Miracle-dz/UniFAR-FTUs huggingface dataset:
Carbon ion irradiation plus CTLA4 blockade elicits therapeutic immune responses in a murine tumor model

Radiotherapy can act as an in situ vaccine thereby activating tumor-specific immune responses that prevent tumor outgrowth in treated patients. While carbon ion radiotherapy has shown superior biophysical properties over conventional photon irradiation, the immunological effects induced have remained largely uncovered. The combination of radiotherapy with immune checkpoint inhibition (radioimmunotherapy) aims at further enhancement of anti-tumor immunity; however, studies on the immune cell composition in irradiated and distant tumors following radioimmunotherapy with carbon ions are scarce. We have established a bilateral tumor model by time shifted transplantation of murine, Her2+ EO771 tumor cells onto the flanks of immune competent mice followed by selective irradiation of the primal tumor, while sparing the consecutive tumor. We demonstrate that αCTLA4-but not αPD-L1-based radioimmunotherapy induces complete tumor rejection in our model. Intriguingly, local tumor control caused in situ immunization resulting even in eradication of non-irradiated, distant tumors. Moreover, cured mice were protected against EO771 rechallenge indicative of long lasting, tumor-protective immunological memory. Deconvolution of the treatment induced immunological effects by single cell RNA-sequencing (scRNA-seq) and concomitant flow cytometric analyses revealed in irradiated tumors predominating myeloid cells that developed into distinct tumor-associated macrophage clusters with upregulated expression of TNF and IL1 responsive genes, as well as activation of NK cells. Non-irradiated tumors showed higher frequencies of naïve T cells in irradiated mice, which were activated when combined with CTLA4 blockade. In conclusion, radioimmunotherapy with carbon ions plus CTLA4 inhibition reshapes the tumor-infiltrating immune cell composition and can induce complete rejection even of non-irradiated tumors. Our data present a rationale to combine radiotherapy approach with CTLA4 blockade to achieve durable anti-tumor immunity. Evaluation of future radioimmunotherapy approaches should thus not only focus on the immunological impacts at the site of irradiation but should also consider systemic immunological effects that might affect outgrowth of non-irradiated tumors.
Frequent pulse disturbances influence resistance and resilience in tropical marine microbial communities

The Johor Strait separates the island of Singapore from Peninsular Malaysia. A 1-kilometer causeway built in the early 1920s in the middle of the Strait effectively blocks water flowing to/from either side, resulting in low water turnover rates and build-up of nutrients in the inner Strait. We have previously shown that short-term rather than seasonal environmental changes influence microbial community composition in the Johor Strait. Here, we present a temporally-intensive study that uncovers the drivers keeping the microbial populations in check. We sampled the surface water at four sites in the inner Eastern Johor Strait every other day for two months, measured various water quality parameters, and analysed 16S amplicon sequences and flow-cytometry counts. We discovered that microbial community succession revolves around a common stable state resulting from frequent pulse disturbances. Among these, sporadic riverine freshwater input and regular tidal currents influence bottom-up controls including the availability of the limiting nutrient nitrogen and its biological release in readily available forms. From the top-down, marine viruses and predator bacteria (e.g. Saprospiraceae family) limit the proliferation of microbes in the water. Harmful algal blooms, which have been observed historically in these waters, may occur when there are gaps in the top-down and bottom-up controls. This study uncovers the complex interaction between these factors contributing to a low-resistance but high-resilience microbial community and speculate about the rare events that could lead to the occurrence of an algal bloom.
An assessment of Nano-RECall: Interpretation of Oxford Nanopore sequence data for HIV-1 drug resistance testing

