RNAi-based Gene Therapy for Blood Genetic Diseases

Therapies for blood genetic diseases can be divided into different categories, including chemotherapy, radiotherapy, gene therapy, and hematopoietic stem cell transplantation. Among these treatments, gene targeting is progressively becoming a therapeutic alternative that offers the possibility of a permanent cure for certain blood genetic diseases. In recent years, gene therapy has played a more important role in curing genetic blood disorders. RNA interference (RNAi) is one of the directions for gene therapy, which was intensively studied in the past decades for its potentials in the treatment of diseases. In order to provide useful references and prospective directions for further studies concerning RNAi-based gene therapy for blood genetic diseases, current RNAi-based gene therapies for several typical blood genetic diseases have been summarized and discussed in this chapter

Sampling-Based Approaches for Multimarginal Optimal Transport Problems with Coulomb Cost

The multimarginal optimal transport problem with Coulomb cost arises in quantum physics and is vital in understanding strongly correlated quantum systems. Its intrinsic curse of dimensionality can be overcome with a Monge-like ansatz. A nonconvex quadratic programmming then emerges after employing discretization and $\ell_1$ penalty. To globally solve this nonconvex problem, we adopt a grid refinements-based framework, in which a local solver is heavily invoked and hence significantly determines the overall efficiency. The block structure of this nonconvex problem suggests taking block coordinate descent-type methods as the local solvers, while the existing ones can get seriously afflicted with the poor scalability induced by the associated sparse-dense matrix multiplications. In this work, borrowing the tools from optimal transport, we develop novel methods that favor highly scalable schemes for subproblems and are completely free of the full matrix multiplications after introducing entrywise sampling. Convergence and asymptotic properties are built on the theory of random matrices. The numerical results on several typical physical systems corroborate the effectiveness and better scalability of our approach, which also allows the first visualization for the approximate optimal transport maps between electrons in three-dimensional contexts.Comment: 31 pages, 6 figures, 3 table

Intercalibration of Boreal and Tethyan timescales: the magneto-biostratigraphy of the Middle Triassic and the latest Early Triassic from Spitsbergen, Arctic Norway

An integrated bio-magnetostratigraphic study of the latest Early Triassic to the upper parts of the Middle Triassic, at Milne Edwardsfjellet in central Spitsbergen, Svalbard, allows a detailed correlation of Boreal and Tethyan biostratigraphies. The biostratigraphy consists of ammonoid and palynomorph zonations, supported by conodonts, through some 234 m of succession in two adjacent sections. The magnetostratigraphy consists of ten substantive normal–reverse polarity chrons defined by sampling at 150 stratigraphic levels. The magnetization is carried by magnetite and an unidentified magnetic sulphide, and is difficult to fully separate from a strong present-day like magnetization. The bio-magnetostratigraphy from the late Olenekian (Vendomdalen Member) is supplemented by data from nearby Vikinghøgda. The early and mid-Anisian has a high sedimentation rate, comprising over half the ca. 140-m thickness of the Botneheia Formation, whereas the late Anisian and lower Ladinian is condensed into about 20 m. The two latest Boreal Ladinian ammonoid zones are absent due to erosional truncation below the Tschermakfjellet Formation. Correlation to Tethyan bio-magnetostratigraphies shows the traditional base of the Boreal Anisian (base of G. taimyrensis Zone) precedes the base Anisian (using here definitions based on the Desli Caira section in Romania). The Boreal upper Anisian G. rotelliforme and F. nevadanus ammonoid zones correlate to most of the Tethyan Pelsonian and Illyrian substages. The base Ladinian defined in the Tethyan global boundary stratotype and point (GSSP) is closely equivalent to the traditional base of the Boreal Ladinian at the I. oleshkoi Zone. The latest Olenekian to early Anisian magnetic polarity timescale is refined using the Spitsbergen data

Compact hollow waveguide mid-infrared gas sensor for simultaneous measurements of ambient CO2 and water vapor

