Variation Of Tau Research Articles

Electrical impedance tomography provides information of brain injury during total aortic arch replacement through its correlation with relative difference of neurological biomarkers

Postoperative neurological dysfunction (PND) is one of the most common complications after a total aortic arch replacement (TAAR). Electrical impedance tomography (EIT) monitoring of cerebral hypoxia injury during TAAR is a promising technique for preventing the occurrence of PND. This study aimed to explore the feasibility of electrical impedance tomography (EIT) for warning of potential brain injury during total aortic arch replacement (TAAR) through building the correlation between EIT extracted parameters and variation of neurological biomarkers in serum. Patients with Stanford type A aortic dissection and requiring TAAR who were admitted between December 2021 to March 2022 were included. A 16-electrode EIT system was adopted to monitor each patient’s cerebral impedance intraoperatively. Five parameters of EIT signals regarding to the hypothermic circulatory arrest (HCA) period were extracted. Meanwhile, concentration of four neurological biomarkers in serum were measured regarding to time before and right after surgery, 12 h, 24 h and 48 h after surgery. The correlation between EIT parameters and variation of serum biomarkers were analyzed. A total of 57 TAAR patients were recruited. The correlation between EIT parameters and variation of biomarkers were stronger for patients with postoperative neurological dysfunction (PND(+)) than those without postoperative neurological dysfunction (PND(−)) in general. Particularly, variation of S100B after surgery had significantly moderate correlation with two parameters regarding to the difference of impedance between left and right brain which were MRAIabs and TRAIabs (0.500 and 0.485 with p < 0.05, respectively). In addition, significantly strong correlations were seen between variation of S100B at 24 h and the difference of average resistivity value before and after HCA phase (ΔARVHCA), the slope of electrical impedance during HCA (kHCA) and MRAIabs (0.758, 0.758 and 0.743 with p < 0.05, respectively) for patients with abnormal S100B level before surgery. Strong correlations were seen between variation of TAU after surgery and ΔARVHCA, kHCA and the time integral of electrical impedance for half flow of perfusion (TARVHP) (0.770, 0.794 and 0.818 with p < 0.01, respectively) for patients with abnormal TAU level before surgery. Another two significantly moderate correlations were found between TRAIabs and variation of GFAP at 12 h and 24 h (0.521 and 0.521 with p < 0.05, respectively) for patients with a normal GFAP serum level before surgery. The correlations between EIT parameters and serum level of neurological biomarkers were significant in patients with PND, especially for MRAIabs and TRAIabs, indicating that EIT may become a powerful assistant for providing a real-time warning of brain injury during TAAR from physiological perspective and useful guidance for intensive care units.

Situating tau pathology and neuroinflammation along the principal gradients of brain organisation in Alzheimer’s disease

AbstractBackgroundThe spread of abnormal tau along connectivity‐based networks is a hallmark of Alzheimer’s disease (AD). In addition, activated microglia was shown to affect tau spread across networks. However, traditional network approaches using atlas‐defined regions suffer from assuming within‐region homogenous connectivity, as well as abrupt and linear connectivity changes between the regions; while, in fact, brain structure and function exist as complex overlapping axes of connectivity variation. Here, we studied smooth/continuous spatial transitions or ‘gradients’ of connectivity and their link to gradients of pathology in AD. This work provides novel insights into brain architecture driving pathology spread.MethodWe enrolled 220 individuals including 106 cognitively normal Aβ‐negative (A‐) and 37 A+, and 77 MCI/AD A+ (TRIAD). From diffusion‐weighted MRI and fMRI data, we estimated region‐to‐region fiber count and correlated timeseries, respectively, and averaged subject‐wise connectivity matrices to create structural and functional ‘template connectomes’. From 18F‐MK6240 and 11C‐PBR28 PET data, we extracted regional tau and neuroinflammation SUVR values, respectively, and created covariance matrices for each disease stage. Next, the template connectomes/covariance matrices were subjected to non‐linear dimensionality reduction to extract embedded components (‘gradients’). We correlated the primary gradients of functional or structural connectivity (G1FC/G1SC) with the primary and secondary gradients of tau or neuroinflammation (G1TAU/G2TAU; G1INFLAM/G2INFLAM). We employed three brain atlases for validation: high‐resolution customized Glasser‐atlas (1332 equally‐sized subregions), DKT, and Schaefer‐100.ResultG1FC replicated the previously reported ‘uni‐to‐transmodal’ functional gradient (Margulies 2016) and correlated strongly with G1TAU in cognitively impaired A+ (Fig.1 A); illustrating a common topographic variation in tau spread and functional connectivity in symptomatic stages. Conversely, G1SC ran between medial‐temporal‐lobe (MTL)/posterior and frontal/anterior regions, and correlated strongly with both G2TAU (Fig.1 B) and G1INFLAM (Fig.1 C) in cognitively (un)impaired A+; illustrating a common topographic variation in tau/microglia and structural connectivity already present at early disease stages. Different brain atlases led to similar results.ConclusionWe identified two gradients of continuous topographic variation in tau and neuroinflammation, potentially reflecting heterogeneity of AD‐subgroups. While microglial activation and early‐stage tau propagation may be largely dominated by structural organisation, later‐stage tau propagation may be more heterogeneously associated with variation in structural and particularly functional connectivity.

Molecular depletion times and the CO-to-H2conversion factor in metal-poor galaxies

Tracing molecular hydrogen content with carbon monoxide in low-metallicity galaxies has been exceedingly difficult. Here we present a new effort, with IRAM 30-m observations of 12CO(1-0) of a sample of 8 dwarf galaxies having oxygen abundances ranging from 12+logO/H=7.7 to 8.4. CO emission is detected in all galaxies, including the most metal-poor galaxy of our sample (0.1 Zsun); to our knowledge this is the largest number of 12CO(1-0) detections ever reported for galaxies with 12+logO/H<=8 (0.2 Zsun) outside the Local Group. We calculate stellar masses (Mstar) and star-formation rates (SFRs), and analyze our results by combining our observations with galaxy samples from the literature. Extending previous results for a correlation of the molecular gas depletion time, tau(dep), with Mstar and specific SFR (sSFR), we find a variation in tau(dep) of a factor of 200 or more (from <50 Myr to 10 Gyr) over a spread of 1000 in sSFR and Mstar. We exploit the variation of tau(dep) to constrain the CO-to-H2 mass conversion factor alpha(CO) at low metallicity, and assuming a power-law variation find alpha(CO) \propto (Z/Zsun)^1.9, similar to results based on dust continuum measurements compared with gas mass. By including HI measurements, we show that the fraction of total gas mass relative to the baryonic mass is higher in galaxies that are metal poor, of low mass, and of high sSFR. Finally, comparisons of the data with star-formation models of the molecular gas phases suggest that, at metallicities Z/Zsun<=0.2, there are some discrepancies with model predictions.

Variations in local calcium signaling in adjacent cardiac myocytes of the intact mouse heart detected with two-dimensional confocal microscopy.

Dyssynchronous local Ca release within individual cardiac myocytes has been linked to cellular contractile dysfunction. Differences in Ca kinetics in adjacent cells may also provide a substrate for inefficient contraction and arrhythmias. In a new approach we quantify variation in local Ca transients between adjacent myocytes in the whole heart. Langendorff-perfused mouse hearts were loaded with Fluo-8 AM to detect Ca and Di-4-ANEPPS to visualize cell membranes. A spinning disc confocal microscope with a fast camera allowed us to record Ca signals within an area of 465 μm by 315 μm with an acquisition speed of 55 fps. Images from multiple transients recorded at steady state were registered to their time point in the cardiac cycle to restore averaged local Ca transients with a higher temporal resolution. Local Ca transients within and between adjacent myocytes were compared with regard to amplitude, time to peak and decay at steady state stimulation (250 ms cycle length). Image registration from multiple sequential Ca transients allowed reconstruction of high temporal resolution (2.4 ± 1.3 ms) local CaT in 2D image sets (N = 4 hearts, n = 8 regions). During steady state stimulation, spatial Ca gradients were homogeneous within cells in both directions and independent of distance between measured points. Variation in CaT amplitudes was similar across the short and the long side of neighboring cells. Variations in TAU and TTP were similar in both directions. Isoproterenol enhanced the CaT but not the overall pattern of spatial heterogeneities. Here we detected and analyzed local Ca signals in intact mouse hearts with high temporal and spatial resolution, taking into account 2D arrangement of the cells. We observed significant differences in the variation of CaT amplitude along the long and short axis of cardiac myocytes. Variations of Ca signals between neighboring cells may contribute to the substrate of cardiac remodeling.

