings\n\nMesenchymal stem/stromal cells (MSCs) are known for their tropism towards certain tumours, but now we find that cross-talk between tumours and MSCs leads to greater tumour motility and metastasis. Two closely related populations of immature myeloid cells, so-called ‘cap cells’ and myeloid-derived suppressor cells (MDSCs) also crosstalk with tumour cells, promoting invasion and metastasis through matrix metalloproteinase (MMP) secretion, as well as contributing to neovascularization and T-cell tolerance. The contribution of bone marrow-derived cells (BMDCs) to tumour neovascularization is controversial, but BMD – endothelial progenitor cells (EPCs) are strongly implicated in the angiogenic switch in a mouse model. BMDCs are also credited with the creation of premetastatic niches to which metastatic cells adhere via integrins.\n\nSummary\n\nThere is no doubt that BMDCs are not simply bystanders in the tumour battleground.

MethodsThere were 110 patients with RA and 110 age- and sex-matched healthy controls who were concurrently

studied. All of the patients underwent the following measurements: erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, and serum 25OHD. Dual-energy X-ray absorptiometry (DEXA) was also used to measure the BMD of the left femur at the time of recruitment. Patients taking vitamin D supplement GS-7977 order or corticosteroids were excluded. ResultsThe incidences of osteopenia (45.6% vs. 36.4%, P=0.170) and osteoporosis (33.6% vs. 5.45%, P=0.000) were higher in the RA patients than in the healthy controls. There was a significant negative correlation between vitamin D levels and DAS28 (r=-0.325, P=0.001) and a significant positive correlation between vitamin D levels and BMD (r=0.422, P=0.000). The multiple regression analysis revealed that 25OHD levels were significantly correlated with disease activity

and BMD (F=11.087, P=0.000). Stepwise multiple regression analysis showed that serum 25OHD levels were the significant predictors for low BMD and high disease activity (DAS28) in RA Bucladesine patients. ConclusionThe incidences of osteoporosis and osteopenia were higher in RA patients compared to the age- and gender-matched healthy controls. Low serum 25OHD levels correlate with low BMD and high disease activity in RA patients.”
“BackgroundDefining suitable markers to diagnose and monitor allergy and its severity is essential to correctly assign patients for specific immunotherapy. Circulating levels of specific IgE are good markers of sensitization, but not of clinically symptomatic Anlotinib molecular weight allergy. ObjectiveTo quantify circulating interleukin (IL)-4- and IL-13-secreting T cells specific for house dust mite (HDM) in children presenting HDM-allergic asthma associated or not with rhinitis and correlate results with clinical symptoms. MethodsWe analysed 26 children with HDM respiratory disease (allergic rhinitis and asthma) together with six children with non-allergic asthma. Peripheral blood

mononuclear cells were stimulated with HDM extract in a 24-h ELISpot assay to quantify the number of HDM-specific IL-4- and IL-13-secreting T cells. Asthma severity and control, and rhinitis severity were scored according to the Global Initiative for Asthma (GINA) and the Allergic Rhinitis and its Impact on Asthma (ARIA) Guidelines. ResultsThe number of HDM-specific IL-4- and IL-13-secreting T cells was higher in patients with allergic asthma as compared to patients with non-allergic asthma. It varied with the season of blood sampling with two peaks in the fall and early spring. Independently of the season, the number of HDM-specific IL-4-secreting T cells correlated with rhinitis severity (OR=2; 95% IC:1.1-3.8; P=0.04).

$5,566). This study shows that DVA management provided in a FOC has multiple advantages over that provided in a HOPD.”
“Background: Unexplained infertility

is still a challenging issue as to its causes, appropriate management and treatment. Evidence implicates early embryopathy or implantation failure as likely causes.\n\nObjective: This study aims PF-00299804 cost to investigate the effect of local endometrial injury on pregnancy rate in selected unexplained infertile patients.\n\nMaterials and Methods: This was a randomized clinical trial conducted in Shiraz University Infertility Clinic of Ghadir Hospital. A total of 217 women with unexplained infertility aged 23-35 years old were randomly divided into two study groups through block randomization. After superovulation by clomiphene-citrate and gonadotropins and when the dominant follicles reached 18-20 mm, patients were randomly assigned to undergo endometrial local injury at posterior uterine wall by piplle endometrial sampling (n=114) or mock pipette biopsy (n=103) during preovulatory days (when spontaneous urinary LH surge was detected). Then all the patients were instructed to follow a regularly timed intercourse.\n\nResults: Bafilomycin A1 The pregnancy rate was significantly higher in the endometrial injury group compared to the control

group [17/114 (14.9%) vs. 6/103 (5.8%) (OR: 2.83 95% CI: 1.07-7.49, p=0.03]. The abortion rate was comparable between two groups Nepicastat inhibitor (17.64% vs. 14.28%; p=0.701).\n\nConclusion: Local mechanical injury of the endometrium can enhance the uterine receptivity and facilitates the embryo implantation. This simple, easy, and cost effective procedure is worth considering in selective unexplained infertility patients who implantation failure is the likely causes of infertility before complex treatments. This procedure may help reduce psychological tensions and high expenses imposed through such interventions.”
“A

GaN/Si nanoheterostructure is prepared by growing wurtzite GaN on a silicon nanoporous pillar array (Si-NPA) with a chemical vapor deposition method. The temperature evolution of the photoluminescence (PL) of GaN/Si-NPA is measured and the PL mechanism is analyzed. It is found that the PL spectrum is basically composed of two narrow ultraviolet peaks and a broad blue peak, corresponding to the near band edge emission of GaN and its phonon replicas, and the emission from Si-NPA. No GaN defect-related PL is observed in the as-prepared GaN/Si-NPA. Our experiments prove that Si-NPA might be an ideal substrate for preparing high-quality Si-based GaN nanomaterials or nanodevices.”
“In both humans and mice there are numerous reports of Y chromosome abnormalities that interfere with sex determination. Recent studies in the mouse of one such mutation have identified Y chromosome nondisjunction during preimplantation development as the cause of abnormal testis determination that results in a high frequency of true hermaphroditism.