Local Suppression Research Articles

Abstract IA005: Generating T cell responses against pancreatic cancer

Abstract The ultimate promise of tumor immunotherapy is dependent on the generation of an effective immune response against cancer, including CD4 and CD8 T cells. However, driving T cell responses in tumors such as pancreatic ductal adenocarcinoma (PDAC) requires overcoming significant hurdles in the tumor microenvironment (TME). Local and systemic suppression of dendritic cell function depresses endogenous T cell immunity against PDAC, which is further exacerbated by tumor cell intrinsic recruitment of suppressive myeloid cells and macrophages to the tumor site. To bypass these barriers, we’ve utilized agonistic anti-CD40 antibody, which mimics the endogenous CD40 ligand, to license and mature dendritic cells and re-educate tumor-associated myeloid cells towards a Th1/M1 phenotype in the PDAC TME. Using the KrasLSL-G12D/+,Trp53LSL-R172H/+,Pdx1-Cre (KPC) genetically engineered mouse model of pancreatic cancer, we show that combining standard-of-care chemotherapy with CD40 agonism promotes clonal T cell activation and expansion locally in the tumor site, resulting in regressions and cures of established tumors. This CD40-induced T cell response was further enhanced by the addition of dual immune checkpoint blockade (anti-PD-1 and anti-CTLA-4), but was independent of classical innate immune sensors such as Type I interferon receptor (IFNAR) and toll-like receptors (TLRs) previously thought to be critical for the generation of T cell immunity against tumors. These studies formed the preclinical rationale for trials investigating the use of agonistic CD40 therapy for patients with resectable or metastatic PDAC, and provided insight for immunological correlates of response in the clinical setting. More recently, we have reported on the negative impact of chemotherapy on the developing anti-tumor T cell response, emphasizing the need for additional investigations into the combination and sequencing of treatment modalities for enhanced outcomes in patients with PDAC. These studies reveal the potency of using an immunologically relevant mouse model to interrogate immune interventions in PDAC for patients with the greatest unmet clinical need. Citation Format: Katelyn T. Byrne. Generating T cell responses against pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA005.

Abstract B028: Bacterial cytotoxin therapy limits tumor growth for pancreatic ductal adenocarcinoma

Abstract Treating pancreatic ductal adenocarcinoma (PDAC) with systemic chemotherapeutic drugs has remained a challenge, due in part to the hypovascularized and poorly perfused nature of PDAC tumors, impeding the accumulation of systemically delivered drugs. Several clinical trials aimed at improving drug delivery in PDAC, through targeting of ECM components (HALO-301) or stromal angiogenic signaling (IPI-926-03) have unfortunately not been effective. However, the features that have interfered with systemic therapy in PDAC are potential advantages for the use of bacterial therapies, as bacteria can actively migrate through tissues, thrive in hypoxic microenvironments, and benefit from local immune suppression. Recent developments in the field of synthetic biology have made it possible to engineer complex logic circuits into bacteria, enabling the production of anticancer therapies directly within the tumor parenchyma. Furthermore, live bacteria, once colonized within the tumor niche, are capable of providing a stable source of anticancer compounds directly, rather than relying on repeated systemic doses. We have therefore worked to develop novel bacterial strains and demonstrate preclinical efficacy of a novel strain of therapeutic bacteria for targeting PDAC. We began by testing a range of bacteria-produced toxins and identified the pore-forming protein theta toxin as having the greatest effect in both 2D cell culture and PDAC explant (tissue slice) models. We then engineered a non-toxic probiotic bacteria, E. coli Nissle 1917, to produce either theta toxin or GFP following induction with acyl-homoserine lactone (AHL). To assess preclinical efficacy, we performed intratumoral injections of live GFP- and theta-expressing bacteria into the “KPC” genetically engineered mouse model (Kras LSL.G12D/+; Tp53 LSL.R172H/+; PdxCre tg/+). While GFP-producing bacteria did not induce a change in tumor growth kinetics, treatment with theta toxin-producing bacteria demonstrated prolonged stabilization of tumor growth, increasing the doubling time from 13.7 days (GFP) to 32.5 days (theta) without additional therapy. Indeed, one theta-treated KPC animal lived 113 days following a single bacterial injection, compared to a median of ~12 days for vehicle- or gemcitabine-treated historical controls. Histological analyses demonstrated that diffuse populations of bacteria co-localized with regions of tumor necrosis and cell death, but that bacterial presence and evidence of increased cell death was not observed in healthy tissues, such as the lung, liver, intestine, and diaphragm. Strikingly, while there was minimal spread of bacteria to non-tumor tissues, we observed translocation of the bacteria to regions of liver metastases and distant papillomas following injection of the primary pancreatic tumor, suggesting a mechanism for targeting both known and unknown metastases following local administration. Together these studies demonstrate potent preclinical activity of cytotoxic bacterial therapy as a novel strategy to circumvent the challenges of systemic treatment of PDAC. Citation Format: Amanda R. Decker, Tetsuhiro Harimoto, Steve A. Sastra, Tal Danino, Kenneth Olive. Bacterial cytotoxin therapy limits tumor growth for pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B028.

