Nigrostriatal blood-brain barrier opening in Parkinson's disease.

BACKGROUND: The nigrostriatal system is especially vulnerable to neurodegeneration in Parkinson's disease (PD) and the blood-brain barrier (BBB) is a limiting factor for delivery of therapeutic agents to the brain. This pilot study aimed to demonstrate safety, feasibility and tissue penetration (by 18F-Choline-positron emission tomography (PET)) of MR-guided focused ultrasound (MRgFUS) simultaneous BBB opening (BBB-O) in the substantia nigra (SN) and putamen in PD. METHODS: Three patients underwent MRgFUS for midbrain and putamen BBB-O. Patients were evaluated clinically and underwent brain MRI with gadolinium (baseline, 24 hours, 14 days and 3 months postprocedure). In two patients, BBB-O was repeated after 2-3 weeks, and 18F-Choline-PET was performed immediately after. RESULTS: The right SN and putamen were simultaneously opened unilaterally in 3 patients once and the left SN in 1 patient in a different session. No severe clinical or neuroimaging adverse events developed in any patient. 18F-Choline-PET uptake was enhanced in the targeted SN and putamen regions. CONCLUSION: BBB-O of the nigrostriatal system is a feasible and well-tolerated approach in patients with PD. 18F-Choline-PET uptake indicates penetration into the parenchyma after BBB-O, which suggests that the opening is functionally effective. This minimally invasive technique could facilitate delivery of putative neurorestorative molecules to brain regions vulnerable to neurodegeneration.

Residential exposure to traffic pollution and mammographic density in premenopausal women.

BACKGROUND: Mammographic density (MD) is the most important breast cancer biomarker. Ambient pollution is a carcinogen, and its relationship with MD is unclear. This study aims to explore the association between exposure to traffic pollution and MD in premenopausal women. METHODOLOGY: This Spanish cross-sectional study involved 769 women attending gynecological examinations in Madrid. Annual Average Daily Traffic (AADT), extracted from 1944 measurement road points provided by the City Council of Madrid, was weighted by distances (d) between road points and women's addresses to develop a Weighted Traffic Exposure Index (WTEI). Three methods were employed: method-1 (1dAADT), method-2 (1dAADT), and method-3 (e1dAADT). Multiple linear regression models, considering both log-transformed percentage of MD and untransformed MD, were used to estimate MD differences by WTEI quartiles, through two strategies: "exposed (exposure buffers between 50 and 200 m) vs. not exposed (>200 m)"; and "degree of traffic exposure". RESULTS: Results showed no association between MD and traffic pollution according to buffers of exposure to the WTEI (first strategy) for the three methods. The highest reductions in MD, although not statistically significant, were detected in the quartile with the highest traffic exposure. For instance, method-3 revealed a suggestive inverse trend (eßQ1 = 1.23, eßQ2 = 0.96, eßQ3 = 0.85, eßQ4 = 0.85, p-trend = 0.099) in the case of 75 m buffer. Similar non-statistically significant trends were observed with Methods-1 and -2. When we examined the effect of traffic exposure considering all the 1944 measurement road points in every participant (second strategy), results showed no association for any of the three methods. A slightly decreased MD, although not significant, was observed only in the quartile with the highest traffic exposure: eßQ4 = 0.98 (method-1), and eßQ4 = 0.95 (methods-2 and -3). CONCLUSIONS: Our results showed no association between exposure to traffic pollution and MD in premenopausal women. Further research is needed to validate these findings.

Mammographic density in the environs of multiple industrial sources.

