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To evaluate the potential superiority of donanemab vs. aducanumab on the percentage of participants with amyloid plaque clearance (≤24.1 Centiloids [CL]) at 6 months in patients with early symptomatic Alzheimer's disease (AD) in phase 3 TRAILBLAZER-ALZ-4 study. The amyloid cascade in AD involves the production and deposition of amyloid beta (Aβ) as an early and necessary event in the pathogenesis of AD.
Participants (n = 148) were randomized 1:1 to receive donanemab (700 mg IV Q4W [first 3 doses], then 1400 mg IV Q4W [subsequent doses]) or aducanumab (per USPI: 1 mg/kg IV Q4W [first 2 doses], 3 mg/kg IV Q4W [next 2 doses], 6 mg/kg IV Q4W [next 2 doses] and 10 mg/kg IV Q4W [subsequent doses]).
Baseline demographics and characteristics were well-balanced across treatment arms (donanemab [N = 71], aducanumab [N = 69]). Twenty-seven donanemab-treated and 28 aducanumab-treated participants defined as having intermediate tau.
Upon assessment of florbetapir F18 PET scans (6 months), 37.9% donanemab-treated vs. 1.6% aducanumab-treated participants achieved amyloid clearance (p < 0.001). In the intermediate tau subpopulation, 38.5% donanemab-treated vs. 3.8% aducanumab-treated participants achieved amyloid clearance (p = 0.008).
Percent change in brain amyloid levels were −65.2%±3.9% (baseline: 98.29 ± 27.83 CL) and −17.0%±4.0% (baseline: 102.40 ± 35.49 CL) in donanemab and aducanumab arms, respectively (p < 0.001). In the intermediate tau subpopulation, percent change in brain amyloid levels were −63.9%±7.4% (baseline: 104.97 ± 25.68 CL) and −25.4%±7.8% (baseline: 102.23 ± 28.13 CL) in donanemab and aducanumab arms, respectively (p ≤ 0.001).
62.0% of donanemab-treated and 66.7% of aducanumab-treated participants reported an adverse event (AE), there were no serious AEs due to ARIA in donanemab arm and 1.4% serious AEs (one event) due to ARIA were reported in aducanumab arm.
This study provides the first active comparator data on amyloid plaque clearance in patients with early symptomatic AD. Significantly higher number of participants reached amyloid clearance and amyloid plaque reductions with donanemab vs. aducanumab at 6 months.
Previously presented at the Clinical Trials on Alzheimer's Disease - 15th Conference, 2022.
This study investigated the effect of pre-exercise α-lactalbumin ingestion on subsequent endurance exercise performance, muscle pain and mood states. In a two-stage cross-over counterbalance design, eleven male endurance runners (age: 31 (se 2) years, height: 169·5 (se 4·4) cm, weight: 63·6 (se 5·1) kg, V̇O2max: 58·8 (se 6·3) ml/kg per min) consumed two solutions (carbohydrate+α-lactalbumin, CA; carbohydrate+whey protein isolate, CW) 2 h before a self-paced 21-km run. Creatine kinase, IL-6, muscle pain, pressure pain threshold (PPT) and mood states were assessed 2 h before exercise, immediately before exercise (Pre-ex0) and immediately after exercise (Post-ex0). No difference was found in 21-km running performance between two trials (CA v. CW: 115·85 (se 5·20) v. 118·85 (se 5·51) min, P=0·48). Compared with CW, CA led to higher PPT at Pre-ex0 (41·77 (se 2·27) v. 35·56 (se 2·10) N/cm2, P<0·01) and Post-ex0 (38·76 (se 3·23) v. 35·30 (se 3·55) N/cm2, P=0·047). Compared with CW, CA reduced the feeling of fatigue at Post-ex0 (P<0·01); CA also reduced salivary cortisol levels at Post-ex0 (0·72 (se 0·07) v. 0·83 (se 0·13) ng/ml, P<0·01). In conclusion, the ingestion of α-lactalbumin did not improve the 21-km time-trial performance. However, compared with the pre-exercise ingestion of whey protein, that of α-lactalbumin led to superior results during similar levels of endurance exercise: it elevated PPT and reduced the feeling of fatigue and the cortisol levels.
The Baxie loess section, just east of the Tibetan Plateau, contains evidence showing that the Asian monsoon climate experienced an abrupt reversal near the end of the last glacial age. Rapid deposition of dust under cool, dry full-glacial conditions gave way to an interval of soil development and reduced dust influx attributed to a strengthening of the warm, moist summer monsoon. A subsequent abrupt increase in dust deposition, a response to a weakening of the summer monsoon, was later followed by renewed soil formation as summer monsoon circulation again intensified during the early Holocene. By one interpretation, the thin upper loess is a manifestation of the European Younger Dryas oscillation; however, in this case the available 14C ages require either that (1) onset of loess deposition lagged the beginning of the Younger Dryas event in Europe by as much as 2000 calibrated 14C years or (2) all the 14C ages are too young, possibly due to contamination. Alternatively, the late-glacial paleosol, the top of which is synchronous with the abrupt end of the late-glacial δ18O anomaly in the Dye 3 Greenland ice core, records the Younger Dryas event. Such an interpretation is consistent with general circulation model simulations of Younger Dryas climate that show strong seasonality and a strengthened summer monsoon, and with marine cores from the western Pacific Ocean that contain evidence of pronounced cooling of surface waters during Younger Dryas time.
We present the results of an approximately 6 100 deg2 104–196 MHz radio sky survey performed with the Murchison Widefield Array during instrument commissioning between 2012 September and 2012 December: the MWACS. The data were taken as meridian drift scans with two different 32-antenna sub-arrays that were available during the commissioning period. The survey covers approximately 20.5 h < RA < 8.5 h, − 58° < Dec < −14°over three frequency bands centred on 119, 150 and 180 MHz, with image resolutions of 6–3 arcmin. The catalogue has 3 arcmin angular resolution and a typical noise level of 40 mJy beam− 1, with reduced sensitivity near the field boundaries and bright sources. We describe the data reduction strategy, based upon mosaicked snapshots, flux density calibration, and source-finding method. We present a catalogue of flux density and spectral index measurements for 14 110 sources, extracted from the mosaic, 1 247 of which are sub-components of complexes of sources.
This chapter outlines the typical nutritional needs for a pregnant woman, reviews some of the unique issues of administering adequate nutrition for the benefit of the maternal-fetal dyad, and provides an overview of some of the more common clinical situations. Inadequate maternal nutrition may be associated with a low infant birth weight and is significantly correlated with later development of adult diseases such as cardiovascular disease, stroke, obesity and type 2 diabetes mellitus, even when adjusting for lifestyle factors. The initial focus for nutritional supplementation should be to optimize the micronutrients, avoid hypo- or hyperglycemia, and maintain an appropriate fluid balance. As the situation stabilizes, then efforts towards adequate macronutrients and calories can be undertaken, while avoiding refeeding syndrome, avoiding overfeeding, and balancing the iatrogenic complications of aggressive enteral nutrition (EN) or parenteral nutrition (PN) against the risks of underfeeding.
Cabot's tragopan Tragopan caboti is categorized as Vulnerable on the IUCN Red List, listed on Appendix I of CITES and is endemic to China. Habitat loss and fragmentation are believed to be the main causes of decreases in abundance of the species. Wuyishan National Natural Reserve supports a relatively stable population of the tragopan but is bisected by a clay road through the core area. This study used direct observation and radio telemetry to investigate the impact of the road on the species. We found that weather was the most important factor affecting the number of individuals actually seen on the road, and the volume of traffic was the main factor affecting the behaviour of individuals, especially at dusk. The road does not appear to be a barrier for Cabot's tragopan but appropriate management is required to ensure the continued survival of the species at this site.
Inductive learning is proposed as a tool for synthesizing domain knowledge from data generated by a model-based simulator. In order to use an inductive engine to generate decision rules, the pre-classification process becomes more complicated in the presence of multiple competing objectives. Instead of relying on a domain expert to perform this pre-classification task, a clustering algorithm is used to eliminate human biases involved in the selection of a classification function for pre-classification. It is shown that the use of a clustering algorithm for pre-classification not only further automates the process of knowledge by synthesizing, but also improves the quality of the rules generated by the inductive engine.
Complex phase transformation between the hexagonal cylinder (Hex) and double gyroid (G) phases in a polystyrene-block-poly(ethylene oxide) (PS-b-PEO) diblock copolymer was investigated using two-dimensional (2D) synchrotron small-angle X-ray scattering (SAXS), and transmission electron microscope (TEM). The PS-b-PEO sample contained a small population of another bicontinuous cubic phase having an Im3m symmetry. These two bicontinuous cubic phases (G and Im3m) had the same unit cell dimensions. Under a large-amplitude reciprocating shear, the bicontinuous cubic phases transformed into a “single-crystal”-like Hex phase. When annealed at 150 °C for 40 min, the Hex phase partially transformed into well-oriented twinned structures of the G and Im3m phases without significant loss of orientation in 2D SAXS measurements. Epitaxial phase transformation relationships between the Hex/G and Hex/ Im3m phases were identified. The mechanism of the Hex → G transformation was examined by TEM.
We have used synchrotron x-ray diffraction to study the low-T homoepitaxial growth on Ag(001) and Cu(001) surfaces. For both systems, we found that a large, temperature-dependent vacancy concentration is incorporated in films grown below 160K. The vacancy trapping occurs concomitantly with substantial changes in the surface morphology, where a non-monotonic temperature dependence of the mean-square surface roughness has been previously observed. For Cu/Cu(001) we also found that the concentration of vacancies incorporated at 110K evolves, upon heating, according to the vacancy annealing behavior well-known from radiation damage studies of bulk copper and it is consistent with the activation energy for vacancy mobility.
Collaborative engineering design involves various
stakeholders with different perspectives. The design process
is relatively complex and difficult to handle. Various
conflicts always happen among the design tasks and affect
the design team performance. Therefore, to represent the
collaborative design process and capture the evolution
of design perspectives in a structured way, it is critical
to manage the design conflicts and improve the collaborative
design productivity. This article provides a generic collaborative
design process model based on a sociotechnical design framework.
This model has a topological format and adopts process
analysis techniques from Petri Nets. By addressing both
the technical and social aspects of collaborative design
activities, it provides a mechanism to identify the interdependencies
among design tasks and perspectives of different stakeholders.
Based on this design process model, a methodology of detecting
and handling the design conflicts is developed to support
collaborative design coordination.
Turkey ovomucoid third domain (OMTKY3) is a canonical
inhibitor of serine proteinases. Upon complex formation,
the inhibitors fully exposed P1 residue becomes
fully buried in the preformed cavity of the enzyme. All
20 P1 variants of OMTKY3 have been obtained
by recombinant DNA technology and their equilibrium association
constants have been measured with six serine proteinases.
To rationalize the trends observed in this data set, high
resolution crystal structures have been determined for
OMTKY3 P1 variants in complex with the bacterial
serine proteinase, Streptomyces griseus proteinase
B (SGPB). Four high resolution complex structures are being
reported in this paper; the three β-branched variants,
Ile18I, Val18I, and Thr18I, determined to 2.1, 1.6, and
1.7 Å resolution, respectively, and the structure
of the Ser18I variant complex, determined to 1.9 Å
resolution. Models of the Cys18I, Hse18I, and Ape18I variant
complexes are also discussed. The β-branched side chains
are not complementary to the shape of the S1
binding pocket in SGPB, in contrast to that of the wild-type
γ-branched P1 residue for OMTKY3, Leu18I.
χ1 angles of approximately 40° are
imposed on the side chains of Ile18I, Val18I, and Thr18I
within the S1 pocket. Dihedral angles of +60°,
−60°, or 180° are more commonly observed
but 40° is not unfavorable for the β-branched side
chains. Thr18I Oγ1 also forms a hydrogen
bond with Ser195 Oγ in this orientation.
The Ser18I side chain adopts two alternate conformations
within the S1 pocket of SGPB, suggesting that
the side chain is not stable in either conformation.
Androcam is a testis-specific protein of Drosophila
melanogaster, with 67% sequence identity to calmodulin
and four potential EF-hand calcium-binding sites. Spectroscopic
monitoring of the thermal unfolding of recombinant calcium-free
androcam shows a biphasic process characteristic of a two-domain
protein, with the apo-N-domain less stable than the apo-C-domain.
