Dichotomous dynamics of magnetic monopole fluids.

A recent advance in the study of emergent magnetic monopoles was the discovery that monopole motion is restricted to dynamical fractal trajectories [J. N. Hallén et al., Science 378, 1218 (2022)], thus explaining the characteristics of magnetic monopole noise spectra [R. Dusad et al., Nature 571, 234 (2019); A. M. Samarakoon et al., Proc. Natl. Acad. Sci. U.S.A. 119, e2117453119 (2022)]. Here, we apply this novel theory to explore the dynamics of field-driven monopole currents, finding them composed of two quite distinct transport processes: initially swift fractal rearrangements of local monopole configurations followed by conventional monopole diffusion. This theory also predicts a characteristic frequency dependence of the dissipative loss angle for AC field-driven currents. To explore these novel perspectives on monopole transport, we introduce simultaneous monopole current control and measurement techniques using SQUID-based monopole current sensors. For the canonical material Dy2Ti2O7, we measure [Formula: see text], the time dependence of magnetic flux threading the sample when a net monopole current [Formula: see text] is generated by applying an external magnetic field [Formula: see text] These experiments find a sharp dichotomy of monopole currents, separated by their distinct relaxation time constants before and after t ~[Formula: see text] from monopole current initiation. Application of sinusoidal magnetic fields [Formula: see text] generates oscillating monopole currents whose loss angle [Formula: see text] exhibits a characteristic transition at frequency [Formula: see text] over the same temperature range. Finally, the magnetic noise power is also dichotomic, diminishing sharply after t ~[Formula: see text]. This complex phenomenology represents an unprecedented form of dynamical heterogeneity generated by the interplay of fractionalization and local spin configurational symmetry.

Single-molecule characterization of target search dynamics of DNA-binding proteins in DNA-condensed droplets.

Target search models of DNA-binding proteins in cells typically consider search mechanisms that include 3D diffusion and 1D sliding, which can be characterized by single-molecule tracking on DNA. However, the finding of liquid droplets of DNA and nuclear components in cells cast doubt on extrapolation from the behavior in ideal non-condensed DNA conditions to those in cells. In this study, we investigate the target search behavior of DNA-binding proteins in reconstituted DNA-condensed droplets using single-molecule fluorescence microscopy. To mimic nuclear condensates, we reconstituted DNA-condensed droplets using dextran and PEG polymers. In the DNA-condensed droplets, we measured the translational movement of four DNA-binding proteins (p53, Nhp6A, Fis and Cas9) and p53 mutants possessing different structures, sizes, and oligomeric states. Our results demonstrate the presence of fast and slow mobility modes in DNA-condensed droplets for the four DNA-binding proteins. The slow mobility mode capability is correlated strongly to the molecular size and the number of DNA-binding domains on DNA-binding proteins, but only moderately to the affinity to single DNA segments in non-condensed conditions. The slow mobility mode in DNA-condensed droplets is interpreted as a multivalent interaction mode of the DNA-binding protein to multiple DNA segments.

Comparison of body composition and muscle mass by age in amateur soccer players.

[Purpose] This study aimed to elucidate the changes in body composition components associated with aging in amateur male soccer players. Specifically, we investigated the alterations in the phase angle and regional muscle mass distribution. [Participants and Methods] The study included a cohort of 163 male participants categorized into three age groups: U15 (12-15 years), U18 (16-18 years), and O19 (≥19 years). Precise body composition assessments were performed, employing the InBodyS10 body composition scale. [Results] The findings revealed substantial age-related disparities in various body composition parameters. Data revealed a consistent trend of increasing basic body composition metrics with age. Notably, the body fat percentage progressively increased with age. Muscle mass and phase angle exhibited age-related increases with nuanced variations in different anatomical regions. [Conclusion] In the general Japanese population, muscle mass tends to decrease with age after 18 years. However, in this study on amateur soccer players, we observed a plateau in the height and lower limb phase angle around the age of 18 years, whereas muscle mass exhibited an increasing trend.

The Chemoreceptor Sensory Adaptation System Produces Coordinated Reversals of the Flagellar Motors on an Escherichia coli Cell.