Fungal Virus, FgHV1-Encoded p20 Suppresses RNA Silencing through Single-Strand Small RNA Binding.

Fungal viruses are widespread in fungi infecting plants, insects and animals. High-throughput sequencing has rapidly led to the discovery of fungal viruses. However, the interactive exploration between fungi and viruses is relatively limited. RNA silencing is the fundamental antivirus pathway in fungi. Fusarium graminearum small RNA (sRNA) pattern was regulated by Fusarium graminearum hypovirus 1 (FgHV1) infection, indicating the activation of RNA silencing in virus defense. In this study, we focused on the function of an uncharacterized protein sized at 20 kD (p20) encoded by FgHV1. In the agro-infiltration assay, p20 was identified as a novel fungal RNA silencing suppressor. p20 can block systemic RNA silencing signals besides local RNA silencing suppression. We further elucidated the RNA silencing suppression mechanism of p20. The single-strand sRNA, instead of double-strand sRNA, can be incorporated by p20 in electrophoretic mobility shift assay. p20 binds sRNA originating from virus and non-virus sources in a non-sequence-specific manner. In addition, The F. graminearum 22 and 23-nt sRNA abundance and pathways related to RNA processing and redox regulation were regulated by p20. Our study revealed the first fungal virus-encoded RNA silencing suppressor with sRNA binding capability.

Smoking as one of the predictors of the severity of the condition of patients suffering from a new coronavirus infection

The relationship between smoking and the lung damage volume in patients with a confirmed new coronavirus infection diagnosis, hospitalized in a temporary infectious hospital for the treatment of patients suffering from a new coronavirus infection and community-acquired pneumonia was evaluated. This was in the Odintsovo Districts Patriot Park of the Moscow region. Smoking cigarettes, both active and passive, as well as exposure to tobacco smoke on the body, are important upper and lower respiratory tract infection risk factors due to local immune response suppression. Nevertheless, data from a number of international studies indicate a significantly lower number of hospitalized smoking patients compared to non-smokers. These indicators were investigated as the percentage and degree of lung damage, smoking history, the number of cigarettes smoked per day, and the smoker's index. In the course of the study, the data on a smaller percentage of smokers admitted to inpatient treatment were confirmed in comparison with non-smokers and smokers in the general population. There was no statistically significant difference in the volume of lung damage between smoking and non-smoking patients according to the chest organs computed tomography. At the same time, there was an increase in the volume of lung tissue damage, depending on the smoking experience. This is apparently due to the irreversible changes formation in lung tissue against a long-term smoking background. The median age of smoking patients was 56 years with a variation from 46 to 68 years. The minimum and maximum ages were 29 and 82. The median lung lesion was 32% with a variation from 23% to 39%. The minimum and maximum lung damage is 10% and 40%, respectively. A moderate correlation was found between the smoking experience and the volume of lung damage. An increase in lung damage by 0.309% should be expected with an increase in smoking experience by one full year. There was also no statistically significant difference in the number of cigarettes smoked per day and the smokers index.

