Search

Simple Summary: Addressing RB1-deficient cancers poses substantial challenges. Dysfunctional or deleted RB1 can enhance the proliferation and spread of different cancer types. Scientists strive to grasp the intricate role of RB1 in regulating various biological processes and molecular pathways to devise innovative therapeutic strategies tailored to RB1-deficient cancers. Recent advancements have revealed encouraging tactics for combating these malignancies, heralding a path toward more precise and efficacious treatments. This review underscores the pivotal role of RB1 in cancer research and highlights its potential as a focal point for personalized therapies. The retinoblastoma (RB) transcriptional corepressor 1 (RB1) is a critical tumor suppressor gene, governing diverse cellular processes implicated in cancer biology. Dysregulation or deletion in RB1 contributes to the development and progression of various cancers, making it a prime target for therapeutic intervention. RB1′s canonical function in cell cycle control and DNA repair mechanisms underscores its significance in restraining aberrant cell growth and maintaining genomic stability. Understanding the complex interplay between RB1 and cellular pathways is beneficial to fully elucidate its tumor-suppressive role across different cancer types and for therapeutic development. As a result, investigating vulnerabilities arising from RB1 deletion-associated mechanisms offers promising avenues for targeted therapy. Recently, several findings highlighted multiple methods as a promising strategy for combating tumor growth driven by RB1 loss, offering potential clinical benefits in various cancer types. This review summarizes the multifaceted role of RB1 in cancer biology and its implications for targeted therapy. [ABSTRACT FROM AUTHOR]

Waterfall plots have gained popularity as a visualization tool to present antitumor activity of treatments in oncology, especially for phase I and II trials. The typical waterfall plot in oncology is a bar plot with each bar representing the best percent tumor size reduction from baseline for a patient sorted in descending order along the x -axis. As new therapies are routinely developed in combination with standard of care or other investigational treatments, waterfall plot comparison between combination therapy and monotherapy may facilitate development decisions in addition to overall response rate or duration of response. However, waterfall plots are often assessed heuristically in practice with lack of statistical rigor. In this work, we examine the correspondence between the waterfall plot and the empirical cumulative distribution function. We demonstrate how to derive key summary statistics directly from the waterfall plot. Using real examples from published waterfall plots, we show how comparisons of waterfall plots can elucidate clinically meaningful information, such as treatment effect patterns in progression-free survival and overall survival. Statistical interpretation and comparison of waterfall plots [ABSTRACT FROM AUTHOR]

(1) Background: Analysis of tumor DNA by next-generation sequencing (NGS) plays various roles in the classification and management of cancer. This study aimed to assess the performance of two similar and large, comprehensive gene panels with a focus on clinically relevant variant detection and tumor mutation burden (TMB) assessment; (2) Methods: DNA from 19 diagnostic small cell lung cancer biopsies and an AcroMetrix™ assessment sample with >500 mutations were sequenced using Oncomine™ Comprehensive Assay Plus (OCAP) on the Ion Torrent platform and TruSight Oncology 500 Assay (TSO500) on the Illumina platform; (3) Results: OCAP and TSO500 achieved comparable NGS quality, such as mean read coverage and mean coverage uniformity. A total of 100% of the variants in the diagnostic samples and 80% of the variants in the AcroMetrix™ assessment sample were detected by both panels, and the panels reported highly similar variant allele frequency. A proportion of 14/19 (74%) samples were classified in the same TMB category; (4) Conclusions: Comparable results were obtained using OCAP and TSO500, suggesting that both panels could be applied to screen patients for enrolment in personalized cancer treatment trials. [ABSTRACT FROM AUTHOR]

This article presents a radio frequency (RF) rectifier with a wide incident angle of incoming waves, based on a rat-race coupler (RRC). Two identical sub-rectifiers replace the two load circuits of the conventional RRC. When compared with the previous Wilkinson power combiner (WPC)-based rectifier, the proposed topology advances with a smaller variation in power conversion efficiency (PCE) over the incident angle. In addition, it simplifies the matching network (MN) design and enables a lower input return loss due to the fully symmetric circuitry between 0° and 180°. Furthermore, it allows a higher design flexibility on the rectifier topology. For validation, we designed and fabricated two wide-angle rectifiers, one working at single band (2.45 GHz) and the other at dual band (0.9 and 2.4 GHz). The single-band rectifier achieved a 67.3% peak PCE and 7.9% efficiency variation within the 0°–360° incident angle range. For the dual-band rectifier, the peak PCE is 78.4% and 70.2%, while the variation is 4% and 8.8%, for 0.9 and 2.4 GHz, respectively. The PCE variation is the smallest among previous works. [ABSTRACT FROM AUTHOR]

By dissecting and comparing the transcriptional trajectories and epigenomic traits of reprogramming and transforming cells at the single-cell resolution, Huyghe et al discovered Bcl11b and Atoh8, two key transcription factors controlling cell plasticity during pluripotent reprogramming and oncogenic transformation. [ABSTRACT FROM AUTHOR]

Bacterial RNA polymerase (RNAP) is a validated drug target for broad‐spectrum antibiotics, and its "switch region" is considered as the promising binding site for novel antibiotics. Based on the core scaffold of dithiolopyrrolone, a series of N‐aryl pyrrothine derivatives was designed, synthesized, and evaluated for their antibacterial activity. Compounds generally displayed more active against Gram‐positive bacteria, but less against Gram‐negative bacteria. Among them, compound 6e exhibited moderate antibacterial activity against clinical isolates of rifampin‐resistant Staphylococcus aureus with minimum inhibition concentration value of 1–2 μg/ml and inhibited Escherichia coli RNAP with IC50 value of 12.0 ± 0.9 μM. In addition, compound 6e showed certain degree of cytotoxicity against HepG2 and LO2 cells. Furthermore, molecular docking studies suggested that compound 6e might interact with the switch region of bacterial RNAP in a similar conformation to myxopyronin A. Together, the N‐aryl pyrrothine scaffold is a promising lead for discovery of antibacterial drugs acting against bacterial RNAP. [ABSTRACT FROM AUTHOR]

