Specificity of mouse GM2 activator protein and beta-N-acetylhexosaminidases A and B. Similarities and differences with their human counterparts in the catabolism of GM2.

Tay-Sachs disease, an inborn lysosomal disease featuring a buildup of GM2 in the brain, is caused by a deficiency of β-hexosaminidase A (Hex A) or GM2activator. Of the two human lysosomal Hex isozymes, only Hex A, not Hex B, cleaves GM2 in the presence of GM2activator. In contrast, mouse Hex B has been reported to be more active than Hex A in cleaving GM2 (Burg, J., Banerjee, A., Conzelmann, E., and Sandhoff, K. (1983) Hoppe Seyler's Z. Physiol. Chem. 364, 821–829). In two independent studies, mice with the targeted disruption of the Hexa gene did not display the severe buildup of brain GM2 or the concomitant abnormal behavioral manifestations seen in human Tay-Sachs patients. The results of these two studies were suggested to be attributed to the reported GM2 degrading activity of mouse Hex B. To clarify the specificity of mouse Hex A and Hex B and to better understand the observed results of the mouse model of Tay-Sachs disease, we have purified mouse liver Hex A and Hex B and also prepared the recombinant mouse GM2 activator. Contrary to the findings of Burget al., we found that the specificities of mouse Hex A and Hex B toward the catabolism of GM2 were not different from the corresponding human Hex isozymes. Mouse Hex A, but not Hex B, hydrolyzes GM2 in the presence of GM2activator, whereas GM2 is refractory to mouse Hex B with or without GM2 activator. Importantly, we found that, in contrast to human GM2 activator, mouse GM2activator could effectively stimulate the hydrolysis of GA2by mouse Hex A and to a much lesser extent also by Hex B. These results provide clear evidence on the existence of an alternative pathway for GM2 catabolism in mice by converting GM2 to GA2 and subsequently to lactosylceramide. They also provide the explanation for the lack of excessive GM2 accumulation in the Hexa gene-disrupted mice

My Social Comfort Zone: Attachment Anxiety Shapes Peripersonal and Interpersonal Space

Our perception of our personal space extends beyond the body to incorporate the space where inter-actions with the environment occur, i.e. peripersonal space (PPS), and the distance we feel comforta-ble in maintaining while interacting with other people, termed interpersonal space. Studies suggest that after positive interpersonal exchanges, PPS expands in order to create a space for interaction, while interpersonal space becomes smaller. However, little is known about how this malleability of our peripersonal and interpersonal space based on social context can be shaped by key individual traits of interpersonal relating, such as attachment style. In a first, exploratory study (N=48) using a visuo-tactile detection task in augmented reality, we found that when people scoring higher in attachment anxiety are in the presence of a stranger, relative to alone, their PPS becomes less defined, whereas the reverse pattern is observed in people scoring lower in attachment anxiety. In a follow-up, prereg-istered study (N=68), targeting individuals with high versus low levels of attachment anxiety, we found that the former has a sharp differentiation between peripersonal and extrapersonal space not only in a social context (i.e., presence of a stranger) but also in a non-social context. In a final, pre-registered, large-scale survey of the UK population (N=19,417), we enquired about the role of at-tachment anxiety in a self-report measure of the interpersonal distance people felt comfortable with during habitual conversion and as expected, we found that the greater the anxiety the closer the pre-ferred interpersonal distance, irrespective of their perceived social closeness to others. We conclude that attachment anxiety reduces the social malleability of both peripersonal and interpersonal space

Italian family with two independent mutations:3358T/A in BRCA1 and 8756delA in BRCA2 genes.

