Seasonal Plasticity in GABA\u3csup\u3eA\u3c/sup\u3e Signaling is Necessary for Restoring Phase Synchrony in the Master Circadian Clock Network

Annual changes in the environment threaten survival, and numerous biological processes in mammals adjust to this challenge via seasonal encoding by the suprachiasmatic nucleus (SCN). To tune behavior according to day length, SCN neurons display unified rhythms with synchronous phasing when days are short, but will divide into two sub-clusters when days are long. The transition between SCN states is critical for maintaining behavioral responses to seasonal change, but the mechanisms regulating this form of neuroplasticity remain unclear. Here we identify that a switch in chloride transport and GABAA signaling is critical for maintaining state plasticity in the SCN network. Further, we reveal that blocking excitatory GABAA signaling locks the SCN into its long day state. Collectively, these data demonstrate that plasticity in GABAA signaling dictates how clock neurons interact to maintain environmental encoding. Further, this work highlights factors that may influence susceptibility to seasonal disorders in humans

A note on structured pseudospectra of block matrices

In this note we consider the question of equivalence of pseudospectra and structured pseudospectra of block matrices. The structures we study are all so called double structures; that is, the blocks of the given matrix are of the same structure as the block matrix. The approach is based on that of non-block matrices, which are also briefly studied, and the use of distance to singularity. We also list some open problems and conjectures

Canonical matrices of bilinear and sesquilinear forms

Canonical matrices are given for (a) bilinear forms over an algebraically closed or real closed field; (b) sesquilinear forms over an algebraically closed field and over real quaternions with any nonidentity involution; and (c) sesquilinear forms over a field F of characteristic different from 2 with involution (possibly, the identity) up to classification of Hermitian forms over finite extensions of F. A method for reducing the problem of classifying systems of forms and linear mappings to the problem of classifying systems of linear mappings is used to construct the canonical matrices. This method has its origins in representation theory and was devised in [V.V. Sergeichuk, Math. USSR-Izv. 31 (1988) 481-501].Comment: 44 pages; misprints corrected; accepted for publication in Linear Algebra and its Applications (2007

Replication protein A physically interacts with the Bloom's syndrome protein and stimulates its helicase activity.

Bloom's syndrome is a rare autosomal recessive disorder characterized by genomic instability and predisposition to cancer. BLM, the gene defective in Bloom's syndrome, encodes a 159-kDa protein possessing DNA-stimulated ATPase and ATP-dependent DNA helicase activities. We have examined mechanistic aspects of the catalytic functions of purified recombinant BLM protein. Through analyzing the effects of different lengths of DNA cofactor on ATPase activity, we provide evidence to suggest that BLM translocates along single-stranded DNA in a processive manner. The helicase reaction catalyzed by BLM protein was examined as a function of duplex DNA length. We show that BLM catalyzes unwinding of short DNA duplexes (/=259-bp). The presence of the human single-stranded DNA-binding protein (human replication protein A (hRPA)) stimulates the BLM unwinding reaction on the 259-bp partial duplex DNA substrate. Heterologous single-stranded DNA-binding proteins fail to stimulate similarly the helicase activity of BLM protein. This is the first demonstration of a functional interaction between BLM and another protein. Consistent with a functional interaction between hRPA and the BLM helicase, we demonstrate a direct physical interaction between the two proteins mediated by the 70-kDa subunit of RPA. The interactions between BLM and hRPA suggest that the two proteins function together in vivo to unwind DNA duplexes during replication, recombination, or repair

An ISS Small-Gain Theorem for General Networks

We provide a generalized version of the nonlinear small-gain theorem for the case of more than two coupled input-to-state stable (ISS) systems. For this result the interconnection gains are described in a nonlinear gain matrix and the small-gain condition requires bounds on the image of this gain matrix. The condition may be interpreted as a nonlinear generalization of the requirement that the spectral radius of the gain matrix is less than one. We give some interpretations of the condition in special cases covering two subsystems, linear gains, linear systems and an associated artificial dynamical system.Comment: 26 pages, 3 figures, submitted to Mathematics of Control, Signals, and Systems (MCSS

Targeting Telomere Biology in Acute Lymphoblastic Leukemia.