In isotropic environments, an Escherichia coli cell exhibits coordinated rotational switching of its flagellar motors, produced by fluctuations in the intracellular concentration of phosphorylated CheY (CheY-P) emanating from chemoreceptor signaling arrays. In this study, we show that these CheY-P fluctuations arise through modifications of chemoreceptors by two sensory adaptation enzymes: the methyltransferase CheR and the methylesterase CheB. A cell containing CheR, CheB, and the serine chemoreceptor Tsr exhibited motor synchrony, whereas a cell lacking CheR and CheB or containing enzymatically inactive forms did not. Tsr variants with different combinations of methylation-mimicking Q residues at the adaptation sites also failed to show coordinated motor switching in cells lacking CheR and CheB. Cells containing CheR, CheB, and Tsr [NDND], a variant in which the adaptation site residues are not substrates for CheR or CheB modifications, also lacked motor synchrony. TsrΔNWETF, which lacks a C-terminal pentapeptide-binding site for CheR and CheB, and the ribose-galactose receptor Trg, which natively lacks this motif, failed to produce coordinated motor switching, despite the presence of CheR and CheB. However, addition of the NWETF sequence to Trg enabled Trg-NWETF to produce motor synchrony, as the sole receptor type in cells containing CheR and CheB. Finally, CheBc, the catalytic domain of CheB, supported motor coordination in combination with CheR and Tsr. These results indicate that the coordination of motor switching requires CheR/CheB-mediated changes in receptor modification state. We conclude that the opposing receptor substrate-site preferences of CheR and CheB produce spontaneous blinking of the chemoreceptor array's output activity. IMPORTANCE Under steady-state conditions with no external stimuli, an Escherichia coli cell coordinately switches the rotational direction of its flagellar motors. Here, we demonstrate that the CheR and CheB enzymes of the chemoreceptor sensory adaptation system mediate this coordination. Stochastic fluctuations in receptor adaptation states trigger changes in signal output from the receptor array, and this array blinking generates fluctuations in CheY-P concentration that coordinate directional switching of the flagellar motors. Thus, in the absence of chemoeffector gradients, the sensory adaptation system controls run-tumble swimming of the cell, its optimal foraging strategy.

Oxidative [4 + 2] annulation of 1-naphthols with alkynes accelerated by an electron-deficient rhodium(III) catalysts.

The 1,3-diethoxycarbonyl-2,4,5-trimethylcyclopentadienyl (CpE) rhodium(III) complex displayed high efficacy in the catalytic oxidative annulation of 1-naphthols with internal alkynes under mild conditions. DFT calculations revealed that lower activation energies for the concerted metalation-deprotonation and the reductive elimination steps are the key to improved reactivity.

Spontaneous closure of non-cavernous sinus dural arteriovenous fistulas: A case series and systematic review of the literature.

BACKGROUND AND PURPOSE: To report 9 new cases of non-cavernous sinus dural arteriovenous fistulas (NCS-DAVFs) that closed spontaneously and systematically review reports of other cases in the literature. MATERIAL AND METHODS: We performed a retrospective analysis of 9 cases from 2 institutions of NCS-DAVFs that closed spontaneously. Using PubMed and Scopus in accordance with the PRISMA guidelines, we systematically reviewed English language articles about NCS-DAVFs showing spontaneous closure. RESULTS: Review of the cases from 2 institutions identified 9 cases of NCS-DAVFs showing spontaneous closure in follow-up magnetic resonance angiography (MRA), and the systematic review of the literature yielded an additional 38 cases, which had been diagnosed by repeated arteriography. Collectively, the patients included 23 men and 24 women with a mean age of 54 years. The shunts were located in the transverse-sigmoid sinus in 24 cases (51%), anterior condylar confluence in 11, and other locations in 12. Based on the venous drainage pattern on arteriography, 27 cases (57%) were classified as low-risk NCS-DAVF (without cortical venous reflux) and 17 were classified as high-risk NCS-DAVF (with cortical venous reflux). Shunt closure was observed within 3 months in 17 cases (36%). Extrinsic predisposing factors for shunt closure were detected in 14 cases (30%). These included angiography in 7 cases, sinus recanalization in 4, development of sinus occlusion in 2, and sinus compression by a newly developed hematoma in 1. CONCLUSION: Spontaneous closures of NCS-DAVFs can occur for both high- and low-risk types. One-third of these closures occur within 3 months.