High accuracy and reliable predictions of the bias of in-orbit atomic clocks are crucial to the application of satellites, while their clocks cannot transfer time information with the earth stations. It brings forward a new short-term, mid-long-term, and long-term prediction approach with the grey predicting model (GM(1, 1)) improved by the least absolute deviations (GM(1, 1)-LAD) when there are abnormal cases (larger fluctuations, jumps, and/or singular points) in SCBs. Firstly, it introduces the basic GM(1, 1) models. As the parameters of the conventional GM(1, 1) model determined by the least squares method (LSM) is not the best in these cases, leading to magnify the fitting errors at the abnormal points, the least absolute deviations (LAD) is used to optimize the conventional GM(1, 1) model. Since the objective function is a nondifferentiable characteristic, some function transformation is inducted. Then, the linear programming and the simplex method are used to solve it. Moreover, to validate the prediction performances of the improved model, six prediction experiments are performed. Compared with those of the conventional GM(1, 1) model and autoregressive moving average (ARMA) model, results indicate that (1) the improved model is more adaptable to SCBs predictions of the abnormal cases; (2) the root mean square (RMS) improvement for the improved model are 5.7%∼81.7% and 6.6%∼88.3%, respectively; (3) the maximum improvement of the pseudorange errors (PE) and mean absolute errors (MAE) for the improved model could reach up to 88.30%, 89.70%, and 87.20%, 85.30%, respectively. These results suggest that our improved method can enhance the prediction accuracy and PE for these abnormal cases in SCBs significantly and effectively and deliver a valuable insight for satellite navigation. [ABSTRACT FROM AUTHOR]

The flipped-voltage-follower-based low-dropout regulator (LDO) has drawn attention for its fast response and reduced complexity, while super source follower can be combined to push the pole at the gate of the pass device to high frequency. But the maximum load current and minimum load capacitance of this topology are limited, especially when the poles and zero from the SSF are omitted in previous designs. This paper proposes a solution to extend the ranges of the load current and load capacitance, by implementing a small feed-forward capacitor ($C_{F}$) and a damping factor control circuitry. In addition, a slew rate enhancement circuit is applied to reduce the voltage undershoot. The proposed LDO is verified in a 65-nm CMOS process with 0.008 mm2 active area. The measured voltage undershoot is 80 mV with a load steps from 100 μA to 50 mA with 2-ns edge times, with no external capacitor. And the maximum load capacitance can be extended to 2 nF. A figure-of-merit of 0.8 mV is achieved. [ABSTRACT FROM AUTHOR]

Battery-to-battery (B2B) wireless charging can take place in many scenarios, such as using a mobile phone to charge another mobile phone, wearable devices, or low-power sensor nodes. To facilitate this wireless power transfer (WPT) function with the minimum additional cost, we propose a monolithic reconfigurable bidirectional WPT transceiver designed for the first time in CMOS, which can be reconfigured between a differential class-D power amplifier (PA) and a full-wave rectifier. Meanwhile, we employed a maximum current charging mode to maximize the B2B charging efficiency, by directly charging the loading battery with the rectifier, and by powering the PA with the sourcing battery. Then, we reduced the number of cascaded WPT stages from five in the conventional design to three. This bidirectional WPT transceiver fabricated in 0.35 μm CMOS occupies 3.9 mm2 of silicon area. The bidirectional WPT function, verified at 6.78 MHz with only one off-chip capacitor, exhibits peak efficiencies of 91.5% and 58.6% for the receiver and the overall system, respectively, when the output power is 1.55 W. [ABSTRACT FROM AUTHOR]

This paper presents an automatic impedance transforming technique to extend the radio frequency rectifier input power range with high conversion efficiency. The rectifier employs two branches of subrectifier, each achieving impedance matching at high and low input power ranges. Then, the two branches are connected by a $\lambda/4 $ T-junction power divider. With such configuration, the input impedance of the two subrectifiers are transformed automatically, allowing the impedance matching over a wide input power range. In this way, the injected power can be optimally delivered to the subrectifiers, achieving a high efficiency over this wide input power range. This scheme manages to eliminate the power detetor for branch selection and can be applied to both single- and dual-band rectifiers with a reduced design difficulty. For validation, a single-band rectifier working at 915 MHz and a dual-band rectifier at 915/2450 MHz are implemented. Design analysis on the single- and dual-band rectifiers is carried out. The measurement results show that 68% maximum efficiency is achieved for the single-band (915 MHz) rectifier, and the input power range for the efficiency >70% of the peak efficiency is from −5 to 31 dBm. Besides, the dual-band rectifier shows 66% and 58% peak efficiencies at 915 and 2450 MHz, respectively. The input power range is from −6 to 33 dBm for the efficiency >70% of its peak value at 915 MHz, while from 10 to 32 dBm at 2450 MHz. These indicate that the input power range with high efficiency is extended. [ABSTRACT FROM AUTHOR]

NLRP12 is a NOD-like receptor that plays multiple roles in both inflammation and tumorigenesis. Despite the importance, little is known about its mechanism of action at the molecular level. Here, we report the crystal structure of NLRP12 PYD domain at 1.70 Å fused with an maltose-binding protein (MBP) tag. Interestingly, the PYD domain forms a dimeric configuration through a disulfide bond in the crystal. The possible biological significance is discussed in the context of ROS induced NF-κB activation. [ABSTRACT FROM AUTHOR]

This letter presents a 6.78 MHz wireless power transfer (WPT) system for wirelessly powered flash drives that need multiple supplies with a total power of sub-1 W. A new architecture that merges an N-level single-inductor multiple-output switching converter with a multistage rectifier is proposed for the WPT receiver, and the regulated outputs attain small ripples. A prototype of a 2X active rectifier that merges with a three-level single-inductor dual-output dc–dc converter is implemented in a 0.35 μm CMOS process. [ABSTRACT FROM PUBLISHER]