Hereditary breast/ovarian cancer is a well-characterized clinical entity, largely attributed to the inheritance of BRCA1 or BRCA2 mutations. Among general population, the mutation's frequency of these genes is very low; therefore, the identification of two independent mutations in the same family is a rare event. This study reports the presence of two mutations, one in the BRCA1 and the second in the BRCA2 gene in an Italian Caucasian kindred. This family is composed of more than 250 individuals, spanning through five generations, among which endogamy was a common phenomenon. Considering the tumor spectrum, this family is characterized by a high incidence of different types of cancer. In our study, we considered only three out of seven family units for BRCA1 and BRCA2 analysis. In one of the family units, we found independent mutations of both BRCA genes. The BRCA1 mutation on exon 11 (3358TA) was identified originally in the index case and subsequently in 18 members of this family, whereas the same mutation was not detected in a related family member with male breast cancer. The male breast cancer patient led to the identification, through mutational analysis, of a new BRCA2 mutation (8756delA). This BRCA2 mutation was also found in the male breast cancer patient's daughter. The discovery of the BRCA2 mutation allowed us to alert the patient's daughter who, otherwise, could be falsely reassured since she had a negative BRCA1 test

Post-replicative pairing of sister ter regions in Escherichia coli involves multiple activities of MatP

Funder: Université Toulouse III - Paul Sabatier (University of Toulouse III Paul Sabatier); doi: https://doi.org/10.13039/501100009160Abstract: The ter region of the bacterial chromosome, where replication terminates, is the last to be segregated before cell division in Escherichia coli. Delayed segregation is controlled by the MatP protein, which binds to specific sites (matS) within ter, and interacts with other proteins such as ZapB. Here, we investigate the role of MatP by combining short-time mobility analyses of the ter locus with biochemical approaches. We find that ter mobility is similar to that of a non ter locus, except when sister ter loci are paired after replication. This effect depends on MatP, the persistence of catenanes, and ZapB. We characterise MatP/DNA complexes and conclude that MatP binds DNA as a tetramer, but bridging matS sites in a DNA-rich environment remains infrequent. We propose that tetramerisation of MatP links matS sites with ZapB and/or with non-specific DNA to promote optimal pairing of sister ter regions until cell division

Sensorimotor computation underlying phototaxis in zebrafish

Animals continuously gather sensory cues to move towards favourable environments. Efficient goal-directed navigation requires sensory perception and motor commands to be intertwined in a feedback loop, yet the neural substrate underlying this sensorimotor task in the vertebrate brain remains elusive. Here, we combine virtual-reality behavioural assays, volumetric calcium imaging, optogenetic stimulation and circuit modelling to reveal the neural mechanisms through which a zebrafish performs phototaxis, i.e. actively orients towards a light source. Key to this process is a self-oscillating hindbrain population (HBO) that acts as a pacemaker for ocular saccades and controls the orientation of successive swim-bouts. It further integrates visual stimuli in a state-dependent manner, i.e. its response to visual inputs varies with the motor context, a mechanism that manifests itself in the phase-locked entrainment of the HBO by periodic stimuli. A rate model is developed that reproduces our observations and demonstrates how this sensorimotor processing eventually biases the animal trajectory towards bright regions

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation

Disease-specific and general health-related quality of life in newly diagnosed prostate cancer patients: The Pros-IT CNR study

Background: The National Research Council (CNR) prostate cancer monitoring project in Italy (Pros-IT CNR) is an observational, prospective, ongoing, multicentre study aiming to monitor a sample of Italian males diagnosed as new cases of prostate cancer. The present study aims to present data on the quality of life at time prostate cancer is diagnosed. Methods: One thousand seven hundred five patients were enrolled. Quality of life is evaluated at the time cancer was diagnosed and at subsequent assessments via the Italian version of the University of California Los Angeles-Prostate Cancer Index (UCLA-PCI) and the Short Form Health Survey (SF-12). Results: At diagnosis, lower scores on the physical component of the SF-12 were associated to older ages, obesity and the presence of 3+ moderate/severe comorbidities. Lower scores on the mental component were associated to younger ages, the presence of 3+ moderate/severe comorbidities and a T-score higher than one. Urinary and bowel functions according to UCLA-PCI were generally good. Almost 5% of the sample reported using at least one safety pad daily to control urinary loss; less than 3% reported moderate/severe problems attributable to bowel functions, and sexual function was a moderate/severe problem for 26.7%. Diabetes, 3+ moderate/severe comorbidities, T2 or T3-T4 categories and a Gleason score of eight or more were significantly associated with lower sexual function scores at diagnosis. Conclusions: Data collected by the Pros-IT CNR study have clarified the baseline status of newly diagnosed prostate cancer patients. A comprehensive assessment of quality of life will allow to objectively evaluate outcomes of different profile of care