Sarcoidosis Presenting As Late‐Onset Dementia: Are Cerebrospinal Fluid Biomarkers Analyses Helpful?

To the Editor: Neurosarcoidosis is uncommon in elderly adults1 and is strongly associated with dementia.2 Biopsy of the central nervous system (CNS) is usually required to confirm the diagnosis.3 The case of a 71-year-old man with rapidly progressive onset of memory deficit and finally with signs of dementia syndrome, apathetic state, and abrupt weight loss (20 kg) is reported. His medical history was positive for high blood pressure and depression. Initial physical examination demonstrated bilateral Babinski signs, and initial cognitive assessment revealed a Mini-Mental State Examination (MMSE) score of 23 that rapidly declined to 9. Executive disorder and storage memory deficit were also initially noticed. Magnetic resonance imaging (MRI) of the brain showed minor hyperintense white matter lesions at T2, with an irregular aspect of the cerebral gyri and microbleeding next to the frontal horn of the lateral ventricle. Ethylcysteinate dimer enhanced single-photon emission computed tomography of the brain showed hypoperfusion in frontal lobes. With subsequent imaging and biological findings (Table 1) indicating systemic sarcoidosis, bronchial biopsy revealed an epithelial and giant cell inflammatory granuloma (EGG) without caseous necrosis.1 Rapid improvement of cognitive function and general health status (weight gain and partial regression of the apathetic state) was observed with cortiosteroid theraphy (1 mg/kg per day). The cortiosteroid theraphy dose was reduced to 0.5 mg/kg per day and maintained. The diagnosis of neurosarcoidosis was made based on the above-mentioned findings, which matched the diagnostic criteria for probable neurosarcoidosis.3 Thus, clinical findings, cognitive profile, laboratory test results supporting CNS inflammation (high cerebrospinal fluid (CSF) protein levels, presence of oligoclonal band), and pathology-confirmed systemic sarcoidosis (EGG), were compatible with the diagnosis of neurosarcoidosis. With no leptomeningeal or cerebral parenchyma damage, which would have been biopsied, there was no indication for brain biopsy. Unspecific brain imaging results do not exclude a diagnosis of neurosarcoidosis.4 Abnormalities of the white matter detected using computed tomography and degenerative changes affecting the perivascular spaces or the brain parenchyma in the form of small granulomas have been described in biopsy material.5 The microbleeding might also have been related to neurosarcoidosis in the present case.6 Additional support for the diagnosis of neurosarcoidosis was discovered. Over the following 44 months, the situation continued to improve while cortiosteroid theraphy was progressively reduced and finally stopped. Although he returned to independence in activities of daily living with stimulation (but not in instrumental activities of daily living), his cognitive deficit persisted (MMSE score 15). He was able to perform a description task from the Boston Diagnostic Aphasia Examination 7 and to read a text and the time on a clock, but his verbal fluency was poor, as well as his results on the Frontal Assessment Battery (5/18). In addition, some verbal (utterances repeated multiple times such as inappropriate laughter) and gestural (rubbing hands together; rubbing the face) stereotypies appeared and become almost permanent. He no longer exhibited disinhibited or aggressive behavior, but apathy persisted. The combination of a dementia syndrome of degenerative origin such as frontotemporal dementia (FTD) and pulmonary sarcoidosis could not be excluded.8 Normal CSF cytology does not exclude neurosarcoidosis, and positive oligoclonal bands are seen in at least 19% of neurosarcoidosis cases.9 Although FTD, which is a neurodegenerative disease with different behavioral subtypes, might easily explain the apathy and hypoperfusion in the frontal lobes, the inflammation and continuing improvement with corticotherapy are not consistent with this diagnosis. Moreover, during follow-up, as shown in Table 1, repeated measurements of CSF biomarkers at Months 3, 17, 21, and 27 showed variations in Tau and PhosphoTau-181 protein levels with subsequent normalization, whereas Aβ1–40 and Aβ1–42 levels remained abnormal. Although these CSF biomarker levels demonstrated acute cerebral stress and alteration of β-amyloid clearance, normalization of Tau and PhosphoTau-181 were not indicative of Alzheimer's disease and even contributed to the exclusion of this diagnosis10 and of FTD.11 Variations in CSF biomarkers were relevant for determining the differential diagnosis between FTD with pulmonary sarcoidosis and sequelae of neurosarcoidosis with symptoms mimicking, which was the case here. In the present clinical case, the variation in CSF biomarkers levels probably indicates brain tissue damage associated with the inflammatory process. If this raises interest in measuring CSF biomarkers for the diagnosis of rapidly progressing non-Alzheimer's dementia syndromes, further studies are necessary to better interpret value variations in Aβ1–40, Aβ1–42, Tau and PhosphoTau-181 proteins, although the measurement of CSF biomarkers would never replace pathological analysis of the brain tissue to confirm the origin of cognitive disorders. Conflict of Interest: None of the authors has any conflict of interest to declare. Author Contributions: MK, POL, RC, OB, TV, and GK wrote the manuscript. Sponsor's Role: There was no sponsor for this manuscript.

