MEC-17, a newly identified alpha-tubulin-N-acetyltransferase 1, serves as the major α-tubulin acetyltransferase to promote α-tubulin acetylation in vitro and in vivo. Alteration of α-tubulin ...acetylation may be involved in morphology regulation, cell migration, and tumour metastasis. However, MEC-17's role in cell physiology and its effect on epithelial-mesenchymal transition (EMT) and cell polarity remain elusive. In the present study, we characterized the overexpressed or downregulated cell models through gene targeting as MEC-17 gain- or loss-of-function. Overexpression of MEC-17 enhanced the cell spreading area, suppressed pseudopods formation in a three-dimensional (3D) culture system, and inhibited cancer cell migratory and invasive ability and tumour metastasis by orthotopic lung cancer animal model. Furthermore, morphological change and migration inhibition of cancer cells were accompanied by EMT repression, Golgi reorientation, and polarity disruption caused by alteration of cdc42 activity via a decrease in Rho-GAP, ARHGAP21. By contrast, a reduction in endogenous MEC-17 accelerated the pseudopods formation and EMT, and facilitated cell migration and invasion. These results demonstrated the crucial role of MEC-17 in the modulation of intrinsic cell morphogenesis, migration, and invasive function through regulation of EMT and cell polarity.
Salvinal is a natural lignan isolated from the roots of
Bunge (Danshen). Previous studies have demonstrated its anti-proliferative activity in both drug-sensitive and -resistant cancer cell lines, ...with IC
values ranging from 4-17 µM. In this study, a series of salvinal derivatives was synthesized and evaluated for the structure-activity relationship. Among the twenty-four salvinal derivatives, six compounds showed better anticancer activity than salvinal. Compound
displayed excellent anticancer activity, with IC
values of 0.13-0.14 µM against KB, KB-Vin10 (overexpress MDR/Pgp), and KB-7D (overexpress MRP) human carcinoma cell lines. Based on our in vitro microtubule depolymerization assay, compound
showed depolymerization activity in a dose-dependent manner. Our findings indicate that compound
is a promising anticancer agent with depolymerization activity that has potential for the management of malignance.
We report a new multidimensional measure of visual complexity (GraphCom) that captures variability in the complexity of graphs within and across writing systems. We applied the measure to 131 written ...languages, allowing comparisons of complexity and providing a basis for empirical testing of GraphCom. The measure includes four dimensions whose value in capturing the different visual properties of graphs had been demonstrated in prior reading research—(1) perimetric complexity, sensitive to the ratio of a written form to its surrounding white space (Pelli, Burns, Farell, & Moore-Page,
2006
); (2) number of disconnected components, sensitive to discontinuity (Gibson,
1969
); (3) number of connected points, sensitive to continuity (Lanthier, Risko, Stolz, & Besner,
2009
); and (4) number of simple features, sensitive to the strokes that compose graphs (Wu, Zhou, & Shu,
1999
). In our analysis of the complexity of 21,550 graphs, we (a) determined the complexity variation across writing systems along each dimension, (b) examined the relationships among complexity patterns within and across writing systems, and (c) compared the dimensions in their abilities to differentiate the graphs from different writing systems, in order to predict human perceptual judgments (
n
= 180) of graphs with varying complexity. The results from the computational and experimental comparisons showed that GraphCom provides a measure of graphic complexity that exceeds previous measures in its empirical validation. The measure can be universally applied across writing systems, providing a research tool for studies of reading and writing.
Polymers with an abundant amorphous domain should facilitate energy dissipation upon stretching, making near amorphous π-conjugated polymers have immense potential in realizing intrinsically ...stretchable field-effect transistor (FET) devices. In this study, high mobility preservation under the stretched state is attempted by replacing typical alkyl-monothienyl (T-R) on a benzo1,2-b:4,5-b’dithiophene-difluorobenzothiadiazole backbone with three other biaxially extended side-chains, including alkyl-dithienyl (2T-R), branching alkyl-trithienyl (3T-R), and alkyl-benzotrithienyl (B3T-R) groups. Despite showing near amorphous features, the semi-2D BDT-based polymers with bulkier biaxially extended side chains (PBDT-2T, PBDT-3T, and PBDT-B3T) still present comparable mobility to the reference semicrystalline polymer (PBDT-T). Although these four polymers yield comparable mobility, they show distinctly different mobility retention in the stretched state. From the study of their mobility-stretchability relationship, the interdigitating and/or entanglement of these biaxially extended conjugated side chains are shown to play a nontrivial role in the resultant mechanical robustness against the stretching force. Owing to the proper spatial mobility and geometry, the branched 3T-R side chain possesses a more intense interdigitating and/or entanglement capability than the linear 2T-R one and the fused B3T-R one, providing better mechanical strength under stretched states. Meanwhile, it maintains sufficient interchain connectivity for intermittent interchain hopping to compensate for the 1D charge transport along the backbone, ensuring good charge transport even in the stretched state. As a result, the printed PBDT-3T film is demonstrated to deliver a high mobility retention of 73% at a 60% strain exerted parallel to the charge-transporting direction and a very stable mobility retention of 88% after 1000 stretching-releasing cycles at a 60% strain, being one of the best stretchable near amorphous conjugated polymers reported thus far. Our result underlines the effectiveness of using biaxially extended conjugated side chains to realize high-performance stretchable polymers.
