Ankle dorsiflexion range of motion and hip abductor strength can predict Lower Quarter Y-Balance Test performance in healthy males.

OBJECTIVES: The aim of the study was to assess whether strength and range of motion (ROM) of the hip and ankle are the factors determining performance in the Lower Quarter Y-Balance test (YBT-LQ). DESIGN: Cross-sectional study. PARTICIPANTS: 66 healthy males (age: 25.2±6.8 years) participated in this study. MAIN OUTCOME MEASURES: Participants underwent assessments of ankle dorsiflexion (DF) ROM, hip internal rotation (IR) ROM, external rotation (ER) ROM and isometric strength of hip abductor (ABD), extensor (EXT) and external rotators (ERS) muscles together with YBT-LQ for both legs. A forward 2-steps multiple linear regression analysis was conducted to examine the relationship between the predictor variables and the criterion variable. RESULTS: Ankle DF ROM predicted anterior (ANT) reach (R2 = 0.49; R2 = 0.33; p < 0.001). The model with hip ABD strength and ankle DF ROM explained posteromedial (PM) reach variance for stance leg (R2 = 0.35; p < 0.001), while only hip ABD strength was included for kicking leg (R2 = 0.19; p = 0.007). The model with ankle DF ROM and hip ABD strength explained posterolateral (PL) reach for stance leg (R2 = 0.41; p < 0.001). Hip ABD was the only predictor for kicking leg PL reach (R2 = 0.15; p < 0.001). YBT-LQ composite score was explained by ankle DF ROM and hip ABD strength for both legs (R2 = 0.44; p < 0.001) and (R2 = 0.25; p = 0.002). CONCLUSION: Hip ABD strength and ankle DF ROM can determine performance in the YBT-LQ. Strength of hip EXT, ERS as well as ROM of hip IR and ER did not predict YBT-LQ performance.

Efficacy of Single- and Dual-Docking Robotic Surgery of Paraaortic and Pelvic Lymphadenectomy in High-Risk Endometrial Cancer.

(1) The surgical method of choice for the treatment of endometrial cancer is minimally invasive surgery. In cases of high-risk endometrial cancer, completed paraaortic and pelvic lymphadenectomy are indicated. The aim of this study was to analyze the types of docking during robotic surgery assisted with the da Vinci X system while performing paraaortic and pelvic lymphadenectomy. (2) Methods: A total of 25 patients with high-risk endometrial cancer, with a mean age of 60.07 ± 10.67 (range 34.69-83.23) years, and with a mean body mass index (BMI) of 28.4 ± 5.62 (range 18-41.5) kg/m2, were included in this study. The analyzed population was divided into groups that underwent single or dual docking during surgery. (3) Results: No statistical significance was observed between single and dual docking during paraaortic and pelvic lymphadenectomy and between the type of docking and the duration of the operation. However, there was a statistically significant correlation between the duration of the operation and previous surgery (p < 0.005). The number of removed lymph nodes was statistically associated with BMI (p < 0.005): 15.87 ± 6.83 and 24.5 ± 8.7 for paraaortic and pelvic lymph nodes, respectively, in cases of single docking, and 18.05 ± 7.92 and 24.88 ± 11.75 for paraaortic and pelvic lymph nodes, respectively, in cases of dual docking. (4) Conclusions: The robot-assisted approach is a good surgical method for lymphadenectomy for obese patients, and, despite the type of docking, there are no differences in the quality of surgery.

Robotic surgery in endometrial cancer: first Polish experience.

