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2024
AbstractRadiotherapy (RT), is a fundamental treatment for malignant tumors and is used in over half of cancer patients. As radiation can promote anti-tumor immune effects, a promising therapeutic strategy is to combine radiation with immune checkpoint inhibitors (ICIs). However, the genetic determinants that impact therapeutic response in the context of combination therapy with radiation and ICI have not been systematically investigated. To unbiasedly identify the tumor intrinsic genetic factors governing such responses, we perform a set of genome-scale CRISPR screens in melanoma cells for cancer survival in response to low-dose genotoxic radiation treatment, in the context of CD8 T cell co-culture and with anti-PD1 checkpoint blockade antibody. Two actin capping proteins,Capza3andCapg, emerge as top hits that upon inactivation promote the survival of melanoma cells in such settings.Capza3andCapgknockouts (KOs) in mouse and human cancer cells display persistent DNA damage due to impaired homology directed repair (HDR); along with increased radiation, chemotherapy, and DNA repair inhibitor sensitivity. However, when cancer cells with these genes inactivated were exposed to sublethal radiation, inactivation of such actin capping protein promotes activation of the STING pathway, induction of inhibitoryCEACAM1ligand expression and resistance to CD8 T cell killing. Patient cancer genomics analysis reveals an increased mutational burden in patients with inactivating mutations inCAPGand/orCAPZA3, at levels comparable to other HDR associated genes. There is also a positive correlation betweenCAPGexpression and activation of immune related pathways and CD8 T cell tumor infiltration. Our results unveil the critical roles of actin binding proteins for efficient HDR within cancer cells and demonstrate a previously unrecognized regulatory mechanism of therapeutic response to radiation and immunotherapy.- Book : ()
- Pub. Date : 2024
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2024
AbstractTrilobite cephalic morphology impacted the autecology of individuals, and is critical for high- and low-level taxonomic assignments. Disparity in trilobite cephalon shape varied through time and was integral to the occupation of a diversity of ecological niches. To fully appreciate trilobite cephalic evolution, we must understand how this disparity varies, and what factors control cephalon morphometry. We explore the disparity of trilobite cephala through the Palaeozoic, and analyse the associations between cephalic morphometry and taxonomic assignment and geological Period, using a dataset of 983 2D trilobite cephalon outlines. Elliptical Fourier transformation visualised as a Principal Components Analysis suggests significant differences in morphospace occupation for order and Period groups, and comparisons of disparity measures also suggest significantly different disparities between the groups. Trilobite cephalic disparity peaks in the Ordovician and Devonian. The Cambrian–Ordovician expansion of morphospace occupation appears a result of radiation to new niches, and thus all trilobite orders were established by the late Ordovician. In comparison, the morphospace expansion from the Silurian to Devonian seems solely a result of within-niche diversification rather than novel niche occupation. However, analyses interrogating the regions of morphospace occupied, including centroid distances, average pairwise shape comparisons and Linear Discriminant Analysis demonstrate that, except for the order Harpida and the Cambrian and Ordovician Periods, order and geological Period could not be robustly predicted for an unknown trilobite. Further, Kmeans clustering analyses suggest the total dataset naturally subdivides into only seven groups that do not correspond with taxonomic orders, though Kmeans clusters do decrease in number through the Palaeozoic, aligning with findings of decreasing disparity.- Book : ()
- Pub. Date : 2024
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2024
AbstractThe functional consequences of structural variants (SVs) in mammalian genomes are challenging to study. This is due to several factors, including: 1) their numerical paucity relative to other forms of standing genetic variation such as single nucleotide variants (SNVs) and short insertions or deletions (indels); 2) the fact that a single SV can involve and potentially impact the function of more than one gene and/orcisregulatory element; and 3) the relative immaturity of methods to generate SVs, either randomly or in targeted fashion, inin vitroorin vivomodel systems. Towards addressing some of these challenges, we developedGenome-Shuffle-seq, a straightforward method that enables the multiplex generation of several major forms of SVs (deletions, inversions, translocations) throughout a mammalian genome.Genome-Shuffle-seqis based on the random integration of “shuffle cassettes” to the genome, wherein each shuffle cassette contains components that facilitate its site-specific recombination (SSR) with other integrated shuffle cassettes (via Cre-loxP), its mapping to a specific genomic location (via T7-mediatedin vitrotranscription or IVT), and its identification in single-cell RNA-seq (scRNA-seq) data (via T7-mediatedin situtranscription or IST). In this proof-of-concept, we applyGenome-Shuffle-seqto induce and map thousands of genomic SVs in mouse embryonic stem cells (mESCs) in a single experiment. Induced SVs are rapidly depleted from the cellular population over time, possibly due to some combination of Cre-mediated toxicity and negative selection on the rearrangements themselves. We demonstrate that we can efficiently genotype which SVs are present in association with each of many single cell transcriptomes in scRNA-seq data. Finally, preliminary evidence suggests our method may be a powerful means of generating extrachromosomal circular DNAs (ecDNAs). Looking forward, we anticipate thatGenome-Shuffle-seqmay be broadly useful for the systematic exploration of the functional consequences of SVs on gene expression, the chromatin landscape, and 3D nuclear architecture. We further anticipate potential uses forin vitromodeling of ecDNAs, as well as in paving the path to a minimal mammalian genome.- Book : ()
- Pub. Date : 2024
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2024
Abstract
Background:Lymphovascular infiltration(LVI) reduced cervical cancer patients overall survival(OS),while it was not easily discovered by routine HE staining,while the role of tumor-associated macrophages(TAMs) in this course need define.
Methods: Early stage cervical cancer patients were received carbon nanoparticles(CNP) for sentinel lymph nodes(SLNs) mapping,laparotomy pelvic lymph node dissection and radical hysterectomy.The samples were detected for ultra staging,cocktail double immunohistochemical(IHC) staining,Western blot anlysis.Single cell data from(GEO) for cervical cancer were obtained and analysis.
Results: The combine of CNP mapping,ultra staging and double IHC staining enhance determining ratio for tumor LVI than that of HE staining alone(41.8% (41/98) vs. 20.4% (20/98), P=0.046)).
When the number of vascular invasion foci>2.0,or the number of cancer emboli cells ≥5.0, there was negative correlation with the OS for patients (p < 0.05).
More M2 macrophage emerged surrounding the tumor vasculature than surroungding normal cervix(P<0.05).Western blot analysis,TAMs related genes MMP2,SPARC and GNLY expessed higher level in tumor, while the OS of the patients decreased accordingly.
Single cell data were screened, reduced dimensions, and constructed pseudo-trajectories. Differentially expressed genes (DEGs) analysis showed, M2 macrophage clusters related genes expession level MMP2,SPARC and GNLY were obviosely higher than that of M1 clusters in cervical cancer; M1/M2 ratio decreased significantly. MMP2,GNLY could destroy tumor vasculauture basement membrane; SPARC anti-adhesion, played a key role in EMT and tumor invasion.
M1 macrophages cluster anti-inflammatory, immune surveillance and anti-immune escape scores were obviously higher than that of M2 macrophages cluster.
Gene Ontology(GO) analysis showed innate immune response gene expression for M2 macrophage clusters decreased obviously than that of M1 macrophages.Kyoto Encyclopedia of Genes and Genomes(KEGG) showed that normal cervix and precancerous lesions higher enrichement of M1 macrophage clusters, presenting positive regulation of response stimulus signaling pathway,while cervical cancer and metastatic lymph nodes enriched M2 clusters presenting negative regulation to these signaling pathway.
Conclusions:CNP mapping could be as a SLN tracer in early cervical cancer LVI screening.Cocktail double IHC staining could enhance diagnostic efficiency than HE staining in determining LVI. M2 TAMs activity increased from precancerous lesions to cervical cancer forming a immunosuppressive envioment gradually, TAMs related genes could play a key role in this process.- Book : ()
- Pub. Date : 2024
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2024
The studies were carried out to simulate the distribution of the electromagnetic field to assess the efficiency of three types of emitters according to the following parameters: standing wave coefficient, which makes it possible to compare the consistency of emitters; radiation efficiency, showing the amount of energy transferred to the grain layer; microwave field radiation pattern, which allows one to evaluate the uniformity of the field distribution in the grain layer. For evaluation and comparison, three types of waveguides were considered: horn, rectangular with slot emitters; semicircular with slot emitters. The distribution of the electromagnetic field was modeled using the CST Microwave Studio program. The use of horn waveguides in ultra-high-frequency convective installations makes it possible to produce fairly simple devices for grain processing. The standing wave coefficient for the operating frequency in this case is 1.3, with a radiation efficiency of 78 dB. However, they do not ensure uniform distribution of the ultrahigh frequency field at the exit from the waveguide, which affects the efficiency of grain processing. The use of rectangular waveguides 55 mm × 110 mm with slot emitters ensures more uniform radiation of the electromagnetic field across the entire spectrum of wave types. The standing wave ratio is 1.0 and the radiation efficiency is 94.43 dB. However, their use requires additional design developments to ensure the supply of coolant to the processing zone. Semicircular waveguides with slot emitters provide a standing wave ratio of 1.0 over the entire frequency range from 2 to 3 GHz. Radiation efficiency is 94.28 dB. The uniformity of the electromagnetic field distribution along a semicircular waveguide is better than along a rectangular one.- Book : 19(1)
- Pub. Date : 2024
- Page : pp.34-41
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2024
Background: The proliferation of mobile phone usage has given rise to concerns about the potential health effects of electromagnetic fields (EMF), particularly in relation to heart rate variability (HRV), a key indicator of cardiac health. Previous studies have yielded inconsistent results using lower-order statistical measures, leaving a gap in understanding the nonlinear interactions between EMF exposure and HRV.
Objective: This study aimed to investigate the effects of mobile phone EMF on HRV by employing bicoherence analysis of ECG data. It sought to determine whether the position of EMF exposure relative to the heart and the duration of exposure affected HRV parameters.
Methods: Twenty subjects were recruited for the study, with ECG and EEG data collected under EMF and non-EMF conditions. ECG data were captured using a 12-lead system, with electrodes placed according to standard guidelines. EEG electrodes were positioned following the 10-20 system. Bicoherence and coherence analyses were conducted to assess nonlinear interactions in HRV activity and the relationship between heart and brain signals. The study also considered the duration of EMF exposure, comparing the effects of 10-minute and 40-minute sessions.
Results: The bicoherence values for ECG data during EMF exposure at the left ear showed negligible differences, with values ranging between 0.0 to 0.04. However, chest positions V1 and V2 revealed statistically significant larger bicoherence values during non-EMF trials as opposed to EMF trials. Coherence analysis between ECG and EEG demonstrated significantly higher values across the 16-30Hz frequency band during EMF trials. No significant differences were observed for 10-minute EMF exposure, whereas 40-minute exposure sessions indicated a correlation with changes in HRV.
Conclusion: The study's findings suggest that mobile phone EMF can affect HRV parameters, with the effects being more pronounced during longer exposure durations and when the source of EMF is closer to the heart. These results support the need for guidelines on safe mobile phone usage and further research into the effects of EMF on cardiac function.- Book : 4(1)
- Pub. Date : 2024
- Page : pp.1479-1483
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2024
Abstract
The CyberKnife, a renowned non-invasive stereotactic radiotherapy technique, has gained widespread adoption for its effective treatment of various cancers. The success of CyberKnife treatment relies significantly on the accurate placement of fiducial markers. This study introduces a Fiducial marker placement planning algorithm, specifically for superficial tumors that are located 20-50 mm beneath the epidermis. Three patients with treatment sites of thymus, breast, and submandibular gland were retrospectively selected for this study. The algorithm proposes numerous potential implantation sites by constructing and optimizing a B-spline surface. The site selection is predominantly based on the distance between markers, the angles among them, and the necessity for all fiducial markers to be visible in 45° oblique views without overlap. By leveraging the kd-tree, we enhanced spatial querying and addressed the challenge using graph theory, specifically through the Bron-Kerbosch algorithm. The time complexity of the algorithm proposed in this study is \(O(m\log m + m^2 + 3^{\frac{n}{3}})\), significantly faster than the brute-force \(O(n^3)\) approach. Experimental outcomes show that our algorithm can efficiently plan Fiducial marker placements, simplifying the planning process and providing valuable technical support for CyberKnife treatments.- Book : ()
- Pub. Date : 2024
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2024
According to the UN Charter (Article 26), the UN Security Council is the primary organ responsible for the maintenance of international peace and security. Nuclear states agreed to the adoption of a UN Security Council Resolution that provided positive security assurances. The adoption of UN Security Council Resolution №255 on June 19, 1968, was of particular significance. This resolution stipulated that instances of aggression involving the use of nuclear weapons or the threat of such aggression against a non-nuclear-weapon state would require immediate action by the UN Security Council and its permanent members, who are nuclear-armed states.
The aim of the work is to determine the role of the UN Security Council in the system of preventing the proliferation of nuclear weapons. The methodological basis of the study will focus on the analysis and understanding of the impact of the UN Security Council on strategies and measures aimed at preventing the spread of nuclear weapons in the international context.
The results of our research have shown that the role of the UN Security Council in the disarmament of Iraq’s nuclear program, which could have led to the development of nuclear weapons, proved to be significant. To achieve this, in accordance with UN Security Council Resolution №687 adopted on April 3, 1991, the Special Commission (UNSCOM) was established.
During an extraordinary meeting of the UN Security Council at the highest level on September 24, 2009, Resolution UN Security Council Resolution № 1887 was adopted, aimed at supporting nuclear non-proliferation, criticizing Iran and North Korea. Resolution №1887 outlines measures to strengthen control and the rights of nuclear-weapon states to demand the return of nuclear materials and equipment in case of violations of the Non-Proliferation Treaty or withdrawal from it. It also involves enhancing security measures for the storage of nuclear materials and strict export controls.
Conclusions. In our opinion, the powers of the UN Security Council in the field of non-proliferation of weapons of mass destruction should be utilized more promptly and effectively. The insufficient effectiveness of this international mechanism in preventing proliferation remains a cause for serious concern among UN members worldwide. To enhance the effectiveness of the UN Security Council, we propose the adoption of a comprehensive resolution that includes provisions on the procedure for a state’s withdrawal from the Treaty on the Non-Proliferation of Nuclear Weapons (NPT) and its violation of commitments to refrain from acquiring nuclear weapons. This resolution should stipulate the imposition of sanctions against such a state based on a special report from the International Atomic Energy Agency (IAEA). Such a mechanism can ensure an effective impact of the international community on states that withdraw from the NPT.- Book : (6)
- Pub. Date : 2024
- Page : pp.114-118
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2024
Environmental pollution increases due to the large amounts of waste production and raw material consumption depending on the increasing population. Agricultural and industrial wastes which are some of the sources of the pollution need to be reuse to reduce the negative impact on the environment and also con-tribute positive effect to the economy. In this context, industrial wastes such as clay types (red and green) and agricultural wastes such as egg shell, walnut shell and banana shell were used to prepare materials which can be used as replacement materials for construction industry. Radiation attenuation parameters (mass attenuation coefficients, effective atomic number, linear attenuation coefficients, mean free path, half-value layer, exposure and energy absorption build up factors, fast neutron removal cross-section) were acquired by Phy-X/PSD code. Spectroscopic techniques (XRD, EPR, SEM-EDS) were performed for the structural analysis. The existence of calcite main phase peaks as well as SiO2 and cellulose phases were observed by XRD. Mn+2 sextet lines with five weak doublets attributed to the forbidden transition lines of Mn+2 and a singlet with a g value of ≈2.00 were recorded by EPR. All samples examined with good protection performances can be used as substitute materials instead of cement or aggregate for the aim of reusing the wastes and supporting the environmental and economic benefits.- Book : ()
- Pub. Date : 2024
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2024
Currently, the Russian-American dialogue on nuclear arms control is in a state of deep crisis. If this dialogue is resumed, the parties will face a number of serious problems: the emergence of fundamentally new strategic weapons (nuclear and non-nuclear); prospects for China's transformation into a third nuclear superpower, and an ideological impasse in Russian-American relations.- Book : (2)
- Pub. Date : 2024
- Page : pp.0-0
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