Antimicrobial Mechanism of pBD2 against Staphylococcus aureus.

Antimicrobial peptides (AMPs) show high antibacterial activity against pathogens, which makes them potential new therapeutics to prevent and cure diseases. Porcine beta defensin 2 (pBD2) is a newly discovered AMP and has shown antibacterial activity against different bacterial species including multi-resistant bacteria. In this study, the functional mechanism of pBD2 antibacterial activity against Staphylococcus aureus was investigated. After S. aureus cells were incubated with different concentrations of pBD2, the morphological changes in S. aureus and locations of pBD2 were detected by electron microscopy. The differentially expressed genes (DEGs) were also analyzed. The results showed that the bacterial membranes were broken, bulging, and perforated after treatment with pBD2; pBD2 was mainly located on the membranes, and some entered the cytoplasm. Furthermore, 31 DEGs were detected and confirmed by quantitative real-time PCR (qRT-PCR). The known functional DEGs were associated with transmembrane transport, transport of inheritable information, and other metabolic processes. Our data suggest that pBD2 might have multiple modes of action, and the main mechanism by which pBD2 kills S. aureus is the destruction of the membrane and interaction with DNA. The results imply that pBD2 is an effective bactericide for S. aureus, and deserves further study as a new therapeutic substance against S. aureus.

Effective Prevention and Treatment of Acute Leukemias in Mice by Activation of Thermogenic Adipose Tissues.

Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are common hematological malignancies in adults. Despite considerable research advances, the development of standard therapies, supportive care, and prognosis for the majority of AML and ALL patients remains poor and the development of new effective therapy is urgently needed. Here, it is reported that activation of thermogenic adipose tissues (TATs) by cold exposure or ß3-adrenergic receptor agonists markedly alleviated the development and progression of AML and ALL in mouse leukemia models. TAT activation (TATA) monotherapy substantially reduces leukemic cells in bone marrow and peripheral blood, and suppresses leukemic cell invasion, including hepatomegaly and splenomegaly. Notably, TATA therapy prolongs the survivals of AML- and ALL-bearing mice. Surgical removal of thermogenic brown adipose tissue (BAT) or genetic deletion of uncoupling protein 1 (UCP1) largely abolishes the TATA-mediated anti-leukemia effects. Metabolomic pathway analysis demonstrates that glycolytic metabolism, which is essential for anabolic leukemic cell growth, is severely impaired in TATA-treated leukemic cells. Moreover, a combination of TATA therapy with chemotherapy produces enhanced anti-leukemic effects and reduces chemotoxicity. These data provide a new TATA-based therapeutic paradigm for the effective treatment of AML, ALL, and likely other types of hematological malignancies.

Cloning, expression and characterization of antimicrobial porcine ß defensin 1 in Escherichia coli.

Porcine ß defensin 1 (pBD1) is a cationic antimicrobial peptide with three pairs of disulfide bonds. When expressed in insect cells, two polypeptides of different length (pBD1(38) and pBD1(42)) accumulated, which differed by N-terminal truncation. However, only pBD1(42) was found in pigs. pBD1(42) had stronger antimicrobial activity than pBD1(38), and thus could be a good candidate as a bactericidal agent for pigs. In this study, pBD1(42) gene, obtained by RT-PCR using the tongue total RNA as a template, was cloned into pET30a expression vector and transformed into Escherichia coli BL21 (DE3) plysS. The recombinant pBD1(42) was expressed after induction by IPTG and purified by His tag affinity column with 90% purity. The recombinant pBD1(42) exhibited antimicrobial activity against both Gram-positive Staphylococcus aureus and Gram-negative E. coli including the multi-resistant E. coli. The minimum inhibitory concentrations (MICs) of recombinant pBD1(42) against tested bacteria were 100 µg/mL for E. coli and 80 µg/mL for S. aureus. In addition, pBD1(42) showed low hemolytic activity and high thermal stability. These properties are relevant for the biotechnological applications of the peptide.

Simulation of Total Ionizing Dose Effects Technique for CMOS Inverter Circuit.

The total ionizing dose (TID) effect significantly impacts the electrical parameters of fully depleted silicon on insulator (FDSOI) devices and even invalidates the on-off function of devices. At present, most of the irradiation research on the circuit level is focused on the single event effect, and there is very little research on the total ionizing dose effect. Therefore, this study mainly analyzes the influence of TID effects on a CMOS inverter circuit based on 22 nm FDSOI transistors. First, we constructed and calibrated an N-type FDSOI metal-oxide semiconductor (NMOS) structure and P-type FDSOI metal-oxide semiconductor (PMOS) structure. The transfer characteristics and trapped charge distribution of these devices were studied under different irradiation doses. Next, we studied the TID effect on an inverter circuit composed of these two MOS transistors. The simulation results show that when the radiation dose was 400 krad (Si), the logic threshold drift of the inverter was approximately 0.052 V. These results help further investigate the impact on integrated circuits in an irradiation environment.

A Novel DTSCR Structure with High Holding Voltage and Enhanced Current Discharge Capability for 28 nm CMOS Technology ESD Protection.

To cope with the much narrower ESD design window in 28 nm CMOS technology, a novel diode-triggered silicon-controlled rectifier with an extra discharge path (EDP-DTSCR) for ESD protection is proposed in this paper. Compared with the traditional DTSCR, the proposed DTSCR has an enhanced current discharge capability that is achieved by creating a slave SCR path in parallel with the master SCR path. Moreover, the improved triggering and holding characteristic can be obtained by the proposed EDP-DTSCR. By sharing the anode emitter junction, a slave SCR path is constructed that is symmetrical to the position of the master SCR path to add an additional ESD discharge path to the EDP-DTSCR. In this way, the current discharge capability of the entire device is obviously improved. The TCAD simulation result shows that the proposed device has a remarkably lower on-resistance compared with the traditional DTSCR and the DTSCR with p-type guard ring (PGR-DTSCR). In addition, it is structurally optimized to further increase the holding voltage and reduce the trigger voltage to improve the anti-latching capability of the device, which is more conducive to the ESD protection window application of 28 nm CMOS technology.

MOSs-String-Triggered Silicon-Controlled Rectifier (MTSCR) ESD Protection Device for 1.8 V Application.

In this work, a new low voltage-triggered silicon-controlled rectifier named MTSCR is realized in a 65 nm CMOS process for low voltage-integrated circuits electrostatic discharge (ESD) protections. The MTSCR incorporates an external NMOSs-string, which drives the internal NMOS (INMOS) of MTSCR to turn on, and then the INMOS drive SCR structure to turn on. Compared with the existing low trigger voltage (Vt1) ESD component named diodes-string-triggered SCR (DTSCR), the MTSCR can realize the same low Vt1 characteristic but less area penalty of ~44.3% reduction. The results of the transmission line pulsing (TLP) measurement shows that the MTSCR possesses above 2.42 V holding voltage (Vh) and a low Vt1 of ~5.03 V, making it very suitable for the ESD protections for 1.8 V input/output (I/O) ports in CMOS technologies.

Ultra-Low-Voltage-Triggered Silicon Controlled Rectifier ESD Protection Device for 2.5 V Nano Integrated Circuit.

In this paper, an improved low-voltage-triggered silicon-controlled rectifier (LVTSCR) called an ultra-low-voltage-triggered SCR (ULVTSCR) is proposed and fabricated in a 40-nm CMOS process. By adding an external NMOSs-chain triggering component to the conventional LVTSCR, the proposed ULVTSCR can realize ~2 V lower trigger voltage. Meanwhile, the trigger voltage of the ULVTSCR is adjustable with the number of its incorporated NMOS transistors. Compared with the existing Diodes-chain Triggered SCR (DTSCR) scheme, the NMOSs-chain triggered ULVTSCR possesses a 25% lowered overshoot voltage in the same area consumption, and thus it is more suitable for 2.5 V circuits ESD protections considering the CDM protection applications.

