Development of Space-Time-Controlled Multi-Stage Pulsed Magnetic Field Forming and Manufacturing Technology at the WHMFC*

In November 2011, the Project of Basic Research of Forming by Space-Time-Controlled Multi-Stage Pulsed Magnetic Field (Stic-Must-PMF) was supported by the National Basic Research Program of China (973 Project, 2011.11-2016.08). It is aimed at achieving breakthroughs in manufacturing technology to solve current problems in forming largescale and complex sheet and tube parts and components, imposed by the limitations of existing equipment and materials forming properties. The objective of our research group focuses on the design principles and structural layout optimization of Stic-Must-PMF facility. And this paper will report the development of Stic-Must-PMF forming and manufacturing technology at the Wuhan National High Magnetic Field Center (WHMFC) including numerical modeling, experimental setup and experimental studies

A Unique Human Immunoglobulin Heavy Chain Variable Domain-Only CD33 CAR for the Treatment of Acute Myeloid Leukemia

Acute myeloid leukemia (AML) remains a challenging pediatric and adult disease. Given the elevated expression of the CD33 antigen on leukemic blasts, therapeutic approaches to AML now feature the approved antibody drug conjugate (Mylotarg, GO) and investigational CART cell approaches incorporating CD33-binding domains derived from humanized scFvs. We designed a functional chimeric antigen receptor utilizing a human targeting sequence, derived from a heavy chain variable domain, termed CAR33VH. Lentiviral-based expression vectors which encoded CAR constructs incorporating the novel binding domain (CAR33VH), or the My96 scFv control binder (My96CAR) in frame with a CD8 hinge and transmembrane domain, a 4-1BB costimulatory domain and a CD3 zeta activation domain, were transduced into primary human CD4+ and CD8+ T cells, and CAR expression was confirmed by flow cytometry. CAR33VH, similar to My96CAR, demonstrated robust and specific cytotoxicity in short-term and long-term co-incubation killing assays against CD33+ AML lines. In overnight cytokine release assays in which CAR T cells were challenged with the CD33+ tumor cells HL-60, MOLM-14 and KG-1a, CAR33VH elicited IFN-gamma, TNF-alpha and IL-2. This was seen with CD33+ cell lines, but not when CAR T were cultured alone. Studies with a CD33− cell line engineered to stably express the full length CD33 variant 1, or the naturally occurring CD33 splice variant 2, revealed that both CAR33VH and My96CAR, target the V domain of CD33, suggesting a similar therapeutic profile. Colony-formation assays utilizing peripheral blood CD34+ hematopoietic stem cells treated with CAR33VH, My96CAR, or with an untransduced T cell control, yielded similar numbers of BFU-E erythroid and CFU-GM myeloid colonies, suggesting a lack of CAR-related overt toxicity. In an in vivo AML model, NSG mice engrafted with MOLM-14 cells stably expressing firefly luciferase, both CAR33VH and CARMy96 efficiently eliminated tumors. In conclusion, we demonstrate for the first time the feasibility and efficacy of employing human variable domain-only binder derived from a phage display library in an anti-AML CAR design. CAR33VH, comprised of a human heavy-chain variable fragment-only antigen binding domain, was efficient in tumor killing in vitro and in vivo, and showed comparable functionality to the scFv-based My96CAR

Graphene Quantum Dots Doped PVDF(TBT)/PVP(TBT) Fiber Film with Enhanced Photocatalytic Performance

We report the fabrication of polyvinylidene fluoride (tetrabutyl titanate)/polyvinyl pyrrolidone ((tetrabutyl titanate))-graphene quantum dots [PVDF(TBT)/PVP(TBT)-GQDs] film photocatalyst with enhanced photocatalytic performance. The polyvinylidene fluoride (tetrabutyl titanate)/polyvinyl pyrrolidone ((tetrabutyl titanate)) [PVDF(TBT)/PVP(TBT)] film was first prepared with a dual-electrospinning method and then followed by attaching graphene quantum dots (GQDs) to the surface of the composite film through a hydrothermal method. Later, part of the PVP in the composite film was dissolved by a hydrothermal method. As a result, a PVDF(TBT)/PVP(TBT)-GQDs film photocatalyst with a larger specific surface area was achieved. The photocatalytic degradation behavior of the PVDF(TBT)/PVP(TBT)-GQDs film photocatalyst was examined by using Rhodamine B as the target contaminant. The PVDF(TBT)/PVP(TBT)-GQDs photocatalyst showed a higher photocatalytic efficiency than PVDF(TBT)-H2O, PVDF(TBT)/PVP(TBT)-H2O, and PVDF(TBT)-GQDs, respectively. The enhanced photocatalytic efficiency can be attributed to the broader optical response range of the PVDF(TBT)/PVP(TBT)-GQDs photocatalyst, which makes it useful as an effective photocatalyst under white light irradiation

