A passive vibration isolation stack for LIGO: Design, modeling, and testing

Multiple-stage seismic vibration isolation stacks, which consist of alternating layers of stiff masses and compliant springs, can provide significant passive filtering of ground vibration for experiments and equipment that are sensitive to mechanical noise. We describe the design, modeling and testing of a prototype of a stack suitable for use in the Laser Interferometer Gravitational-wave Observatory (LIGO). This is a four-stage elastomer (spring) and stainless steel (mass) stack, consisting of a table resting on three separate legs of three layers each. The viscoelastic properties of elastomer springs are exploited to damp the stack's normal modes while providing rapid roll-off of stack transmission above these modal frequencies. The stack's transmission of base motion to top motion was measured in vacuum and compared with three-dimensional finite-element models. In one tested configuration, at 100 Hz, horizontal transmission was 10^–7, vertical transmission was 3×10^–6, and the cross-coupling terms were between these values

Global feed-forward vibration isolation in a km scale interferometer

Using a network of seismometers and sets of optimal filters, we implemented a feed-forward control technique to minimize the seismic contribution to multiple interferometric degrees of freedom of the Laser Interferometer Gravitational-wave Observatory interferometers. The filters are constructed by using the Levinson–Durbin recursion relation to approximate the optimal Wiener filter. By reducing the RMS of the interferometer feedback signals below ~10 Hz, we have improved the stability and duty cycle of the joint network of gravitational wave detectors. By suppressing the large control forces and mirror motions, we have dramatically reduced the rate of non-Gaussian transients in the gravitational wave signal stream

Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway

<p>Abstract</p> <p>Background</p> <p>Dominantly inherited missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease, but its normal physiological function remains unclear. We previously reported that loss of LRRK2 causes impairment of protein degradation pathways as well as increases of apoptotic cell death and inflammatory responses in the kidney of aged mice.</p> <p>Results</p> <p>Our analysis of <it>LRRK2</it>-/- kidneys at multiple ages, such as 1, 4, 7, and 20 months, revealed unique age-dependent development of a variety of molecular, cellular, and ultrastructural changes. Gross morphological abnormalities of the kidney, including altered size, weight, texture, and color, are evident in <it>LRRK2</it>-/- mice at 3-4 months of age, along with increased accumulation of autofluorescent granules in proximal renal tubules. The ratio of kidney/body weight in <it>LRRK2</it>-/- mice is increased at 1, 4, and 7 months of age (~10% at 1 month, and ~20% at 4 and 7 months), whereas the ratio is drastically decreased at 20 months of age (~50%). While kidney filtration function evaluated by levels of blood urea nitrogen and serum creatinine is not significantly affected in <it>LRRK2</it>-/- mice at 12-14 months of age, expression of kidney injury molecule-1, a sensitive and specific biomarker for epithelial cell injury of proximal renal tubules, is up-regulated (~10-fold). Surprisingly, loss of LRRK2 causes age-dependent bi-phasic alterations of the autophagic activity in <it>LRRK2</it>-/- kidneys, which is unchanged at 1 month of age, enhanced at 7 months but reduced at 20 months, as evidenced by corresponding changes in the levels of LC3-I/II, a reliable autophagy marker, and p62, an autophagy substrate. Levels of α-synuclein and protein carbonyls, a general oxidative damage marker, are also decreased in <it>LRRK2</it>-/- kidneys at 7 months of age but increased at 20 months. Interestingly, the age-dependent bi-phasic alterations in autophagic activity in <it>LRRK2</it>-/- kidneys is accompanied by increased levels of lysosomal proteins and proteases at 1, 7, and 20 months of age as well as progressive accumulation of autolysosomes and lipofuscin granules at 4, 7-10, and 20 months of age.</p> <p>Conclusions</p> <p>LRRK2 is important for the dynamic regulation of autophagy function <it>in vivo</it>.</p