BACKGROUND: Mammographic density (MD), defined as the percentage of dense fibroglandular tissue in the breast, is a modifiable marker of the risk of developing breast cancer. Our objective was to evaluate the effect of residential proximity to an increasing number of industrial sources in MD. METHODS: A cross-sectional study was conducted on 1225 premenopausal women participating in the DDM-Madrid study. We calculated distances between women's houses and industries. The association between MD and proximity to an increasing number of industrial facilities and industrial clusters was explored using multiple linear regression models. RESULTS: We found a positive linear trend between MD and proximity to an increasing number of industrial sources for all industries, at distances of 1.5 km (p-trend = 0.055) and 2 km (p-trend = 0.083). Moreover, 62 specific industrial clusters were analyzed, highlighting the significant associations found between MD and proximity to the following 6 industrial clusters: cluster 10 and women living at ≤1.5 km (ß = 10.78, 95 % confidence interval (95%CI) = 1.59; 19.97) and at ≤2 km (ß = 7.96, 95%CI = 0.21; 15.70); cluster 18 and women residing at ≤3 km (ß = 8.48, 95%CI = 0.01; 16.96); cluster 19 and women living at ≤3 km (ß = 15.72, 95%CI = 1.96; 29.49); cluster 20 and women living at ≤3 km (ß = 16.95, 95%CI = 2.90; 31.00); cluster 48 and women residing at ≤3 km (ß = 15.86, 95%CI = 3.95; 27.77); and cluster 52 and women living at ≤2.5 km (ß = 11.09, 95%CI = 0.12; 22.05). These clusters include the following industrial activities: surface treatment of metals/plastic, surface treatment using organic solvents, production/processing of metals, recycling of animal waste, hazardous waste, urban waste-water treatment plants, inorganic chemical industry, cement and lime, galvanization, and food/beverage sector. CONCLUSIONS: Our results suggest that women living in the proximity to an increasing number of industrial sources and those near certain types of industrial clusters have higher MD.

Developmental Ultrasound Characteristics in Guinea Pigs: Similarities with Human Pregnancy.

BACKGROUND: Biometrical and blood flow examinations are fundamental for assessing fetoplacental development during pregnancy. Guinea pigs have been proposed as a good model to study fetal development and related gestational complications; however, longitudinal growth and blood flow changes in utero have not been properly described. This study aimed to describe fetal and placental growth and blood flow of the main intrauterine vascular beds across normal guinea pig pregnancy and to discuss the relevance of this data for human pregnancy. METHODS: Pregnant guinea pigs were studied from day 25 of pregnancy until term (day ~70) by ultrasound and Doppler assessment. The results were compared to human data from the literature. RESULTS: Measurements of biparietal diameter (BPD), cranial circumference (CC), abdominal circumference, and placental biometry, as well as pulsatility index determination of umbilical artery, middle cerebral artery (MCA), and cerebroplacental ratio (CPR), were feasible to determine across pregnancy, and they could be adjusted to linear or nonlinear functions. In addition, several of these parameters showed a high correlation coefficient and could be used to assess gestational age in guinea pigs. We further compared these data to ultrasound variables from human pregnancy with high similarities. CONCLUSIONS: BPD and CC are the most reliable measurements to assess fetal growth in guinea pigs. Furthermore, this is the first report in which the MCA pulsatility index and CPR are described across guinea pig gestation. The guinea pig is a valuable model to assess fetal growth and blood flow distribution, variables that are comparable with human pregnancy.

The transcription factor DDIT3 is a potential driver of dyserythropoiesis in myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis, with increased incidence in older individuals. Here we analyze the transcriptome of human HSCs purified from young and older healthy adults, as well as MDS patients, identifying transcriptional alterations following different patterns of expression. While aging-associated lesions seem to predispose HSCs to myeloid transformation, disease-specific alterations may trigger MDS development. Among MDS-specific lesions, we detect the upregulation of the transcription factor DNA Damage Inducible Transcript 3 (DDIT3). Overexpression of DDIT3 in human healthy HSCs induces an MDS-like transcriptional state, and dyserythropoiesis, an effect associated with a failure in the activation of transcriptional programs required for normal erythroid differentiation. Moreover, DDIT3 knockdown in CD34+ cells from MDS patients with anemia is able to restore erythropoiesis. These results identify DDIT3 as a driver of dyserythropoiesis, and a potential therapeutic target to restore the inefficient erythroid differentiation characterizing MDS patients.

Residential proximity to industrial pollution and mammographic density.