The ionospheric total electron content (TEC) derived from dense ground‐based Global Navigation Satellite System receivers over the continental United States and those from global ionosphere maps are ...utilized to find the ionosphere response to the August 21, 2017 total solar eclipse. Maximum obscurations and their associated TEC major depressions appear simultaneously at midlatitudes, while major depressions elongate toward the magnetic equator with some delays in the equatorial ionization anomaly (EIA) region. The former is due to the photochemical loss process, while the latter is caused by the plasma transport of E×B drifts and lunar gravitation forces. TECs of predawn reductions, morning enhancements, afternoon reductions, and nighttime enhancements reveal that the semidiurnal lunar tide are essential. Since a solar eclipse always occurs on a new moon day, the lunar tide results in the early EIA appearance and major depressions being underestimated/diminished before and overestimated/enhanced after about 14:00 local time.
Plain Language Summary
Observations during an eclipse offer a special opportunity for studying the Earth's ionospheric response to changes in solar ionizing radiation. Although ionospheric solar eclipse signatures in many events have been studied, we report the lunar tide effect on the signatures for the first time. A total solar eclipse swept across the continental United States (CONUS) from the west to east coast on August 21, 2017. The total electron content (TEC) along seven longitudes of the US continent derived from more than 2,200 ground‐based Global Navigation Satellite System receivers in the CONUS and extracted from global ionosphere maps (GIMs) is employed to study ionospheric solar eclipse signatures. The most prominent solar eclipse signature is major depressions (MDs) in both the CONUS and GIM TECs, when the maximum obscuration occurs. TEC extrema of predawn reductions, morning enhancements, afternoon reductions, and nighttime enhancements reveal that the semidiurnal lunar tide of about 12.42‐h period is prominent. The lunar tide causes the early appearance of equatorial ionization anomalies, which further results in the MDs being weakened in the morning and enhanced in the afternoon on the solar eclipse day. The lunar tide has to be taken into consideration for studying ionospheric solar eclipse effects.
Key Points
The lunar tide results in the early appearance of the equatorial ionization anomaly on solar eclipse days
Total electron contents tend to enhance before and decrease after 14:00 local time (LT) on a solar eclipse day
The lunar tide causes major depressions being weakened before and enhanced after 14:00 LT
Computing-in-memory (CIM) based on SRAM is a promising approach to achieving energy-efficient multiply-and-accumulate (MAC) operations in artificial intelligence (AI) edge devices; however, existing ...SRAM-CIM chips support only DNN inference. The flow of training data requires that CIM arrays perform convolutional computation using transposed weight matrices. This article presents a two-way transpose (TWT) multiply cell with high resistance to process variation and a novel read scheme that uses input-aware zone prediction of maximum partial MAC values to enhance the signal margin for robust readout. A 28-nm 64-kb TWT CIM macro fabricated using foundry-provided compact 6T-SRAM cells achieved <inline-formula> <tex-math notation="LaTeX">T_{\text {AC}} </tex-math></inline-formula> of 3.8-21 ns and energy efficiency of 7-61.1 TOPS/W in performing MAC operations using 2-8-b inputs, 4-8-b weights, and 10-20-b outputs.
Cancer susceptibility germline mutations are associated with pancreatic ductal adenocarcinoma (PDAC). However, the hereditary status of PDAC and its impact on survival is largely unknown in the Asian ...population.
Exome sequencing was performed on 527 blood samples from PDAC individuals and analyzed for mutations in 80 oncogenic genes. Pathogenic and likely pathogenic (P/LP) germline variants were diagnosed according to the ACMG variant classification categories. The association between germline homologous recombination gene mutations (gHR
, including BAP1, BRCA1, BRCA2, PALB2, ATM, BLM, BRIP1, CHEK2, NBN, MUTYH, FANCA and FANCC) and the treatment outcomes was explored in patients with stage III/IV diseases treated with first-line (1L) platinum-based versus platinum-free chemotherapy.