Introduction Oxford Nanopore Technologies (ONT) offer sequencing with low-capital-layout sequencing options, which could assist in expanding HIV drug resistance testing to resource limited settings. However, sequence analysis remains time time-consuming and reliant on skilled personnel. Moreover, current ONT bioinformatic pipelines provide a single consensus sequence that is not equivalent to Sanger sequencing, as drug resistance is often detected in mixed populations. We have therefore investigated an integrated bioinformatic pipeline, Nano-RECall, for seamless drug resistance of low read coverage ONT sequence data from affordable Flongle or MinION flow cells. Methods We compared Sanger sequencing to ONT sequencing of the same HIV-1 subtype C polymerase chain reaction (PCR) amplicons, respectively using RECall and the novel Nano-RECall bioinformatics pipelines. Amplicons were from separate assays a) Applied Biosystems HIV-1 Genotyping Kit (ThermoFisher) spanning protease (PR) to reverse transcriptase (RT) (PR-RT) (n=46) and b) homebrew integrase (IN) (n=21). We investigated optimal read-depth by assessing the coefficient of variation (CV) of nucleotide proportions for various read-depths; and between replicates of 400 reads. The agreement between Sanger sequences and ONT sequences were assessed at nucleotide level, and at codon level for Stanford HIV drug resistance database mutations. Results The coefficient of variation of ONT minority variants plateaued after a read depth of 400-fold implying limited benefit of additional depth and replicates of 400 reads showed a CV of ∼6 % for a representative position. The average sequence similarity between ONT and Sanger sequences was 99.3% (95% CI: 99.1-99.4%) for PR-RT and 99.6% (95% CI: 99.4-99.7%) for INT. Drug resistance mutations did not differ for 21 IN sequences; 16 mutations were detected by both ONT- and Sanger sequencing. For the 46 PR and RT sequences, 245 mutations were detected by either ONT or Sanger, of these 238 (97.1%) were detected by both. Conclusions The Nano-RECall pipeline, freely available as a downloadable application on a Windows computer, provides Sanger-equivalent HIV drug resistance interpretation. This novel pipeline combined with a simple workflow and multiplexing samples on ONT flow-cells would contribute to making HIV drug resistance sequencing feasible for resource limited settings.
Mitotic DNA damage promotes chromokinesin-mediated missegregation of polar chromosomes in cancer cells

DNA damage response (DDR) during interphase involves active signalling and repair to ensure genomic stability. However, how mitotic cells respond to DNA damage remains poorly understood. Supported by correlative live-/fixed-cell microscopy analysis we found that mitotic cells exposed to several cancer chemotherapy compounds acquire and signal DNA damage, regardless of how they interact with DNA. In-depth analysis upon long-term DNA damage during mitosis revealed a spindle assembly checkpoint (SAC)-dependent, but DDR-independent, mitotic delay. This delay was due to the presence of misaligned chromosomes that ultimately satisfy the SAC and missegregate, leading to micronuclei formation. Mechanistically, we show that long-term mitotic DNA damage specifically stabilizes kinetochore-microtubule attachments in cancer cells, causing the missegregation of polar chromosomes due to the action of arm-ejection forces by chromokinesins. Overall, these findings unveil that long-term therapeutic DNA damage regimens contribute to genomic instability through a surprising link between the stabilization of kinetochore-microtubule attachments and chromokinesin-mediated missegregation of polar chromosomes in cancer cells.
The novel compensatory reciprocal interplay between neutrophils and monocytes drives cancer progression

Myeloid cells comprise the majority of immune cells in tumors, contributing to tumor growth and therapeutic resistance. Incomplete understanding of myeloid cells response to tumor driver mutation and therapeutic intervention impedes effective therapeutic design. Here, by leveraging CRISPR/Cas9-based genomic editing, we generated a mouse model that is deficient of all monocyte chemoattractant proteins (MCP). Using this strain, we effectively abolished monocyte infiltration in glioblastoma (GBM) and hepatocellular carcinoma (HCC) murine models, which were enriched for monocytes or neutrophils, respectively. Remarkably, eliminating monocyte chemoattraction invokes a significant compensatory neutrophil influx in GBM, but not in HCC. Single-cell RNA sequencing revealed that intratumoral neutrophils promoted proneural-to-mesenchymal transition in GBM, and supported tumor aggression by facilitating hypoxia response via TNF production. Importantly, genetic or pharmacological inhibiting neutrophil in HCC or qMCP-KO GBM extended the survival of tumor-bearing mice. Our findings emphasize the importance of targeting both monocytes and neutrophils simultaneously for cancer immunotherapy. In Brief Eliminating monocyte chemoattraction invokes compensatory neutrophil influx in tumor, and vice versa, rendering current myeloid-targeted therapies ineffective. Using genetic and pharmacological approaches combined with novel mouse models of GBM and HCC, we provide credence advocating for combinational therapies aiming at inhibiting both monocytes and neutrophils simultaneously. Highlights • Blocking monocyte chemoattraction results in increased neutrophil infiltration. • Increased neutrophil recruitment induces GBM PN to MES transition. • Inhibiting neutrophil infiltration in monocyte-deficient tumors improves mouse GBM survival. • Blocking neutrophil, but not monocyte, infiltration in HCC prolongs mouse survival.
GaN-based complementary metal–oxide–semiconductor inverter with normally off Pch and Nch MOSFETs fabricated using polarisation-induced holes and electron channels