Thermo-kinetic orientation study on interface behavior of polycrystalline Cu-Nb composite by crystal plasticity finite element method

In this work, a 3-dimensional (3D) crystal plastic finite element method (CPFEM) combined with the qualitative analysis of slip thermodynamics and kinetics is applied to study the co-deformation behavior of heterophase interface and its relationships with the initial grain orientation or misorientation upon compression of FCC/BCC Cu-Nb polycrystalline metal matrix composites (MMCs). The present simulations well predict the interface instability of the 5-layered polycrystalline Cu-Nb composites arising from the onset and aggregation of the non-crystallographic bandlike concentrated strain. Meanwhile, by changing the grain orientation, the suppression or promotion of plastic shear localization can be realized, where the occurrence of interface instability depends not only on inhomogeneous stress fields, i.e., a single thermodynamic factor, but also on an implicit kinetic factor, i.e., misorientation. On this basis, a so-called artificial “coding” strategy by translating orientation-inhibited strain localization into implicit thermodynamic and kinetic information is presented to tailor the Cu-Nb MMCs, i.e., triggering as much plastic slip as possible from a thermodynamic perspective, while narrowing the misorientation as much as possible from a kinetic selection.

Pregnancy preparation: redistribution of CCR7-positive cells in the rat uterus.

Changes in the endometrium prior to implantation may be critical in predicting pregnancy outcomes. This study shows that the endocrine system directs positional changes in CCR7+ cells before implantation, which may be critical for developing maternal tolerance. Suppression of the maternal immune system is vital for the implantation of the semi-allogeneic embryo. Although progress in understanding the dialogue between mother and embryo has been made, key interactions between maternal immune cells, hormones, and chemokines remain elusive. Uterine expression of the C-C chemokine receptor type 7 (CCR7) could recruit T regulatory cells and facilitate localized immune suppression. To test this concept, Ccr7 mRNA and protein were assessed in uterine tissue. Ccr7 mRNA expression peaked at day 4 in pregnant rat uteri and then declined at days 5 and 6. CCR7 protein showed similar quantitative changes. To test if female sex steroids affected the spatial distribution of CCR7-expressing cells, uteri from ovariectomized rats, progesterone-pretreated rats (2 mg daily), and progesterone-pretreated rats injected with estradiol (0.2 µg) were analyzed. Progesterone increased CCR7-positive (+) cells in the antimesometrial stroma. Progesterone and estradiol increased CCR7+ cells in the mesometrial stroma. Estradiol increased the density of cluster of differentiation 4 (CD4) positive cells in the mesometrial stromal region over progesterone alone. The density of cells expressing the T regulatory cell marker, forkhead box protein 3 (FOXP3), increased in the antimesometrial stroma in response to progesterone alone. Progesterone and estradiol increased FOXP3+ cells in the antimesometrial region of the stroma. Co-localization of CCR7, CD4, and FOXP3 in the stroma suggests CCR7+ cells are T regulatory cells. Polarization of CCR7+ cells in the endometrial stroma was an intrinsic response regulated by sex steroids and did not require the presence of an embryo.

C3d(g), iron nanoparticles, hemin and cytochrome c may induce oxidative cytotoxicity in tumors and reduce tumor-associated myeloid cells-mediated immunosuppression

A variety of tumors are sensitive to cell death by ferroptosis, a type of regulated necrosis characterized by iron accumulation, failure of cellular antioxidant defence systems, unrestrained accumulation of lipid peroxides and membrane rupture. Efficient removal of apoptotic and necrotic cells via tumor-associated phagocytes results in local immune suppression. Phagocytosis inhibition reduces tumor growth and metastasis. Here I hypothesize that accumulating iron nanoparticles, hemin, cytochrome c and preformed lipid peroxides in tumors combined with phagocytosis inhibition may induce the generation of oxidizing species to high levels within tumor tissue, thus causing increased oxidative damage and tumor cell death. I propose that C3d(g), the final degradation product of the third component of complement (C3) can be utilized to limit phagocytosis and stimulate anti-tumor responses. Furthermore, the plasticity and the multiple subtypes of tumor-associated myeloid cells mainly represented by tumor-associated macrophages and myeloid-derived suppressor cells hinder inhibition by targeted approaches or monotherapies. Here I provide insights into a novel, integrative therapeutic model that aims at both killing tumor cells and counteracting tumor-associated myeloid cells via the induction of excessive oxidative conditions in tumors. In conclusion, accumulating iron and lipid peroxides in both tumor- and myeloid cells and extracellularly in the tumor microenvironment combined with limiting phagocytosis due to C3d(g) may synergistically increase the oxidized burden and induce tumor cytotoxicity. Future directions include detailed suggestions on criteria for intermittent administration of the proposed therapeutics so that newly recruited myeloid cells could differentiate/be activated to functional anti-tumor phenotypes in a more antigenic tumor microenvironment. Furthermore, combination with other therapeutic forms might be promising. Optimizing the delivery of ION-containing liposomes at tumor sites is also important, thus enhancing their efficiency and safety profiles.

Tissue-Wide Expression of Genes Related to Vitamin D Metabolism and FGF23 Signaling following Variable Phosphorus Intake in Pigs.

Calcium (Ca) and phosphorus (P) homeostasis is maintained by several regulators, including vitamin D and fibroblast growth factor 23 (FGF23), and their tissue-specific activation and signaling cascades. In this study, the tissue-wide expression of key genes linked to vitamin D metabolism (CYP2R1, CYP27A1, CYP27B1, CYP24A1, GC, VDR) and FGF23 signaling (FGF23, FGFR1-4, KL) were investigated in pigs fed conventional (trial 1) and divergent P diets (trial 2). The tissue set comprised kidney, liver, bone, lung, aorta, and gastrointestinal tract sections. Expression patterns revealed that non-renal tissues and cells (NRTC) express genes to form active vitamin D [1,25(OH)2D3] according to site-specific requirements. A low P diet resulted in higher serum calcitriol and increased CYP24A1 expression in the small intestine, indicating local suppression of vitamin D signaling. A high P diet prompted increased mRNA abundances of CYP27B1 for local vitamin D synthesis, specifically in bone. For FGF23 signaling, analyses revealed ubiquitous expression of FGFR1-4, whereas KL was expressed in a tissue-specific manner. Dietary P supply did not affect skeletal FGF23; however, FGFR4 and KL showed increased expression in bone at high P supply, suggesting regulation to balance mineralization. Specific NRTC responses influence vitamin D metabolism and P homeostasis, which should be considered for a thrifty but healthy P supply.

Deep learning-guided weighted averaging for signal dropout compensation in DWI of the liver.

To develop an algorithm for the retrospective correction of signal dropout artifacts in abdominal DWI resulting from cardiac motion. Given a set of image repetitions for a slice, a locally adaptive weighted averaging is proposed that aims to suppress the contribution of image regions affected by signal dropouts. Corresponding weight maps were estimated by a sliding-window algorithm, which analyzed signal deviations from a patch-wise reference. In order to ensure the computation of a robust reference, repetitions were filtered by a classifier that was trained to detect images corrupted by signal dropouts. The proposed method, named Deep Learning-guided Adaptive Weighted Averaging (DLAWA), was evaluated in terms of dropout suppression capability, bias reduction in the ADC, and noise characteristics. In the case of uniform averaging, motion-related dropouts caused signal attenuation and ADC overestimation in parts of the liver, with the left lobe being affected particularly. Both effects could be substantially mitigated by DLAWA while preventing global penalties with respect to SNR due to local signal suppression. Performing evaluations on patient data, the capability to recover lesions concealed by signal dropouts was demonstrated as well. Further, DLAWA allowed for transparent control of the trade-off between SNR and signal dropout suppression by means of a few hyperparameters. This work presents an effective and flexible method for the local compensation of signal dropouts resulting from motion and pulsation. Because DLAWA follows a retrospective approach, no changes to the acquisition are required.

Competing electronic states emerging on polar surfaces

Excess charge on polar surfaces of ionic compounds is commonly described by the two-dimensional electron gas (2DEG) model, a homogeneous distribution of charge, spatially-confined in a few atomic layers. Here, by combining scanning probe microscopy with density functional theory calculations, we show that excess charge on the polar TaO2 termination of KTaO3(001) forms more complex electronic states with different degrees of spatial and electronic localization: charge density waves (CDW) coexist with strongly-localized electron polarons and bipolarons. These surface electronic reconstructions, originating from the combined action of electron-lattice interaction and electronic correlation, are energetically more favorable than the 2DEG solution. They exhibit distinct spectroscopy signals and impact on the surface properties, as manifested by a local suppression of ferroelectric distortions.

In silico Identification of Immune Cell-Types and Pathways Involved in Chronic Spontaneous Urticaria.