In Poland, robotic surgery is nowadays perceived as a new method of surgical treatment in endometrial cancer patients. We aim to present the first Polish group of endometrial cancer patients treated using robotic surgery. The analysis was based on 79 patients with mean age of 59.72 ± 11.709 (range 27-83) years and endometrial cancer scheduled for surgical treatment. Mean BMI was 31.38 ± 8.78 (range 19.03-65.97) kg/m2. The data were collected based on a questionnaire consisting of 19 questions concerning the patient's perception of robotic surgery before the procedure. Patients with a family history of neoplastic diseases indicate precision of movements as the most important reason for choosing robotic surgery (p = 0.0035). Patients after surgery procedures in the past named shorter hospitalization as a major benefit (p = 0.0037). Patients who chose robotic surgery for financial reasons stressed the cosmetic effect as a priority (p = 0.0319). Shorter length of hospital stay, less blood loss, enlarged view, and good visualization were statistically significant reasons for choosing robotic surgery (p < 0.05). Women who consider work, good material status, and well-being as the most important aspects of their lives cited the cosmetic effect as a benefit of robotic surgery (p = 0.0029 vs. p = 0.0074 vs. p = 0.01745, respectively). In the follow-up after operations, no patients regretted choosing robotic surgery. Good visualization, precise movements, less blood loss, and cosmetic effects are the most frequent reasons for choosing robotic surgery. Even patients after other types of surgery in the past decided on robot-assisted radical hysterectomy because of the clear benefits of this approach.

Circulating microRNAs from plasma as preclinical biomarkers of epileptogenesis and epilepsy.

Epilepsy frequently develops as a result of brain insult; however, there are no tools allowing to predict which patients suffering from trauma will eventually develop epilepsy. microRNAs are interesting candidates for biomarkers, as several of them have been described to change their levels in the brains, and in the plasma of epileptic subjects. This study was conducted to evaluate the usefulness of plasma miRNAs as epileptogenesis/epilepsy biomarkers. In our studies, we used a rat model of temporal lobe epilepsy. An epileptogenic insult was status epilepticus evoked by stimulation of the left lateral nucleus of the amygdala. Next, animals were continuously video and EEG monitored for 3 months. Blood was collected at 14, 30, 60, and 90 days after stimulation. Blood plasma was separated and miRNA levels were analyzed. We compared miRNA levels between sham-operated and stimulated animals, and between animals with high and low numbers of seizures. We propose three miRNAs that could be biomarkers of epilepsy: miR-671, miR-9a-3p and miR-7a-5p. According to us, miR-206-5p is a potential biomarker of epileptogenesis, and miR-221-3p is a potential biomarker of epilepsy severity. We think that these five miRNAs can be considered in the future as potential treatment targets.

Cross cultural adaptation, reliability and validity of the Polish version of the Cumberland Ankle Instability Tool.

Purpose: The aim of this study was to develop a Polish version of the Cumberland Ankle Instability Tool (CAIT-PL) questionnaire and perform CAIT-PL cultural adaptation with assessment of its psychometric properties.Methods: The original CAIT was translated into the Polish language using standard guidelines. The CAIT-PL was completed on 2 occasions by 105 participants both with and without a history of ankle sprains. Psychometric evaluation of CAIT-PL included an assessment of internal consistency, test-retest reliability, standard error of measurement, convergent and construct validity.Results: The CAIT-PL was successfully translated and adapted into Polish culture with satisfactory internal consistency (Cronbach's α = 0.83) and adequate test-retest reliability resulting in ICC2,1 = 0.89 (95% CI: 0.84-0.92). Measurement error was low (SEM = 0.76 and MDC = 2.10). Convergent validity of the CAIT-PL ranged from weak to strong using Spearman's correlation coefficient between CAIT-PL and FAOS subscales (r = 0.39-0.67; p < 0.05). Construct validity was confirmed.Conclusion: The Polish version of the Cumberland Ankle Instability Tool is a valid and reliable questionnaire for assessment of functional ankle instability among the Polish population.

The Cumberland Ankle Instability Tool is broadly used to assess functional ankle instability and its severity.The Polish version of Cumberland Ankle Instability Tool (CAIT-PL) showed adequate psychometric properties.The CAIT-PL is ready to be used in clinical practice and for research applications in Polish-speaking population.

Do Highly Trained Mountain Runners Differ from Recreational Active Non-Runners on Range of Motion and Strength in the Hip and Ankle as Well as Postural Control?