Gallium nitride (GaN)-based P-channel (Pch) and N-channel (Nch) metal-oxide-semiconductor field-effect transistors (MOSFETs) with normally off operations were realised. Both Pch and Nch MOSFETs were monolithically fabricated in a polarisation-junction platform wafer. The platform wafer was constructed with a GaN/aluminium GaN/GaN double heterostructure, which has both two-dimensional hole gas (2DHG) and 2D electron gas (2DEG). The drain currents of Pch and Nch MOSFETs flow through 2DHG and 2DEG, respectively. The threshold gate voltages of the fabricated Pch and Nch MOSFETs were -2.7 and 6.7 V, respectively. It was shown that the threshold voltage and the on-state resistance of the Pch MOSFET can be controlled by adjusting the 2DEG potential. Furthermore, using Pch and Nch MOSFETs, complementary MOS inverter operation was demonstrated.
GLUT1 is redundant in hypoxic and glycolytic nucleus pulposus cells of the intervertebral disc

Glycolysis is central to homeostasis of nucleus pulposus (NP) cells in the avascular intervertebral disc. Since the glucose importer, GLUT1, is a highly enriched phenotypic marker of NP cells, we hypothesized that it is vital for the development and post-natal maintenance of the disc. Surprisingly, primary NP cells treated with two well-characterized GLUT1 inhibitors maintained normal rates of glycolysis and ATP production, indicating intrinsic compensatory mechanisms. We show in vitro that NP cells mitigate GLUT1 loss by rewiring glucose import through GLUT3. Noteworthy, we demonstrate that substrates, such as glutamine and palmitate, do not compensate for glucose restriction resulting from dual inhibition of GLUT1/3 and inhibition compromises long-term cell viability. To investigate the redundancy of GLUT1 function in NP, we generated two NP-specific knockout mice: Krt19CreERT; Glut1f/f and Foxa2Cre; Glut1f/f. Noteworthy, there were no apparent defects in post-natal disc health or development and maturation in mutant mice. Microarray analysis confirmed that GLUT1 loss did not cause transcriptomic alterations in the NP, supporting that cells are refractory to GLUT1 loss. These observations provide the first evidence of functional redundancy in GLUT transporters in the physiologically hypoxic intervertebral disc and underscore the importance of glucose as the indispensable substrate for NP cells.
Review of Anti-Hyperglycemic Effect of Tinospora crispa

Tinospora crispa (Borapet or Wan kab hoi yai) is a climbing plant belonging to family Menispermaceae. In traditional medicine, an extract from the stems of T. crispa has been used for antihyperglycemic activity. The mechanisms of the anti-hyperglycemic actions of T. crispa are due to the stimulation of insulin secretion, enhancement of glucose utilization in peripheral tissues and reduction of hepatic gluconeogenesis. Borapetoside A and C are active ingredients for lower plasma glucose. In human studies, T. crispa extract possesses a significant anti-hyperglycemic effect in metabolic syndrome but this effect is abolished in type 2 diabetes mellitus. More clinical studies are recommended to evaluate the beneficial effect of T. crispa in human models.
Examining the Model of the Curriculum Used by Graphic Design Institutions in Tanzania at Various Levels of Study