Limits of oxygen isotope palaeoaltimetry in Tibet

Measurements of stable water isotopes (oxygen and hydrogen) are commonly used to estimate palaeoelevation and quantify past changes in surface height across Tibet. Isotope palaeoaltimetry is often based on simple Rayleigh fractionation of a “parcel of air”, but must make a considerable number of approximations and assumptions. In this paper, we elaborate on the practicability of oxygen water isotopes in palaeoaltimetry, and evaluate a recent challenge to the palaeoaltimetry community. First, we examine the isotopic composition of oxygen (ẟ18O) versus altitude relationship in a set of five topographic realisations of Tibet using an isotope-enabled palaeoclimate model for the mid-Eocene, a period where a variety of topographic ‘uplift’ models have been proposed, and compare it to modern relationships. Second, we investigate whether isotopic composition is a good predictor of more modest changes in topography, such as the introduction of a valley system or uplift of only part of the Tibetan region. The aim of the paper is not to perform a direct comparison to data, but to use the model to further refine knowledge of the strengths and limitations of using oxygen isotopes in palaeoaltimetry. We find that oxygen isotope palaeoaltimetry works surprisingly well, with the exception that it could not identify low elevation valley systems bounded by high elevations because the isotopic composition of the water in the air becomes depleted at the first high elevation that an air parcel passes over and does not recover when it descends into the valley. Hence, isotope-based elevations are biased towards mountain range peaks. Overall, the application of oxygen isotope palaeoaltimetry does have value, but would be further strengthened when employed together with isotope-enabled models. In conjunction with other techniques such as terrestrial thermal lapse rates and energy conservation approaches, over a wide spatial region, a more accurate and fully three-dimension view of complex palaeo-topography is increasingly possible, which will in turn improve the precision of these palaeoaltimeters

The late Eocene rise of SE Tibet formed an Asian ‘Mediterranean’ climate

Southeastern (SE) Tibet forms the transition zone between the high interior Tibetan Plateau and the lowlands of southwest China. So understanding the elevation history of SE Tibet, a biodiversity hotspot, enlightens our understanding of the interactions between tectonics, monsoon dynamics and biodiversity. Here we reconstruct the uplift history of the Markam Basin, SE Tibet, during the middle−late Eocene based on U − Pb dating, plant fossil assemblages, and stable and clumped isotope analyses. Our results suggest that the floor of the Markam Basin was at an elevation of 2.6 ± 0.9 km between 42 Ma and 39 Ma, where the mean annual air temperature (MAAT) was 13.2 ± 2.4 °C. The basin then rose rapidly to 3.8 (+0.6/−0.8) km before 36 Ma. Integrated with existing paleoelevation data, we propose that the high plateau boundary (∼3.0 km) of SE Tibet formed during the late Eocene. Numerical climate modeling with realistic paleo-landscapes shows that with the rise of SE Tibet, a Mediterranean-like climate developed in the region characterized by bi-modal precipitation with two wet seasons in boreal spring and autumn. The high topographic relief of SE Tibet, coupled with this distinctive Mediterranean-like climate system, helped develop the high biodiversity of the Hengduan Mountains

A distinctive Eocene Asian monsoon and modern biodiversity resulted from the rise of eastern Tibet