BackgroundThe immunopathogenesis of chronic spontaneous urticaria (CSU) is poorly understood, but recent research suggests that patients can be divided into autoallergic and autoimmune subtypes. Given that not all patients can be controlled with current treatment regimens, including anti-IgE monoclonal antibodies, a better understanding of the immune pathways involved in CSU may enable the repurposing of monoclonal antibodies used for other dermatologic diseases (e.g., Th2 and Th17 inhibitors). Therefore, we investigated the implicated immune cells and pathways by reanalyzing publicly available transcriptomic data.MethodsMicroarray data of CSU and healthy control (HC) skin and blood were obtained from the Gene Expression Omnibus (GSE72542, GSE57178). Differentially expressed genes were defined as a false discovery rate <0.05 and a |log2 fold change| ≥1. Pathway analyses were conducted using ToppGene and KEGG. Cell-type enrichment was determined by CIBERSORT and xCell and was correlated with clinical characteristics.ResultsTh2 (IL-4/13 signaling) and Th17-related (IL-17/23 signaling) pathways were upregulated in lesional compared to non-lesional and HC samples. In non-lesional versus lesional samples, CIBERSORT analysis revealed increased regulatory T-cells (Treg) and resting mast cells. xCell analysis established that Th1 and Th2 scores were not significantly different between lesional and HC samples. However, Th2 scores in both lesional and non-lesional samples correlated positively with disease severity. Few differentially expressed genes and pathways were identified between CSU and HC blood samples.ConclusionOur results support the involvement of Th2 and Th17-related genes and pathways in CSU. Th2 scores associate with disease severity, which indicates the clinical relevance of these findings. Increased resting mast cell and Treg scores in non-lesional samples may suggest local suppression of wheal formation. Moreover, disease activity seemed to be restricted to the skin as there were limited findings from blood. Larger studies using next-generation sequencing will be helpful to confirm these results.

The microstructure evolution and abnormal yield asymmetry of extruded Mg-10Gd-0.5Zr alloy

The Mg-10Gd-0.5Zr alloy had a bimodal microstructure and abnormal yield asymmetry (CYS/TYS = 1.4) after extrusion. In this paper, we discussed the origin of this asymmetry and researched the microstructure and texture variation after tensile and compression using EBSD analysis. The deformed grains exhibited intensive basal texture (<10-10>//ED), while the fine DRXed grains showed weak or even random texture. The maximum MUD value of unDRXed grains increased during tension and decreased due to twinning during compression. It was found that the dislocation slip dominated both tensile and compressive deformation. The deformed grains mainly occurred prismatic <a> slip and the DRXed grains were basal slip. Numerous DRXed grains undertaken the main deformation task. Suppression of extension twinning and strain localization were the secondary and main reasons for this abnormal yield asymmetry.

Regulatory T Cells Require CCR6 for Skin Migration and Local Suppression of Vitiligo

Vitiligo is an autoimmune skin disease caused by melanocyte-targeting autoreactive CD8+ T cells. Regulatory T cells (Tregs) have been implicated in restraining vitiligo severity in both mouse models and human patients; however, whether they must be present in the skin for their suppressive function is still unclear. We observed uneven distribution of Tregs within different anatomical locations of mouse skin, which correlated with reduced depigmentation after vitiligo induction. We specifically depleted Tregs in our mouse model of vitiligo and observed increased disease. Next, we found that Tregs contact CD8+ T effector cells in vitiligo lesional skin and that Treg recruitment to the skin inversely correlated with disease severity, suggesting a critical role for Treg suppression within the skin. When we investigated the signals facilitating Treg migration to the skin, we found that although CXCR3 was dispensable for Treg migration and function in vitiligo, Tregs lacking CCR6 exhibited a reduced capacity to migrate to the skin and suppress depigmentation, despite normal systemic numbers in the skin-draining lymph nodes. Our observations highlight a key role for cutaneous Tregs in disease suppression during vitiligo and identify CCR6 as a chemokine receptor that contributes to Treg migration to the skin.

Abstract 2123: Reprogramming of myeloid and lymphoid cells in vitro by the HDAC6 selective inhibitor ITF3756