The rules governing mountain running force athletes to implement into their training programmes uphill and downhill running on unstable surfaces, which are demanding for hip and ankle as well as for the postural control system. The aim of the present cross-sectional study was to compare highly trained mountain runners (MR) and recreational active non-runners (NR) on range of motion (ROM) and strength in the hip and ankle, as well as dynamic postural control. Thirty MR and thirty-two NR were included in the study. ROM was assessed using a digital inclinometer. Strength was measured using a hand-held dynamometer. Postural control was evaluated using the lower quarter Y-balance test (YBT-LQ). The results showed that MR, in relation to NR, had statistically significant smaller hip external rotation ROM (p = 0.007), lower hip external rotator (p = 0.006) and extensor (p = 0.023) strength and greater normalised anterior reach in the YBT-LQ (p = 0.028). Mountain running training may reduce hip external rotation ROM as well as hip external rotator and extensor strength. Moreover, such training may improve postural control. MR should implement exercises targeted at developing hip ROM and strength. Furthermore, it seems that mountain running training may be a good way to improve postural control.

68 Ga-Prostate-Specific Membrane Antigen PET/CT in Ovarian Tumors : Potential to Differentiate Benign and Malignant Tumors Before Surgery: A Preliminary Report.

PURPOSE OF THE REPORT: Ovarian cancer is usually diagnosed in an advanced stage of disease due to the absence of specific symptoms and a lack of sensitive diagnostic methods. Prostate-specific membrane antigen (PSMA) is expressed on prostate cancer cells but can be found in other tumors such as ovarian cancer.The aim of this pilot study was to evaluate the feasibility of using 68 Ga-PSMA-11 PET/CT in detection of ovarian neoplasm before surgical treatment. PATIENTS AND METHODS: Eight women with mean age of 56.0 ± 16.2 years were included in the study. All patients underwent transvaginal ultrasound followed by CT scan of the chest and abdomen as qualification for surgery. Within a 1-week interval, PET/CT was performed on a Siemens Biograph scanner, 60 minutes after injection of 2 MBq/kg 68 Ga-PSMA-11. RESULTS: In 3 cases (37.5%), the 68 Ga-PSMA-11 PET/CT was positive, whereas histological examination confirmed 2 serous ovarian cancer cases and 1 ovarian borderline tumor. The SUV max in the serous ovarian cancer was 8.7 and 4.1, and in the borderline ovarian tumor, it was 13.8. No correlation was found between antigen CA-125 level and 68 Ga-PSMA expression. Range of tumor SUV max was not correlated with stage of disease. The remaining 62.5% (5/8) were negative in 68 Ga-PSMA-11 PET/CT, and histopathology confirmed benign pelvic tumor. CONCLUSIONS: The initial experience supports the potential to use 68 Ga-PSMA-11 in ovarian cancer to differentiate malignant and benign tumors before surgery.This study was approved by the Ethical Committee of the Medical University of Warsaw (KB/2/A/2018).

Chemotherapy of HER2- and MDM2-Enriched Breast Cancer Subtypes Induces Homologous Recombination DNA Repair and Chemoresistance.

Analyzing the TCGA breast cancer database, we discovered that patients with the HER2 cancer subtype and overexpression of MDM2 exhibited decreased post-treatment survival. Inhibition of MDM2 expression in the SKBR3 cell line (HER2 subtype) diminished the survival of cancer cells treated with doxorubicin, etoposide, and camptothecin. Moreover, we demonstrated that inhibition of MDM2 expression diminished DNA repair by homologous recombination (HR) and sensitized SKBR3 cells to a PARP inhibitor, olaparib. In H1299 (TP53-/-) cells treated with neocarzinostatin (NCS), overexpression of MDM2 WT or E3-dead MDM2 C478S variant stimulated the NCS-dependent phosphorylation of ATM, NBN, and BRCA1, proteins involved in HR DNA repair. However, overexpression of chaperone-dead MDM2 K454A variant diminished phosphorylation of these proteins as well as the HR DNA repair. Moreover, we demonstrated that, upon NCS treatment, MDM2 K454A interacted with NBN more efficiently than MDM2 WT and that MDM2 WT was degraded more efficiently than MDM2 K454A. Using a proliferation assay, we showed that overexpression of MDM2 WT, but not MDM2 K454A, led to acquisition of resistance to NCS. The presented results indicate that, following chemotherapy, MDM2 WT was released from MDM2-NBN complex and efficiently degraded, hence allowing extensive HR DNA repair leading to the acquisition of chemoresistance by cancer cells.