BACKGROUND: Mammographic density (MD), expressed as percentage of fibroglandular breast tissue, is an important risk factor for breast cancer. Our objective is to investigate the relationship between MD and residential proximity to pollutant industries in premenopausal Spanish women. METHODS: A cross-sectional study was carried out in a sample of 1225 women extracted from the DDM-Madrid study. Multiple linear regression models were used to assess the association of MD percentage (and their 95% confidence intervals (95%CIs)) and proximity (between 1 km and 3 km) to industries included in the European Pollutant Release and Transfer Register. RESULTS: Although no association was found between MD and distance to all industries as a whole, several industrial sectors showed significant association for some distances: "surface treatment of metals and plastic" (ß = 4.98, 95%CI = (0.85; 9.12) at ≤1.5 km, and ß = 3.00, 95%CI = (0.26; 5.73) at ≤2.5 km), "organic chemical industry" (ß = 6.73, 95%CI = (0.50; 12.97) at ≤1.5 km), "pharmaceutical products" (ß = 4.14, 95%CI = (0.58; 7.70) at ≤2 km; ß = 3.55, 95%CI = (0.49; 6.60) at ≤2.5 km; and ß = 3.11, 95%CI = (0.20; 6.01) at ≤3 km), and "urban waste-water treatment plants" (ß = 8.06, 95%CI = (0.82; 15.30) at ≤1 km; ß = 5.28; 95%CI = (0.49; 10.06) at ≤1.5 km; ß = 4.30, 95%CI = (0.03; 8.57) at ≤2 km; ß = 5.26, 95%CI = (1.83; 8.68) at ≤2.5 km; and ß = 3.19, 95%CI = (0.46; 5.92) at ≤3 km). Moreover, significant increased MD was observed in women close to industries releasing specific pollutants: ammonia (ß = 4.55, 95%CI = (0.26; 8.83) at ≤1.5 km; and ß = 3.81, 95%CI = (0.49; 7.14) at ≤2 km), dichloromethane (ß = 3.86, 95%CI = (0.00; 7.71) at ≤2 km), ethylbenzene (ß = 8.96, 95%CI = (0.57; 17.35) at ≤3 km), and phenols (ß = 2.60, 95%CI = (0.21; 5.00) at ≤2.5 km). CONCLUSIONS: Our results suggest no statistically significant relationship between MD and proximity to industries as a whole, although we detected associations with various industrial sectors and some specific pollutants, which suggests that MD could have a mediating role in breast carcinogenesis.

Occupation, occupational exposures and mammographic density in Spanish women.

INTRODUCTION: Mammographic density (MD), the proportion of radiologically dense breast tissue, is a strong risk factor for breast cancer. Our objective is to investigate the influence of occupations and occupational exposure to physical, chemical, and microbiological agents on MD in Spanish premenopausal women. METHODS: This is a cross-sectional study based on 1362 premenopausal workers, aged 39-50, who attended a gynecological screening in a breast radiodiagnosis unit of Madrid City Council. The work history was compiled through a personal interview. Exposure to occupational agents was evaluated using the Spanish job-exposure matrix MatEmESp. MD percentage was assessed using the validated semi-automated computer tool DM-Scan. The association between occupation, occupational exposures, and MD was quantified using multiple linear regression models, adjusted for age, educational level, body mass index, parity, previous breast biopsies, family history of breast cancer, energy intake, use of oral contraceptives, smoking, and alcohol consumption. RESULTS: Although no occupation was statistically significantly associated with MD, a borderline significant inverse association was mainly observed in orchard, greenhouse, nursery, and garden workers (ß = -6.60; 95% confidence interval (95%CI) = -14.27; 1.07) and information and communication technology technicians (ß = -7.27; 95%CI = -15.37; 0.84). On the contrary, a positive association was found among technicians in art galleries, museums, and libraries (ß = 8.47; 95%CI = -0.65; 17.60). Women occupationally exposed to fungicides, herbicides, and insecticides tended to have lower MD. The percentage of density decreased by almost 2% for every 5 years spent in occupations exposed to the mentioned agents. CONCLUSIONS: Although our findings point to a lack of association with the occupations and exposures analyzed, this study supports a deeper exploration of the role of certain occupational agents in MD, such as pesticides.

