Applications of Hyperpolarized Xenon-129 Nmr and Chemical Exchange Saturation Transfer in Biosensing

Modern clinical applications require precise positional and temporal information regarding pathological changes in cells and tissues. For example, in magnetic resonance microscopy, better than 100 sq. micros per voxel spatial resolution is necessary for imaging capillary blood vessels. And in order to monitor the blood flows in brain tissues, a series of images must be acquired in less than 2 s intervals. Further, molecular imaging aims at visualizing molecules and molecular events that occur at a cellular level, i.e. sensing biological events at a fundamentally microscopic level. When compared to other imaging modalities, the main advantages of magnetic resonance imaging (MRI) are its millimeter-scale spatial resolution and wide applicability achieved with minimal perturbation to in vivo systems, whereas its major drawbacks are limited sensitivity (10 protons in a million contribute to magnetic resonance) and high cost (a million US dollars each MRI scanner). One promising solution to both problems is the combination of hyperpolarized 129Xe MRI with biosensors, which offers significant sensitivity enhancement at a much lower cost. This dissertation reports my progress in hyperpolarized 129Xe nuclear magnetic resonance (NMR) studies for use in future molecular/medical MRI applications. First, I provide an overview of molecular imaging and, specifically, magnetic resonance imaging (MRI). 129Xe NMR/MRI is particularly promising as it solves solves the common problems of signal intensity and specificity (by employing biosensors). In chapter 2, I present our hyperpolarization (nuclear spin polarization) method. A hyperpolarized 129Xe chemical exchange saturation transfer (Hyper-CEST) method was also applied to lower the biosensor detection limits significantly. These experiments were made possible through the development of a home-built 129Xe hyperpolarizer, continuous-flow hyperpolarized Xe delivery setup, Hyper-CEST pulse sequence, and accompanying NMR control programs. In chapter 3, interactions between various biosensors and their target proteins have been characterized and analyzed in finer detail than previous studies. 129Xe NMR studies for biosensors targeting human carbonic anhydrase, alpha_{v}beta_{3} integrin, and pH changes have been carried out. In chapter 4, hyperpolarized 129Xe chemical exchange saturation transfer (Hyper-CEST) NMR experiments have demonstrated unprecedented detection sensitivity for a synthetic xenon host molecule, tri-acetic acid cryptophane. In chapter 5, to describe interactions between xenon and bacterial spores, Hyper-CEST has been successfully applied; Xe is demonstrated to be a good probe of the spore interior structure. Six spores strains with different protective layers were clearly distinguished by Xe exchanges between spore and water, observed by Hyper-CEST. Finally, these results are summarized in chapter 6

Text-Image Conditioned Diffusion for Consistent Text-to-3D Generation

By lifting the pre-trained 2D diffusion models into Neural Radiance Fields (NeRFs), text-to-3D generation methods have made great progress. Many state-of-the-art approaches usually apply score distillation sampling (SDS) to optimize the NeRF representations, which supervises the NeRF optimization with pre-trained text-conditioned 2D diffusion models such as Imagen. However, the supervision signal provided by such pre-trained diffusion models only depends on text prompts and does not constrain the multi-view consistency. To inject the cross-view consistency into diffusion priors, some recent works finetune the 2D diffusion model with multi-view data, but still lack fine-grained view coherence. To tackle this challenge, we incorporate multi-view image conditions into the supervision signal of NeRF optimization, which explicitly enforces fine-grained view consistency. With such stronger supervision, our proposed text-to-3D method effectively mitigates the generation of floaters (due to excessive densities) and completely empty spaces (due to insufficient densities). Our quantitative evaluations on the T$^3$Bench dataset demonstrate that our method achieves state-of-the-art performance over existing text-to-3D methods. We will make the code publicly available

Licarin-B Exhibits Activity Against the Toxoplasma gondii RH Strain by Damaging Mitochondria and Activating Autophagy

Toxoplasma gondii is an obligate intracellular pathogen that infects warm-blooded animals and humans. However, side effects limit toxoplasmosis treatment, and new drugs with high efficiency and low toxicity need to be developed. Natural products found in plants have become a useful source of drugs for toxoplasmosis. In this study, twenty natural compounds were screened for anti-T. gondii activity by Giemsa staining or real-time fluorescence quantitative polymerase chain reaction (qPCR) in vitro. Among these, licarin-B from nutmeg exhibited excellent anti-T. gondii activity, inhibiting T. gondii invasion and proliferation in a dose-dependent manner, with an EC50 of 14.05 ± 3.96 μg/mL. In the in vivo, licarin-B treatment significantly reduced the parasite burden in tissues compared to no treatment, protected the 90% infected mice from to death at 50 mg/kg.bw. Flow cytometry analysis suggested a significant reduction in T. gondii survival after licarin-B treatment. Ultrastructural changes in T. gondii were observed by transmission electron microscopy (TEM), as licarin-B induced mitochondrial swelling and formation of cytoplasmic vacuoles, an autophagosome-like double-membrane structure and extensive clefts around the T. gondii nucleus. Furthermore, MitoTracker Red CMXRos, MDC, and DAPI staining showed that licarin-B promoted mitochondrial damage, autophagosome formation, and nuclear disintegration, which were consistent with the TEM observations. Together, these findings indicate that licarin-B is a promising anti-T. gondii agent that potentially functions by damaging mitochondria and activating autophagy, leading to T. gondii death

Reservoir properties and genesis of tight sandstones—A case study from the Gaotaizi oil layer in the Qijia area, Songliao basin