Zebrafish Microenvironment Elevates EMT and CSC-Like Phenotype of Engrafted Prostate Cancer Cells.

To visually and genetically trace single-cell dynamics of human prostate cancer (PCa) cells at the early stage of metastasis, a zebrafish (ZF) xenograft model was employed. The phenotypes of intravenously transplanted fluorescent cells were monitored by high-resolution, single-cell intravital confocal and light-sheet imaging. Engrafted osteotropic, androgen independent PCa cells were extravasated from caudle vein, invaded the neighboring tissue, proliferated and formed experimental metastases around caudal hematopoietic tissue (CHT) in four days. Gene expression comparison between cells in culture and in CHT revealed that engrafted PCa cells responded to the ZF microenvironment by elevating expression of epithelial-mesenchymal transition (EMT) and stemness markers. Next, metastatic potentials of ALDHhi cancer stem-like cells (CSCs) and ALDHlow non-CSCs were analyzed in ZF. Engraftment of CSCs induced faster metastatic onset, however after six days both cell subpopulations equally responded to the ZF microenvironment, resulting in the same increase of stemness genes expression including Nanog, Oct-4 and Cripto. Knockdown of Cripto significantly reduced the vimentin/E-cadherin ratio in engrafted cells, indicating that Cripto is required for transduction of the microenvironment signals from the ZF niche to increase mesenchymal potential of cells. Targeting of either Cripto or EMT transcriptional factors Snail 1 and Zeb1 significantly suppressed metastatic growth. These data indicated that zebrafish microenvironment governed the CSC/EMT plasticity of human PCa cells promoting metastasis initiation.

Gain-of-Function Mutations in p53 in Cancer Invasiveness and Metastasis.

Forty years of research has proven beyond any doubt that p53 is a key regulator of many aspects of cellular physiology. It is best known for its tumor suppressor function, but it is also a regulator of processes important for maintenance of homeostasis and stress response. Its activity is generally antiproliferative and when the cell is damaged beyond repair or intensely stressed the p53 protein contributes to apoptosis. Given its key role in preventing cancer it is no wonder that it is the most frequently mutated gene in human cancer. Surprisingly, a subset of missense mutations occurring in p53 (gain-of-function) cause it to lose its suppressor activity and acquire new functionalities that turn the tumor suppressor protein into an oncoprotein. A solid body of evidence exists demonstrating increased malignancy of cancers with mutated p53 in all aspects considered "hallmarks of cancer". In this review, we summarize current findings concerning the cellular processes altered by gain-of-function mutations in p53 and their influence on cancer invasiveness and metastasis. We also present the variety of molecular mechanisms regulating these processes, including microRNA, direct transcriptional regulation, protein-protein interactions, and more.

Towards the Properties of Different Biomass-Derived Proteins via Various Extraction Methods.

This study selected three representative protein-rich biomass-brewer's spent grain (BSG), pasture grass (PG), and cyanobacteria (Arthrospira platensis; AP) for protein extraction with different extraction methods (alkaline treatment, aqueous extraction, and subcritical water extraction). The yield, purity, molecular weight, oil-water interfacial tension, and thermal stability of the obtained proteins derived from different biomass and extraction methods were comprehensively characterized and compared. In the view of protein yield and purity, alkaline treatment was found optimal for BSG (21.4 and 60.2 wt.%, respectively) and AP (55.5 and 68.8 wt.%, respectively). With the decreased oil-water interfacial tension, the proteins from all biomass showed the potential to be emulsifier. BSG and AP protein obtained with chemical treatment presented excellent thermal stability. As a novel method, subcritical water extraction is promising in recovering protein from all three biomass with the comparable yield and purity as alkaline treatment. Furthermore, the hydrolyzed protein with lower molecular weight by subcritical water could promote its functions of foaming and emulsifying.

Hydrothermal carbonization of biogas digestate: Effect of digestate origin and process conditions.