Abstract Anti tumor immune response is driven by the concerted action of myeloid and lymphoid cells. Tumor cells have evolved to shape an immune suppressive tumor microenvironment (TME) where the antitumor immune response is dampened in several ways. For instance, local release of cytokines such as TNF-α, leads to the up-regulation of PD-L1 expression in tumor, myeloid and T cells, thereby triggering local immune suppression through the PD-1/PD-L1 axis. Strategies aimed at downregulating the suppressor activity of myeloid cells and at reinvigorating T cell effector functions are a promising approach to drive an effective innate and adaptive anti-tumor immune response. HDAC6 is a member of the Zn-dependent histone deacetylase family of enzymes with peculiar structure and functions, that orchestrates key processes in both innate and adaptive immune cells. Inhibition of HDAC6 enzymatic activity inhibits cytokine-dependent expression of PD-L1 and upregulates the expression of surface molecules involved in T cell activation. Thus, HDAC6 inhibition represents a new approach to enhance antitumor immune response. Here we report the in vitro activity of one of our potent and selective HDAC6 inhibitors, ITF3756, on human monocytes, dendritic cells and T cells. Through the upregulation of co-stimulatory and the downregulation of inhibitory molecules, ITF3756 increased allogenic T cell proliferation induced by monocytes stimulated with TNF-α in a way comparable to an anti PD-L1 antibody. Dendritic cells differentiated from peripheral blood monocytes in the presence of ITF3756 were also more efficient in stimulating allogeneic T cell proliferation. ITF3756 decreased the expression of PD-L1 both in TNF-α activated monocytes and in immature DCs. The effect of ITF3756 on PD-L1 expression was dose dependent and required the continuous presence of ITF3756 for at least 12 hours to achieve the best effect, as determined by washout experiments. CD8 T cell differentiation and exhaustion phenotypes were also modulated by ITF3756. In an in vitro model mimicking the exhaustion process, ITF3756 drove the differentiation of CD8 T cells towards a central memory phenotype and reduced the expression of effector memory markers and the exhaustion markers PD-1 and LAG3. These results were corroborated by qPCR and RNAseq analyses. ITF3756-exposed CD8 T cells had also a higher expression of IFN-γ and Granzyme b. Taken together, these results indicate that ITF3756 can modulate the activity of both myeloid and lymphoid cells and stimulate immune recognition and function. Citation Format: Chiara Ripamonti, Andrea Stevenazzi, Barbara Vergani, Giovanni Sandrone, Mattia Marchini, Christian Steinkuhler, Gianluca Fossati. Reprogramming of myeloid and lymphoid cells in vitro by the HDAC6 selective inhibitor ITF3756 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2123.

Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease

Aberrant localization of proteins to mitochondria disturbs mitochondrial function and contributes to the pathogenesis of Huntington’s disease (HD). However, the crucial factors and the molecular mechanisms remain elusive. Here, we found that heat shock transcription factor 1 (HSF1) accumulates in the mitochondria of HD cell models, a YAC128 mouse model, and human striatal organoids derived from HD induced pluripotent stem cells (iPSCs). Overexpression of mitochondria‐targeting HSF1 (mtHSF1) in the striatum causes neurodegeneration and HD‐like behavior in mice. Mechanistically, mtHSF1 facilitates mitochondrial fission by activating dynamin‐related protein 1 (Drp1) phosphorylation at S616. Moreover, mtHSF1 suppresses single‐stranded DNA‐binding protein 1 (SSBP1) oligomer formation, which results in mitochondrial DNA (mtDNA) deletion. The suppression of HSF1 mitochondrial localization by DH1, a unique peptide inhibitor, abolishes HSF1‐induced mitochondrial abnormalities and ameliorates deficits in an HD animal model and human striatal organoids. Altogether, our findings describe an unsuspected role of HSF1 in contributing to mitochondrial dysfunction, which may provide a promising therapeutic target for HD.

Range-Angle Dependent Beampattern Synthesis Method for OFDM-Based Passive Radar

Frequency diverse array (FDA) radar applies a tiny frequency offset across its adjacent transmitting array elements to generate a range-angle-dependent beampattern. The increased degrees-of-freedom (DOFs) in range domain can help improve the performance of radar in target detection, localization, and clutter suppression. Passive radar utilizes uncontrollable external signal as illuminator, which makes it difficult to apply traditional frequency diverse process method. However, the third-party illuminator such as Orthogonal Frequency Division Multiplexing (OFDM) signal usually consists of several closely spaced modulated carriers, and it has been widely selected as the illuminator for passive radar in recent years. Considering the orthogonality between even separated subcarriers, we propose a new frequency diverse process method by extracting and processing each subcarrier of received data independently and attempt to provide a range-angle dependent beampattern for OFDM passive radar. Numerical results and real data analyses verify the superiority of frequency diversity process on the received data of OFDM passive radar.

Measuring Hot-Spot Interaction Length in Single-Strip SNSPD

Superconducting nanowire single photon detectors (SNSPD) functionality is based on the local suppression of the superconducting order parameter upon photon absorption, causing a change in resistance which can be detected as a DC voltage pulse. Finding the size and the profile of the superconducting order parameter suppression area (the so-called “hot-spot”) experimentally is a challenging task. Here, we report the results of a quantum detector tomography on micron-length SNSPDs. The high internal detection efficiency of our SNSPDs allowed us to extract single and double photon efficiencies from the count rate vs radiation power dependence and extract hot-spot interaction length. We investigated a series of SNSPD samples made of NbN films with different sheet resistance and a MoSi film, with various widths of the stripe. The experimental results confirmed that regardless of the material or the film resistance, the hot-spot interaction length coincides with the strip width which is a promising feature for making a 2-photon counter with high fidelity.

On the inhibition of RNA silencing movement by the tombusvirus P19 protein: reliance on sRNA binding and correlation with local silencing suppression

On the inhibition of RNA silencing movement by the tombusvirus P19 protein: reliance on sRNA binding and correlation with local silencing suppression

Ganglion stellate blockade in the treatment algorithm of the malignant electric storm: one center, five years and 72 procedures in 59 patients

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Malignant electric storm (ES) is a life-threatening condition with a high mortality rate. With years of increasing numbers of implanted ICDs, we witness increasing numbers of patients treated for ES. The role of local suppression of sympathetic nerve activity using ultrasound-guided anesthetic ganglion stellate blockade (GSB) is still under investigation with the first favorable published data from prospective cohorts. Objective To present data from a cohort of consecutive patients treated for ES at our cardiac center using a two-stage algorithm including GSB. Method and Cohort Between 2017 and 2021, 59 patients were treated using the two-stage algorithm ( when the first stage of standard procedures failed - ions, antiarrhythmic drugs, ischemia correction, heart rate modification, sedation, and GSB was performed as the second stage of the algorithm when ventricular arrhythmia recurred) in 72 GSB procedures. 57 GSB in men (79.2%)/15 GSB (20.8%) in women. Mean age 68.1 +/- 12.1 years. Mean LV EF 29.6 +/- 8.9%. 22 GSB in diabetic patients (30.6%). Ischemic etiology of ES in 41 cases (56.9%). Monomorphic ventricular tachycardia dominated among arrhythmias with 53 cases ( 73.6%). Betablocker and amiodarone were administered in 67 and 56 cases, respectively ( 93.1 and 77.8%). A statistically significant decrease of 87.7% in ventricular arrhythmias treated with shock ICD or ATP was seen ( decrease from 57.2 to 1.43 episodes 48 hours before vs. 48 hours after GSB, p&amp;lt;.0001) (Table 1). Hemodynamically unstable patients on continuous catecholamines responded significantly less to the two-step algorithm, including GSB. Horner’s syndrome and other demographic and medication parameters did not appear to predict a better response to GSB (Table 2 ). No serious adverse events were observed. In one case, intermittent ( couple hours) vocal chord paresis after bilateral GSB has been observed. Conclusion The two-stage algorithm for the treatment of ES, including ganglion stellate blockade, has shown stable high efficacy over the years with exceptional safety. However, the actual efficacy must be proven in a double-blinded study to allow the widespread method to the clinical practice.

Strain rate dependence of the mesh objectivity in dynamic fracture analyses with the crack band model

The crack band model (CBM) is one of the most widely employed energy regularization techniques in continuum scale finite element fracture analyses. We demonstrate here that for dynamic fracture problems, the CBM regularization works only below a threshold strain rate, above which it should be bypassed. This is because, in dynamic fracture, higher strain rates make fractures increasingly branched and diffused, implying suppression of localization. This is demonstrated by considering the dynamic fracture of an isotropic brittle material, modeled via a scalar damage model in conjunction with the CBM regularization. Dynamic mode-I fracture in a thin plate is simulated under various strain rates such that results include localized, slightly branched, highly branched, and extensively branched diffused cracks. It is revealed that CBM yields mesh objective results only for a localized or slightly branched crack. For diffused or highly branched cracks, results are mesh size-dependent if CBM is used, but objective results are obtained if CBM is bypassed. CBM is found to work when the energy dissipation scales linearly with element size, which only occurs for localized or slightly branched cracks. This finding has great implications for applications involving finite element modeling of dynamic fracture.