Overall, 104 of 527 (19.7%) patients carried germline P/LP variants. The most common mutated genes were BRCA2 (3.60%), followed by ATR (2.66%) and ATM (1.9%). After a median follow-up duration of 38.3-months (95% confidence interval, 95% CI 35.0-43.7), the median overall survival (OS) was not significantly different among patients with gHR
, non-HR germline mutations, or no mutation (P = 0.43). Among the 320 patients with stage III/IV disease who received 1L combination chemotherapy, 32 (10%) had gHR
. Of them, patients receiving 1L platinum-based chemotherapy exhibited a significantly longer median OS compared to those with platinum-free chemotherapy, 26.1 months (95% CI 12.7-33.7) versus 9.6 months (95% CI 5.9-17.6), P = 0.001. However, the median OS of patients without gHR
was 14.5 months (95% CI 13.2-16.9) and 12.6 months (95% CI 10.8-14.7) for patients receiving 1L platinum-based and platinum-free chemotherapy, respectively (P = 0.22). These results were consistent after adjusting for potential confounding factors including age, tumor stage, performance status, and baseline CA 19.9 in the multivariate Cox regression analysis.
Our study showed that nearly 20% of Taiwanese PDAC patients carried germline P/LP variants. The longer survival observed in gHR
patients treated with 1L platinum-based chemotherapy highlights the importance of germline testing for all patients with advanced PDAC at diagnosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Glutaric aciduria type 1 (GA-1) is a rare disease connected with speech delay and neurological deficits. However, the audiological and otologic profiles of GA-1 have not yet been fully characterized. ...To our knowledge, this is the largest study of comprehensive audiological and otologic evaluation in patients with GA-1 to date.
Thirteen patients diagnosed with GA-1 between January 1994 and December 2019 with audiological, radiological and genetic manifestations were retrospectively analyzed. Hearing tests were performed in all patients. MRI was performed for radiological evaluation.
Hearing loss was found in 76.9% (10/13) of GA-1 patients, including slight hearing loss in 46.1% (6/13) of patients, mild hearing loss in 15.4% (2/13) of patients, and moderate hearing loss in 7.7% (1/13) of patients. Normal hearing thresholds were seen in 23% (3/13) of patients. Patients with intensive care unit (ICU) admission history showed significantly worse hearing than those without (29.17 ± 12.47 vs 13.56 ± 3.93 dB HL, 95% CI 2.92-24.70, p = 0.0176). One patient had moderate sensorineural hearing loss and a past history of acute encephalopathic crisis. No usual causative gene mutations associated with hearing loss were found in these patients. MRI showed a normal vestibulocochlear apparatus and cochlear nerve. One patient with extensive injury of the basal ganglia on MRI after acute encephalopathic crisis was found to have moderate sensorineural hearing loss. Two patients with disability scores above 5 were found to have mild to moderate hearing impairment. No obvious correlation between macrocephaly and hearing loss was found.
A high prevalence of hearing impairment is found in GA-1 patients. Adequate audiological evaluation is essential for these patients, especially for those after encephalopathic crises or with ICU admission history.
Abstract
Clinical trials showed pangenotypic direct-acting antivirals’ (DAAs) excellent efficacy and safety when treating hepatitis C virus (HCV). Two pangenotypic regimens were examined, ...glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir (SOF/VEL), in a real-world Taiwanese setting, including all HCV patients treated with GLE/PIB or SOF/VEL from August 2018 to April 2020. The primary endpoint was sustained virologic response 12 weeks after treatment cessation (SVR12), including adverse events (AEs). A total of 1,356 HCV patients received pangenotypic DAA treatment during the study: 742 and 614 received GLE/PIB and SOF/VEL, respectively. The rates of SVR12 for GLE/PIB and SOF/VEL were 710/718 (98.9%) and 581/584 (99.5%), respectively, by per-protocol analysis, and 710/742 (95.7%) and 581/614 (94.6%), respectively, by evaluable population analysis. Eleven (GLE/PIB: 8, SOF/VEL: 3) did not achieve SVR12. The most common AEs for GLE/PIB and SOF/VEL were pruritus (17.4% vs. 2.9%), abdominal discomfort (5.8% vs. 4.4%), dizziness (4.2% vs. 2%), and malaise (3.1% vs. 2.9%). Laboratory abnormalities were uncommon; only < 1% exhibited elevated total bilirubin or aminotransferase levels with both regimens. Five drug discontinuations occurred due to AEs (bilirubin elevation: 3; dermatological issues: 2). Pangenotypic DAAs GLE/PIB and SOF/VEL are effective and well tolerated, achieving high SVR12 rates for patients with all HCV genotypes.
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