Algebraic Properties of Riemannian Manifolds

Algebraic properties are explored for the curvature tensors of Riemannian manifolds, using the irreducible decomposition of curvature tensors. Our method provides a powerful tool to analyze the irreducible basis as well as an algorithm to determine the linear dependence of arbitrary Riemann polynomials. We completely specify 13 independent basis elements for the quartic scalars and explicitly find 13 linear relations among 26 scalar invariants. Our method provides several completely new results, including some clues to identify 23 independent basis elements from 90 quintic scalars, that are difficult to find otherwise.Comment: A few typos corrected; 40 pages (4 appendices: 16 pages). To appear in General Relativity and Gravitatio

Accurate and complexity-effective spatial pattern prediction

Recent research suggests that there are large variations in a cache's spatial usage, both within and across programs. Unfortunately, conventional caches typically employ fixed cache line sizes to balance the exploitation of spatial and temporal locality, and to avoid prohibitive cache fill bandwidth demands. The resulting inability of conventional caches to exploit spatial variations leads to sub-optimal performance and unnecessary cache power dissipation. This paper describes the Spatial Pattern Predictor (SPP), a cost-effective hardware mechanism that accurately predicts reference patterns within a spatial group (i.e., a contiguous region of data in memory) at runtime. The key observation enabling an accurate, yet low-cost, SPP design is that spatial patterns correlate well with instruction addresses and data reference offsets within a cache line. We require only a small amount of predictor memory to store the predicted patterns. Simulation results for a 64-Kbyte 2-way set- associative L1 data cache with 64-byte lines show that: (1) a 256-entry tag- less direct-mapped SPP can achieve, on average, a prediction coverage of 95%, over-predicting the patterns by only 8%, (2) assuming a 70nm process technology, the SPP helps reduce leakage energy in the base cache by 41% on average, incurring less than 1% performance degradation, and (3) prefetching spatial groups of up to 512 bytes using SPP improves execution time by 33% on average and up to a factor of two

Long-term clinical course of a patient with mucopolysaccharidosis type IIIB

Mucopolysaccharidosis type III (MPS III) is a rare genetic disorder caused by lysosomal storage of heparan sulfate. MPS IIIB results from a deficiency in the enzyme alpha-N-acetyl-D-glucosaminidase (NAGLU). Affected patients begin showing behavioral changes, progressive profound mental retardation, and severe disability from the age of 2 to 6 years. We report a patient with MPS IIIB with a long-term follow-up duration. He showed normal development until 3 years. Subsequently, he presented behavioral changes, sleep disturbance, and progressive motor dysfunction. He had been hospitalized owing to recurrent pneumonia and epilepsy with severe cognitive dysfunction. The patient had compound heterozygous c.1444C>T (p.R482W) and c.1675G>T (p.D559Y) variants of NAGLU. Considering that individuals with MPS IIIB have less prominent facial features and skeletal changes, evaluation of long-term clinical course is important for diagnosis. Although no effective therapies for MPS IIIB have been developed yet, early and accurate diagnosis can provide important information for family planning in families at risk of the disorder

Cryptotanshinone chemosensitivity potentiation by TW-37 in human oral cancer cell lines by targeting STAT3–Mcl-1 signaling

Abstract Background Despite being one of the leading cancer types in the world, the diagnosis of oral cancer and its suitable therapeutic options remain limited. This study aims to investigate the single and chemosensitizing effects of TW-37, a BH3 mimetic in oral cancer, on human oral cancer cell lines. Methods We assessed the single and chemosensitizing effects of TW-37 in vitro using trypan blue exclusion assay, Western blotting, DAPI staining, Annexin V–FITC/PI double staining, and quantitative real-time PCR. Mcl-1 overexpression models were established by transforming vector and transient transfection was performed to test for apoptosis Results TW-37 enhanced the cytotoxicity of human oral cancer cell lines by inducing caspase-dependent apoptosis, which correlates with the reduction of the myeloid cell leukemia-1 (Mcl-1) expression via transcriptional and post-translational regulation. The ectopic expression of Mcl-1 partially attenuated the apoptosis-inducing capacity of TW-37 in human oral cancer cell lines. Besides, TW-37 decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr705 and nuclear translocation in human oral cancer cell lines at the early time points. Furthermore, TW-37 potentiated chemosusceptibility of cryptotanshinone in human oral cancer cell lines by suppressing STAT3–Mcl-1 signaling compared with either TW-37 or cryptotanshinone alone, resulting in potent apoptosis. Conclusions This study not only unravels the single and chemosensitizing effects of TW-37 for treatment of human oral cancer but also highlights the likelihood of TW-37 as a good therapeutic strategy to enhance the prognosis of patients with oral cancer in the future