Okadaic acid-induced Tau phosphorylation in rat brain: Role of NMDA receptor

Okadaic acid (OKA) is a potent inhibitor of protein phosphatases 1/2A (PP2A). Inhibition of PP2A leads to hyperphosphorylation of Tau protein. Hyperphosphorylated Tau protein is present in intraneuronal neurofibrillary tangles a characteristic feature of neuropathology of Alzheimer’s disease. Intracerebroventricular (ICV) administration of OKA causes neurotoxicity, which is associated with increased intracellular Ca2+ level, oxidative stress, and mitochondrial dysfunction in the brain areas. The present study explored Tau phosphorylation in OKA-treated rats in relation to memory function, PP2A activity, intracellular Ca2+, glycogen synthase kinase-3β (GSK-3β) and N-methyl-d-aspartate (NMDA) receptor after 13days of OKA (200ng, ICV) administration in rats, memory was found impaired in the water maze test. OKA-induced memory-impaired rats showed increased mRNA and protein expression of Tau, Ca2+/calmodulin-dependent protein kinase II (CaMKII), Calpain and GSK3β in the hippocampus and cerebral cortex. On the other hand, mRNA expression and activity of PP2A was reduced in these brain areas. OKA treatment also, resulted in decrease in mRNA expression of C and N terminals of Tau. Treatment with NMDA antagonist, MK801 (0.05mg/kg, i.p.) for 13days significantly prevented OKA-induced changes in the expression of PP2A, Tau, GSK3β, CaMKII and Calpain. Further, daily administration of anticholinergic drug, donepezil (5mg/kg, p.o.), and the NMDA receptor antagonist, memantine (10mg/kg, p.o.) initiated after OKA administration for 13days significantly attenuated OKA-induced variation in Tau, Tau-C terminal, Tau-N terminal CaMKII, Calpain, PP2A and GSK3β. These results infer that NMDA antagonist MK801 and memantine are effective against OKA-induced neurotoxicity. Therefore, the present study clearly indicates the involvement of NMDA receptor in OKA (ICV)-induced Tau hyperphosphorylation.