Embedding cognitive framework with self-attention for interpretable knowledge tracing.

Recently, deep neural network-based cognitive models such as deep knowledge tracing have been introduced into the field of learning analytics and educational data mining. Despite an accurate predictive performance of such models, it is challenging to interpret their behaviors and obtain an intuitive insight into latent student learning status. To address these challenges, this paper proposes a new learner modeling framework named the EAKT, which embeds a structured cognitive model into a transformer. In this way, the EAKT not only can achieve an excellent prediction result of learning outcome but also can depict students' knowledge state on a multi-dimensional knowledge component(KC) level. By performing the fine-grained analysis of the student learning process, the proposed framework provides better explanatory learner models for designing and implementing intelligent tutoring systems. The proposed EAKT is verified by experiments. The performance experiments show that the EAKT can better predict the future performance of student learning(more than 2.6% higher than the baseline method on two of three real-world datasets). The interpretability experiments demonstrate that the student knowledge state obtained by EAKT is closer to ground truth than other models, which means EAKT can more accurately trace changes in the students' knowledge state.

MORTALIN-Ca2+ axis drives innate rituximab resistance in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma, with the combination of rituximab and chemotherapy being the standard treatment for it. Although rituximab monotherapy has a remarkable response rate, drug resistance with unclear mechanisms and lack of effective second-line therapy limit the survival benefits of patients with lymphoma. Here, we report that MORTALIN is highly expressed and correlates with resistance to rituximab-based therapy and poor survival in patients with DLBCL. Mechanistically, gain- and loss-of-function experiments revealed that the voltage-dependent anion channel 1-binding protein, MORTALIN, regulated Ca2+ release from the endoplasmic reticulum through mitochondria-associated membrane, facilitating AP1-mediated cell proliferation and YY-1-mediated downregulation of FAS in DLBCL cells. These dual mechanisms contribute to rituximab resistance. In mouse models, genetic depletion of MORTALIN markedly increased the antitumor activity of rituximab. We shed mechanistic light on MORTALIN-Ca2+-CaMKII-AP1-mediated proliferation and MORTALIN-Ca2+-CaMKII-inhibited death receptor in DLBCL, leading to rituximab resistance, and propose MORTALIN as a novel target for the treatment of DLBCL.

Lenvatinib for effectively treating antiangiogenic drug-resistant nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) clinical trials show that antiangiogenic drugs (AADs) fail to achieve the expected efficacy, and combining AAD with chemoradiotherapy does not show superiority over chemoradiotherapy alone. Accumulating evidence suggests the intrinsic AAD resistance in NPC patients with poorly understood molecular mechanisms. Here, we describe NPC-specific FGF-2 expression-triggered, VEGF-independent angiogenesis as a mechanism of AAD resistance. Angiogenic factors screening between AAD-sensitive cancer type and AAD-resistant NPC showed high FGF-2 expression in NPC in both xenograft models and clinical samples. Mechanistically, the FGF-2-FGFR1-MYC axis drove endothelial cell survival and proliferation as an alternative to VEGF-VEGFR2-MYC signaling. Genetic knockdown of FGF-2 in NPC tumor cells reduced tumor angiogenesis, enhanced AAD sensitivity, and reduced pulmonary metastasis. Moreover, lenvatinib, an FDA recently approved multi-kinase inhibitor targeting both VEGFR2 and FGFR1, effectively inhibits the tumor vasculature, and exhibited robust anti-tumor effects in NPC-bearing nude mice and humanized mice compared with an agent equivalent to bevacizumab. These findings provide mechanistic insights on FGF-2 signaling in the modulation of VEGF pathway activation in the NPC microenvironment and propose an effective NPC-targeted therapy by using a clinically available drug.

Dietary ketone body-escalated histone acetylation in megakaryocytes alleviates chemotherapy-induced thrombocytopenia.