The two EF hands of the C-domain of androcam bind calcium
cooperatively with 40-fold higher average affinity than
the corresponding calmodulin sites. Magnesium competes
with calcium binding [Ka(Mg) ∼3
× 103 M−1]. Weak
calcium binding is also detected at one or more N-domain
sites. Compared to apo-calmodulin, apo-androcam has a smaller
conformational response to calcium and a lower α-helical
content over a range of experimental conditions. Unlike
calmodulin, a tryptic cleavage site in the N-domain of
apo-androcam remains trypsin sensitive in the presence
of calcium, suggesting an altered calcium-dependent conformational
change in this domain. The affinity of model target peptides
for androcam is 103–105 times
lower than for calmodulin, and interaction of the N-domain
of androcam with these peptides is significantly reduced.
Thus, androcam shows calcium-induced conformational responses
typical of a calcium sensor, but its properties indicate
calcium sensitivity and target interactions significantly
different from those of calmodulin. From the sequence differences
and the altered calcium-binding properties it is likely
that androcam differs from calmodulin in the conformation
of residues in the second calcium-binding loop. Molecular
modeling supports the deduction that there are significant
conformational differences in the N-domain of androcam
compared to calmodulin, and that these could affect the
surface, conferring a different specificity on androcam
in target interactions related to testis-specific calcium
Extended retro (reversed) peptide sequences have
not previously been accommodated within functional proteins.
Here, we show that the entire transmembrane portion of
the β-barrel of the pore-forming protein α-hemolysin
can be formed by retrosequences comprising a total of 175
amino acid residues, 25 contributed by the central sequence
of each subunit of the heptameric pore. The properties
of wild-type and retro heptamers in planar bilayers are
similar. The single-channel conductance of the retro pore
is 15% less than that of the wild-type heptamer and its
current-voltage relationship denotes close to ohmic behavior,
while the wild-type pore is weakly rectifying. Both wild-type
and retro pores are very weakly anion selective. These
results and the examination of molecular models suggest
that β-barrels may be especially accepting of retro
sequences compared to other protein folds. Indeed, the
ability to form a retro domain could be diagnostic of a
β-barrel, explaining, for example, the activity of
the retro forms of many membrane-permeabilizing peptides.
By contrast with the wild-type subunits, monomeric retro
subunits undergo premature assembly in the absence of membranes,
most likely because the altered central sequence fails
to interact with the remainder of the subunit, thereby
initiating assembly. Despite this difficulty, a technique
was devised for obtaining heteromeric pores containing
both wild-type and retro subunits. Most probably as a consequence
of unfavorable interstrand side-chain interactions, the
heteromeric pores are less stable than either the wild-type
or retro homoheptamers, as judged by the presence of subconductance
states in single-channel recordings. Knowledge about the
extraordinary plasticity of the transmembrane β-barrel
of α-hemolysin will be very useful in the de novo design
of functional membrane proteins based on the β-barrel
Adhesion at fiber-matrix interface in fiber-reinforced composites plays an important role in controlling the mechanical properties and overall performance of composites. Among the many available tests applicable to the composite interfaces, vibration damping technique has the advantages of being nondestructive as well as highly sensitive. We set up an optical system to measure the damping tangent delta of a cantilever beam, and correlated the damping data in glass-fiber reinforced epoxy-resin composites with transverse tensile strength which is also a qualitative measurement of adhesion at fiber-matrix interface. Four different composite systems containing three different glass-fiber surface treatments were tested and compared. Our experimental results showed an inverse relationship between damping contributed by the interface and composite transverse tensile strength.
We describe an approach using thin films on metals as models to study interfacial interactions. Thin films of biphenyl-tetracarboxylic dianhydride (BPDA) - p-phenylene diamine (PPD) based polyimide on Cr and Au surfaces have been investigated using infrared reflection absorption spectroscopy (IRRAS) and x-ray photoelectron spectroscopy (XPS). IRRAS was used for in-situ monitoring of polymer curing processes. Cured polyimide thin films on metals were characterized ex-situ by both XPS and IRRAS. Anhydride was observed to be an intermediate during chemical transformation of polyamic acid to polyimide. Imidization processes were found to be completed after curing at 250°C for thin films. Strong chemical modification of polyimide thin films resulting from interaction with Cr substrates were observed by infrared spectroscopy. These observations were consistent with angle-resolved XPS data showing a different C 1s emission spectrum of polyimide-Cr interfacial region, compared to the polyimide spectrum.