Highlight: Family Ties--New Evidence Simplifies Human Evolutionary Tree

Rest easy, it seems our ancestors were not the interspecies Casanovas once supposed. After humans went their separate way from chimpanzees, we made a clean break of it, each group mating within its species, a new analysis suggested by geneticist Tadashi and coworkers. This is a thorough rewrite of the evolutionary narrative told by David Reich, Nick Patterson, and colleagues at the Broad Institute in Cambridge, MA. In 2006, the popular press rang with near-salacious headlines such as “Late swinging in the evolutionary tree?” from The Philadelphia Inquirer and “Grandpa! Leave that chimp alone! Who knows what it might lead to?” from The Times of London. That year in Nature, Reich and Patterson presented evidence that, following an initial genetic split 6 million years ago, humans and chimpanzees interbred for a time as a hybridized species. The analysis was not universally well received. “We’d like to have a more Victorian view of our genome,” David Page of the Whitehead Institute in Cambridge told the New York Times. ”This reminds us that we are really animals.” However, beyond the giggle-inducing implications, a number of phylogenists did not like it for more practical reasons. The explanation was complicated and based on thin evidence. “In it very small numbers were given large importance,” said Dan Graur, who studies molecular evolution at the University of Houston. “This very complicated model has been making its way into literature and textbooks. But the problem is that people have ignored the fact of recombination.” During meiosis, matching chromosomes can swap whole sections of material, leaving Junior with new-sprung genetic diversity, but phylogenists with a newly complicated picture. However, in a new study published in Genome Biology and Evolution (Hara et al. 2012), researchers from Japan’s National Institute of Advanced Science and Technology in Tokyo and the Graduate University for Advanced Studies in Kanagawa managed to sidestep this problem entirely. “What was done in this case this was quite amazing,” said Graur, who was not involved in the work. “The limits are not contaminated by half-maternal, half-paternal material.” By comparing shorter segments that are unlikely to have recombined since humans shared a common ancestor with the great apes, they were able to trace evolutionary history without seeing any hint that different linages had once converged into one. “Everyone who is doing primate evolution will be affected by this,” Graur said. When asked how much their work negates previous work in the field, Imanishi was modest: “Our estimates of human-ape divergence times and the ancestral population sizes are not much different from those of previous works,” he wrote. “However, by using the largest dataset of genome sequences and applying a much better model to the data, we succeeded in presenting the most accurate estimates ever.” Their work, so far, has been warmly received by colleagues. “It seems that many evolutionary biologists, including Dr. Naruya Saitou of National Institute of Genetics of Japan […] did not like the hypothesis by Patterson et al. and wanted to deny it. We could demonstrate what they intuitively thought.” In addition, the researchers are intrigued by several other aspects of their study. They were also surprised by the finding that each chromosome seems to have an intrinsic mutation rate. “We concluded that variation in tau [speciation time] across the chromosomes would be due to the difference in mutation rate across the chromosomes,” writes Yuichiro Hara. “But we could not find the cause of the variation in mutation rate. We are interested in the mechanisms of genome evolution in closely related lineages (Hara and Imanishi, 2011, BMC Evol. Biol.), too, and thus clarification of this is our next goal.” And beyond that the team is also interested in seeing their novel analytical method applied to other species. Graur is similarly eager to see this method become more widespread, “These days complicated models are used as a first resort rather than a last resort. It’s nice to see such a straightforward and ingenious approach to solve a problem that was quite complicated.” He is especially interested in seeing the relationship between humans, Neanderthals, and Denisovians explored. Some claim that modern Papua New Guineans carry fragments of the Denisovian genome and paleolithic hominids believed to exist based on a tiny amount of DNA extracted from a finger bone found several years ago in a Siberian cave. Graur did have one criticism. “If I was writing up this work, I would have said that everything that was said before about the speciation was junk. The authors are very polite. They could have been more forceful.”

Taxol-stabilized microtubules promote the formation of filaments from unmodified full-length Tau in vitro

Tau is a neuronal protein that stabilizes the microtubule (MT) network, but it also forms filaments associated with Alzheimer's disease. Understanding Tau-MT and Tau-Tau interactions would help to establish Tau function in health and disease. For many years, literature reports on Tau-MT binding behavior and affinity have remained surprisingly contradictory (e.g., 10-fold variation in Tau-MT affinity). Tau-Tau interactions have also been investigated, but whether MTs might affect Tau filament formation is unknown. We have addressed these issues through binding assays and microscopy. We assessed Tau-MT interactions via cosedimentation and found that the measured affinity of Tau varies greatly, depending on the experimental design and the protein concentrations used. To investigate this dependence, we used fluorescence microscopy to examine Tau-MT binding. Strikingly, we found that Taxol-stabilized MTs promote Tau filament formation without characterized Tau-filament inducers. We propose that these novel Tau filaments account for the incongruence in Tau-MT affinity measurements. Moreover, electron microscopy reveals that these filaments appear similar to the heparin-induced Alzheimer's model. These observations suggest that the MT-induced Tau filaments provide a new model for Alzheimer's studies and that MTs might play a role in the formation of Alzheimer's-associated neurofibrillary tangles.

First evaluation of the simultaneous SMOS and ELBARA-II observations in the Mediterranean region

The SMOS (Soil Moisture and Ocean Salinity) mission was launched on November 2, 2009. Over the land surfaces, simultaneous retrievals of surface soil moisture (SM) and vegetation characteristics made from the multi-angular and dual polarization SMOS observations are now available from Level-2 (L2) products delivered by the European Space Agency (ESA). Therefore, first analyses evaluating the SMOS observations in terms of Brightness Temperatures (TB) and L2 products (SM and vegetation optical depth TAU) can be carried out over several calibration/validation (cal/val) sites selected by ESA over all continents. This study is based on SMOS observations and in situ measurements carried out in 2010 over one of the main SMOS cal/val sites in Europe: the VAS (Valencia Anchor Station) site in the region of Utiel–Requena, close to Valencia, Spain. The main vegetation types in the region are vineyards, orchards and natural Mediterranean vegetation. The SMOS observations were analyzed in conjunction with those carried out by the L-band ELBARA-II radiometer over a vineyard which is considered as representative of the main land use of the VAS site. Time series of TB and retrievals of SM and TAU based on both the SMOS (L2 products) and the ELBARA-II observations were compared and evaluated against in situ measurements. A good agreement was found between the time variations in TB and in the retrieved SM values computed over the site from the SMOS and ELBARA-II observations (the determination coefficient R2 was >0.88 for the TB values and R2>0.64 for the retrieved SM values). However, it was found that the SMOS L2 SM products underestimated the SM values retrieved from ELBARA-II by ~0.2m3/m3. It is likely this offset can be partially explained by differences between the observed scenes: while the ELBARA-II footprint includes a single vineyard, the heterogeneous SMOS footprint includes not only a large number of vineyards but also a natural Mediterranean vegetation with persistent leaves overlaying rocky soils. The time variations in TAU retrieved from the ELBARA-II observations were found to be closely related to those of the NDVI (Normalized Difference Vegetation Index) vegetation index obtained from MODIS (Moderate Resolution Imaging Spectroradiometer) (R2=0.61) and revealed the vegetation cycle over the year. Conversely, the time variations in the SMOS Level-2 TAU product did not reveal any trends in relation to the vegetation development over the site.

Circadian Rhythms: Influences of Internal and External Factors on the Period Measured in Constant Conditions1

The article reviews most of the data available on the period tau of freerunning circadian rhythms, measured in constant conditions. Emphasis is placed on the effects of light intensity and ambient temperature on tau, with references to influences of other external as well as internal factors. In the introduction, examples are given of spontaneous and induced variations in tau and its dependence on the experimental history. The discussion concentrates largely on results obtained from arthropods and vertebrates.

Age-Dependent Association between the Q7R Polymorphism in the Saitohin Gene and Sporadic Alzheimer’s Disease

A vigorous controversy exists over whether tau tangles or amyloid-β plaques are the primary cause of neurodegeneration in Alzheimer’s disease (AD), and it is not well established whether genetic variation in tau is associated with AD. A recently identified novel protein, named Saitohin (STH), shares tissue expression pattern with tau, and preliminary evidence in a North American population indicates that a polymorphism at codon 7 (Q7R) of the STH gene is a predisposing factor for sporadic AD. A case-control study utilizing a clinically well-defined group of 315 sporadic AD patients and 307 control subjects was performed to test this association. The current study reveals that increased risk of AD associated with the STH RR genotype (OR 2.17, p = 0.04) is limited to late-onset (after the age of 72 years) AD cases.

Tau polymorphisms are not associated with Alzheimer's disease

Alzheimer's disease (AD) is one of a number of neurodegenerative conditions including frontotemporal dementia and progressive supranuclear palsy that are associated with abnormal tau protein aggregates in neurons. Mutations in the tau gene cause familial forms of frontotemporal dementia and alleles of the tau gene have been associated with risk for progressive supranuclear palsy. However, studies evaluating whether polymorphic variation in tau is associated with AD have produced conflicting results. We investigated the role of the tau exon 2 polymorphism in a large sample of AD cases and controls and found no evidence that polymorphic variation in tau is associated AD.

Variation in tau, the time constant for isovolumic relaxation, along the left ventricular base-to-apex axis.

Tau (tau), the time constant for isovolumic relaxation, is often used as a measure of cardiac diastolic function. However, several methods of calculating tau have been published which may produce different results and, thereby, different conclusions. The purpose of this study was to determine if the method of tau calculation effects the results when left ventricular pressure (LVP) is measured at different positions along the base-to-apex axis. In 16 dogs, we measured LVP at 6 positions along the base-to-apex axis. We calculated tau using three different methods: 1) a monoexponential model (P(t) = [P0-Pasym]eAt + Pasym, where t = time, P0 = LVP at t = 0, Pasym is asymptotic pressure as t-->infinity, A is -1/tau) with a zero asymptote 2) a monoexponential model with a variable asymptote in which the monoexponential decay equation is differentiated with respect to time and substituted into the original equation so that dP/dt vs. LVP is A (-1/tau), and 3) a monoexponential decay model with variable asymptote in which Pasym and A are varied until the best fit line is reached by minimizing the residual sum of squares. When tau is calculated using method 1, tau measured at the LV base is 98.01% +/- 8.85% of tau at the apex. If calculated using method 2, tau measured at the LV base was 75.46 +/- 39.4% of tau measured at the apex. When method 3 is used for tau calculations, base tau increases to 117.76 +/- 4.91% of the apical tau. We conclude: 1) the method used to calculate tau will effect the results and, thus, conclusions drawn from tau data. 2) When using Method 3, which appears to be the best method for tau calculation, tau increases at the LV base compared to the apex.