Chemotherapy-induced thrombocytopenia (CIT) is a severe complication in patients with cancer that can lead to impaired therapeutic outcome and survival. Clinically, therapeutic options for CIT are limited by severe adverse effects and high economic burdens. Here, we demonstrate that ketogenic diets alleviate CIT in both animals and humans without causing thrombocytosis. Mechanistically, ketogenic diet-induced circulating ß-hydroxybutyrate (ß-OHB) increased histone H3 acetylation in bone marrow megakaryocytes. Gain- and loss-of-function experiments revealed a distinct role of 3-ß-hydroxybutyrate dehydrogenase (BDH)-mediated ketone body metabolism in promoting histone acetylation, which promoted the transcription of platelet biogenesis genes and induced thrombocytopoiesis. Genetic depletion of the megakaryocyte-specific ketone body transporter monocarboxylate transporter 1 (MCT1) or pharmacological targeting of MCT1 blocked ß-OHB-induced thrombocytopoiesis in mice. A ketogenesis-promoting diet alleviated CIT in mouse models. Moreover, a ketogenic diet modestly increased platelet counts without causing thrombocytosis in healthy volunteers, and a ketogenic lifestyle inversely correlated with CIT in patients with cancer. Together, we provide mechanistic insights into a ketone body-MCT1-BDH-histone acetylation-platelet biogenesis axis in megakaryocytes and propose a nontoxic, low-cost dietary intervention for combating CIT.

Robust and Latch-Up-Immune LVTSCR Device with an Embedded PMOSFET for ESD Protection in a 28-nm CMOS Process.

Low-voltage-triggered silicon-controlled rectifier (LVTSCR) is expected to provide an electrostatic discharge (ESD) protection for a low-voltage integrated circuit. However, it is normally vulnerable to the latch-up effect due to its extremely low holding voltage. In this paper, a novel LVTSCR embedded with an extra p-type MOSFET called EP-LVTSCR has been proposed and verified in a 28-nm CMOS technology. The proposed device possesses a lower trigger voltage of ~ 6.2 V and a significantly higher holding voltage of ~ 5.5 V with only 23% degradation of the failure current under the transmission line pulse test. It is also shown that the EP-LVTSCR operates with a lower turn-on resistance of ~ 1.8 Ω as well as a reliable leakage current of ~ 1.8 nA measured at 3.63 V, making it suitable for ESD protections in 2.5 V/3.3 V CMOS processes. Moreover, the triggering mechanism and conduction characteristics of the proposed device were explored and demonstrated with TCAD simulation.

Analysis of the antimicrobial mechanism of porcine beta defensin 2 against E. coli by electron microscopy and differentially expressed genes.

Porcine beta defensin 2 (pBD2) is a cationic antimicrobial peptide with broad spectrum antibacterial activity, which makes it a potential alternative to antibiotics to prevent and cure diseases of pigs. However, development of pBD2 as an effective antibiotic agent requires molecular understanding of its functional mechanism against pathogens. In this study, we investigated the functional mechanism of pBD2 antibacterial activity. Escherichia coli was incubated with different pBD2 concentrations for different times. Electron microscopy was used to analyze the locations of pBD2 and its induced morphological changes in E. coli. Gene expression analysis was also performed to further understand the molecular changes of E. coli in response to pBD2 incubation. The results demonstrated that E. coli membranes were broken, holed, and wrinkled after treatment with pBD2, and pBD2 was located on the cell membranes and manly in the cytoplasm. Furthermore, 38 differentially expressed genes (DEGs) were detected, successfully sequenced and confirmed by quantitative real-time PCR (qRT-PCR). Most of the known functional DEGs were associated with DNA transcription and translation and located in the cytoplasm. Collectively, the results suggest that pBD2 could have multiple modes of action and the main mechanism for killing E. coli might be influence on DNA transcription and translation by targeting intracellular molecules after membrane damage, although transport and metabolism proteins were also affected.