Waiting List and Kidney Transplant Vascular Risk: An Ongoing Unmet Concern.

BACKGROUND: Chronic kidney disease (CKD) is an important independent risk factor for adverse cardiovascular events in patients waitlisted for kidney transplantation (KT). Although KT reduces cardiovascular risk, these patients still have a higher all-cause and cardiovascular mortality than the general population. This concerning situation is due to a high burden of traditional and nontraditional risk factors as well as uremia-related factors and transplant-specific factors, leading to 2 differentiated processes under the framework of CKD, atherosclerosis and arteriosclerosis. These can be initiated by insults to the vascular endothelial endothelium, leading to vascular calcification (VC) of the tunica media or the tunica intima, which may coexist. Several pathogenic mechanisms such as inflammation-related endothelial dysfunction, mineral metabolism disorders, activation of the renin-angiotensin system, reduction of nitric oxide, lipid disorders, and the fibroblast growth factor 23-klotho axis are involved in the pathogenesis of atherosclerosis and arteriosclerosis, including VC. SUMMARY: This review focuses on the current understanding of atherosclerosis and arteriosclerosis, both in patients on the waiting list as well as in kidney transplant recipients, emphasizing the cardiovascular risk factors in both populations and the inflammation-related pathogenic mechanisms. Key Message: The importance of cardiovascular risk factors and the pathogenic mechanisms related to inflammation in patients waitlisted for KT and kidney transplant recipients.

Psychometric evaluation and cultural adaptation of the Spanish version of the "Scale for End-of Life Caregiving Appraisal".

OBJECTIVE: To translate, culturally adapt, and psychometrically evaluate the Spanish version of the "Scale for End-of Life Caregiving Appraisal" (SEOLCAS). METHOD: Observational cross-sectional study. Convenience sample of 201 informal end-of-life caregivers recruited in a southern Spanish hospital. The reliability of the questionnaire was assessed through its internal consistency (Cronbach's α) and temporal stability (Pearson's correlation coefficient [r] between test-retest). The content validity index of the items and the scale was calculated. Criterion validity was explored through performing a linear regression analysis to evaluate the SEOLCAS' predictive validity. Exploratory factor analysis was used to examine its construct validity. RESULTS: The SEOLCAS' reliability was very high (Cronbach's α = 0.92). Its content validity was excellent (all items' content validity index = 0.8-1; scale's validity index = 0.88). Evidence of the SEOLCAS' criterion validity showed that the participants' scores on the SEOLCAS explained approximately 79.3% of the between-subject variation of their results on the Zarit Burden Interview. Exploratory factor analysis provided evidence of the SEOLCAS' construct validity. This analysis revealed that two factors ("internal contingencies" and "external contingencies") explained 53.77% of the total variance found and reflected the stoic Hispanic attitude toward adversity.Significance of resultsThe Spanish version of the SEOLCAS has shown to be an easily applicable, valid, reliable, and culturally appropriate tool to measure the impact of end-of-life care provision on Hispanic informal caregivers. This tool offers healthcare professionals the opportunity to easily explore Hispanic informal end-of-life caregivers' experiences and discover the type of support they may need (instrumental or emotional) even when there are communicational and organizational constraints.

Mortality in Elderly Waiting-List Patients Versus Age-Matched Kidney Transplant Recipients: Where is the Risk?

The number of elderly patients on the waiting list (WL) for kidney transplantation (KT) has risen significantly in recent years. Because KT offers a better survival than dialysis therapy, even in the elderly, candidates for KT should be selected carefully, particularly in older waitlisted patients. Identification of risk factors for death in WL patients and prediction of both perioperative risk and long-term post-transplant mortality are crucial for the proper allocation of organs and the clinical management of these patients in order to decrease mortality, both while on the WL and after KT. In this review, we examine the clinical results in studies concerning: a) risk factors for mortality in WL patients and KT recipients; 2) the benefits and risks of performing KT in the elderly, comparing survival between patients on the WL and KT recipients; and 3) clinical tools that should be used to assess the perioperative risk of mortality and predict long-term post-transplant survival. The acknowledgment of these concerns could contribute to better management of high-risk patients and prophylactic interventions to prolong survival in this particular population, provided a higher mortality is assumed.