Hydrothermal carbonization (HTC) solids were produced in a 250-ml batch reactor from three different digestates at varying temperatures (170, 190, 210, 230, and 250 °C) and 2 and 5 h reaction time. Three potential feedstocks of biogas plants were tested: organic household waste, cow manure, and energy crops. The proximate composition, elemental composition, heating values, and thermal stability of the HTC solids were characterized. The dry ash-free basis yields and carbon recovery of HTC solids decreased with increasing HTC temperature and time. The HTC solids from energy crop digestate had the highest yields (dry ash-free basis) except at the temperature of 250 °C. Increased HTC severity was found to have a positive effect on the dry basis carbon content and leads to a higher heating values (HHV) of cow manure digestate HTC solids. The preferred reaction condition for organic household waste digestate and energy crop digestate HTC solids was found to be 210 °C for 5 h, because of the highest HHV (dry basis) and the overall combustion performance was reached. Enhancing HTC temperature increased the peak intensity of functional groups of cow manure digestate HTC solids. Scanning electron microscopy imaging showed the fibrous structure of the plants from the digestates was mostly deconstructed at 250 °C-5 h. Experimental results indicated that both digestate origin and HTC condition influenced the properties of the HTC solids.

Diverse and cancer type­specific roles of the p53 R248Q gain­of­function mutation in cancer migration and invasiveness.

Gain­of­function (GOF) mutations in the TP53 gene lead to acquisition of new functions by the mutated tumor suppressor p53 protein. A number of the over­represented 'hot spot' mutations, including the ones in codons 175, 248 or 273, convey GOF phenotypes. Such phenotypes may include resistance to chemotherapeutics or changes in motility and invasiveness. Whereas the prevalent notion is that the acquisition of the p53 GOF phenotype translates into poorer prognosis for the patient, the analysis of a human somatic p53 mutations dataset demonstrated earlier tumor onset, but decreased frequency and altered location of metastases in patients with the p53­R248Q allele. Therefore, the GOF activities of p53­R248Q and p53­D281G were analyzed in triple negative breast cancer MDA­MB­231 and lung adenocarcinoma H1299 cell lines with regard to invasive and metastatic traits. The expression of p53­D281G increased the motility and invasiveness of the lung cancer cells, but not those of the breast cancer cells. In contrast, the expression of p53­R248Q decreased the motility and invasiveness of the breast and lung cancer cells in a p53 transactivation­dependent manner. The intravenous xenotransplantation of MDA­MB­231 cells expressing p53­R248Q into zebrafish embryos resulted in an alteration of the distribution of cancer cells in the body of the fish. In p53­R248Q­expressing H1299 cells a decrease in the expression of TCF8/ZEB1 and N­cadherin was observed, suggesting partial mesenchymal­to­epithelial transition. In the two cell lines expressing p53­R248Q a decrease was noted in the expression of myosin light chain 2, a protein involved in actomyosin­based motility. To the best of our knowledge, the present study is one of only few reports demonstrating the mutated p53 GOF activity resulting in a decrease of a malignant trait in human cancer.

Molecular chaperones in the acquisition of cancer cell chemoresistance with mutated TP53 and MDM2 up-regulation.

Utilizing the TCGA PANCAN12 dataset we discovered that cancer patients with mutations in TP53 tumor suppressor and overexpression of MDM2 oncogene exhibited decreased survival post treatment. Interestingly, in the case of breast cancer patients, this phenomenon correlated with high expression level of several molecular chaperones belonging to the HSPA, DNAJB and HSPC families. To verify the hypothesis that such a genetic background may promote chaperone-mediated chemoresistance, we employed breast and lung cancer cell lines that constitutively overexpressed heat shock proteins and have shown that HSPA1A/HSP70 and DNAJB1/HSP40 facilitated the binding of mutated p53 to the TAp73α protein. This chaperone-mediated mutated p53-TAp73α complex induced chemoresistance to DNA damaging reagents, like Cisplatin, Doxorubicin, Etoposide or Camptothecin. Importantly, when the MDM2 oncogene was overexpressed, heat shock proteins were displaced and a stable multiprotein complex comprising of mutated p53-TAp73α-MDM2 was formed, additionally amplifying cancer cells chemoresistance. Our findings demonstrate that molecular chaperones aid cancer cells in surviving the cytotoxic effect of chemotherapeutics and may have therapeutic implications.