A passive vibration isolation stack for LIGO: Design, modeling, and testing

Multiple-stage seismic vibration isolation stacks, which consist of alternating layers of stiff masses and compliant springs, can provide significant passive filtering of ground vibration for experiments and equipment that are sensitive to mechanical noise. We describe the design, modeling and testing of a prototype of a stack suitable for use in the Laser Interferometer Gravitational-wave Observatory (LIGO). This is a four-stage elastomer (spring) and stainless steel (mass) stack, consisting of a table resting on three separate legs of three layers each. The viscoelastic properties of elastomer springs are exploited to damp the stack's normal modes while providing rapid roll-off of stack transmission above these modal frequencies. The stack's transmission of base motion to top motion was measured in vacuum and compared with three-dimensional finite-element models. In one tested configuration, at 100 Hz, horizontal transmission was 10^–7, vertical transmission was 3×10^–6, and the cross-coupling terms were between these values

A Whole Cell Assay to Measure Caspase-6 Activity by Detecting Cleavage of Lamin A/C

Caspase-6 is a cysteinyl protease implicated in neurodegenerative conditions including Alzheimer's and Huntington's disease making it an attractive target for therapeutic intervention. A greater understanding of the role of caspase-6 in disease has been hampered by a lack of suitable cellular assays capable of specifically detecting caspase-6 activity in an intact cell environment. This is mainly due to the use of commercially available peptide substrates and inhibitors which lack the required specificity to facilitate development of this type of assay. We report here a 384-well whole-cell chemiluminescent ELISA assay that monitors the proteolytic degradation of endogenously expressed lamin A/C during the early stages of caspase-dependent apoptosis. The specificity of lamin A/C proteolysis by caspase-6 was demonstrated against recombinant caspase family members and further confirmed in genetic deletion studies. In the assay, plasma membrane integrity remained intact as assessed by release of lactate dehydrogenase from the intracellular environment and the exclusion of cell impermeable peptide inhibitors, despite the induction of an apoptotic state. The method described here is a robust tool to support drug discovery efforts targeting caspase-6 and is the first reported to specifically monitor endogenous caspase-6 activity in a cellular context

Management of acute diverticulitis with pericolic free gas (ADIFAS). an international multicenter observational study

Background: There are no specific recommendations regarding the optimal management of this group of patients. The World Society of Emergency Surgery suggested a nonoperative strategy with antibiotic therapy, but this was a weak recommendation. This study aims to identify the optimal management of patients with acute diverticulitis (AD) presenting with pericolic free air with or without pericolic fluid. Methods: A multicenter, prospective, international study of patients diagnosed with AD and pericolic-free air with or without pericolic free fluid at a computed tomography (CT) scan between May 2020 and June 2021 was included. Patients were excluded if they had intra-abdominal distant free air, an abscess, generalized peritonitis, or less than a 1-year follow-up. The primary outcome was the rate of failure of nonoperative management within the index admission. Secondary outcomes included the rate of failure of nonoperative management within the first year and risk factors for failure. Results: A total of 810 patients were recruited across 69 European and South American centers; 744 patients (92%) were treated nonoperatively, and 66 (8%) underwent immediate surgery. Baseline characteristics were similar between groups. Hinchey II-IV on diagnostic imaging was the only independent risk factor for surgical intervention during index admission (odds ratios: 12.5, 95% CI: 2.4-64, P =0.003). Among patients treated nonoperatively, at index admission, 697 (94%) patients were discharged without any complications, 35 (4.7%) required emergency surgery, and 12 (1.6%) percutaneous drainage. Free pericolic fluid on CT scan was associated with a higher risk of failure of nonoperative management (odds ratios: 4.9, 95% CI: 1.2-19.9, P =0.023), with 88% of success compared to 96% without free fluid ( P &lt;0.001). The rate of treatment failure with nonoperative management during the first year of follow-up was 16.5%. Conclusion: Patients with AD presenting with pericolic free gas can be successfully managed nonoperatively in the vast majority of cases. Patients with both free pericolic gas and free pericolic fluid on a CT scan are at a higher risk of failing nonoperative management and require closer observation