Assessment of Characteristics of Imaging Biomarkers for Quantifying Anterior Cingulate Cortex Changes: A Twin Study of Middle- to Advanced-Aged Populations in East Asia.

Background and Objectives: Our aim was to assess genetic and environmental effects on surface morphological parameters for quantifying anterior cingulate cortex (ACC) changes in middle- to advanced-age East Asians using twin analysis. Materials and Methods: Normal twins over 39 years old comprising 37 monozygotic pairs and 17 dizygotic pairs underwent 3-dimensional (3D) T1-weighted imaging of the brain at 3T. Freesurfer-derived ACC parameters including thickness, standard deviation of thickness (STDthickness), volume, surface area, and sulcal morphological parameters (folding, mean, and Gaussian curvatures) were calculated from 3D T1-weighted volume images. Twin analysis with a model involving phenotype variance components of additive genetic effects (A), common environmental effects (C), and unique environmental effects (E) was performed to assess the magnitude of each genetic and environmental influence on parameters. Results: Most parameters fit best with an AE model. Both thickness (A: left 0.73/right 0.71) and surface area (A: left 0.63/right 0.71) were highly heritable. STDthickness was low to moderately heritable (A: left 0.48/right 0.29). Volume was moderately heritable (A: left 0.37). Folding was low to moderately heritable (A: left 0.44/right 0.28). Mean curvature (A: left 0.37/right 0.65) and Gaussian curvature (A: right 0.79) were moderately to highly heritable. Right volume and left Gaussian curvature fit best with a CE model, indicating a relatively weak contribution of genetic factors to these parameters. Conclusions: When assessing ACC changes in middle- to advanced-age East Asians, one must keep in mind that thickness and surface area appear to be strongly affected by genetic factors, whereas sulcal morphological parameters tend to involve environmental factors.

Visual illusions in Parkinson's disease: an interview survey of symptomatology.

BACKGROUND: Several types of visual illusions can occur in Parkinson's disease (PD). However, the prevalence and types of specific illusions experienced by patients with PD remain unclear. This study aimed to investigate the types of illusions. METHODS: A questionnaire of visual illusions was developed through a literature review in consultation with clinicians and neurologists. Based on the questionnaire, 40 consecutive patients with PD were asked a series of Yes/No questions regarding 20 types of visual illusions since the onset of PD. If participants answered 'Yes', they were then asked to detail their experience(s). RESULTS: In total, 30 patients with PD had experienced visual illusions since disease onset; among them, 25 were still experiencing them at the time of the study. The most commonly observed illusion types were dysmorphopsia, complex visual illusions, metachromatopsia, and diplopia. Other observed illusions included textural illusions, macropsia, micropsia, teleopsia, pelopsia, kinetopsia, akinetopsia, Zeitraffer/Zeitlupen phenomena, tilt illusion, upside-down illusion, and palinopsia. Additionally, aberrant perception of surface orientation (inclination) was reported, which is yet to be reported in association with any disease. Visual illusions had detrimental effects on the patients' daily lives in some cases. CONCLUSIONS: Systematic interviews regarding the incidence and details of visual illusions experienced by patients with PD could offer important information regarding their quality of life.

Improvement of the diagnostic accuracy for intracranial haemorrhage using deep learning-based computer-assisted detection.

PURPOSE: To elucidate the effect of deep learning-based computer-assisted detection (CAD) on the performance of different-level physicians in detecting intracranial haemorrhage using CT. METHODS: A total of 40 head CT datasets (normal, 16; haemorrhagic, 24) were evaluated by 15 physicians (5 board-certificated radiologists, 5 radiology residents, and 5 medical interns). The physicians attended 2 reading sessions without and with CAD. All physicians annotated the haemorrhagic regions with a degree of confidence, and the reading time was recorded in each case. Our CAD system was developed using 433 patients' head CT images (normal, 203; haemorrhagic, 230), and haemorrhage rates were displayed as corresponding probability heat maps using U-Net and a machine learning-based false-positive removal method. Sensitivity, specificity, accuracy, and figure of merit (FOM) were calculated based on the annotations and confidence levels. RESULTS: In patient-based evaluation, the mean accuracy of all physicians significantly increased from 83.7 to 89.7% (p < 0.001) after using CAD. Additionally, accuracies of board-certificated radiologists, radiology residents, and interns were 92.5, 82.5, and 76.0% without CAD and 97.5, 90.5, and 81.0% with CAD, respectively. The mean FOM of all physicians increased from 0.78 to 0.82 (p = 0.004) after using CAD. The reading time was significantly lower when CAD (43 s) was used than when it was not (68 s, p < 0.001) for all physicians. CONCLUSION: The CAD system developed using deep learning significantly improved the diagnostic performance and reduced the reading time among all physicians in detecting intracranial haemorrhage.

Silent susceptibility-weighted angiography to detect hemorrhagic lesions in the brain: a clinical and phantom study.

PURPOSE: To compare the effectiveness of silent susceptibility-weighted angiography (sSWAN), a new imaging technique with lower acoustic noise, with conventional susceptibility-weighted angiography (cSWAN) in the detection of intracranial hemorrhagic lesions. METHODS: We measured the acoustic and background noise during sSWAN and cSWAN imaging and calculated the contrast-to-noise ratio (CNR) of the phantom consisting of eight chambers with different concentrations of superparamagnetic iron oxide. In the clinical study, we calculated the CNRs of hemorrhagic lesions in 15 patients and evaluated the images for conspicuity and artifact on each sequence and scored them on a 4-point scale. We also evaluated whether hypointense areas observed on sSWAN or cSWAN increased in size from those on T2*-weighted imaging (T2*-WI). RESULTS: Acoustic noise for sSWAN (57.9 ± 0.32 dB [background noise 51.3 dB]) was significantly less than that for cSWAN (89.0 ± 0.22 dB [background noise 50.9 dB]). The CNRs of phantoms for sSWAN were slightly but not significantly lower than those for cSWAN (P = 0.18). The CNRs of hemorrhagic lesions did not show significant differences between sSWAN and cSWAN (P = 0.17). There were no significant differences between sSWAN and cSWAN with respect to the scores for conspicuity, artifact, and change in size of hypointense areas from T2*-WI. CONCLUSION: sSWAN is equivalent to cSWAN with respect to the image quality for the detection of hemorrhagic lesions but has lower acoustic noise.

Light-Wavelength-Based Quantitative Control of Dihydrofolate Reductase Activity by Using a Photochromic Isostere of an Inhibitor.

Photopharmacology has attracted research attention as a new tool for achieving optical control of biomolecules, following the methods of caged compounds and optogenetics. We have developed an efficient photopharmacological inhibitor-azoMTX-for Escherichia coli dihydrofolate reductase (eDHFR) by replacing some atoms of the original ligand, methotrexate, to achieve photoisomerization properties. This fine molecular design enabled quick structural conversion between the active "bent" Z isomer of azoMTX and the inactive "extended" E isomer, and this property afforded quantitative control over the enzyme activity, depending on the wavelength of irradiating light applied. Real-time photoreversible control over enzyme activity was also achieved.

Quantifying the Severity of Parkinson Disease by Use of Dopaminergic Neuroimaging.

OBJECTIVE. Parkinson disease is characterized by dopaminergic neuron loss in the substantia nigra pars compacta resulting in presynaptic nigrostriatal dopamine dysfunction. The purpose of this study was to search for an optimal image biomarker to quantify the severity of Parkinson disease by comparing neuromelanin MRI and dopamine transporter SPECT. SUBJECTS AND METHODS. Forty patients with Parkinson disease (Hoehn and Yahr [HY] stage 1, four patients; stage 2, 18 patients; stage 3, eight patients; stage 4, six patients; stage 5, four patients) who underwent neuromelanin MRI and dopamine transporter SPECT were included. The signal-to-noise ratio (SNR) in the substantia nigra pars compacta on neuromelanin MR images and the striatal specific binding ratio (SBR) on dopamine transporter SPECT images were calculated on the basis of the value of each background region. The Mann-Whitney U test was used to test the significance of difference between the early-stage group (HY stages 1 and 2) and the advanced-stage group (HY stages 3-5) for each SNR and SBR. ROC analysis was used to compare intergroup discriminating performance. The correlation of each SNR and SBR with clinical rating scale was assessed. RESULTS. Both SNR and SBR were significantly greater in the early-stage group than in the advanced-stage group (p < 0.05). The ROC AUCs for differentiating the two groups were 0.73 for SNR and 0.89 for SBR. The coefficients of correlation were -0.47 for SNR versus HY stage and -0.67 for SBR versus HY stage. CONCLUSION. Dopaminergic neuroimaging, particularly dopamine transporter SPECT, is a potentially useful imaging biomarker of the severity of Parkinson disease.