Attitudes, Beliefs and Predictors of Male Circumcision Promotion among Medical University Students in a Traditionally Non-Circumcising Region.

Objective: To evaluate the beliefs of medical university students regarding male circumcision (MC), as well as attitudes and the predictors of its promotion in the case of adults at risk of HIV. Methods: A cross-sectional survey was conducted between 2013-2016 at the Medical University in Szczecin, Poland, among final year Polish/foreign students from Northern Europe, using a standardized questionnaire. Results: There were 539 participants, median age 25 years, 40.8% males, and 66.8% were Polish nationals. The MC rate was 16.7%. Regarding HIV/AIDS knowledge, 66.6% of the students scored more than 75%; and, 34.2% knew that MC reduces the risk of HIV infection. One in eleven respondents (9.1%) believed that circumcised men felt more intense sexual pleasure. More than half of the respondents (54.8%) declared that they would recommend MC to adult patients at risk for HIV. The belief that circumcised men felt more intense sexual pleasure, and knowledge on MC regarding HIV risk reduction was associated with greater odds of recommending adult MC (OR = 3.35 and OR = 2.13, respectively). Conclusions: Poor knowledge of its benefits and a low willingness to promote the procedure-strongly dependent on personal beliefs-suggest that medical students may need additional training to help them to discuss MC more openly with adult men at risk for HIV infection. Knowledge may be an effective tool when making decisions regarding MC promotion.

LFP Oscillations in the Mesencephalic Locomotor Region during Voluntary Locomotion.

Oscillatory rhythms in local field potentials (LFPs) are thought to coherently bind cooperating neuronal ensembles to produce behaviors, including locomotion. LFPs recorded from sites that trigger locomotion have been used as a basis for identification of appropriate targets for deep brain stimulation (DBS) to enhance locomotor recovery in patients with gait disorders. Theta band activity (6-12 Hz) is associated with locomotor activity in locomotion-inducing sites in the hypothalamus and in the hippocampus, but the LFPs that occur in the functionally defined mesencephalic locomotor region (MLR) during locomotion have not been determined. Here we record the oscillatory activity during treadmill locomotion in MLR sites effective for inducing locomotion with electrical stimulation in rats. The results show the presence of oscillatory theta rhythms in the LFPs recorded from the most effective MLR stimulus sites (at threshold ≤60 µA). Theta activity increased at the onset of locomotion, and its power was correlated with the speed of locomotion. In animals with higher thresholds (>60 µA), the correlation between locomotor speed and theta LFP oscillations was less robust. Changes in the gamma band (previously recorded in vitro in the pedunculopontine nucleus (PPN), thought to be a part of the MLR) were relatively small. Controlled locomotion was best achieved at 10-20 Hz frequencies of MLR stimulation. Our results indicate that theta and not delta or gamma band oscillation is a suitable biomarker for identifying the functional MLR sites.

Effects of NMDA receptor antagonists and antipsychotics on high frequency oscillations recorded in the nucleus accumbens of freely moving mice.

RATIONALE: Abnormal oscillatory activity associated with N-methyl-D-aspartate (NMDA) receptor hypofunction is widely considered to contribute to the symptoms of schizophrenia. OBJECTIVE: This study aims to characterise the changes produced by NMDA receptor antagonists and antipsychotics on accumbal high-frequency oscillations (HFO; 130-180 Hz) in mice. METHODS: Local field potentials were recorded from the nucleus accumbens of freely moving mice. RESULTS: Systemic injection of ketamine and MK801 both dose-dependently increased the power of HFO and produced small increases in HFO frequency. The atypical antipsychotic drug, clozapine, produced a robust dose-dependent reduction in the frequency of MK801-enhanced HFO, whilst haloperidol, a typical antipsychotic drug, had little effect. Stimulation of NMDA receptors (directly or through the glycine site) as well as activation of 5-HT1A receptors, reduced the frequency of MK801-enhanced HFO, but other receptors known to be targets for clozapine, namely 5-HT2A, 5-HT7 and histamine H3 receptors had no effect. CONCLUSIONS: NMDA receptor antagonists and antipsychotics produce broadly similar fundamental effects on HFO, as reported previously for rats, but we did observe several notable differences. In mice, HFO at baseline were weak or not detectable unlike rats. Post-injection of NMDA receptor antagonists HFO was also weaker but significantly faster. Additionally, we found that atypical antipsychotic drugs may reduce the frequency of HFO by interacting with NMDA and/or 5-HT1A receptors.

