An established conceptualization of visual cortical function is one in which ventral regions mediate object perception while dorsal regions support spatial information processing and visually guided ...action. This division has been contested by evidence showing that dorsal regions are also engaged in the representation of object shape, even when actions are not required. The critical question is whether these dorsal, object-based representations are dissociable from ventral representations, and whether they play a functional role in object recognition. We examined the neural and behavioral profile of patients with impairments in object recognition following ventral cortex damage. In a functional magnetic resonanace imaging experiment, the blood oxygen level-dependent response in the ventral, but not dorsal, cortex of the patients evinced less sensitivity to object 3D structure compared with that of healthy controls. Consistently, in psychophysics experiments, the patients exhibited significant impairments in object perception, but still revealed residual sensitivity to object-based structural information. Together, these findings suggest that, although in the intact system there is considerable crosstalk between dorsal and ventral cortices, object representations in dorsal cortex can be computed independently from those in ventral cortex. While dorsal representations alone are unable to support normal object perception, they can, nevertheless, support a coarse description of object structural information.
Magnetically driven implosions are susceptible to magnetohydrodynamic instabilities, including the magneto-Rayleigh-Taylor instability (MRTI). To reduce MRTI growth in solid-metal liner implosions, ...the use of a dynamic screw pinch (DSP) has been proposed P. F. Schmit et al., Phys. Rev. Lett. 117, 205001 (2016). In a DSP configuration, a helical return-current structure surrounds the liner, resulting in a helical magnetic field that drives the implosion. Here, we present the first experimental tests of a solid-metal liner implosion driven by a DSP. Using the 1-MA, 100–200-ns COBRA pulsed-power driver, we tested three DSP cases (with peak axial magnetic fields of 2 T, 14 T, and 20 T) and a standard z -pinch (SZP) case (with a straight return-current structure and thus zero axial field). The liners had an initial radius of 3.2 mm and were made from 650-nm-thick aluminum foil. Images collected during the experiments reveal that helical MRTI modes developed in the DSP cases, while nonhelical (azimuthally symmetric) MRTI modes developed in the SZP case. Additionally, the MRTI amplitudes for the 14-T and 20-T DSP cases were smaller than in the SZP case. Specifically, when the liner had imploded to half of its initial radius, the MRTI amplitudes for the SZP case and for the 14-T and 20-T DSP cases were, respectively, 1.1 ± 0.3 mm , 0.7 ± 0.2 mm , and 0.3 ± 0.1 mm . Relative to the SZP, the stabilization obtained using the DSP agrees reasonably well with theoretical estimates.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM
ATR-101 is a novel, oral drug candidate currently in development for the treatment of adrenocortical cancer. ATR-101 is a selective and potent inhibitor of acyl-coenzyme A:cholesterol ...O-acyltransferase 1 (ACAT1), an enzyme located in the endoplasmic reticulum (ER) membrane that catalyzes esterification of intracellular free cholesterol (FC). We aimed to identify mechanisms by which ATR-101 induces adrenocortical cell death. In H295R human adrenocortical carcinoma cells, ATR-101 decreases the formation of cholesteryl esters and increases FC levels, demonstrating potent inhibition of ACAT1 activity. Caspase-3/7 levels and terminal deoxynucleotidyl transferase 2′-deoxyuridine 5′-triphosphate nick end labeled-positive cells are increased by ATR-101 treatment, indicating activation of apoptosis. Exogenous cholesterol markedly potentiates the activity of ATR-101, suggesting that excess FC that cannot be adequately esterified increases caspase-3/7 activation and subsequent cell death. Inhibition of calcium release from the ER or the subsequent uptake of calcium by mitochondria reverses apoptosis induced by ATR-101. ATR-101 also activates multiple components of the unfolded protein response, an indicator of ER stress. Targeted knockdown of ACAT1 in an adrenocortical cell line mimicked the effects of ATR-101, suggesting that ACAT1 mediates the cytotoxic effects of ATR-101. Finally, in vivo treatment of dogs with ATR-101 decreased adrenocortical steroid production and induced cellular apoptosis that was restricted to the adrenal cortex. Together, these studies demonstrate that inhibition of ACAT1 by ATR-101 increases FC, resulting in dysregulation of ER calcium stores that result in ER stress, the unfolded protein response, and ultimately apoptosis.
We use 20 years of continuous magnetic field measurements from the Ørsted, CHAMP and
Swarm
satellite missions, supplemented by calibrated platform magnetometer data from the CryoSat-2 satellite, to ...study time variations of the Earth’s core field at satellite altitude and at the core–mantle boundary (CMB). From the satellite data we derive composite time series of the core field secular variation (SV) with 4-month cadence, at 300 globally distributed Geomagnetic Virtual Observatories (GVO). A previous gap in the GVO series between 2010 and 2014 is successfully filled using CryoSat-2, and sub-decadal variations are identified during this period. Tests showed that similar sub-decadal SV patterns were obtained from the CryoSat-2 data regardless of whether IGRF-13 or CHAOS-6x9 was used in their calibration. Cryosat-2 radial field SV series at non-polar latitudes have a mean standard deviation level compared to smoothing spline fits of 3.5 nT/yr compared to 1.8 nT/yr for CHAMP and 0.9 nT/yr for
Swarm
. GVO radial SV series display regional fluctuations with 5–10 years duration and amplitudes reaching 20 nT/yr, most notably at low latitudes over Indonesia (2014), over South America and the South Atlantic (2007, 2011 and 2014), and over the central Pacific (2017). Applying the Subtractive Optimally Localized Averages (SOLA) method, we also map the radial SV at the CMB as a collection of locally averaged SV estimates. We demonstrate that using 2-year windows of CryoSat-2 data, it is possible to reliably estimate the SV and its time derivative, the secular acceleration (SA), at the CMB, with a spatial resolution, corresponding to spherical harmonic degree 10. Along the CMB geographic equator, we find strong SA features with amplitude
±
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under Indonesia from 2011–2014, under central America from 2015 to 2019, and sequences of SA with alternating sign under the Atlantic during 2004–2019. We find that platform magnetometer data from CryoSat-2 make a valuable contribution to the emerging picture of sub-decadal core field variations. Using 1-year windows of data from the
Swarm
satellites, we show that it is possible to study SA changes at low latitudes on timescales down to 1 year, with spatial resolution corresponding to spherical harmonic degree 10. We find strong positive and negative SA features appearing side-by-side in the Pacific in 2017, and thereafter drift westward.
Adrenocortical carcinoma (ACC) is an endocrine malignancy with a poor prognosis. The association of adult-onset ACC with inherited cancer predisposition syndromes is poorly understood. Our study ...sought to define the prevalence of Lynch syndrome (LS) among patients with ACC.
One hundred fourteen patients with ACC were evaluated in a specialized endocrine oncology clinic and were prospectively offered genetic counseling and clinical genetics risk assessment (group 1). In addition, families with known mismatch repair (MMR) gene mutations that were recorded in the University of Michigan Cancer Genetics Registry were retrospectively reviewed for the presence of ACC (group 2). ACC tumors from patients with LS were tested for microsatellite instability and immunohistochemistry (IHC) to evaluate for MMR deficiency.
Ninety-four (82.5%) of 114 patients with ACC underwent genetic counseling (group 1). Three individuals (3.2%) had family histories suggestive of LS. All three families were found to have MMR gene mutations. Retrospective review of an additional 135 MMR gene-positive probands identified two with ACC (group 2). Four ACC tumors were available (group 1, 3; group 2, 1). All four tumors were microsatellite stable; three had IHC staining patterns consistent with germline mutation status.
The prevalence of LS among patients with ACC is 3.2%, which is comparable to the prevalence of LS in colorectal and endometrial cancer. Patients with ACC and a personal or family history of LS tumors should be strongly considered for genetic risk assessment. IHC screening of all ACC tumors may be an effective strategy for identifying patients with LS.
Curli are functional extracellular amyloid fibers produced by uropathogenic Escherichia coli (UPEC) and other Enterobacteriaceae. Ring-fused 2-pyridones, such as FN075 and BibC6, inhibited curli ...biogenesis in UPEC and prevented the in vitro polymerization of the major curli subunit protein CsgA. The curlicides FN075 and BibC6 share a common chemical lineage with other ring-fused 2-pyridones termed pilicides. Pilicides inhibit the assembly of type 1 pili, which are required for pathogenesis during urinary tract infection. Notably, the curlicides retained pilicide activities and inhibited both curli-dependent and type 1-dependent biofilms. Furthermore, pretreatment of UPEC with FN075 significantly attenuated virulence in a mouse model of urinary tract infection. Curli and type 1 pili exhibited exclusive and independent roles in promoting UPEC biofilms, and curli provided a fitness advantage in vivo. Thus, the ability of FN075 to block the biogenesis of both curli and type 1 pili endows unique anti-biofilm and anti-virulence activities on these compounds.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background Controversy surrounds the use of laparoscopy for resection of adrenocortical carcinoma. We evaluated the hypothesis that outcome is equivalent in patients undergoing laparoscopic ...adrenalectomy versus open adrenalectomy. Methods This is a retrospective review of 217 patients (156 patients with stage I–III cancer) with adrenocortical carcinoma referred to a single institution between 2005 and 2011. Outcome and operative data were assessed for the subset undergoing resection with curative intent. Student t and Fisher exact tests and the Kaplan–Meier method were used to compare data ( P ≤ .05 was considered statistically significant). Results One hundred fifty-six patients (64% female; median age, 47 years range, 18–80; median follow-up, 26.5 months range, 1–188) were identified. Forty-six patients underwent laparoscopic adrenalectomy, and 110 underwent open adrenalectomy. Twenty-seven percent of laparoscopic adrenalectomy patients had stage III cancer. After laparoscopic adrenalectomy, 30% had positive margins or intraoperative tumor spill compared to 16% of the open adrenalectomy patients ( P = .04). Overall survival for patients with stage II cancer was longer in those undergoing open adrenalectomy ( P = .002). Time to visible tumor bed recurrence or peritoneal recurrence in stage II patients was shorter in laparoscopic adrenalectomy patients ( P = .002). Conclusion Open adrenalectomy is superior to laparoscopic adrenalectomy for adrenocortical carcinoma based on completeness of resection, site and timing of initial tumor recurrence, and survival in stage II patients. Intraoperative evaluation is insensitive for the detection of stage III tumors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
BACKGROUND AND PURPOSE—In patients identified at referring facilities with acute ischemic stroke caused by a large vessel occlusion, bypassing the emergency department (ED) with direct transport to ...the neuroangiography suite may safely shorten reperfusion times.
METHODS—We conducted a single-center retrospective review of consecutive patients transferred to our facility for consideration of endovascular therapy. Patients were identified as admitted directly to the neuroangiography suite (DAN), transferred to the ED before intra-arterial therapy (ED-IA), and transferred to the ED but did not receive IA therapy (ED-IV).
RESULTS—A retrospective review of a prospectively maintained database of transfer patients between January 2013 and October 2016 with large vessel occlusions identified 108 ED-IV patients and 261 patients who underwent mechanical thrombectomy (DAN=111 patients and ED-IA=150 patients). There were no differences in baseline characteristics among the 3 groups. The median computed tomography ASPECTS (Alberta Stroke Program Early CT Score) was lower in the ED-IV group versus the ED-IA and DAN groups (8 versus 9; P=0.001). In the DAN versus ED-IA cohort, there were comparable rates of TICI2b/3 recanalization and access to recanalization time. There was significantly faster hospital arrival to groin access time in the DAN cohort (81 minutes versus 22 minutes; P=0.001). Functional independence at 90 days was comparable in the DAN versus ED-IA cohorts but worse in the ED-IV group (43% versus 44% versus 22%; P=0.001).
CONCLUSIONS—DAN is safe, feasible, and associated with faster times of hospital arrival to recanalization. The clinical benefit of this approach should be assessed in a prospective randomized trial.
To ascertain risk factors for the development of overweight in children at 9.5 years of age.
This was a prospective study of 150 children from birth to 9.5 years of age, with assessment of multiple ...hypothesized risk factors drawn from research reports.
Five independent risk factors for childhood overweight were found. The strongest was parent overweight, which was mediated by child temperament. The remaining risk factors were low parent concerns about their child's thinness, persistent child tantrums over food, and less sleep time in childhood. Possible mechanisms by which each of these factors influence weight gain are outlined. Two different pathways to childhood overweight/obesity were found, depending on degree of parental overweight.
There is evidence of considerable interaction between parent and child characteristics in the development of overweight. Several of the identified risk factors are amenable to intervention possibly leading to the development of early prevention programs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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