Structure–activity relationship analysis identified (+)-N-(3-aminopropyl)-N-1-(5-benzyl-3-methyl-4-oxo-1,2thiazolo5,4-dpyrimidin-6-yl)-2-methylpropyl-4-methylbenzamide (AZD4877), from a series of ...novel kinesin spindle protein (KSP) inhibitors, as exhibiting both excellent biochemical potency and pharmaceutical properties suitable for clinical development. The selected compound arrested cells in mitosis leading to the formation of the monopolar spindle phenotype characteristic of KSP inhibition and induction of cellular death. A favorable pharmacokinetic profile and notable in vivo efficacy supported the selection of this compound as a clinical candidate for the treatment of cancer.
Many proteins, sugars and pharmaceuticals crystallize into two forms that are mirror images of each other (enantiomers) like our right and left hands. Tellurium is one enantiomer having a space group ...pair, P3(1)21 (right-handed screw) and P3(2)21 (left-handed screw). X-ray diffraction with dispersion correction terms has been playing an important role in determining the handedness of enantiomers for a long time. However, this approach is not applicable for an elemental crystal such as tellurium or selenium. We have demonstrated that positive and negative circularly polarized x-rays at the resonant energy of tellurium can be used to absolutely distinguish right from left tellurium. This method is applicable to chiral motifs that occur in biomolecules, liquid crystals, ferroelectrics and antiferroelectrics, multiferroics, etc.
Chromosome translocations in the common epithelial cancers are abundant, yet little is known about them. They have been thought to be almost all unbalanced and therefore dismissed as mostly mediating ...tumour suppressor loss. We present a comprehensive analysis by array painting of the chromosome translocations of breast cancer cell lines HCC1806, HCC1187 and ZR-75-30. In array painting, chromosomes are isolated by flow cytometry, amplified and hybridized to DNA microarrays. A total of 200 breakpoints were identified and all were mapped to 1 Mb resolution on bacterial artificial chromosome (BAC) arrays, then 40 selected breakpoints, including all balanced breakpoints, were further mapped on tiling-path BAC arrays or to around 2 kb resolution using oligonucleotide arrays. Many more of the translocations were balanced at 1 Mb resolution than expected, either reciprocal (eight in total) or balanced for at least one participating chromosome (19 paired breakpoints). Second, many of the breakpoints were at genes that are plausible targets of oncogenic translocation, including balanced breaks at CTCF, EP300/p300 and FOXP4. Two gene fusions were demonstrated, TAX1BP1-AHCY and RIF1-PKD1L1. Our results support the idea that chromosome rearrangements may play an important role in common epithelial cancers such as breast cancer.
This article uses two dimensions of Black feminist standpoint epistemology to investigate Black political economy. It suggests that centering on Black women's experiences and analyzing those ...experiences via intersectional paradigms fosters rethinking the significance of family within gender, sexuality, race, class, and nation. The article concludes by identifying how these new views of family might inform gendered analyses of Black political economy.
Unique among known human herpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) encodes chemokine-like proteins (vMIP-I and vMIP-II). vMIP-II was shown to block infection of human ...immunodeficiency virus-type 1 (HIV-1) on a CD4-positive cell line expressing CCR3 and to a lesser extent on one expressing CCR5, whereas both vMIP-I and vMIP-II partially inhibited HIV infection of peripheral blood mononuclear cells. Like eotaxin, vMIP-II activated and chemoattracted human eosinophils by way of CCR3. vMIP-I and vMIP-II, but not cellular MIP-1α or RANTES, were highly angiogenic in the chorioallantoic assay, suggesting a possible pathogenic role in Kaposi's sarcoma.
Resonant diffraction of x-rays by crystals with anisotropic optical properties is investigated theoretically, to assess how the intensity of a Bragg spot is influenced by effects related to ...dispersion (birefringence) and absorption (dichroism). Starting from an exact but opaque expression, simple analytic results are found to expose how intensity depends on dispersion and absorption in the primary and secondary beams and, also, the azimuthal angle (rotation of the crystal about the Bragg wavevector). If not the full story for a given application, our results are more than adequate to explore consequences of dispersion and absorption in the intensity of a Bragg spot. Results are evaluated for antiferromagnetic copper oxide, and low quartz. For CuO, one of our results reproduces all salient features of a previously published simulation of the azimuthal-angle dependence of a magnetic Bragg peak. It is transparent in our analytic result that dispersion and absorption effects alone cannot reproduce published experimental data. Available data for the azimuthal-angle dependence of space-group forbidden reflections (0,0, l), with l ≠ 3n, of low quartz depart from symmetry imposed by the triad axis of rotation symmetry. The observed asymmetry can be induced by dispersion and absorption even though absorption coefficients are constant, independent of the azimuthal angle, in this class of reflections.