The clathrin-binding and J-domains of GAK support the uncoating and chaperoning of clathrin by Hsc70 in the brain.

Cyclin-G-associated kinase (GAK), the ubiquitously expressed J-domain protein, is essential for the chaperoning and uncoating of clathrin that is mediated by Hsc70 (also known as HSPA8). Adjacent to the C-terminal J-domain that binds to Hsc70, GAK has a clathrin-binding domain that is linked to an N-terminal kinase domain through a PTEN-like domain. Knocking out GAK in fibroblasts caused inhibition of clathrin-dependent trafficking, which was rescued by expressing a 62-kDa fragment of GAK, comprising just the clathrin-binding and J-domains. Expressing this fragment as a transgene in mice rescued the lethality and the histological defects caused by knocking out GAK in the liver or in the brain. Furthermore, when both GAK and auxilin (also known as DNAJC6), the neuronal-specific homolog of GAK, were knocked out in the brain, mice expressing the 62-kDa GAK fragment were viable, lived a normal life-span and had no major behavior abnormalities. However, these mice were about half the size of wild-type mice. Therefore, the PTEN-like domains of GAK and auxilin are not essential for Hsc70-dependent chaperoning and uncoating of clathrin, but depending on the tissue, these domains appear to increase the efficiency of these co-chaperones.

Aberrant high frequency oscillations recorded in the rat nucleus accumbens in the methylazoxymethanol acetate neurodevelopmental model of schizophrenia.

BACKGROUND: Altered activity of the nucleus accumbens (NAc) is thought to be a core feature of schizophrenia and animal models of the disease. Abnormal high frequency oscillations (HFO) in the rat NAc have been associated with pharmacological models of schizophrenia, in particular the N-methyl-d-aspartate receptor (NMDAR) hypofunction model. Here, we tested the hypothesis that abnormal HFO are also associated with a neurodevelopmental rat model. METHODS: Using prenatal administration of the mitotoxin methylazoxymethanol acetate (MAM) we obtained the offspring MAM rats. Adult MAM and Sham rats were implanted with electrodes, for local field potential recordings, in the NAc. RESULTS: Spontaneous HFO (spHFO) in MAM rats were characterized by increased power and frequency relative to Sham rats. MK801 dose-dependently increased the power of HFO in both groups. However, the dose-dependent increase in HFO frequency found in Sham rats was occluded in MAM rats. The antipsychotic compound, clozapine reduced the frequency of HFO which was similar in both MAM and Sham rats. Further, HFO were modulated in a similar manner by delta oscillations in both MAM and Sham rats. CONCLUSION: Together these findings suggest that increased HFO frequency represents an important feature in certain animal models of schizophrenia. These findings support the hypothesis that altered functioning of the NAc is a core feature in animal models of schizophrenia.

Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease.

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause inherited Parkinson disease (PD), and common variants around LRRK2 are a risk factor for sporadic PD. Using protein-protein interaction arrays, we identified BCL2-associated athanogene 5, Rab7L1 (RAB7, member RAS oncogene family-like 1), and Cyclin-G-associated kinase as binding partners of LRRK2. The latter two genes are candidate genes for risk for sporadic PD identified by genome-wide association studies. These proteins form a complex that promotes clearance of Golgi-derived vesicles through the autophagy-lysosome system both in vitro and in vivo. We propose that three different genes for PD have a common biological function. More generally, data integration from multiple unbiased screens can provide insight into human disease mechanisms.