Prognostic significance of respiratory quotient in patients undergoing extracorporeal cardiopulmonary resuscitation in Korea

Background Respiratory quotient (RQ) may be used as a tissue hypoxia marker in various clinical settings but its prognostic significance in patients undergoing extracorporeal cardiopulmonary resuscitation (ECPR) is not known. Methods Medical records of adult patients admitted to the intensive care units after ECPR in whom RQ could be calculated from May 2004 to April 2020 were retrospectively reviewed. Patients were divided into good neurologic outcome and poor neurologic outcome groups. Prognostic significance of RQ was compared to other clinical characteristics and markers of tissue hypoxia. Results During the study period, 155 patients were eligible for analysis. Of them, 90 (58.1%) had a poor neurologic outcome. The group with poor neurologic outcome had a higher incidence of out-of-hospital cardiac arrest (25.6% vs. 9.2%, P=0.010) and longer cardiopulmonary resuscitation to pump-on time (33.0 vs. 25.2 minutes, P=0.001) than the group with good neurologic outcome. For tissue hypoxia markers, the group with poor neurologic outcome had higher RQ (2.2 vs. 1.7, P=0.021) and lactate levels (8.2 vs. 5.4 mmol/L, P=0.004) than the group with good neurologic outcome. On multivariable analysis, age, cardiopulmonary resuscitation to pump-on time, and lactate levels above 7.1 mmol/L were significant predictors for a poor neurologic outcome but not RQ. Conclusions In patients who received ECPR, RQ was not independently associated with poor neurologic outcome

Direct Observation of Defects and Increased Ion Permeability of a Membrane Induced by Structurally Disordered Cu/Zn-Superoxide Dismutase Aggregates

Interactions between protein aggregates and a cellular membrane have been strongly implicated in many protein conformational diseases. However, such interactions for the case of Cu/Zn superoxide dismutase (SOD1) protein, which is related to fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS), have not been explored yet. For the first time, we report the direct observation of defect formation and increased ion permeability of a membrane induced by SOD1 aggregates using a supported lipid bilayer and membrane patches of human embryonic kidney cells as model membranes. We observed that aggregated SOD1 significantly induced the formation of defects within lipid membranes and caused the perturbation of membrane permeability, based on surface plasmon resonance spectroscopy, atomic force microscopy and electrophysiology. In the case of apo SOD1 with an unfolded structure, we found that it bound to the lipid membrane surface and slightly perturbed membrane permeability, compared to other folded proteins (holo SOD1 and bovine serum albumin). The changes in membrane integrity and permeability were found to be strongly dependent on the type of proteins and the amount of aggregates present. We expect that the findings presented herein will advance our understanding of the pathway by which structurally disordered SOD1 aggregates exert toxicity in vivo

Disruption of nucleocytoplasmic trafficking as a cellular senescence driver

Senescent cells exhibit a reduced response to intrinsic and extrinsic stimuli. This diminished reaction may be explained by the disrupted transmission of nuclear signals. However, this hypothesis requires more evidence before it can be accepted as a mechanism of cellular senescence. A proteomic analysis of the cytoplasmic and nuclear fractions obtained from young and senescent cells revealed disruption of nucleocytoplasmic trafficking (NCT) as an essential feature of replicative senescence (RS) at the global level. Blocking NCT either chemically or genetically induced the acquisition of an RS-like senescence phenotype, named nuclear barrier-induced senescence (NBIS). A transcriptome analysis revealed that, among various types of cellular senescence, NBIS exhibited a gene expression pattern most similar to that of RS. Core proteomic and transcriptomic patterns common to both RS and NBIS included upregulation of the endocytosis-lysosome network and downregulation of NCT in senescent cells, patterns also observed in an aging yeast model. These results imply coordinated aging-dependent reduction in the transmission of extrinsic signals to the nucleus and in the nucleus-to-cytoplasm supply of proteins/RNAs. We further showed that the aging-associated decrease in Sp1 transcription factor expression was critical for the downregulation of NCT. Our results suggest that NBIS is a modality of cellular senescence that may represent the nature of physiological aging in eukaryotes. © 2021, The Author(s).1