This paper examines the model of curricula used by graphic design institutions in Tanzania and proposes more effective means that graphic design institutions could adopt for offering the most appropriate and relevant training in graphic design at certificate, diploma and bachelor’s degree levels of education. Most big cities in Tanzania are populated with graphic design work with common errors that reflect the designers’ lack of graphic design skills. Most of those designers have received some training in the many computer training centres in these areas due to the huge demand for graphic designers, but they have mostly been trained in some basic computer essentials and information communication technology rather than graphic design per se. Various curricula of different institutions and scholars from different countries are scrutinized in this study. Keywords: Art education, Graphic Design Curriculum, Graphic Design in Tanzania, Model of Curriculum.
Cysteine-Dependent Conformational Heterogeneity of Shigella flexneri Autotransporter IcsA and Implications of Its Function

Shigella species are the leading cause of diarrheal-related death globally by causing bacillary dysentery. The surface virulence factor IcsA, which is essential for Shigella pathogenesis, is a unique multifunctional autotransporter that is responsible for cell adhesion, and actin-based motility, yet detailed mechanistic understanding is lacking. ABSTRACT Shigella IcsA is a versatile surface virulence factor required for early and late pathogenesis stages extracellularly and intracellularly. Despite IcsA serving as a model Type V secretion system (T5SS) autotransporter to study host-pathogen interactions, its detailed molecular architecture is poorly understood. Recently, IcsA was found to switch to a different conformation for its adhesin activity upon sensing the host stimuli by Shigella Type III secretion system (T3SS). Here, we reported that the single cysteine residue (C130) near the N terminus of the IcsA passenger had a role in IcsA adhesin activity. We also showed that the IcsA passenger (IcsAp) existed in multiple conformations, and the conformation populations were influenced by a central pair of cysteine residues (C375 and C379), which was not previously reported for any Type V autotransporter passengers. Disruption of either or both central cysteine residues altered the exposure of IcsA epitopes to polyclonal anti-IcsA antibodies previously shown to block Shigella adherence, yet without loss of IcsA intracellular functions in actin-based motility (ABM). Anti-IcsA antibody reactivity was restored when the IcsA-paired cysteine substitution mutants were expressed in an ΔipaD background with a constitutively active T3SS, highlighting an interplay between T3SS and T5SS. The work here uncovered a novel molecular switch empowered by a centrally localized, short-spaced cysteine pair in the Type V autotransporter IcsA that ensured conformational heterogeneity to aid IcsA evasion of host immunity. IMPORTANCE Shigella species are the leading cause of diarrheal-related death globally by causing bacillary dysentery. The surface virulence factor IcsA, which is essential for Shigella pathogenesis, is a unique multifunctional autotransporter that is responsible for cell adhesion, and actin-based motility, yet detailed mechanistic understanding is lacking. Here, we showed that the three cysteine residues in IcsA contributed to the protein’s distinct functions. The N-terminal cysteine residue within the IcsA passenger domain played a role in adhesin function, while a centrally localized cysteine pair provided conformational heterogeneity that resulted in IcsA molecules with different reactivity to adhesion-blocking anti-IcsA antibodies. In synergy with the Type III secretion system, this molecular switch preserved biological function in distinct IcsA conformations for cell adhesion, actin-based motility, and autophagy escape, providing a potential strategy by which Shigella evades host immunity and targets this essential virulence factor.
MapLite 2.0: Online HD Map Inference Using a Prior SD Map

Deploying fully autonomous vehicles has been a subject of intense research in both industry and academia. However, the majority of these efforts have relied heavily on High Definition (HD) prior maps. These are necessary to provide the planning and control modules a rich model of the operating environment. While this approach has shown success, it drastically limits both the scale and scope of these deployments as creating and maintaining HD maps for very large areas can be prohibitive. In this work, we present a new method for building the HD map online by starting with a Standard Definition (SD) prior map such as a navigational road map, and incorporating onboard sensors to infer the local HD map. We evaluate our method extensively on 100 sequences of real-world vehicle data and demonstrate that it can infer a highly structured HD map-like model of the world accurately using only SD prior maps and onboard sensors.
Effects of Mineral Additives on Cold Recycled Foamed Asphalt Mixtures Cured in Laboratory and Field Conditions