The torsional strength of reinforced concrete members that fail by yielding of the reinforcement can be accurately predicted by design codes such as ACI 318-19 and the Canadian design standard CSA ...A23.3:19. However, these codes are relatively poor at predicting the strength of heavily reinforced members that fail by crushing. This paper presents a rational model which can predict the strength of such members. A key feature of the model is that the variation in torsional stresses through the thickness of a member is explicitly considered using stress block factors derived from the stressstrain curve of the concrete. The model predicts the strength of 31 experiments with an average test-to-predicted ratio of 1.20 and a coefficient of variation (COV) of 14.4%. This is significantly better than the maximum torsion limits in ACI 318-19 (mean 1.62, COV 21.0%) and CSA A23.3:19 (mean 0.79, COV 41.1%). Simple equations suitable for design are presented. Keywords: crushing; design; high strength; maximum torsion strength; shear; space truss; torsion.
Cubital tunnel syndrome (CuTS) is the second most common compressive neuropathy of the upper extremity. We aimed to determine a consensus among experts using the Delphi method for clinical criteria ...that could be validated further for the diagnosis of CuTS.
The Delphi method was used for establishing a consensus among a group of expert panelists, comprising 12 hand and upper-extremity surgeons, who ranked the diagnostic clinical importance of 55 items related to CuTS on a scale from 1 (least important) to 10 (most important). The average and SDs of each item were calculated, and Cronbach α was used to assess homogeneity among the panelist-ranked items.
All panelists answered the 55-item questionnaire. A Cronbach α value of 0.963 was obtained on the first iteration. The top criteria that were considered most clinically relevant to the diagnosis of CuTS among the group were determined based on the most highly ranked and correlated items among the expert panelist group. The criteria based on which there was agreement were as follows: (1) paresthesias in ulnar nerve distribution, (2) symptoms precipitated by increased elbow flexion/positive elbow flexion tests, (3) positive Tinel sign at the medial elbow, (4) atrophy/weakness/ late findings (eg, claw hand of the ring/small finger and Wartenberg or Froment sign) of ulnar nerve-innervated muscles of the hand, (5) loss of two-point discrimination in ulnar nerve distribution, and (6) similar symptoms on the involved side after successful treatment on the contralateral side.
Our study demonstrated a consensus among an expert panelist group of hand and upper-extremity surgeons on potential diagnostic criteria for CuTS. This consensus on diagnostic criteria may help clinicians readily diagnose CuTS in a standardized form; however, further weighting and validation are necessary prior to the development of a formal diagnostic scale.
This study is the first step in producing a consensus on how to diagnose CuTS.
Ocean acidification effects on fish hearing Radford, C A; Collins, S P; Munday, P L ...
Proceedings of the Royal Society. B, Biological sciences,
03/2021, Letnik:
288, Številka:
1946
Journal Article
Recenzirano
Odprti dostop
Humans are rapidly changing the marine environment through a multitude of effects, including increased greenhouse gas emissions resulting in warmer and acidified oceans. Elevated CO
conditions can ...cause sensory deficits and altered behaviours in marine organisms, either directly by affecting end organ sensitivity or due to likely alterations in brain chemistry. Previous studies show that auditory-associated behaviours of larval and juvenile fishes can be affected by elevated CO
(1000 µatm). Here, using auditory evoked potentials (AEP) and micro-computer tomography (microCT) we show that raising juvenile snapper,
, under predicted future CO
conditions resulted in significant changes to their hearing ability. Specifically, snapper raised under elevated CO
conditions had a significant decrease in low frequency (less than 200 Hz) hearing sensitivity. MicroCT demonstrated that these elevated CO
snapper had sacculus otolith's that were significantly larger and had fluctuating asymmetry, which likely explains the difference in hearing sensitivity. We suggest that elevated CO
conditions have a dual effect on hearing, directly effecting the sensitivity of the hearing end organs and altering previously described hearing induced behaviours. This is the first time that predicted future CO
conditions have been empirically linked through modification of auditory anatomy to changes in fish hearing ability. Given the widespread and well-documented impact of elevated CO
on fish auditory anatomy, predictions of how fish life-history functions dependent on hearing may respond to climate change may need to be reassessed.
Research on how people learn shows that teaching using active learning is more effective than just lecturing. We outline four concrete ways instructors can begin to apply active learning in their ...teaching: backward instruction design; expecting students to learn more than facts; posing "messy" problems for students to solve; and expecting students to talk, write, and collaborate. Each tactic is supported with references demonstrating its efficacy and advice and links to resources for getting started with active learning.
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