The Dendrites of CA2 and CA1 Pyramidal Neurons Differentially Regulate Information Flow in the Cortico-Hippocampal Circuit.

The impact of a given neuronal pathway depends on the number of synapses it makes with its postsynaptic target, the strength of each individual synapse, and the integrative properties of the postsynaptic dendrites. Here we explore the cellular and synaptic mechanisms responsible for the differential excitatory drive from the entorhinal cortical pathway onto mouse CA2 compared with CA1 pyramidal neurons (PNs). Although both types of neurons receive direct input from entorhinal cortex onto their distal dendrites, these inputs produce a 5- to 6-fold larger EPSP at the soma of CA2 compared with CA1 PNs, which is sufficient to drive action potential output from CA2 but not CA1. Experimental and computational approaches reveal that dendritic propagation is more efficient in CA2 than CA1 as a result of differences in dendritic morphology and dendritic expression of the hyperpolarization-activated cation current (Ih). Furthermore, there are three times as many cortical inputs onto CA2 compared with CA1 PN distal dendrites. Using a computational model, we demonstrate that the differences in dendritic properties of CA2 compared with CA1 PNs are necessary to enable the CA2 PNs to generate their characteristically large EPSPs in response to their cortical inputs; in contrast, CA1 dendritic properties limit the size of the EPSPs they generate, even to a similar number of cortical inputs. Thus, the matching of dendritic integrative properties with the density of innervation is crucial for the differential processing of information from the direct cortical inputs by CA2 compared with CA1 PNs.SIGNIFICANCE STATEMENT Recent discoveries have shown that the long-neglected hippocampal CA2 region has distinct synaptic properties and plays a prominent role in social memory and schizophrenia. This study addresses the puzzling finding that the direct entorhinal cortical inputs to hippocampus, which target the very distal pyramidal neuron dendrites, provide an unusually strong excitatory drive at the soma of CA2 pyramidal neurons, with EPSPs that are 5-6 times larger than those in CA1 pyramidal neurons. We here elucidate synaptic and dendritic mechanisms that account quantitatively for the marked difference in EPSP size. Our findings further demonstrate the general importance of fine-tuning the integrative properties of neuronal dendrites to their density of synaptic innervation.

Comparative study of pulsed-continuous arterial spin labeling and dynamic susceptibility contrast imaging by histogram analysis in evaluation of glial tumors.

PURPOSE: Arterial spin labeling (ASL) is a non-invasive perfusion technique that may be an alternative to dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) for assessment of brain tumors. To our knowledge, there have been no reports on histogram analysis of ASL. The purpose of this study was to determine whether ASL is comparable with DSC-MRI in terms of differentiating high-grade and low-grade gliomas by evaluating the histogram analysis of cerebral blood flow (CBF) in the entire tumor. METHODS: Thirty-four patients with pathologically proven glioma underwent ASL and DSC-MRI. High-signal areas on contrast-enhanced T1-weighted images or high-intensity areas on fluid-attenuated inversion recovery images were designated as the volumes of interest (VOIs). ASL-CBF, DSC-CBF, and DSC-cerebral blood volume maps were constructed and co-registered to the VOI. Perfusion histogram analyses of the whole VOI and statistical analyses were performed to compare the ASL and DSC images. RESULTS: There was no significant difference in the mean values for any of the histogram metrics in both of the low-grade gliomas (n = 15) and the high-grade gliomas (n = 19). Strong correlations were seen in the 75th percentile, mean, median, and standard deviation values between the ASL and DSC images. The area under the curve values tended to be greater for the DSC images than for the ASL images. CONCLUSIONS: DSC-MRI is superior to ASL for distinguishing high-grade from low-grade glioma. ASL could be an alternative evaluation method when DSC-MRI cannot be used, e.g., in patients with renal failure, those in whom repeated examination is required, and in children.