In this work, a power-area-efficient, 3-band, 2-RX MIMO, and TD-LTE (backward compatible with the HSPA+, HSUPA, HSDPA, and TD-SCDMA) CMOS receiver is presented and implemented in 0.13- μm CMOS technology. The continuous-time delta-sigma A/D converters (CT ∆Σ ADCs) are directly coupled to the outputs of the transimpedance amplifiers, eliminating the need of analog anti-aliasing filters between RX front-end and ADCs in conventional structures. The strong adjacent channel interference without low-pass filter attenuation is handled by proper gain control. A low-power small-area solution for excess loop delay compensation is implemented in the CT ∆Σ ADC. At 20 MHz bandwidth, the CT ∆Σ ADC achieves 66 dB dynamic range and 3.5 dB RX chip noise figure is measured. A maximum of 2.4 dB signal-to-noise ratio degradation is measured in all the adjacent channel selectivity (ACS) and blocking tests, demonstrating the effectiveness of the strategy against the low-pass filter removal from the conventional architecture. The receiver dissipates a maximum of 171 mW at 2-RX MIMO mode. To our best knowledge, it is the first research paper on the design of fully integrated commercial TD-LTE receiver. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In this work, a tri-band (Band 39: 1880–1920 MHz, Band 40: 2300–2400 MHz, and Band 38: 2570–2620 MHz), 2-receiver (RX) multiple-in-multiple-out (MIMO), 1-transmitter (TX) TD-LTE (Time Division Long Term Evolution) CMOS transceiver is presented and fabricated in 0.13-μm CMOS technology. The continuous-time delta–sigma A/D converters (CT ΔΣ ADCs) are directly coupled to the RX front-end outputs to achieve low power. With proper gain allocation and a novel carrier leakage calibration, the TX section ensures at least –40 dBc carrier leakage suppression over 86-dB gain range. The transceiver dissipates maximum 171 mW at 2-RX MIMO mode and 183 mW at 1-TX maximum gain mode. To the best of our knowledge, this is the first research paper on fully integrated commercial TD-LTE transceiver. [ABSTRACT FROM AUTHOR]

The caspase-recruitment domain (CARD) mediates homotypic protein-protein interactions that assemble large oligomeric signaling complexes such as the inflammasomes during innate immune responses. Structural studies of the mammalian CARDs demonstrate that their six-helix bundle folds belong to the death-domain superfamily, whereas such studies have not been reported for other organisms. Here, the zebrafish interferon-induced guanylate-binding protein 1 (zIGBP1) was identified that contains an N-terminal GTPase domain and a helical domain typical of the mammalian guanylate-binding proteins, followed by a FIIND domain and a C-terminal CARD similar to the mammalian inflammasome proteins NLRP1 and CARD8. The structure of the zIGBP1 CARD as a fusion with maltose-binding protein was determined at 1.47 Å resolution. This revealed a six-helix bundle fold similar to the NLRP1 CARD structure with the bent α1 helix typical of all known CARD structures. The zIGBP1 CARD surface contains a positively charged patch near its α1 and α4 helices and a negatively charged patch near its α2, α3 and α5 helices, which may mediate its interaction with partner domains. Further studies using binding assays and other analyses will be required in order to address the physiological function(s) of this zebrafish protein. [ABSTRACT FROM AUTHOR]

The therapeutic landscape for the treatment of cancer has evolved significantly in recent decades, aided by the development of effective oncology drugs. However, many cancer drugs are often poorly tolerated by the body and in particular the cardiovascular system, causing adverse and sometimes fatal side effects that negate the chemotherapeutic benefits. The prevalence and severity of chemotherapy-induced cardiotoxicity warrants a deeper investigation of the mechanisms and implicating factors in this phenomenon, and a consolidation of scientific efforts to develop mitigating strategies. Aiding these efforts is the emergence of induced pluripotent stem cells (iPSCs) in recent years, which has allowed for the generation of iPSC-derived cardiomyocytes (iPSC-CMs): a human-based, patient-derived, and genetically variable platform that can be applied to the study of chemotherapy-induced cardiotoxicity and beyond. After surveying chemotherapy-induced cardiotoxicity and the associated chemotherapeutic agents, we discuss the use of iPSC-CMs in cardiotoxicity modeling, drug screening, and other potential applications. Improvements to the iPSC-CM platform, such as the development of more adult-like cardiomyocytes and ongoing advances in biotechnology, will only enhance the utility of iPSC-CMs in both basic science and clinical applications. [ABSTRACT FROM AUTHOR]

CARD8 plays crucial roles in regulating apoptotic and inflammatory signaling pathways through the association of its caspase-recruitment domain (CARD) with those of procaspase-9 and procaspase-1. The CARD8 CARD has also been predicted to form an intramolecular complex with its FIIND domain. Here, the first crystal structure of the CARD8 CARD is reported; it adopts a six-helix bundle fold with a unique conformation of the α6 helix that is described here for the first time. The surface of the CARD8 CARD displays a prominent acidic patch at its α2, α3 and α5 helices that may interact with the procaspase-9 CARD, whereas an adjacent charged surface at its α3 and α4 helices may associate with the CARD8 FIIND domain without interfering with the CARD-CARD interaction. This suggests that the function of CARD8 may be regulated by both intramolecular and intermolecular interactions involving electrostatic attractions. [ABSTRACT FROM AUTHOR]

Abstract: The applications of quartz crystal microbalance (QCM) in biointerfaces are limited by its quantitative ambiguities caused by viscoelasticity and solution effects. Although many studies clearly indicated that the quantitative interpretation of QCM data needed caution, none of those studies provided a practical solution that enabled general and quantitative interpretation of QCM data. Recently we proposed a “solidified liquid layer” model that enabled QCM to be used as a biomolecular ruler. Here we applied five kinds of proteins with significant differences in their sizes and shapes to further validate this model. The effective thickness (T eff) of surface immobilized, hydrated proteins were 10.2, 4.7, 1.8 and 4.8nm for rabbit IgG, streptavidin, lysozyme, and bovine serum albumin, respectively. The critical number of stakes needed for the formation of a solidified liquid layer was found to be protein dependent. We believed this “solidified liquid layer” model will facilitate the popularization of QCM as a valuable tool in biointerface studies, such as protein adsorption process or the conformational change on surface. [Copyright &y& Elsevier]

YqjH and YqjW are Bacillus subtilis homologs of the UmuC/DinB or Y superfamily of DNA polymerases that are involved in SOS-induced mutagenesis in Escherichia coli. While the functions of YqjH and YqjW in B. subtilis are still unclear, the comparisons of protein structures demonstrate that YqjH has 36% identity to E. coli DNA polymerase IV (DinB protein), and YqjW has 26% identity to E. coli DNA polymerase V (UmuC protein). In this report, we demonstrate that both YqjH and the products of the yqjW operon are involved in UV-induced mutagenesis in this bacterium. Furthermore, resistance to UV-induced damage is significantly reduced in cells lacking a functional YqjH protein. Analysis of stationary-phase mutagenesis indicates that absences of YqjH, but not that of YqjW, decreases the ability of B. subtilis to generate revertants at the hisC952 allele via this system. These data suggest a role for YqjH in the generation of at least some types of stationary-phase-induced mutagenesis. [ABSTRACT FROM AUTHOR]

Adaptive (stationary-phase) mutagenesis occurs in the gram-positive bacterium Bacillus subtilis. Furthermore, taking advantage of B. subtilis as a paradigm for the study of prokaryotic differentiation and development, we have shown that this type of mutagenesis is subject to regulation involving at least two of the genes that are involved in the regulation of post-exponential phase prokaryotic differentiation, i.e., comA and comK. On the other hand, a functional RecA protein was not required for this type of mutagenesis. The results seem to suggest that a small subpopulation(s) of the culture is involved in adaptive mutagenesis and that this subpopulation(s) is hypermutable. The existence of such a hypermutable subpopulation(s) raises important considerations with respect to evolution, the development of specific mutations, the nature of bacterial populations, and the level of communication among bacteria in an ecological niche. [ABSTRACT FROM AUTHOR]

The classification and recognition of radar clutter is helpful to improve the efficiency of radar signal processing and target detection. In order to realize the effective classification of uniform circular array (UCA) radar clutter data, a classification method of ground clutter data based on the chaotic genetic algorithm is proposed. In this paper, the characteristics of UCA radar ground clutter data are studied, and then the statistical characteristic factors of correlation, non-stationery and range-Doppler maps are extracted, which can be used to classify ground clutter data. Based on the clustering analysis, results of characteristic factors of radar clutter data under different wave-controlled modes in multiple scenarios, we can see: in radar clutter clustering of different scenes, the chaotic genetic algorithm can save 34.61% of clustering time and improve the classification accuracy by 42.82% compared with the standard genetic algorithm. In radar clutter clustering of different wave-controlled modes, the timeliness and accuracy of the chaotic genetic algorithm are improved by 42.69% and 20.79%, respectively, compared to standard genetic algorithm clustering. The clustering experiment results show that the chaotic genetic algorithm can effectively classify UCA radar's ground clutter data. [ABSTRACT FROM AUTHOR]

The spaceborne interferometric synthetic aperture radar (InSAR) is expected to measure the sea surface height (SSH) with high accuracy over a wide swath. Since centimeter-level accuracy is required to monitor the ocean sub-mesoscale dynamics, the high accuracy implies that the altimetric errors should be totally understood and strictly controlled. However, for the dynamic waves, they move randomly all the time, and this will lead to significant altimetric errors. This study proposes an analytical method for the dynamic wave-related errors of InSAR SSH measurement based on the wave spectrum and electromagnetic scattering model. Additionally, the mechanisms of the dynamic wave-related errors of InSAR altimetry are analyzed, and the detailed numerical model is derived. The proposed analytical method is validated with NASA's Surface Water and Ocean Topography (SWOT) project error budget, and the Root-Mean-Square Errors (RMSEs) are in good agreement (0.2486 and 0.2470 cm on a 0.5 km2 grid, respectively). Instead of analysis for a typical project, the proposed method can be applied to different radar parameters under multiple sea states. The RMSEs of Ka-band under low sea state, moderate sea state, and high sea state are 0.2670, 1.3154, and 6.6361 cm, respectively. Moreover, the RMSEs of X-band and Ku-band are also simulated and presented. The experimental results demonstrate that the dynamic wave-related errors of InSAR altimetry are not sensitive to the frequencies but are sensitive to the sea states. The error compensation method is necessary for moderate and higher sea states for centimetric accuracy requirements. This can provide feasible suggestions on system design and error budget for the future interferometric wide-swath altimeter. [ABSTRACT FROM AUTHOR]

In conformal array radar, due to the directivity of antennas, the responses of the echo signals between different antennas are distinct, and some antennas cannot even receive the target echo signal. These phenomena significantly affect the accuracy of direction-of-arrival (DOA) estimation. To implement accurate DOA estimation in a conformal uniform circular array (UCA) composed of directional antennas, the two-stage fast DOA estimation algorithm is proposed. In the pre-processing stage, multi-target decoupling and target detection are mainly used to obtain the targets' range bin indexes set; in the rough-precise DOA estimation stage, the amplitude and phase information of each antenna are used for rough DOA estimation and precise DOA estimation, respectively. Based on simulation and actual anechoic chamber radar experiments, and through quantitative analyses of the accuracy, validity and elapsed time of the two-stage fast DOA estimation algorithm compared with the directional antenna MUSIC (DA-MUSIC), sub-array MUSIC (S-MUSIC) and Capon-like algorithms, results indicate that the two-stage fast DOA estimation algorithm can rapidly and accurately estimate DOAs in a multi-target scenario without the range-angle pair-matching procedure. Lower computational complexity and superior estimation accuracy provide the two-stage fast DOA estimation algorithm a broader application prospect in the practical engineering field. [ABSTRACT FROM AUTHOR]

The two-phase operation of a dc–dc converter has several benefits, when compared with the single phase, including higher efficiency, smaller ripple, faster response, etc. However, it suffers from unbalanced currents between the two phases. This article presents a two-phase three-level buck converter with cross-connected flying capacitors (X-CFLY). The proposed converter suppresses the unbalanced inductor currents in a two-phase operation, through the alternate connection of flying capacitors across the branches. Meanwhile, two-phase and three-level techniques help to achieve a fast transient response and a small output ripple. In addition, we derive the transfer function of the proposed generalized multiphase three-level buck converter with interconnected CFLY for analysis, and design accordingly its power stage and feedback loop. Finally, we validate the proposed converter through the fabrication in a 65 nm CMOS GP process. It achieves a low unbalanced current close to 5 mA and a small output ripple of 50 mV for a load current around 110 mA, and a peak efficiency of about 86%. [ABSTRACT FROM AUTHOR]

Reports on the finding that the Bacillus subtilis bacterium exhibits a transient growth requirement for two nonessential amino acids during a type of postexponential growth on a minimal medium. Complexity of parameters associated with the growth of B. subtilis; Explanation for discrepancies in literature related to transformation frequencies of B. subtilis.

A partial analogue‐assisted (AA) digital low dropout regulator (D‐LDO) with also a transient body‐drive (BD) technique is proposed. The body of the power switches can be driven by the VOUT transient spike that is high‐pass coupled from the D‐LDO output when a load step occurs, for a temporary threshold voltage change. The BD technique thereby manages to provide more than 10% momentary output current. In addition, since the effectiveness of the AA loop is proportional to the ratio of the coupling capacitance and the parasitic capacitance, here, only about 1/5 of the most significant bit of the power switches are connected to the AA and BD networks. Therefore, the coupling capacitors are much reduced, comparing to the previous work. A simulated 100 mV undershoot is obtained under a 2‐to‐12 mA load step within 1 ns edge time, using only 40 pF total capacitor. A 0.09 ps figure‐of‐merit (FOM) of speed is thereby achieved, which is at least 2.5× better than state‐of‐the‐art works. [ABSTRACT FROM AUTHOR]

Phenotypic variation can arise from differences in the protein coding sequence and in the regulatory elements. However, little is known about the contribution of regulatory difference to the expression divergence, especially the cis and trans regulatory variation to the expression divergence in intraspecific populations. In this study, we used two different yeast strains, BY4743 and RM11‐1a/α, to study the regulatory variation to the expression divergence between BY and RM under oxidative stress condition. Our results indicated that the expression divergence of BY and RM is mainly due to trans regulatory variations under both normal and oxidative stress conditions. However, cis regulatory variation seems to play a very important role in oxidative stress response in yeast because 36% of genes showed an increase in cis regulatory variation effect compared with 13% of genes that showed an increase in trans regulatory variation effect after oxidative stress. Our data also indicated that genes located on the longer arm of the chromosomes are more susceptible to cis variation effect under oxidative stress than genes on the shorter arm of the chromosomes. [ABSTRACT FROM AUTHOR]

Changes in expression patterns of serum carcinoembryonic antigen at initial diagnosis (CEAIn) and disease progression (CEAPd) in lung cancer patients under EGFR-tyrosine kinase inhibitors (TKI) treatment may reflect different tumor progression profiles. Of the 1736 lung cancer patients identified from the cancer registry group between 2011 to 2016, we selected 517 patients with advanced stage adenocarcinoma, data on EGFR mutation status and CEAIn, among whom were 288 patients with data on CEAPd, eligible for inclusion in the correlation analysis of clinical characteristics and survival. Multivariable analysis revealed that CEAIn expression was associated with poor progression-free survival in patients harboring mutant EGFR. Moreover, CEAIn and CEAPd were associated with the good and poor post-progression survival, respectively, in the EGFR-mutant group. Cell line experiments revealed that CEA expression and cancer dissemination can be affected by EGFR-TKI selection. EGFR-mutant patients, exhibiting high CEAIn (≥5 ng/mL) and low CEAPd (<5 ng/mL), showed a potential toward displaying new metastasis. Taken together, these findings support the conclusion that EGFR mutation status is a critical factor in determining prognostic potential of CEAIn and CEAPd in patients under EGFR-TKI treatment, and CEAIn and CEAPd are associated with distinct cancer progression profiles. [ABSTRACT FROM AUTHOR]

Background: In this first‐in‐human phase 1b study (ClinicalTrials.gov identifier NCT02761694) of advanced solid tumors with PIK3CA/AKT/PTEN mutations, the authors investigated the safety and efficacy of the pan‐AKT inhibitor vevorisertib (MK‐4440; ARQ 751) as monotherapy or with paclitaxel or fulvestrant. Methods: Patients with histologically confirmed, advanced or recurrent, PIK3CA/AKT/PTEN‐mutated solid tumors, measurable disease according to Response Evaluation Criteria in Solid Tumors, version 1.1, and an Eastern Cooperative Oncology Group performance status ≤1 received vevorisertib (dose range, 5–100 mg) alone or with paclitaxel 80 mg/m2 or fulvestrant 500 mg. The primary end point was safety and tolerability. Secondary end points included pharmacokinetics and the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1. Results: Of 78 patients enrolled, 58 received vevorisertib monotherapy, 10 received vevorisertib plus paclitaxel, and nine received vevorisertib plus fulvestrant. Dose‐limiting toxicity occurred in three patients (vevorisertib monotherapy, n = 2 [grade 3 pruritic and maculopapular rashes]; vevorisertib plus paclitaxel, n = 1 [grade 1 asthenia]). Across doses, treatment‐related AEs occurred in 46 patients (79%) with vevorisertib monotherapy, in 10 patients (100%) with vevorisertib plus paclitaxel, and in nine patients (100%) with vevorisertib plus fulvestrant; and grade 3 treatment‐related AEs occurred in 13 (22%), 7 (70%), and 3 (33%) patients, respectively. No grade 4/5 treatment‐related AEs occurred. Maximum vevorisertib concentrations were reached 1–4 hours after dosing; the elimination half‐life ranged from 8.8 to 19.3 hours. The objective response rate was 5% with vevorisertib monotherapy (three partial responses), 20% with vevorisertib plus paclitaxel (two partial responses), and 0% with vevorisertib plus fulvestrant. Conclusions: Vevorisertib alone or with paclitaxel or fulvestrant had a manageable safety profile, and vevorisertib alone or with paclitaxel had minimal to modest antitumor activity in this patient population with PIK3CA/AKT/PTEN‐mutated advanced solid tumors. Clinical trial registration: ClinicalTrials.gov, NCT02761694. In this first‐in‐human phase 1b study, the pan‐AKT inhibitor vevorisertib as monotherapy or in combination with either paclitaxel or fulvestrant had a generally manageable safety profile in patients with PIK3CA/AKT/PTEN‐mutated advanced solid tumors. In addition, vevorisertib as monotherapy or in combination with paclitaxel had minimal to modest antitumor activity. [ABSTRACT FROM AUTHOR]

This paper presents a low power bandgap reference (BGR) with 573 mV average output voltage and 0.95-V minimum supply voltage. Here, the resistor ratio of two types of resistors that have opposite temperature coefficient (TC) realizes a second-order curvature compensation. In addition, to reduce the supply voltage we adopt a voltage divider, and we also employ proportional to absolute temperature (PTAT) voltage generators to reduce the resistor values for low power applications. The proposed BGR fabricated in 65-nm CMOS achieves an average TC of 57 ppm/°C from 0 to 100 °C with 8 samples. The power dissipation at room temperature is 78 nA and the power supply ripple rejection (PSRR) is −67 dB at DC with 1.2 V supply. [ABSTRACT FROM AUTHOR]

Both cis- and trans-regulatory mutations contribute to gene expression divergence within and between species. To estimate their relative contributions, we examined two yeast strains, BY (a laboratory strain) and RM (a wild strain), for their gene-expression divergence by microarray. Using these data and published ChIP-chip data, we obtained a set of single-regulator-regulated genes that showed expression divergence between BY and RM. We randomly selected 50 of these genes for further study. We developed a step-by-step approach to assess the relative contributions of cis- and trans-variations to expression divergence by using pyrosequencing to quantify the mRNA levels of the BY and RM alleles in the same culture (co-culture) and in hybrid diploids. Forty genes showed expression divergence between the two strains in co-culture, and pyrosequencing of the BY/RM hybrid diploids showed that 45% (18/40) can be attributed to differences in trans-acting factors alone, 17.5% (7/40) mainly to trans-variations, 20% (8/40) to both cis- and trans-acting factors, 7.5% (3/40) mainly to cis-variations, and 10% (4/40) to cis-acting factors alone. In addition, we replaced the BY promoter by the RM promoter in each of 10 BY genes that were found from our microarray data to have expression divergence between BY and RM, and in each case our quantitative PCR analysis revealed a cis effect of the promoter replacement on gene expression. In summary, our study suggests that trans-acting factors play the major role in expression evolution between yeast strains, but the role of cis variation is also important. [ABSTRACT FROM AUTHOR]

Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma, small stature, skeletal anomalies, sparse brows/lashes, cataracts, and predisposition to cancer. Type 2 RTS patients with biallelic RECQL4 pathogenic variants have multiple skeletal anomalies and a significantly increased incidence of osteosarcoma. Here, we generated RTS patient-derived induced pluripotent stem cells (iPSCs) to dissect the pathological signaling leading to RTS patient-associated osteosarcoma. RTS iPSC-derived osteoblasts showed defective osteogenic differentiation and gain of in vitro tumorigenic ability. Transcriptome analysis of RTS osteoblasts validated decreased bone morphogenesis while revealing aberrantly upregulated mitochondrial respiratory complex I gene expression. RTS osteoblast metabolic assays demonstrated elevated mitochondrial respiratory complex I function, increased oxidative phosphorylation (OXPHOS), and increased ATP production. Inhibition of mitochondrial respiratory complex I activity by IACS-010759 selectively suppressed cellular respiration and cell proliferation of RTS osteoblasts. Furthermore, systems analysis of IACS-010759-induced changes in RTS osteoblasts revealed that chemical inhibition of mitochondrial respiratory complex I impaired cell proliferation, induced senescence, and decreased MAPK signaling and cell cycle associated genes, but increased H19 and ribosomal protein genes. In summary, our study suggests that mitochondrial respiratory complex I is a potential therapeutic target for RTS-associated osteosarcoma and provides future insights for clinical treatment strategies. Author summary: Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disease characterized by an array of clinical phenotypes affecting multiple tissues. Type 2 RTS is caused by pathogenic variants in the RECQL4 gene encoding the RECQL4 DNA helicase. Type 2 RTS patients are prone to developing multiple primary osteosarcomas and have limited chemotherapy options due to organ toxicities or lifetime limits on active agents such as anthracyclines. There is currently no available RTS model that recapitulates the bone malignancy phenotype in this disease, severely limiting the ability to explore new treatment avenues which are greatly needed for these patients. To overcome this problem, we established a Type 2 RTS disease model using a human induced pluripotent stem cell platform. We then applied an unbiased approach to explore novel molecular mechanisms involved in RECQL4 mutation-induced osteosarcoma to explore therapeutic interventions. Our findings indicate that mitochondrial respiratory complex I is an "Achilles' heel" of RTS osteosarcoma and that cancers harboring RECQL4 mutations/deletions, in general, may be vulnerable to mitochondrial respiratory complex I inhibition. [ABSTRACT FROM AUTHOR]

Abstract: Phenotypic variation among individuals in a population can be due to DNA sequence variation in protein coding regions or in regulatory elements. Recently, many studies have indicated that mutations in regulatory elements may be the major cause of phenotypic evolution. However, the mechanisms for evolutionary changes in gene expression are still not well understood. Here, we studied the relative roles of cis and trans regulatory changes in Saccharomyces cerevisiae cells to cope with heat stress. It has been found that the expression level of ~300 genes was induced at least two fold and that of ~500 genes was repressed at least two fold in response to heat shock. From the former set of genes, we randomly selected 65 genes that showed polymorphism(s) between the BY and RM strains for pyrosequencing analysis to explore the relative contributions of cis and trans regulatory variations to the expression divergence between BY and RM. Our data indicated that the expression divergence between BY and RM was mainly due to trans regulatory variations under either the normal condition or the heat stress condition. However, the relative contribution of trans regulatory variation was decreased from 76.9% to 61.5% after the heat shock stress. These results indicated that the cis regulatory variation may play an important role in the adaption to heat stress. In our data, 43.1% (28 genes) of the 65 genes showed the same trend of cis or trans variation effect after the heat shock stress, 35.4% (23 genes) showed an increased cis variation effect and 21.5% (14 genes) showed an increased trans variation effect after the heat shock stress. Thus, our data give insights into the relative roles of cis and trans variations in response to heat shock in yeast. [Copyright &y& Elsevier]

Abstract: Here we present a simple, highly efficient, universal automatic kinetics switch (AKS) gene synthesis method that enables synthesis of DNA up to 1.6kbp from 1nM oligonucleotide with just one polymerase chain reaction (PCR) process. This method eliminates the interference between the PCR assembly and amplification in one-step gene synthesis and simultaneously maximizes the amplification of emerged desired DNA by using a pair of flanked primers. In addition, we describe an analytical model of PCR gene synthesis based on the thermodynamics and kinetics of DNA hybridization. The kinetics difference between standard PCR amplification and one-step PCR gene synthesis is analyzed using this model and is validated using real-time gene synthesis with eight gene segments (318–1656bp). The effects of oligonucleotide concentration, stringency of annealing temperature, annealing time, extension time, and PCR buffer conditions are examined systematically. Analysis of the experimental results leads to new insights into the gene synthesis process and aids in optimizing gene synthesis conditions. We further extend this method for multiplexing gene assembly with a total DNA length up to 5.74kbp from 1nM oligonucleotide. [ABSTRACT FROM AUTHOR]

Abstract: Internal duplication can enhance the function of a gene or provide raw material for the emergence of a new function in a gene. Therefore, it is interesting to see whether the frequency of internal duplication has increased during metazoan evolution. The growing number of sequenced eukaryotic genomes provides an excellent opportunity to study the change in the pattern of internal duplication in the course of metazoan evolution. We studied repeated segments in proteins in the proteomes of 11 eukaryotes. We found that the frequency of internal duplication in Caenorhabditis elegans and Drosophila melanogaster (two protostomes) is higher than that in fungi but lower than that in chordates. Moreover, the frequencies of internal duplication for the chordates studied are largely similar. We classified orthologous proteins of chordates into three antiquity groups and found that more recently derived proteins in the metazoan lineage have higher repetitiveness than older ones. Our analysis suggests that lineage-specific internal duplication in protein evolution increases with organismal complexity before the emergence of chordates but not so afterward. Proteins with repeated regions might have been preferred before the protostome–chordate split. This finding supports the suggestion that exon-shuffling occurred more frequently after the first multicellular organism appeared and might have contributed to the metazoan radiation. [Copyright &y& Elsevier]

Microbial volatile organic compounds (mVCs) are formed in the metabolism of microorganisms and widely distributed in nature and pose threats to human health. However, the air pollution by microorganisms is a situation which is poorly understood. In this study, the cytotoxicity of E. aerogenes VCs was evaluated in the model organism Saccharomyces cerevisiae. E. aerogenes VCs inhibited the survival of yeast and triggered the formation of intracellular reactive oxygen species (ROS). The hypersensitive of MAP kinase mpk1 / slt2 and 19S regulatory assembly chaperone adc17 mutants to the E. aerogenes VCs indicated cell wall integrity (CWI) pathway together with stress-inducible proteasome assembly regulation are essentially involved in mVCs tolerance mechanism. Furthermore, exposure to the mVCs resulted in the transcriptional upregulation of the CWI pathway, the regulatory particle assembly chaperones, and genes involved in proteasome regulations. Our research suggested that the ROS/MAPK signaling and proteasome regulatory pathway play pivotal roles in the integration and fine-tuning of the mVCs stress response. This study provides a molecular framework for future study of the effects of mVCs on more complex organisms, such as humans. Image 1 • MVCs impose toxicity to yeast by oxdative stress. • Mpk1/Slt2 protects yeast cell from mVCs toxicity. • The exposure of mVCs affects CWI pathway in yeast. • Proteasome homeostasis is required for mVCs stress tolerance in yeast. [ABSTRACT FROM AUTHOR]

This paper presents a novel design of a wideband millimeter-wave balanced bandpass filter (BPF) for use in a high-sensitivity Q-band reception system for solar radio spectrum observation. The balanced BPF has differential-mode (DM) band-pass and common-mode (CM) band-stop characteristics, which effectively suppress noise and reduce electromagnetic interference in its operating frequency band. The filter design incorporates half-wavelength rectangular micro-coaxial transmission lines as resonators and coupling between resonators is achieved through J-inverters. The wideband CM suppression is improved by adjusting the distribution of CM transmission zeros by adding open-circuited branches on the symmetrical plane. The micro-coaxial structure is fabricated on a 4-inch silicon wafer through a three-dimensional additive manufacturing process. The compactness, low loss, and wideband performance make it ideal for this application. As a design example, a fifth-order Chebyshev balanced BPF was fabricated and measured to demonstrate the design method. The measured results indicate that the balanced BPF operates within a frequency range of 30–50 GHz, with an insertion loss of 1.63 dB and over 26 dB CM suppression in the DM passband. These results are in general agreement with simulation results. To the best of our knowledge, this is the first time that a micro-coaxial structure has been proposed for this application. [ABSTRACT FROM AUTHOR]

This paper presents a switched-capacitor (SC) bandgap reference (BGR) with second-order curvature compensation for ultra-low power systems. The gate-source voltage of a sub-threshold MOSFET is proposed to implement the second-order curvature compensation voltage in this work. And then, a SC network is used, not only to add the second-order voltage and the first-order one together, but also to fulfill the summing weight effectively and precisely. In this way, the silicon area and power consumption can be reduced simultaneously. Furthermore, the design methodology of summing weight is investigated, and thus the temperature coefficient (TC) can be significantly reduced. The proposed SC-BGR was implemented and simulated in a CMOS 0.18 μm process, the average output voltage is 426.1 mV, achieving a TC of 17.6 ppm/°C from −20 to 100 °C under a 0.5 V minimum supply voltage. With the help of the SC architecture, a small chip area of 0.0975 mm2 is achieved with only 37.8-nW power consumption. [ABSTRACT FROM AUTHOR]

The article offers study of several clonal evolutionary pattern analysis of paediatric acute lymphoblastic leukaemia (ALL) based on B-cell receptor/T-cell receptor (BCR/TCR) genes to trace the clonality. Topics include diagnosis of patients and mapping of RNA sequencing to the BCR/TCR sequence database; and study highlights the power of examining the BCR/TCR gene rearrangement using transcriptome sequencing and insights into paediatric ALL evolution and disease progression.