A compact, sensitive and stable hollow waveguide (HWG) mid-infrared gas sensor, based on gas absorption lines using wavelength modulation spectroscopy with a second harmonic (WMS-2f) detection scheme, was developed for simultaneous measurements of ambient CO 2 and water vapor. Optimization of the laser modulation parameters and pressure parameter in the HWG are performed to improve the strength of the WMS-2f signal and hence the detection limit, where 14.5-time for CO 2 and 8.5-time for water vapor improvement in system detection limit is achieved compared to those working at 1 atm. The stability of the sensor has been improved significantly by optimizing environmental disturbances, incoupling alignment of the HWG and laser scanning frequency. An Allan variance analysis shows detection limit of the developed sensor of ~3 ppmv for CO 2 and 0.018% for water vapor, which correspond to an absorbance of 2.4 × 10 -5 and 2.7 × 10 -5 , with a stability time of 160 s, respectively. Ambient CO 2 and water vapor measurement have been performed in two days in winter and spring separately. The measurement precision is further improved by applying a Kalman adaptive filter. The HWG gas sensor demonstrates the ability in environmental monitoring and the potential to be used in other areas, such as industrial production and biomedical diagnosis

The agreement of low lean mass with obesity using different definitions and its correlation with hyperuricemia

BackgroundThe agreement on the identification of sarcopenic obesity remains elusive, and its association with hyperuricemia remains unestablished. This study sought to evaluate the agreement of low lean mass (LLM) with obesity and its correlation with hyperuricemia.MethodsA total of 25,252 study participants, comprising 4,597 individuals with hyperuricemia, were obtained from the National Health and Nutrition Examination Survey spanning the years 1999–2006 and 2011–2018. LLM with obesity was characterized by the coexistence of LLM, determined by the ratio of appendicular lean mass to body mass index (BMI), and three categories of obesity including BMI, body fat percentage (BF%), and waist circumference (WC). We employed Cohen’s kappa to evaluate the agreement among the different diagnostic criteria and implemented survey multiple logistic regression and stratified analyses to explicate the connection between LLM with obesity and the risk of hyperuricemia.ResultsWhen defining obesity using BF%, BMI, and WC, the prevalence of LLM with obesity varied from 6.6 to 10.1%, with moderate-to-strong agreement. In the fully adjusted model, individuals with LLM or any of the three types of obesity exhibited notably elevated odds of developing hyperuricemia. Likewise, participants with LLM and obesity had 2.70 (LLM + BMI), 2.44 (LLM + BF%), and 3.12 (LLM + WC) times the risk of hyperuricemia, respectively, compared with healthy individuals. The association between LLM with obesity and hyperuricemia remained stable and significant across different age and sex subgroups.ConclusionWhen employing the three definitions of obesity, the incidence of LLM with obesity was not high, and the diagnostic agreement was relatively good. The participants with LLM and obesity exhibited an increased risk of hyperuricemia

FT4/FT3 ratio: A novel biomarker predicts coronary microvascular dysfunction (CMD) in euthyroid INOCA patients.

Background Ischemia and no obstructive coronary artery disease (INOCA) patients who presented coronary microvascular dysfunction (CMD) demonstrate a poor prognosis, yet the risk factors for CMD remain unclear. Subtle changes in thyroid hormone levels within the normal range, especially the free thyroxine (FT4)/free triiodothyronine (FT3) ratio, have been shown to regulate the cardiovascular system. This prospective study investigated the correlation between FT4/FT3 ratio and CMD in euthyroid patients with INOCA. Methods This prospective study (www.chictr.org.cn/, ChiCTR2000037112) recruited patients with myocardial ischemia symptoms who underwent both coronary angiography (CAG) and myocardial perfusion imaging (MPI) with dynamic single-photon emission computed tomography (D-SPECT). INOCA was defined as coronary stenosis< 50% and CMD was defined as coronary flow reserve (CFR)<2.5. All patients were excluded from abnormal thyroid function and thyroid disease history. Results Among 71 INOCA patients (15 [21.1%] CMD), FT4 and FT4/FT3 ratio in CMD group were significantly higher and both showed significantly moderate correlation with CFR (r=-0.25, p=0.03; r=-0.34, p=0.003, respectively). The ROC curve revealed that FT4/FT3 ratio had the highest efficacy for predicting CMD with an optimized cutoff value>3.39 (AUC 0.78, p<0.001, sensitivity, 80.0%; specificity, 71.4%). Multivariate logistic regression showed that FT4/FT3 ratio was an independent predictor of CMD (OR 7.62, 95% CI 1.12-51.89, p=0.038, P for trend=0.006). Conclusion In euthyroid INOCA patients, increased FT4/FT3 ratio levels are associated with the occurrence of CMD, presenting a novel biomarker for improving the risk stratification

Context-Dependent T-Box Transcription Factor Family: From Biology to Targeted Therapy

T-BOX factors belong to an evolutionarily conserved family of transcription factors. T-BOX factors not only play key roles in growth and development but are also involved in immunity, cancer initiation, and progression. Moreover, the same T-BOX molecule exhibits different or even opposite effects in various developmental processes and tumor microenvironments. Understanding the multiple roles of context-dependent T-BOX factors in malignancies is vital for uncovering the potential of T-BOX-targeted cancer therapy. We summarize the physiological roles of T-BOX factors in different developmental processes and their pathological roles observed when their expression is dysregulated. We also discuss their regulatory roles in tumor immune microenvironment (TIME) and the newly arising questions that remain unresolved. This review will help in systematically and comprehensively understanding the vital role of the T-BOX transcription factor family in tumor physiology, pathology, and immunity. The intention is to provide valuable information to support the development of T-BOX-targeted therapy

CXCL9 expression in breast cancer and its correlation with the characteristics of tumor immunoinfiltration

Objective·To explore the effect of C-X-C motif chemokine ligand 9 (CXCL9) expression on the prognosis of breast cancer patients and its correlation with tumor-infiltrating immune cells (TIICs).Methods·Transcriptome data of 1 100 breast tumor tissues and 112 adjacent tissues were obtained from The Cancer Genome Atlas (TCGA) database. CIBERSORT deconvolution algorithm was used to analyze the proportion of TIIC subgroups in breast cancer immune microenvironment and its effect on the prognosis of patients. Differentially expressed genes, immune-related genes and breast cancer prognostic-related genes were downloaded from TCGA database, ImmPort database and GEPIA2 data platform, respectively. The intersection relationships of the three gene sets were analyzed by using R language, and the target genes were screened. Based on the downloaded transcriptome data, CXCL9 positive-related genes, the difference of CXCL9 mRNA expression in breast cancer tissues and adjacent tissues and its effect on the prognosis of patients were analyzed. STRING data platform was used to analyze the protein-protein interaction (PPI) network of CXCL9. Gene Ontology (GO) function analysis and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analysis were performed on CXCL9 positive correlation genes and the genes corresponding to the interacting proteins obtained from the PPI network by using R language. Spearman correlation coefficient was used to analyze the correlation between CXCL9 mRNA expression and TIIC subgroups and immune checkpoint-related genes. Paraffin tissue samples of 60 clinical breast cancer patients were collected and made into tissue chips. The correlation between CXCL9 expression and CD8+ T cells infiltration in the tissue chips was detected by immunohistochemical staining (IHC). The types of CXCL9+ cells in breast cancer interstitium were analyzed by multiplex immunohistochemistry staining (mIHC). Kaplan-Meier (KM) survival curve was used to analyze the effect of CXCL9 mRNA expression and CD8+ T cell infiltration on the prognosis of breast cancer patients.Results·CIBERSORT algorithm analysis showed that the distribution proportion of TIIC subgroups in breast cancer immune microenvironment varied greatly, and their effect on patients′ prognosis was also different. The Venn diagram of three types of gene sets was drawn, and CXCL9 was screened out. The top 150 positive correlation genes with CXCL9 were obtained. CXCL9 mRNA expression levels in four molecular types of breast cancer were higher than those in adjacent tissues (all P=0.000), and their high expressions were significantly associated with good prognosis of patients (P=0.013). A total of 41 interacting proteins were obtained through PPI network analysis. GO and KEGG analysis showed that CXCL9 and its related genes were mainly enriched in biological functions and pathways related to immune regulation. Spearman correlation coefficient analysis showed that the expression level of CXCL9 mRNA was positively correlated with CD8+ T cells infiltration ratio, negatively correlated with M2-type macrophages infiltration ratio, and positively correlated with most immune checkpoint genes expression (all P<0.05). IHC experiments showed that CXCL9 was highly expressed in breast cancer tissues compared with adjacent tissues, accompanied by an increased percentage of CD8+ T cells infiltration (P=0.000). mIHC results showed that CXCL9 was expressed in some CD68+ tumor-associated macrophages (TAMs) and CD11c+ dendritic cells (DCs) in the stroma of breast cancer. KM survival curve showed that when CXCL9 was highly expressed, CD8+ T cells high infiltration could prolong the survival of breast cancer patients.Conclusion·CXCL9 can be used as a biomarker for good prognosis of breast cancer patients. The high expression of CXCL9 in the microenvironment of breast cancer is positively correlated with the infiltration ratio of CD8+ T cells and may activate its anti-tumor effect. The expression of CXCL9 may be closely related to the recruitment of lymphocytes into the tumor microenvironment for anti-tumor immune response