Usefulness of perfusion- and diffusion-weighted imaging to differentiate between pilocytic astrocytomas and high-grade gliomas: a multicenter study in Japan.

PURPOSE: Imaging findings of pilocytic astrocytoma (PA) vary widely, sometimes resembling those of high-grade glioma (HGG). This study aimed to identify the imaging parameters that can be used to differentiate PA from HGG. METHODS: Altogether, 60 patients with PAs and 138 patients with HGGs were included in the study. Tumor properties and the presence of hydrocephalus, peritumoral edema, and dissemination were evaluated. We also measured the maximum relative cerebral blood flow (rCBFmax) and volume (rCBVmax) and determined the minimum apparent diffusion coefficient (ADCmin) in the tumor's solid components. The relative T1 (rT1), T2 (rT2), and contrast-enhanced T1 (rCE-T1) intensity values were evaluated. Parameters were compared between PAs and HGGs using the Mann-Whitney U test. Receiver operating characteristic (ROC) curve analysis was also used to evaluate these imaging parameters. A value of P < .05 was considered to indicate significance. RESULTS: Intratumoral hemorrhage and calcification were observed in 10.0% and 21.7% of PAs, respectively. The rCBFmax and rCBVmax values were significantly lower in PAs (0.50 ± 0.35, 1.82 ± 1.21) than those in HGGs (2.98 ± 1.80, 9.54 ± 6.88) (P < .0001, P = .0002, respectively). The ADCmin values were significantly higher in PAs (1.36 ± 0.56 × 10-3 mm2/s) than those in HGGs (0.86 ± 0.37 × 10-3 mm2/s) (P < .0001). ROC analysis showed that the best diagnostic performance was achieved with rCBFmax. CONCLUSION: The rCBFmax, rCBVmax, and ADCmin can differentiate PAs from HGGs.

Quantitative Comparison of Virtual Monochromatic Images of Dual Energy Computed Tomography Systems: Beam Hardening Artifact Correction and Variance in Computed Tomography Numbers: A Phantom Study.

OBJECTIVE: The aim of this study was to quantitatively compare the reduction in beam hardening artifact (BHA) and variance in computed tomography (CT) numbers of virtual monochromatic energy (VME) images obtained with 3 dual-energy computed tomography (DECT) systems at a given radiation dose. METHODS: Five different iodine concentrations were scanned using dual-energy and single-energy (120 kVp) modes. The BHA and CT number variance were evaluated. RESULTS: For higher iodine concentrations, 40 and 80 mgI/mL, BHA on VME imaging was significantly decreased when the energy was higher than 50 keV (P = 0.003) and 60 keV (P < 0.001) for GE, higher than 80 keV (P < 0.001) and 70 keV (P = 0.002) for Siemens, and higher than 40 keV (P < 0.001) and 60 keV (P < 0.001) for Toshiba, compared with single-energy CT imaging. CONCLUSIONS: Virtual monochromatic energy imaging can decrease BHA and improve CT number accuracy in different dual-energy computed tomography systems, depending on energy levels and iodine concentrations.

One-Dimensional Search Dynamics of Tumor Suppressor p53 Regulated by a Disordered C-Terminal Domain.

Tumor suppressor p53 slides along DNA and finds its target sequence in drastically different and changing cellular conditions. To elucidate how p53 maintains efficient target search at different concentrations of divalent cations such as Ca2+ and Mg2+, we prepared two mutants of p53, each possessing one of its two DNA-binding domains, the CoreTet mutant having the structured core domain plus the tetramerization (Tet) domain, and the TetCT mutant having Tet plus the disordered C-terminal domain. We investigated their equilibrium and kinetic dissociation from DNA and search dynamics along DNA at various [Mg2+]. Although binding of CoreTet to DNA becomes markedly weaker at higher [Mg2+], binding of TetCT depends slightly on [Mg2+]. Single-molecule fluorescence measurements revealed that the one-dimensional diffusion of CoreTet along DNA consists of fast and slow search modes, the ratio of which depends strongly on [Mg2+]. In contrast, diffusion of TetCT consisted of only the fast mode. The disordered C-terminal domain can associate with DNA irrespective of [Mg2+], and can maintain an equilibrium balance of the two search modes and the p53 search distance. These results suggest that p53 modulates the quaternary structure of the complex between p53 and DNA under different [Mg2+] and that it maintains the target search along DNA.