Owing to its relatively high efficiency, extended transmission range, and less exposure to radio frequency radiation, near-field resonant wireless power transfer (R-WPT) has been widely used in consumer electronics and bio-implants. For most applications, a well-regulated output voltage is required against the coupling and loading variations, and thus a regulation scheme should be employed in an R-WPT system. To achieve an optimal receiver (RX) or overall efficiency, together with a reduced cost overhead, several regulation schemes have been proposed in recent years, where the regulation can be implemented at either the RX or transmitter (TX) side, or both. These regulation schemes have been reviewed and comprehensively discussed in this paper. Hence, the main contribution of this paper is to provide a guideline for designing the regulation scheme in R-WPT systems. Moreover, potential new topologies of regulation are investigated here. [ABSTRACT FROM AUTHOR]

In this study, the design of the optimal decentralised full‐state‐feedback controllers is derived for wireless networked control systems with network‐induced delays. In particular, the authors formulate the optimal decentralised control problem as a non‐cooperative linear quadratic game. Then, the optimal control strategy of each controller is obtained that is based on the current plant state and the last control strategies of decentralised controllers. The proposed optimal decentralised controllers reduce to the known controller under certain conditions. Moreover, the authors illustrate the application of the proposed decentralised state feedback control to load frequency control in power grid systems. [ABSTRACT FROM AUTHOR]

Background: Mycoheterotrophic orchids are achlorophyllous plants that obtain carbon and nutrients from their mycorrhizal fungi. They often show strong preferential association with certain fungi and may obtain nutrients from surrounding photosynthetic plants through ectomycorrhizal fungi. Gastrodia is a large genus of mycoheterotrophic orchids in Asia, but Gastrodia species' association with fungi has not been well studied. We asked two questions: (1) whether certain fungi were preferentially associated with G. flavilabella, which is an orchid in Taiwan and (2) whether fungal associations of G. flavilabella were affected by the composition of fungi in the environment. Results: Using next-generation sequencing, we studied the fungal communities in the tubers of Gastrodia flavilabella and the surrounding soil. We found (1) highly diversified fungi in the G. flavilabella tubers, (2) that Mycena species were the predominant fungi in the tubers but minor in the surrounding soil, and (3) the fungal communities in the G. flavilabella tubers were clearly distinct from those in the surrounding soil. We also found that the fungal composition in soil can change quickly with distance. Conclusions: G. flavilabella was associated with many more fungi than previously thought. Among the fungi in the tuber of G. flavilabella, Mycena species were predominant, different from the previous finding that adult G. elata depends on Armillaria species for nutritional supply. Moreover, the preferential fungus association of G. flavilabella was not significantly influenced by the composition of fungi in the environment. [ABSTRACT FROM AUTHOR]

Background: Comparative genomics provides insights into the diversification of bacterial species. Bacterial speciation usually takes place with lasting homologous recombination, which not only acts as a cohering force between diverging lineages but brings advantageous alleles favored by natural selection, and results in ecologically distinct species, e.g., frequent host shift in Xanthomonas pathogenic to various plants. Results: Using whole-genome sequences, we examined the genetic divergence in Xanthomonas campestris that infected Brassicaceae, and X. citri, pathogenic to a wider host range. Genetic differentiation between two incipient races of X. citri pv. mangiferaeindicae was attributable to a DNA fragment introduced by phages. In contrast to most portions of the genome that had nearly equivalent levels of genetic divergence between subspecies as a result of the accumulation of point mutations, 10% of the core genome involving with homologous recombination contributed to the diversification in Xanthomonas, as revealed by the correlation between homologous recombination and genomic divergence. Interestingly, 179 genes were under positive selection; 98 (54.7%) of these genes were involved in homologous recombination, indicating that foreign genetic fragments may have caused the adaptive diversification, especially in lineages with nutritional transitions. Homologous recombination may have provided genetic materials for the natural selection, and host shifts likely triggered ecological adaptation in Xanthomonas. To a certain extent, we observed positive selection nevertheless contributed to ecological divergence beyond host shifting. Conclusion: Altogether, mediated with lasting gene flow, species formation in Xanthomonas was likely governed by natural selection that played a key role in helping the deviating populations to explore novel niches (hosts) or respond to environmental cues, subsequently triggering species diversification. [ABSTRACT FROM AUTHOR]

High quality fully integrated power supplies could notably improve the performances of the noise‐sensitive building block in the UWB communication systems. Double buffers are inserted into the cascode flipped‐voltage‐follower (FVF) topology to enable designing the dominant pole at the output node for better power supply rejection (PSR) and less voltage variation during load transient. An enhanced super source follower (E‐SSF) is proposed to further reduce the output impedance of the buffer that drives the power transistor. The FVF‐based low dropout regulator (LDO) with E‐SSF achieves a worst‐case PSR of −18.9 dB across the full spectrum and a transient response time of 312 ps. The proposed LDO is designed in a 28 nm CMOS process and consumes 100 μA quiescent current with 1.0 V input and 0.8 V output voltages. In total, 120 pF on‐chip capacitors are used for filtering. [ABSTRACT FROM AUTHOR]

Background: As a strong fermentator, Saccharomyces cerevisiae has the potential to be an excellent host forethanol production by consolidated bioprocessing. For this purpose, it is necessary to transform cellulose genesinto the yeast genome because it contains no cellulose genes. However, heterologous protein expression in S.cerevisiae often suffers from hyper-glycosylation and/or poor secretion. Thus, there is a need to genetically engineerthe yeast to reduce its glycosylation strength and to increase its secretion ability. Results: Saccharomyces cerevisiae gene-knockout strains were screened for improved extracellular activity of arecombinant exocellulase (PCX) from the cellulose digesting fungus Phanerochaete chrysosporium. Knockoutmutants of 47 glycosylation-related genes and 10 protein-trafficking-related genes were transformed with a PCX expression construct and screened for extracellular cellulase activity. Twelve of the screened mutants were found tohave a more than 2-fold increase in extracellular PCX activity in comparison with the wild type. The extracellular PCX activities in the glycosylation-related mnn10 and pmt5 null mutants were, respectively, 6 and 4 times higherthan that of the wild type; and the extracellular PCX activities in 9 protein-trafficking-related mutants, especially inthe chc1, clc1 and vps21 null mutants, were at least 1.5 times higher than the parental strains. Site-directed mutagenesis studies further revealed that the degree of N-glycosylation also plays an important role inheterologous cellulase activity in S. cerevisiae. Conclusions: Systematic screening of knockout mutants of glycosylation- and protein trafficking-associated genesin S. cerevisiae revealed that: (1) blocking Golgi-to-endosome transport may force S. cerevisiae to export cellulases; and (2) both over- and under-glycosylation may alter the enzyme activity of cellulases. This systematic gene-knockout screening approach may serve as a convenient means for increasing the extracellular activities of recombinant proteins expressed in S. cerevisiae. [ABSTRACT FROM AUTHOR]