The uplift of eastern Tibet, Asian monsoon development and the evolution of globally significant Asian biodiversity are all linked, but in obscure ways. Sedimentology, geochronology, clumped isotope thermometry, and fossil leaf-derived numerical climate data from the Relu Basin, eastern Tibet, show at ∼50–45 Ma the basin was a hot (mean annual air temperature, MAAT, ∼27 °C) dry desert at low-elevation of 0.6 ± 0.6 km. Rapid basin rise to 2.0 ± 0.9 km at 45–42 Ma and to 2.9 ± 0.9 km at 42–40 Ma, with MAATs of ∼20 and ∼16 °C, respectively, accompanied seasonally varying increased annual precipitation to >1500 mm. From ∼39 to 34 Ma, the basin attained 3.5 ± 1.0 km, near its present-day elevation (∼3.7 km), and MAAT cooled to ∼6 °C. Numerically-modelled Asian monsoon strength increased significantly when this Eocene uplift of eastern Tibet was incorporated. The simulation/proxy congruence points to a distinctive Eocene Asian monsoon, quite unlike that seen today, in that it featured bimodal precipitation and a winter-wet regime, and this enhanced biodiversity modernisation across eastern Asia. The Paleogene biodiversity of Asia evolved under a continually modifying monsoon influence, with the modern Asian monsoon system being unique to the present and a product of a long gradual development in the context of an ever-changing Earth system

The rise and demise of the Paleogene Central Tibetan Valley

Reconstructing the Paleogene topography and climate of central Tibet informs understanding of collisional tectonic mechanisms and their links to climate and biodiversity. Radiometric dates of volcanic/sedimentary rocks and paleotemperatures based on clumped isotopes within ancient soil carbonate nodules from the Lunpola Basin, part of an east-west trending band of basins in central Tibet and now at 4.7 km, suggest that the basin rose from 4.0 km by 29 Ma. The height change is quantified using the rates at which wet-bulb temperatures ( ) decline at land surfaces as those surface rise. In this case, fell from ~8°C at ~38 Ma to ~1°C at 29 Ma, suggesting at least ~2.0 km of surface uplift in ~10 Ma under warm Eocene to Oligocene conditions. These results confirm that a Paleogene Central Tibetan Valley transformed to a plateau before the Neogene

Metabolic Brain Network Analysis of FDG-PET in Alzheimer’s Disease Using Kernel-Based Persistent Features

Recent research of persistent homology in algebraic topology has shown that the altered network organization of human brain provides a promising indicator of many neuropsychiatric disorders and neurodegenerative diseases. However, the current slope-based approach may not accurately characterize changes of persistent features over graph filtration because such curves are not strictly linear. Moreover, our previous integrated persistent feature (IPF) works well on an rs-fMRI cohort while it has not yet been studied on metabolic brain networks. To address these issues, we propose a novel univariate network measurement, kernel-based IPF (KBI), based on the prior IPF, to quantify the difference between IPF curves. In our experiments, we apply the KBI index to study fluorodeoxyglucose positron emission tomography (FDG-PET) imaging data from 140 subjects with Alzheimer’s disease (AD), 280 subjects with mild cognitive impairment (MCI), and 280 healthy normal controls (NC). The results show the disruption of network integration in the progress of AD. Compared to previous persistent homology-based measures, as well as other standard graph-based measures that characterize small-world organization and modular structure, our proposed network index KBI possesses more significant group difference and better classification performance, suggesting that it may be used as an effective preclinical AD imaging biomarker

ANP32E induces tumorigenesis of triple‐negative breast cancer cells by upregulating E2F1

Triple‐negative breast cancer (TNBC) lacks expression of estrogen receptor (ER), progesterone receptor, and the HER2 receptor; it is highly proliferative and becomes the deadliest forms of breast cancer. Effective prognostic methods and therapeutic targets for TNBC are required to improve patient outcomes. Here, we report that acidic nuclear phosphoprotein 32 family member E (ANP32E), which promotes cell proliferation in mammalian development, is highly expressed in TNBC cells compared to other types of breast cancer. High expression of ANP32E correlates significantly with worse overall survival (OS; P < 0.001) and higher risks of disease recurrence (P < 0.001) in patients with TNBC. Univariate and multivariate Cox‐regression models show that ANP32E is an independent prognostic factor in TNBC. Furthermore, we discovered that ANP32E promotes tumor proliferation in vitro by inducing G1/S transition, and ANP32E inhibition suppresses tumor formation in vivo. By examining the expression of E2F1, cyclin E1, and cyclin E2, we discovered that ANP32E promotes the G1/S transition by transcriptionally inducing E2F1. Taken together, our study shows that ANP32E is an efficient prognostic marker, and it promotes the G1/S transition and induces tumorigenesis of TNBC cells by transcriptionally inducing E2F1