The primary focus of oil and gas exploration for tight sandstone reservoirs is on a quantitative characterization of reservoir properties. This paper uses the tight sandstone reservoir developed in the Gaotaizi oil layer in the Qijia area of the Songliao Basin as an example. The petrology, physical properties, pore–throat characteristics, and the genesis of the densification of the oil-bearing sandstones are elucidated using casting thin-sections, scanning electron microscopy, 3D computerized tomography (CT), and petrophysical experimental techniques. The results show that the Gaotaizi oil layer is mainly composed of clastic rocks and contains small amounts of shell limestone. The clastic rocks are mainly lithic feldspar sandstone and feldspar lithic sandstone, while residual intergranular pores, intergranular dissolved pores, intragranular dissolved pores, intragranular pores and intercrystalline pores constitute the different pore types. Mercury intrusion and 3D computerized tomography analysis showed that micro-nano pores account for 53% of the total pores present. The pore–throat coordination number is distributed between 1 and 4, with an average of 1.8. The pores and throats in the Gaotaizi reservoir have poor connectivity. The porosity distribution of the Gaotaizi oil layer is 1.4%–22.5%, with an average of 9.5%, while the permeability distribution ranges from 0.01 to 27.10 mD, with an average of 0.41 mD. It is an ultra-low porosity and ultra-low permeability tight reservoir. The Gaotaizi oil layer is divided into three types of reservoirs through a systematic study of its pore developmental characteristics. Diagenetic processes like compaction and cementation result in a reduction in porosity and permeability. Compaction, calcite and siliceous cementation, and illite packing are primarily responsible for reservoir densification

Spermine Synthase and MYC Cooperate to Maintain Colorectal Cancer Cell Survival by Repressing Bim Expression

Dysregulation of polyamine metabolism has been linked to the development of colorectal cancer (CRC), but the underlying mechanism is incompletely characterized. Here, we report that spermine synthase (SMS), a polyamine biosynthetic enzyme, is overexpressed in CRC. Targeted disruption of SMS in CRC cells results in spermidine accumulation, which inhibits FOXO3a acetylation and allows subsequent translocation to the nucleus to transcriptionally induce expression of the proapoptotic protein Bim. However, this induction is blunted by MYC-driven expression of miR-19a and miR-19b that repress Bim production. Pharmacological or genetic inhibition of MYC activity in SMS-depleted CRC cells dramatically induces Bim expression and apoptosis and causes tumor regression, but these effects are profoundly attenuated by silencing Bim. These findings uncover a key survival signal in CRC through convergent repression of Bim expression by distinct SMS- and MYC-mediated signaling pathways. Thus, combined inhibition of SMS and MYC signaling may be an effective therapy for CRC

Ultra-small topological spin textures with size of 1.3nm at above room temperature in Fe78Si9B13 amorphous alloy

Topologically protected spin textures, such as skyrmions1,2 and vortices3,4, are robust against perturbations, serving as the building blocks for a range of topological devices5-9. In order to implement these topological devices, it is necessary to find ultra-small topological spin textures at room temperature, because small size implies the higher topological charge density, stronger signal of topological transport10,11 and the higher memory density or integration for topological quantum devices5-9. However, finding ultra-small topological spin textures at high temperatures is still a great challenge up to now. Here we find ultra-small topological spin textures in Fe78Si9B13 amorphous alloy. We measured a large topological Hall effect (THE) up to above room temperature, indicating the existence of highly densed and ultra-small topological spin textures in the samples. Further measurements by small-angle neutron scattering (SANS) reveal that the average size of ultra-small magnetic texture is around 1.3nm. Our Monte Carlo simulations show that such ultra-small spin texture is topologically equivalent to skyrmions, which originate from competing frustration and Dzyaloshinskii-Moriya interaction12,13 coming from amorphous structure14-17. Taking a single topological spin texture as one bit and ignoring the distance between them, we evaluated the ideal memory density of Fe78Si9B13, which reaches up to 4.44*104 gigabits (43.4 TB) per in2 and is 2 times of the value of GdRu2Si218 at 5K. More important, such high memory density can be obtained at above room temperature, which is 4 orders of magnitude larger than the value of other materials at the same temperature. These findings provide a unique candidate for magnetic memory devices with ultra-high density.Comment: 26 pages, 4 figure

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The Molecular Signature Underlying the Thymic Migration and Maturation of TCRαβ+CD4+CD8- Thymocytes

BACKGROUND: After positive selection, the newly generated single positive (SP) thymocytes migrate to the thymic medulla, where they undergo negative selection to eliminate autoreactive T cells and functional maturation to acquire immune competence and egress capability. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the genetic program underlying this process, we analyzed changes in gene expression in four subsets of mouse TCRαβ(+)CD4(+)CD8(-) thymocytes (SP1 to SP4) representative of sequential stages in a previously defined differentiation program. A genetic signature of the migration of thymocytes was thus revealed. CCR7 and PlexinD1 are believed to be important for the medullary positioning of SP thymocytes. Intriguingly, their expression remains at low levels in the newly generated thymocytes, suggesting that the cortex-medulla migration may not occur until the SP2 stage. SP2 and SP3 cells gradually up-regulate transcripts involved in T cell functions and the Foxo1-KLF2-S1P(1) axis, but a number of immune function-associated genes are not highly expressed until cells reach the SP4 stage. Consistent with their critical role in thymic emigration, the expression of S1P(1) and CD62L are much enhanced in SP4 cells. CONCLUSIONS: These results support at the molecular level that single positive thymocytes undergo a differentiation program and further demonstrate that SP4 is the stage at which thymocytes acquire the immunocompetence and the capability of emigration from the thymus

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions