Search

Summary: Self‐renewal and differentiation arrest are two features of leukaemia stem cells (LSCs) responsible for the high relapse rate of acute myeloid leukaemia (AML). To screen drugs to overcome differentiation blockade for AML, we conducted screening of 2040 small molecules from a library of United States Food and Drug Administration‐approved drugs and found that the cyclin‐dependent kinase (CDK)4/6 inhibitor, abemaciclib, exerts high anti‐leukaemic activity. Abemaciclib significantly suppressed proliferation and promoted the differentiation of LSCs in vitro. Abemaciclib also efficiently induced differentiation and impaired self‐renewal of LSCs, thus reducing the leukaemic cell burden and improving survival in various preclinical animal models, including patient‐derived xenografts. Importantly, abemaciclib strongly enhanced anti‐tumour effects in combination with venetoclax, a B‐cell lymphoma 2 (Bcl‐2) inhibitor. This treatment combination led to a marked decrease in LSC‐enriched populations and resulted in a synergistic anti‐leukaemic effect. Target screening revealed that in addition to CDK4/6, abemaciclib bound to and inhibited CDK9, consequently attenuating the protein levels of global p‐Ser2 RNA Polymerase II (Pol II) carboxy terminal domain (CTD), Myc, Bcl‐2, and myeloid cell leukaemia‐1 (Mcl‐1), which was important for the anti‐AML effect of abemaciclib. Collectively, these data provide a strong rationale for the clinical evaluation of abemaciclib to induce LSC differentiation and treat highly aggressive AML as well as other advanced haematological malignancies. [ABSTRACT FROM AUTHOR]

Surface mounds and depressions are the basic patterns of microtopography. Their geometric forms and physical properties affect rainfall infiltration, runoff generation and runoff confluence process. In this study, soil beds were set up with seven different types of microtopography to study the effects of surface mounds and depressions on runoff. They were the control check (CK), alternate mounds (AM), continuous mounds (CM), alternate depressions (AD), continuous depressions (CD), alternate mounds and depressions (AMD) and continuous mounds and depressions (CMD). There was only one microtopography type for monomorphic surface relief (MSR) while two for compound surface relief (CSR). All soil beds were exposed under 60, 90 or 120 mm/h rainfall intensity for 90 min. The main results are as follows: surface mounds could promote surface runoff, triggering and shortening runoff generation time, while surface depressions showed contrary results. Whether there was an interval between mounds or depressions also affected the characteristics of runoff. The runoff generation time was 3.8–5.0 times higher for continuous slope than for interval slope, while the runoff yield and runoff coefficient both decreased by approximately 40%. CSR can significantly neutralize the flow-promoting effects of the mounds and the flow-inhibiting effects of the depressions, making the runoff yield and runoff process present a neutral state between the mounds and depressions. CSR prolongs runoff generation time from 1–10 min of MSR to 5–16 min. The runoff yield of CSR presented as 0.12, between 0.17 for mounds and 0.10 for depressions, and so did the runoff coefficient and hydrodynamic parameters. In addition, with rainfall intensity increased, the runoff pattern of CSR and MSR became more similar to each other, and the retarding effects of topography on overland flow were more effective. [ABSTRACT FROM AUTHOR]

To date, the miRNA expression profile of plasma exosomes in women whose pregnancy is complicated by gestational diabetes mellitus (GDM) has not been fully clarified. In this study, differentially expressed miRNAs in plasma exosomes were identified by high-throughput small-RNA sequencing in 12 pregnant women with GDM and 12 with normal glucose tolerance (NGT) and validated in 102 pregnant women with GDM and 101 with NGT. A total of 22 exosomal miRNAs were found, five of which were verified by real-time qPCR. Exosomal miR-423-5p was upregulated, whereas miR-122-5p, miR-148a-3p, miR-192-5p, and miR-99a-5p were downregulated in women whose pregnancy was complicated by GDM. IGF1R and GYS1 as target genes of miR-423-5p, and G6PC3 and FDFT1 as target genes of miR-122-5p were associated with insulin and AMPK signaling pathways and may participate in the regulation of metabolism in GDM. The five exosomal miRNAs had an area under the curve of 0.82 (95%CI, 0.73, ∼0.91) in early prediction of GDM. Our study demonstrates that dysregulated exosomal miRNAs in plasma from pregnant women with GDM might influence the insulin and AMPK signaling pathways and could contribute to the early prediction of GDM. [ABSTRACT FROM AUTHOR]

Integration of thermoelectric generators with phase change materials (PCMs) is expected to be a promising technology for harvesting and converting waste heat to electricity, thus alleviating energy shortage and ecological damage. However, the low output electricity and inherent hardness of PCMs have limited their wide application. Herein, a multifunctional phase-change organohydrogel filled with paraffin wax (PW) microspheres is prepared using Pickering emulsion technology and UV-initiated polymerization. The PW was encapsulated in cellulose nanofibril (CNF)–MXene–Fe3O4 hybrid shells and then inlaid into a flexible polyacrylamide (PAAm) matrix. This unique structural feature provides enhanced thermoelectric conversion, superior shape stability, and excellent mechanical properties. The resultant organohydrogel can continuously harvest waste heat, transfer it into a thermoelectric generation system, and output electrical energy. The generated output voltage and power can reach 627.0 mV and 65.7 mW, respectively. The thermoelectric generator also exhibited good thermal cycling stability (for more than 50 cycles). Besides, the composite organohydrogel possesses satisfactory thermosensing capacity to monitor real-time temperature variation and hot steam behavior. This work opens up opportunities for highly efficient conversion of waste heat to electricity. [ABSTRACT FROM AUTHOR]