Social Support for Female Sexual Dysfunction in Fibromyalgia.

The aim of this study is to describe and understand experiences related to social support for women with fibromyalgia who suffer from sexual dysfunction. An interpretive qualitative research methodology based on Gadamer's philosophical hermeneutics was used. Data collection included a focus group and in-depth interviews with 13 women who averaged 44.8 years of age and 14.3 years since being diagnosed with fibromyalgia. Data were analyzed using Fleming's method and two themes were identified: "searching for understanding in socio-family support" and "lack of formal support regarding fibromyalgia patient's sexuality." The partner constitutes the main support for women with fibromyalgia. Although they can find understanding and social support in patient associations, they lack formal support from health care professionals. Women demand trusted and expert professionals, like sexologists and nurses, to carry out a multidisciplinary approach to tackle sexual dysfunction associated with fibromyalgia.

Perceptions about the sexuality of women with fibromyalgia syndrome: a phenomenological study.

AIMS: The aim of this study was to explore and understand the perceptions and experiences of women with fibromyalgia syndrome regarding their sexuality. BACKGROUND: Fibromyalgia syndrome is a chronic pathology, which compromises a woman's physical, mental and emotional health. Although concerns related to sexuality are commonly reported, research has tended to focus on the physical symptoms. DESIGN: An interpretive qualitative research methodology using Gadamer's philosophical hermeneutics was carried out. METHODS: This qualitative study explores the sexuality of women with fibromyalgia syndrome. A focus group and semi-structured interviews were conducted with 13 women with fibromyalgia syndrome. Data were collected between April - June 2014. Participants were recruited until findings reached saturation. FINDINGS: Three themes define the perception of sexuality for these women: (i) Physical impact: don't touch, don't look; (ii) Sexuality and identity: fighting against their loss; (iii) Impact on the relationship: sexuality as a way of connecting the couple. CONCLUSION: Despite limitations, sexuality is important for the identity and quality of life of women with fibromyalgia syndrome. Together with the physical symptomology, guilt, fear and a lack of understanding compromise the coping process. Women need the support of their partner, their socio-family environment and health professionals. Nurses can aid the successful adjustment to sexual problems related to fibromyalgia syndrome.

RE-PLAN: An Extensible Software Architecture to Facilitate Disaster Response Planning.

Computational tools are needed to make data-driven disaster mitigation planning accessible to planners and policymakers without the need for programming or GIS expertise. To address this problem, we have created modules to facilitate quantitative analyses pertinent to a variety of different disaster scenarios. These modules, which comprise the REsponse PLan ANalyzer (RE-PLAN) framework, may be used to create tools for specific disaster scenarios that allow planners to harness large amounts of disparate data and execute computational models through a point-and-click interface. Bio-E, a user-friendly tool built using this framework, was designed to develop and analyze the feasibility of ad hoc clinics for treating populations following a biological emergency event. In this article, the design and implementation of the RE-PLAN framework are described, and the functionality of the modules used in the Bio-E biological emergency mitigation tool are demonstrated.

Regulation of HFE expression by poly(ADP-ribose) polymerase-1 (PARP1) through an inverted repeat DNA sequence in the distal promoter.

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder of iron overload among Caucasians of northern European descent. Over 85% of all cases with HH are due to mutations in the hemochromatosis protein (HFE) involved in iron metabolism. Although the importance in iron homeostasis is well recognized, the mechanism of sensing and regulating iron absorption by HFE, especially in the absence of iron response element in its gene, is not fully understood. In this report, we have identified an inverted repeat sequence (ATGGTcttACCTA) within 1700bp (-1675/+35) of the HFE promoter capable to form cruciform structure that binds PARP1 and strongly represses HFE promoter. Knockdown of PARP1 increases HFE mRNA and protein. Similarly, hemin or FeCl3 treatments resulted in increase in HFE expression by reducing nuclear PARP1 pool via its apoptosis induced cleavage, leading to upregulation of the iron regulatory hormone hepcidin mRNA. Thus, PARP1 binding to the inverted repeat sequence on the HFE promoter may serve as a novel iron sensing mechanism as increased iron level can trigger PARP1 cleavage and relief of HFE transcriptional repression.

Experimental demonstration of a cognitive quality of transmission estimator for optical communication systems.

The impact of physical layer impairments in optical network design and operation has received significant attention in the last years, thereby requiring estimation techniques to predict the quality of transmission (QoT) of optical connections before being established. In this paper, we report on the experimental demonstration of a case-based reasoning (CBR) technique to predict whether optical channels fulfill QoT requirements, thus supporting impairment-aware networking. The validation of the cognitive QoT estimator is performed in a WDM 80 Gb/s PDM-QPSK testbed, and we demonstrate that even with a very small and not optimized underlying knowledge base, it achieves between 79% and 98.7% successful classifications based on the error vector magnitude (EVM) parameter, and approximately 100% when the classification is based on the optical signal to noise ratio (OSNR).

Activity of the Na,K-ATPase α4 isoform is regulated during sperm capacitation to support sperm motility.

The α4 polypeptide is a testis-specific isoform of the catalytic subunit of the Na,K-ATPase, which is essential for sperm motility and fertility. In the present study, we have investigated the regulation of activity of the α4 isoform and the relevance of this event for sperm capacitation. We have performed this by taking advantage of the selective high affinity of α4 for the inhibitor ouabain. Our results show that ouabain-sensitive hydrolysis of ATP and uptake of (86)Rb, corresponding to the enzymatic and ion transport activities of α4, respectively, increased during sperm capacitation in a time-dependent manner. Specific labeling of α4 with the fluorescent indicator bodipy-ouabain and immunoblot analysis of biotinylated and streptavidin-precipitated sperm plasma membrane proteins indicated a capacitation- and time-dependent rise in levels of active α4 isoform at the sperm surface. Ouabain inhibition of α4 blocked the increase in total sperm motility and the hyperactive motility pattern characteristic of sperm capacitation. Moreover, interference of α4 activity with ouabain partially prevented the intracellular decrease in Na(+) and the plasma membrane hyperpolarization that typically accompany sperm capacitation. In contrast, ouabain inhibition of α4 did not affect the spontaneous sperm acrosomal reaction following capacitation. Together, these results demonstrate that Na,K-ATPase α4 activity is up-regulated during sperm capacitation through mechanisms that involve both increases in molecular activity and levels of α4 at the sperm plasma membrane. This increase in α4 activity helps maintain the changes in motility that are associated with sperm capacitation, emphasizing the biologic relevance of the Na,K-ATPase α4 isoform in sustaining sperm function.

A Novel Space Partitioning Algorithm to Improve Current Practices in Facility Placement.

In the presence of naturally occurring and man-made public health threats, the feasibility of regional bio-emergency contingency plans plays a crucial role in the mitigation of such emergencies. While the analysis of in-place response scenarios provides a measure of quality for a given plan, it involves human judgment to identify improvements in plans that are otherwise likely to fail. Since resource constraints and government mandates limit the availability of service provided in case of an emergency, computational techniques can determine optimal locations for providing emergency response assuming that the uniform distribution of demand across homogeneous resources will yield and optimal service outcome. This paper presents an algorithm that recursively partitions the geographic space into sub-regions while equally distributing the population across the partitions. For this method, we have proven the existence of an upper bound on the deviation from the optimal population size for sub-regions.

Increased expression of the Na,K-ATPase alpha4 isoform enhances sperm motility in transgenic mice.

The Na,K-ATPase alpha4 (ATP1A4) isoform is specifically expressed in male germ cells and is highly prevalent in spermatozoa. Although selective inhibition of alpha4 activity with ouabain has been shown to affect sperm motility, a more direct analysis of the role of this isoform in sperm movement has not yet been demonstrated. To establish this, we engineered transgenic mice that express the rat alpha4 isoform fused to green fluorescent protein in male germ cells, under the control of the mouse protamine 1 promoter. We showed that the rat Atp1a4 transgene is expressed in mouse spermatozoa and that it is localized to the sperm flagellum. In agreement with increased expression of the alpha4 isoform, sperm from transgenic mice displayed higher alpha4-specific Na,K-ATPase activity and binding of fluorescently labeled ouabain than wild-type mice. In contrast, expression and activity of ATP1A1 (alpha1), the other Na,K-ATPase alpha isoform present in sperm, remained unchanged. Similar to wild-type mice, mice expressing the alpha4 transgene exhibited normal testis and sperm morphology and no differences in fertility. However, compared to wild-type mice, sperm from transgenic mice displayed plasma membrane hyperpolarization and higher total and progressive motility. Other parameters of motility also increased, including straight-line, curvilinear, and average path velocities and amplitude of lateral head displacement. In addition, sperm from the transgenic mice showed enhanced sperm hyperactive motility, but no changes in progesterone-induced acrosome reaction. Altogether, these results provide new genetic evidence for the role of the ATP1A4 isoform in sperm motility, under both noncapacitating and capacitating conditions.

Na,K-ATPase alpha4 isoform is essential for sperm fertility.

Regulation of ion balance in spermatozoa has been shown to be essential for sperm motility and fertility. Control of intracellular ion levels requires the function of distinct ion-transport mechanisms at the cell plasma membrane. Active Na(+) and K(+) exchange in sperm is under the control of the Na,K-ATPase. Two molecular variants of the catalytic subunit of the Na,K-ATPase, α1 and α4, coexist in sperm. These isoforms exhibit different biochemical properties; however, their function in sperm fertility is unknown. In this work, we show that Na,K-ATPase α4 is essential for sperm fertility. Knockout male mice lacking α4 are completely sterile and spermatozoa from these mice are unable of fertilizing eggs in vitro. Furthermore, α4 deletion results in severe reduction in sperm motility and hyperactivation typical of sperm capacitation. In addition, absence of α4 causes a characteristic bend in the sperm flagellum, indicative of abnormal sperm ion regulation. Accordingly, α4-null sperm present increased intracellular Na(+) and cell plasma membrane depolarization. These results are unique in demonstrating the absolute requirement of α4 for sperm fertility. Moreover, the inability of α1 to compensate for α4 suggests that α4 is the Na,K-ATPase-α isoform directly involved in sperm fertility. Our findings show α4 as an attractive target for male contraception and open the possibility for the potential use of this Na,K-ATPase isoform as a biomarker for male fertility.

MAP/ERK kinase kinase 1 (MEKK1) mediates transcriptional repression by interacting with polycystic kidney disease-1 (PKD1) promoter-bound p53 tumor suppressor protein.

Mitogen-activated protein kinase (MAPK) cascades regulate a wide variety of cellular processes that ultimately depend on changes in gene expression. We have found a novel mechanism whereby one of the key MAP3 kinases, Mekk1, regulates transcriptional activity through an interaction with p53. The tumor suppressor protein p53 down-regulates a number of genes, including the gene most frequently mutated in autosomal dominant polycystic kidney disease (PKD1). We have discovered that Mekk1 translocates to the nucleus and acts as a co-repressor with p53 to down-regulate PKD1 transcriptional activity. This repression does not require Mekk1 kinase activity, excluding the need for an Mekk1 phosphorylation cascade. However, this PKD1 repression can also be induced by the stress-pathway stimuli, including TNFα, suggesting that Mekk1 activation induces both JNK-dependent and JNK-independent pathways that target the PKD1 gene. An Mekk1-p53 interaction at the PKD1 promoter suggests a new mechanism by which abnormally elevated stress-pathway stimuli might directly down-regulate the PKD1 gene, possibly causing haploinsufficiency and cyst formation.