Cold recycling with foamed asphalt has been considered a sustainable pavement rehabilitation technology. During the mix design process, the dry and wet indirect tensile strengths (ITS) and tensile strength ratio (TSR) are important parameters for evaluating performance of a cold mix. These performance parameters can be significantly influenced by the type of mineral additive used in the mixture and conditions in which test specimens are cured before testing. In this study, the objective was to determine the effects of mineral additives on the dry and wet ITS and TSR results of the cold recycled foamed asphalt mixtures in laboratory- and field-curing conditions. Mixtures with four different additives (cement, hydrated lime, baghouse fines, and Class C fly ash) at varied contents were compared to a control mixture without a mineral additive. Specimens were cured in the laboratory and in a field-simulated condition. The results from laboratory curing show that cement and hydrated lime improved both the dry and wet ITS results. Baghouse fines increased the dry ITS but not the wet ITS, while the fly ash only enhanced the wet ITS. Higher additive contents did not improve dry or wet ITS results, except for cement. The field-simulated curing results show all the additives improved the dry ITS over long periods of time but were not effective in the short term. The ITS results from long-term field-simulated curing and laboratory curing ranked these mixtures similarly. Confinement during curing did not have a significant effect on the dry ITS.
Effect of vehicle vibration environment of high-speed train on dynamic performance of axle box bearing

ABSTRACT In this study, we developed a comprehensive three-dimensional vehicle–track coupled dynamics model considering the traction drive system and axle box bearing. In this model, dynamic interactions between the axle box bearing and other components, such as the wheelset and bogie frame, are considered based on a detailed analysis of the structural properties and working mechanism of the axle box bearing. A few complicated dynamic excitations, such as the time-varying mesh stiffness of gears, time-varying stiffness of bearing, bearing gaps and track irregularities, are considered. Then, the dynamic responses of the vehicle–track system are demonstrated via numerical simulations based on the established dynamics model. The results indicate that the traction drive system and track irregularities can significantly influence the dynamic interactions of the axle box bearing. The necessity of considering the excitation caused by gear meshing and track irregularities when assessing the dynamic performance of the axle box bearing is demonstrated.
Blood Volume Pulse Extraction for Non-Contact Heart Rate Measurement by Digital Camera Using Singular Value Decomposition and Burg Algorithm

Conventional photoplesthymograph (PPG) measurements for heart rate (HR) determination require direct contact between the patient and the PPG device sensor. When using the conventional method, it is possible for users to suffer undesirable skin irritation, discomfort and soreness. Thus, the development of non-contact PPG has been investigated with various technologies and methods. One of the technologies that able to measure PPG in a non-contact way and at low cost is using digital cameras such as webcams. Various filters have been implemented to do non-contact PPG using digital cameras. This paper proposes a non-contact PPG filter system utilizing singular value decomposition (SVD) and Burg’s algorithm. The main role of SVD is for noise removal and as PPG signal extractor. As for the Burg algorithm, it was utilized for estimating the heart rate value from the filtered PPG signal. In this paper, we show and analyze an experiment for HR measurement using our method and a previous method that used independent component analysis (ICA). We compare and contrast both of them with HR measurements acquired by a commercial oximeter. The experiments were conducted at various distance between 30~110 cm and light intensities between 5~2000 lux. The estimated HR showed 2.25 bpm of mean error and 0.73 of Pearson correlation coefficient. The optimal distance between the mirror and user for HR measurement was 50 cm with medium light intensity, around 550 lux.
Performance validation of battery management system under prediction error for photovoltaic based distribution system

An effective reduction in power prediction error profile and an improved battery management system design for photovoltaic (PV) based microgrid application are presented in this study, where battery life and power loss are considered to be effectiveness measures. For local energy management the prediction error has a direct influence on distributed generator (DG) control reference calculation and thus in system stability. The silent effect of prediction error in battery energy storage life deterioration is highlighted in terms of battery temperature and power losses. The PV power prediction challenge (null versus positive volatility nature) is addressed with effective error reduction by kernel-based feature mapping function. To obtain fast prediction (operational references to DG primary control) in an online manner, a new fast reduced Morlet kernel-based online sequential extreme learning machine is proposed in this study. The battery (lithium-ion) temperature effect is addressed by introducing a new secondary controller, which comprises battery temperature reference model (model reference) along with rule-based temperature tolerance switching of stacks. The effectiveness of the proposed design is presented by rigorous case studies (MATLAB and TMS320 C6713), where extreme performance is achieved by simultaneous prediction error and local uncertainty.