The relationship between protein aggregation and molecular mobility below the glass transition temperature of lyophilized formulations containing a monoclonal antibody.

To find out if the physical instability of a lyophilized dosage form is related to molecular mobility below the glass transition temperature. Further, to explore if the stability data generated at temperatures below the glass transition temperature can be used to predict the stability of a lyophilized solid under recommended storage conditions. The temperature dependence of relaxation time constant, tau, was obtained for sucrose and trehalose formulations of the monoclonal antibody (5 mg protein/vial) from enthalpy relaxation studies using differential scanning calorimetry. The non-exponentiality parameter, beta, in the relaxation behavior was also obtained using dielectric relaxation spectroscopy. For both sucrose and trehalose formulations, the variation in tau with temperature could be fitted Vogel-Tammann-Fulcher (VTF) equation. The two formulations exhibited difference sensitivities to temperature. Sucrose formulation was more fragile and exhibited a stronger non-Arrhenius behavior compared to trehalose formulation below glass transition. Both formulations exhibited < 2% aggregation at t/tau values < 10, where t is the time of storage. Since the relaxation times for sucrose and trehalose formulations at 5 degrees C are on the order of 10(8) and 10(6) hrs, it is likely that both formulations would undergo very little (< 2%) aggregation in a practical time scale under refrigerated conditions.

Positron lifetime in oxide superconductors YBa2(Cu1-xMx)O7-y (M=Fe, Ni, Zn)

The authors present the temperature dependence of positron lifetime parameters measured on a series of specimens of YBa2(Cu1-xMx)3O7-y (M=Fe, Ni, Zn) in the temperature range 20-300 K. In a non-doped specimen, the defect-related component tau 2 showed a step-like increase in the temperature range 40-100 K. Above 180 K, the mean lifetime tau mean decreased with increasing temperature. These variations in tau 2 or tau mean are explained in terms of a thermally activated escape of positrons from the two kinds of trapping centres. The bulk lifetime tau bulk showed a slight decrease in the region 100-300 K. The iron doping moved the shift of the transition region of tau 2 towards a higher temperature and removed the decrease of tau mean out of the temperature range in which experiments were performed. These phenomena are ascribed to the enhancement of the positron-defect binding energies, which is theoretically predicted. On the other hand, nickel and zinc did not much alter the behaviour of tau 2, but affected that of tau bulk. A direct correlation between the superconducting critical temperature (Tc) and the lifetime-temperature curve was not found.

Product activation of pancreatic lipase. Lipolytic enzymes as probes for lipid/water interfaces.

During the action of pancreatic lipase and colipase on racemic 1,2-didodecanoylglycerol monolayers in the absence of bile salts, biphasic kinetics was observed under conditions of high lipid packing. Similar kinetics has earlier been reported using phospholipid-emulsified triolein droplets (Borgström, B. (1980) Gastroenterology 78, 954-962). These kinetics are characterized by a lag time tau d, dependent on products accumulation at the substrate/water interface. This lag time is differentiated from the previously described enzyme concentration independent lag time tau i in systems of low lipid packing (Verger, R., Mieras, M. C. E., and de Haas, G. H. (1973) J. Biol. Chem. 248, 4023-4034). Both tau i and tau d reflect a rate-limiting step due to the slow enzyme penetration into the substrate interface. The variation of tau d under different conditions (change in pH and concentration of Ca2+, enzyme, bovine serum albumin, and lipolytic products) lead us to propose a model for the product activation during lipolysis. We will discuss the use of the pancreatic lipase-colipase system to probe the lipid packing of emulsified triglyceride particles and lipoproteins using tau d as a reference value.