This work discusses the electrical break down of tungsten oxide films that form on contacting surfaces of tungsten electrodes in micro-electro-mechanical (MEM) relays. Electrical tests were applied to the contacts of 27 devices to measure the voltage, current and charge required to break down the oxide films, and also to measure the change in current through the contacts as the film healed. The oxide breaks down when an average of 58 $\mu \text{C}$ of electronic charge passes through the oxide, which usually requires applying 1–2 V to drive 100 nA- $10~\mu \text{A}$ of current through the contact. The tungsten oxide heals quickly in laboratory ambient conditions: applying 0.5 V to a contact immediately after breaking down an oxide results in a contact current greater than $5~\mu \text{A}$ , but the same test only induces 1 nA of current 1–5 minutes later. The reduction in contact current with time follows a power law, which is characteristic of charge relaxation in oxides. Additionally, Holm’s experiment shows that current conduction through the contacts is dominated by tunneling through an oxide. These facts together suggest that the break down and healing are electrical processes related to trap accumulation and relaxation in the tungsten oxide. [2021-0161] [ABSTRACT FROM AUTHOR]

Micro-electro-mechanical relays with multiple gate electrodes (i.e., multiple input voltage signals), operated with a tunable body bias voltage, are investigated for more compact and energy-efficient implementation of digital logic circuits. Specifically, a relay design with three gate electrodes of equal area is demonstrated to be capable of performing different digital logic functions for the same input operating voltage (${V} _{\textbf {DD}}$), by adjusting the body bias voltage. Since the lower limit for ${V} _{\textbf {DD}}$ is equal to the switching hysteresis voltage (${V} _{\textbf {H}}$), the magnitude of ${V} _{\textbf {H}}$ is investigated for different combinations of transitioning input voltage signals. It is found that ${V} _{\textbf {H}}$ is larger for fewer transitioning input voltage signals, i.e., reduced effective actuation area of the switching input voltage signal. This can set a practical upper limit for the number of independent gates in a single relay. [ABSTRACT FROM AUTHOR]

Body-biased micro-electro-mechanical (MEM) relays previously have been demonstrated to be a promising alternative to transistors for ultra-low voltage digital logic applications. A basic requirement for reliable relay-based circuit operation is suitably low and stable relay ON-state resistance ($R_{\mathbf {ON}}$). In this work, the effect of body biasing on $\text{R}_{\mathbf {ON}}$ is investigated for relays of different contact designs. It is found that a single direct contact design not only provides for the smallest hysteresis voltage but also the smallest $R_{\mathbf {ON}}$ , making it the most suitable for low voltage applications. Body-biased operation is found to degrade $R_{\mathbf {ON}}$ stability over many ON/OFF switching cycles, however, due to a reduction in contact velocity. [2020-0297] [ABSTRACT FROM AUTHOR]

Introduction: To investigate the expression of asprosin, a novel insulin resistance-related factor, in plasma and placenta of pregnant women with and without gestational diabetes mellitus (GDM).Methods: This is a nested case-control study within the prospective study named Early Diagnosis of Gestational Diabetes Mellitus (EDoGDM). Forty pregnant women with GDM and forty control cases with normal glucose tolerance (NGT) were recruited in the present study. Asprosin levels were tested by ELISA in maternal plasma at 18-20 and 24-28 gestational weeks and before delivery, as well as in umbilical plasma. Asprosin concentrations were compared between GDM and NGT groups, and the relationship between asprosin and other parameters were analyzed. Expression of asprosin in placenta was examined by Western blot and immunohistochemistry.Results: Asprosin was elevated in plasma of GDM pregnant women and their offspring, after adjusted by maternal and neonatal clinical characteristics and lipid profiles. Asprosin was expressed in placenta from both GDM and NGT pregnant women.Discussion: Protein asprosin is expressed in human placenta and is elevated in the plasma of pregnant women complicated with GDM and their offspring. As an insulin resistance-related factor increased before 20 gestational weeks, asprosin may play a role as a potential early biomarker of GDM. [ABSTRACT FROM AUTHOR]

To enable energy-efficient electronic devices for the future, nano-electro-mechanical (NEM) relays are promising due to their high ON/OFF current ratio and potential for low operating voltage. To minimize hysteresis and, consequently, relay operating voltage, it is imperative to reduce the relay contact adhesion, which can be achieved by coating the contacts with anti-stiction self-assembled monolayers. Herein we report a 71% reduction in hysteresis voltage by utilizing a branched perfluorocarbon antistiction molecule: Perfluoro (2,3-Dimethylbutan-2-ol) (PDB) on top of the tungsten contact surfaces. Experimental results show the operation of a PDB-coated NEM relay with abrupt switching, undetectably low OFF-state current, hysteresis voltage as low as 20 mV, and a large ON/OFF current ratio (>107). [ABSTRACT FROM AUTHOR]

The energy efficiency of a CMOS digital logic circuit is fundamentally limited by the nonideal switching behavior of transistors, specifically their nonzero off-state current and finite subthreshold slope. In contrast, mechanical switches (relays) can achieve zero off-state current and perfectly abrupt switching characteristics; therefore, they have attracted growing interest for ultralow-power computing applications. A challenge for electro-mechanical relay technology is to reduce the hysteresis voltage, because this sets the minimum operating voltage of the relays. Herein, we report a surface-micromachinedelectrostatically actuated relaywith <70-mV hysteresis voltage, achieved by designing it to have relatively large structural stiffness and to operate in nonpull-inmode. A relay-based inverter circuit is demonstrated to operate reliably with a switching voltage below 100 mV, representing a significant milestone toward ultralow-power mechanical computing. [ABSTRACT FROM AUTHOR]

Mutations of Tsc1 or Tsc2 can lead to excessive activation of mTORC1 and cause Tuberous Sclerosis Complex (TSC), which is an autosomal dominant genetic disease prominently characterized by seizures, mental retardation and multiorgan hamartoma. In TSC, pathological changes in the central nervous system are the leading cause of death and disability. In decades, series of rodent models have been established by mutating Tsc1 or Tsc2 genes in diverse neural cell lineages to investigate the underlying cellular and molecular mechanisms, however, the cellular origin triggering neural pathological changes in TSC is undetermined. In this study, we generated a novel mouse model involving conditional deletion of Tsc1 in lysozyme 2 (Lyz2)-positive cells which replicated several features of brain lesions including epileptic seizures, megalencephaly, highly enlarged pS6-positive neurons and astrogliosis. In addition, we confirmed that bone marrow-derived myeloid cells including microglia with Tsc1 deficiency are not the decisive lineage in the cerebral pathologies in TSC. These histological assays in our murine model indicate an essential contribution of Lyz2-positive neurons to TSC progression. The Lyz2-positive neural population-specific onset of Tsc1 loss in murine postnatal brain might be the key to pathological phenotypes. Our findings thus provided evidences supporting new insights into the role of Lyz2-positive neurons in TSC events. • A population of Lyz2-positive neurons presents in murine cerebral cortex. • Loss of Tsc1 in Lyz2-positive neuronal cells generate a mouse model mimicking TSC. • Lyz2-positive neuronal cells are expressing GAD67. • Tsc1 deficiency in myeloid cells has less impact on TSC pathology. [ABSTRACT FROM AUTHOR]

Background: Haploidentical donor stem cell transplantation (HID-SCT) based on antithymocyte globulin (ATG) for graft-versus-host disease (GVHD) prophylaxis had achieved a similar incidence of chronic graft-versus-host disease (cGVHD) with human leukocyte antigen (HLA)-matched sibling donor stem cell transplantation (MSD-SCT). However, bronchiolitis obliterans syndrome (BOS), which serves as pulmonary cGVHD, was rarely compared between HID and MSD transplantation., Methods: One thousand four hundred five patients with hematologic malignancies who underwent allogeneic SCT were enrolled in this retrospective study. Based on donor type, we divided the patients into three groups: HID, MSD, and match unrelated donor (MUD) groups. The cumulative incidences and risk factors of BOS were analyzed., Results: The 5-year cumulative incidence of BOS was 7.2% in the whole population. HID transplantation had a lower 5-year cumulative incidence of BOS than MSD transplantation (4.1% vs. 10.0%, p < 0.001) and a similar incidence with MUD transplantation (4.1% vs. 6.2%, p = 0.224). The 5-year cumulative incidence of BOS was lower in the ATG group than that in the non-ATG group in both the whole and MSD populations (4.6% vs. 11.2%, p < 0.001, and 4.1% vs. 11.2%, p = 0.042, respectively). The 5-year incidence of BOS in mixed grafts [peripheral blood stem cell (PBSC) plus bone marrow] group was also lower than that in the PBSC group (4.2% vs. 9.1, p = 0.001). Multivariate analysis showed that HID, ATG, and mixed grafts were protective factors for BOS [odds ratio (OR) 0.3, 95% CI 0.2-0.6, p < 0.001; OR 0.3, 95% CI 0.2-0.7, p = 0.001; OR 0.3, 95% CI 0.1-0.8, p = 0.013], and acute graft-versus-host disease (aGVHD) and cGVHD were independent risk factors for BOS (OR 2.1, 95% 1.1-4.3, p = 0.035; OR 10.1, 95% CI 4.0-25.0, p < 0.001)., Conclusions: HID transplantation had a lower incidence of BOS than MSD transplantation, which might be associated with ATG and mixed grafts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Weng, Fan, Xue, Huang, Xu, Jin, Yu, Ye, Fan, Xuan and Liu.)