The Disordered Linker in p53 Participates in Nonspecific Binding to and One-Dimensional Sliding along DNA Revealed by Single-Molecule Fluorescence Measurements.

The tumor suppressor p53 is a multidomain transcription factor that can quickly bind to its target DNA by sliding along the DNA strand. We hypothesized that the intrinsically disordered and positively charged linker of p53 regulates its search dynamics first by directly interacting with DNA and second by modulating hopping of the core domain. To test the two hypotheses, we prepared five variants of p53 in which the length and charge of the linker were modulated. The affinity for and sliding along nonspecific DNA of p53 were altered by the charge of the linker, but not by the linker length. In particular, charge neutralization significantly reduced the affinity, suggesting that the linker directly contacts the DNA. Charge neutralization eliminated the slow mode of sliding, in which the core domain was assumed to contact nonspecific DNA. In contrast, the affinity of p53 for the target DNA was not affected by linker mutations. These results demonstrate that the linker participates in a target search of p53 by contacting nonspecific DNA and recruiting the core domain to contact DNA.

Vessel-Masked Perfusion Magnetic Resonance Imaging With Histogram Analysis Improves Diagnostic Accuracy for the Grading of Glioma.

OBJECTIVE: Dynamic susceptibility contrast magnetic resonance imaging is widely used to assess glioma grade; histogram analyses are used for precise tumor perfusion evaluations. We evaluated the effect of vessel contamination in normalized cerebral blood volume (nCBV) to differentiate high- and low-grade gliomas. METHODS: Thirty-four patients with gliomas underwent dynamic susceptibility contrast magnetic resonance imaging. Both traditional and vessel-masked nCBV maps were constructed. Histogram analyses of whole tumors and statistical comparisons were performed to compare traditional and vessel-masked images. RESULTS: Mean values of all the histogram metrics were lower in vessel-masked images than in traditional images. Receiver operating characteristic curve analyses for every histogram metric showed a higher area under the curve for vessel-masked images than for traditional images. The integrated discrimination improvement showed that the vessel-masked images were superior to the traditional images significantly for predicting the glioma grading. CONCLUSIONS: Vessel-masked nCBV maps can prevent overestimations of CBV measurements and can improve diagnostic accuracy for glioma grading.

Single-cell E. coli response to an instantaneously applied chemotactic signal.

In response to an attractant or repellant, an Escherichia coli cell controls the rotational direction of its flagellar motor by a chemotaxis system. When an E. coli cell senses an attractant, a reduction in the intracellular concentration of a chemotaxis protein, phosphorylated CheY (CheY-P), induces counterclockwise (CCW) rotation of the flagellar motor, and this cellular response is thought to occur in several hundred milliseconds. Here, to measure the signaling process occurring inside a single E. coli cell, including the recognition of an attractant by a receptor cluster, the inactivation of histidine kinase CheA, and the diffusion of CheY and CheY-P molecules, we applied a serine stimulus by instantaneous photorelease from a caged compound and examined the cellular response at a temporal resolution of several hundred microseconds. We quantified the clockwise (CW) and CCW durations immediately after the photorelease of serine as the response time and the duration of the response, respectively. The results showed that the response time depended on the distance between the receptor and motor, indicating that the decreased CheY-P concentration induced by serine propagates through the cytoplasm from the receptor-kinase cluster toward the motor with a timing that is explained by the diffusion of CheY and CheY-P molecules. The response time included 240 ms for enzymatic reactions in addition to the time required for diffusion of the signaling molecule. The measured response time and duration of the response also revealed that the E. coli cell senses a similar serine concentration regardless of whether the serine concentration is increasing or decreasing. These detailed quantitative findings increase our understanding of the signal transduction process that occurs inside cells during bacterial chemotaxis.