Increased cell proliferation is a hallmark of acute lymphoblastic leukemia (ALL), and genetic alterations driving clonal proliferation have been identified as prognostic factors. To evaluate replicative history and its potential prognostic value, we determined telomere length (TL) in lymphoblasts, B-, and T-lymphocytes, and measured telomerase activity (TA) in leukocytes of patients with ALL. In addition, we evaluated the potential to suppress the in vitro growth of B-ALL cells by the telomerase inhibitor imetelstat. We found a significantly lower TL in lymphoblasts (4.3 kb in pediatric and 2.3 kb in adult patients with ALL) compared to B- and T-lymphocytes (8.0 kb and 8.2 kb in pediatric, and 6.4 kb and 5.5 kb in adult patients with ALL). TA in leukocytes was 3.2 TA/C for pediatric and 0.7 TA/C for adult patients. Notably, patients with high-risk pediatric ALL had a significantly higher TA of 6.6 TA/C compared to non-high-risk patients with 2.2 TA/C. The inhibition of telomerase with imetelstat ex vivo led to significant dose-dependent apoptosis of B-ALL cells. These results suggest that TL reflects clonal expansion and indicate that elevated TA correlates with high-risk pediatric ALL. In addition, telomerase inhibition induces apoptosis of B-ALL cells cultured in vitro. TL and TA might complement established markers for the identification of patients with high-risk ALL. Moreover, TA seems to be an effective therapeutic target; hence, telomerase inhibitors, such as imetelstat, may augment standard ALL treatment

ruvA Mutants that resolve Holliday junctions but do not reverse replication forks

RuvAB and RuvABC complexes catalyze branch migration and resolution of Holliday junctions (HJs) respectively. In addition to their action in the last steps of homologous recombination, they process HJs made by replication fork reversal, a reaction which occurs at inactivated replication forks by the annealing of blocked leading and lagging strand ends. RuvAB was recently proposed to bind replication forks and directly catalyze their conversion into HJs. We report here the isolation and characterization of two separation-of-function ruvA mutants that resolve HJs, based on their capacity to promote conjugational recombination and recombinational repair of UV and mitomycin C lesions, but have lost the capacity to reverse forks. In vivo and in vitro evidence indicate that the ruvA mutations affect DNA binding and the stimulation of RuvB helicase activity. This work shows that RuvA's actions at forks and at HJs can be genetically separated, and that RuvA mutants compromised for fork reversal remain fully capable of homologous recombination

Cognitive and emotional empathy in individuals at clinical high risk of psychosis

Background Impairments of social cognition are considered core features of schizophrenia and are established predictors of social functioning. However, affective aspects of social cognition including empathy have far less been studied than its cognitive dimensions. The role of empathy in the development of schizophrenia remains largely elusive. Methods Emotional and cognitive empathy were investigated in large sample of 120 individuals at Clinical High Risk of Psychosis (CHR-P) and compared with 50 patients with schizophrenia and 50 healthy controls. A behavioral empathy assessment, the Multifaceted Empathy Test, was implemented, and associations of empathy with cognition, social functioning, and symptoms were determined. Results Our findings demonstrated significant reductions of emotional empathy in individuals at CHR-P, while cognitive empathy appeared intact. Only individuals with schizophrenia showed significantly reduced scores of cognitive empathy compared to healthy controls and individuals at CHR-P. Individuals at CHR-P were characterized by significantly lower scores of emotional empathy and unspecific arousal for both positive and negative affective valences compared to matched healthy controls and patients with schizophrenia. Results also indicated a correlation of lower scores of emotional empathy and arousal with higher scores of prodromal symptoms. Conclusion Findings suggest that the tendency to 'feel with' an interaction partner is reduced in individuals at CHR-P. Altered emotional reactivity may represent an additional, early vulnerability marker, even if cognitive mentalizing is grossly unimpaired in the prodromal stage. Different mechanisms might contribute to reductions of cognitive and emotional empathy in different stages of non-affective psychotic disorders and should be further explored