Unfair competition governs the interaction of pCPI-17 with myosin phosphatase (PP1-MYPT1).

The small phosphoprotein pCPI-17 inhibits myosin light-chain phosphatase (MLCP). Current models postulate that during muscle relaxation, phosphatases other than MLCP dephosphorylate and inactivate pCPI-17 to restore MLCP activity. We show here that such hypotheses are insufficient to account for the observed rapidity of pCPI-17 inactivation in mammalian smooth muscles. Instead, MLCP itself is the critical enzyme for pCPI-17 dephosphorylation. We call the mutual sequestration mechanism through which pCPI-17 and MLCP interact inhibition by unfair competition: MLCP protects pCPI-17 from other phosphatases, while pCPI-17 blocks other substrates from MLCP\u27s active site. MLCP dephosphorylates pCPI-17 at a slow rate that is, nonetheless, both sufficient and necessary to explain the speed of pCPI-17 dephosphorylation and the consequent MLCP activation during muscle relaxation

Kick stability in groups and dynamical systems

We consider a general construction of ``kicked systems''. Let G be a group of measure preserving transformations of a probability space. Given its one-parameter/cyclic subgroup (the flow), and any sequence of elements (the kicks) we define the kicked dynamics on the space by alternately flowing with given period, then applying a kick. Our main finding is the following stability phenomenon: the kicked system often inherits recurrence properties of the original flow. We present three main examples. 1) G is the torus. We show that for generic linear flows, and any sequence of kicks, the trajectories of the kicked system are uniformly distributed for almost all periods. 2) G is a discrete subgroup of PSL(2,R) acting on the unit tangent bundle of a Riemann surface. The flow is generated by a single element of G, and we take any bounded sequence of elements of G as our kicks. We prove that the kicked system is mixing for all sufficiently large periods if and only if the generator is of infinite order and is not conjugate to its inverse in G. 3) G is the group of Hamiltonian diffeomorphisms of a closed symplectic manifold. We assume that the flow is rapidly growing in the sense of Hofer's norm, and the kicks are bounded. We prove that for a positive proportion of the periods the kicked system inherits a kind of energy conservation law and is thus superrecurrent. We use tools of geometric group theory and symplectic topology.Comment: Latex, 40 pages, revised versio

Cohesin Removal along the Chromosome Arms during the First Meiotic Division Depends on a NEK1-PP1γ-WAPL Axis in the Mouse

SummaryMammalian NIMA-like kinase-1 (NEK1) is a dual-specificity kinase highly expressed in mouse germ cells during prophase I of meiosis. Loss of NEK1 induces retention of cohesin on chromosomes at meiotic prophase I. Timely deposition and removal of cohesin is essential for accurate chromosome segregation. Two processes regulate cohesin removal: a non-proteolytic mechanism involving WAPL, sororin, and PDS5B and direct cleavage by separase. Here, we demonstrate a role for NEK1 in the regulation of WAPL loading during meiotic prophase I, via an interaction between NEK1 and PDS5B. This regulation of WAPL by NEK1-PDS5B is mediated by protein phosphatase 1 gamma (PP1γ), which both interacts with and is a phosphotarget of NEK1. Taken together, our results reveal that NEK1 phosphorylates PP1γ, leading to the dephosphorylation of WAPL, which, in turn, results in its retention on chromosome cores to promote loss of cohesion at the end of prophase I in mammals

Increased frequency and nocturia in a middle aged male may not always be due to Benign Prostatic Hypertrophy (BPH): a case report

Primary signet ring cell carcinoma of urinary bladder is a rare type of bladder tumor and carries a very high mortality rate. It may have a clinical presentation similar to common diseases like Benign Prostatic Hypertrophy (BPH) and the management options are extremely limited. We report a case of 58 year old Caucasian male who presented with a 5 month history of increased frequency of urination, nocturia and weight loss without any fever or hematuria. He was found to have an increased creatinine of 2.8 mg/dl and a prostate specific antigen level of 0.18 ng/ml. His azotemia was thought to be secondary to BPH. A foley catheter was initially placed with a plan for outpatient follow up. On removal of the catheter his problems persisted and he returned to the hospital. Diagnostic work up including abdominal ultrasonography, computed tomography (CT) scan, retrograde pyelogram, cystography and cystoscopic biopsies revealed the diagnosis of primary signet ring cell carcinoma of urinary bladder. Although cystectomy was planned, our patient passed away before this could be done

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes