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Services for smart cities are required to improve productivity, sustainability, and quality of life. They can maximise resource usage, enhance public safety, accelerate economic growth, and promote civic engagement. In the past, cities relied on unreliable and limited-range radio and wired telephone networks. The capabilities of networked city services have significantly increased with the development of technologies like Ethernet and passive optical network (PON). These technologies enable real-time data collecting and analysis by delivering higher data transfer speeds and greater coverage areas. PON connections offer higher bandwidth, greater reliability, and longer lifetimes; 50 Gigabit-PON has the capacity to support different commercial services with notable performance to meet service requirements; and Ethernet networks have lower deployment costs as well as greater flexibility in terms of adding or removing devices. The various use-case scenarios of high-speed network technologies are evaluated. The technology ultimately chosen will be determined by the specific requirements and objectives of the smart city project.

In this paper, advanced DC-Link (DCL) based reversing voltage type Multilevel Inverter (MLI) topologies by compensating the difficulties in the conventional MLIs are reviewed. These topologies consist of less switching components and driver circuits when compared with conventional MLIs predominantly in higher levels. Consequently, installation area, total cost and hardware difficulties are reduced by increasing the voltage levels. The unipolar based Pulse Width Modulation Schemes (PWMS) will improve DCL inverters performance. This paper presents unipolar Multi-Reference (MR) based sine and space vector PWMS with single triangular carrier wave for generating required levels in output voltage. Comparison between UMR sine and space vector PWMS for DCL inverter topologies is presented in terms of Fundamental Output Voltage (FOV) and Total Harmonic Distortion (THD). The research tries to establish the survey analysis for single-phase 7-level DCL based reversing voltage type MLI topologies with UMR based sine and space vector PWMs. Finally, to confirm the feasibility of proposed DCL-MLIs in terms of FOV and THD the simulation results are incorporated. Further, the prototype model is developed for single-phase 7-level DCL inverter with Field Programmable Gate Array (FPGA) based UMR sine and space vector PWMS to authenticate simulation results. The efficiency of the proposed cascaded MLI achieves the value of 99.003%.

Objectives: Microcirculation is bound to be altered during cardiac surgery due to multiple factors, mainly the intense systemic inflammatory response syndrome which peaks in the first 24-h postoperatively. Decreased microvascular flow associated with increased postoperative morbidity has been reported. The literature suggests a potential independence of macrocirculation and microcirculation during fluid loading. The present study was conducted to assess thenar muscle tissue oxygen saturation (StO2) changes during vascular occlusion test (VOT) in response to hypovolemia and to assess the dynamic responses of the StO2 variables post-volume expansion (VE). Material and Methods: Thirty-five adult post-cardiac surgical patients, with stroke volume (SV) variation >12% were included in the study. Fifty-two fluid challenges were studied. Functional evaluation of microcirculation using VOT and near infrared spectroscopy (NIRS) variables along with monitoring of macrocirculatory indices was performed before and after VE. Statistical analysis was done using Student t-test. Results: Post-VE, 34 were responders with increase in SV ≥15% and 18 were non-responders (SV P = 0.0293 vs. P = 0.1480). However, macrocirculatory indices including cardiac output, SV, and delivery of oxygen showed significant improvement in both responders and non-responders. Conclusion: Preload dependence is associated with significant change in the StO2 recovery slope measured at the thenar eminence in volume responders. Functional evaluation of microcirculation using VOT and StO2 can be a useful complimentary tool along with the macrocirculatory indices for optimal fluid rescuscitaion in adult post-cardiac surgical patients.

In this paper, a multistring-multilevel inverter (M-MLI) for renewable-energy-source applications has been proposed with reduced switch count and harmonics along with single-switch fault analysis for various levels. It requires only ‘m+1’ power switches for ‘m’ voltage levels. The proposed work achieves the fine-tuning of switching angles using a metaheuristic technique, i.e. the teaching–learning-based optimization algorithm (TLBOA), to mitigate the total harmonic distortion (THD) of the M-MLI. Furthermore, the proposed TLBOA has been compared with conventional modulation techniques such as equal phase (EP), half-equal phase (HEP), near-level control (NLC) and Newton–Raphson (NR) to verify the effectiveness of TLBOA for various voltage levels in terms of % voltage-THD (%V-THD), computational time and methodology. By fine-tuning the switching angles, the %V-THD is improved significantly when compared with EP, HEP, NLC and NR modulation techniques. For an 11-level single-phase M-MLI, the %V-THD using TLBOA at 0.91 modulation index (MI) is 5.051%. The lower-order harmonics, i.e. 5, 7, 11 and 13, are eliminated to improve the power quality. Furthermore, MLIs are often prone to failure, resulting in waveform distortion. The extreme reduction in power quality impacts the load and significant damage is likely. The location of the open-circuit fault to be identified becomes more tedious under the faulty conditions with increased switch counts and voltage levels since the mathematical modelling fails to address the scenario in less computational time. Hence, the machine-learning approach, i.e. support vector machine (SVM) with Bayesian optimization, has been discussed to locate the faulty switch. Finally, the proposed M-MLI configuration has been modelled, simulated and validated using MATLAB® and Simulink®. The results of the M-MLI configuration have been verified for 7, 9 and 11 levels using TLBOA along with fault analysis using the SVM approach.

bstract: In the scenario of large organizations device management and maintenance plays an important role in proper functioning of network connected devices. SNMP (Simple NetworkManagement Protocol) is an internet Protocol running in the application layer of the OSI modelthat governs the functioning of the network devices such as routers, switches and access points. The implementation of SNMP is done mainly using UDP (User Datagram Protocol) which is best effort protocol leaving the responsibility of error correction to the application layer. Whatcan be gathered from the local device and what may be modified and set are specified by SNMPManagement Information Bases, or MIBs for short.

In this paper, the Enhanced Z-Source Switched Capacitor Multi-Level Inverter (EZSC-MLI) is presented, which can generate a greater number of levels and magnitude in output. The proposed MLI has greater recognition due to its low harmonic profile, fewer switching components, compact size, low switch stress, isolated DC supply, high efficiency, and low cost. A high voltage boost factor is achieved by using the Z-Source. The Switched Capacitor module is used for charging all the capacitors to equal voltage magnitude based on a self-balanced scheme. The proposed topology for grid integration requires dual control loops, a primary voltage control loop, and a secondary current control loop. The performance of the proposed 7-level topology for grid integrated systems is verified with multi-carrier advanced modulation schemes and by simulations carried out in Matlab/Simulink.

Solar photovoltaic (SPV) modules have a low output voltage and are load-dependent. Therefore, it is critical that the SPV system has an adequate DC–DC converter to regulate and improve the output voltage to get maximum output voltage. To meet load requirements, the voltage must be increased, necessitating the use of energy-efficient power electronic converters. The performance of an SPV system coupled to a high-gain quadratic boost converter (HG-QBC) with a load is investigated in this paper. The suggested HG-QBC for the SPV system at a lower value of duty ratio provides high voltage gain with a boost factor of four times. An analytical comparison is carried out with the various existing boost converters in terms of the components and the boost factor. The issue of locating the maximum power generation point from the SPV system is crucial. As a result, choosing an appropriate maximum power point tracker (MPPT)-based technique to obtain the peak power output of the SPV system under the rapidly varying atmospheric conditions is vital. To determine the highest output power of an SPV system, a hybrid-based MPPT with a neural network assisted by a perturb and observe (P&O) technique is proposed. For the HG-QBC, a comparison of the proposed MPPT with a traditional P&O-based MPPT is illustrated. The comparative analysis takes into account rise time, settling time and voltage ripples. The output voltage and power characteristics of the proposed model are analysed under constant and varying irradiation conditions using MATLAB®/Simulink®. The results of a hybrid-based MPPT show that the oscillations are minimum at the maximum power point with fewer ripples of 0.20% and a settling time of 1.2 s in comparison with the other two techniques.

In this paper, the performance of a permanent magnet synchronous generator (PMSG)-based wind energy conversion system (WECS) supplied to an uncontrolled rectifier-fed boost converter (BC) interfaced with a three-phase T-type three-level inverter (TLI) has been analysed. The proposed WECS involves three converters, namely an uncontrolled rectifier that is used for conversion from AC to DC; a BC supplied by a PMSG-fed rectifier used to enhance the voltage gain; and a grid-connected three-phase T-type TLI is proposed to eliminate power-quality issues with synchronization of grid voltage and current. The main goal of this research is to model and control the grid-connected T-type TLI using a d–q synchronous frame for wind energy for regulating the DC-link voltage and transferring the generated wind power from the BC to the grid. Furthermore, the perturb & observe (P&O)-based maximum power point (MPP) approach is recommended to keep track of the MPP for a BC that is supplied from a PMSG-based WECS under constant and variable wind speeds. The proposed PMSG-based WECS interfaced with grid-connected T-type TLI using d–q control has been computationally modelled, simulated and validated with constant and variable speeds using MATLAB® and Simulink®. It is confirmed that the P&O-based MPP approach ensures maximum power for varying wind speeds, and the total harmonic distortion of the T-type TLI grid current value is 3.18%, which is within IEEE-519 limits. Furthermore, with grid synchronization, the power factor of the T-type TLI is maintained at unity to avoid power-quality issues.

The COVID-19 pandemic has recently become a threat all across the globe with the rising cases every day and many countries experiencing its outbreak. According to the WHO, the virus is capable of spreading at an exponential rate across countries, and India is now one of the worst-affected country in the world. Researchers all around the world are racing to come up with a cure or treatment for COVID-19, and this is creating extreme pressure on the policy makers and epidemiologists. However, in India the recovery rate has been far better than in other countries, and is steadily improving. Still in such a difficult situation with no effective medicine, it is essential to know if a patient with the COVID-19 is going to recover or die. To meet this end, a model has been developed in this article to estimate the probability of a recovery of a patient based on the demographic characteristics. The study used data published by the Ministry of Health and Family Welfare of India for the empirical analysis.

Nanostring miRNA data

Supplementary Figure 1. Representative OVCAR3-inoculated mice after aflibercept, Dll4-Fc, and the combination. Supplementary Figure 2. In vivo study of Dll4 blockade, aflibercept, and docetaxel, alone and in combinations, in A2780 and HeyA8 models. Supplementary Figure 3. Immunohistochemical staining of CX3CL1 in the tumor stroma of mice inoculated with A2780 ovarian cancer cells. Supplementary Figure 4. Quantitative real-time PCR of CX3CL1 expression in A2780 cells cultured with primary dendritic cells isolated from C57/BL6 mice. Supplementary Figure 5. ELISA analysis of plasma IFN-gamma in the mice inoculated with A2780 ovarian cancer cells. Supplementary Figure 6. RT-PCR analysis of E-cadherin expression in tumors (tumor cells and stroma) obtained from A2780 mice treated with a single agent or a combination.

Supplementary Figure 1. In vitro effects of PR silencing on onapristone sensitivity in PR-high-expressing uterine cancer cell line (Ishikawa). Supplementary Figure 2. In vitro effects of onapristone and trametinib in PR-weak-expressing uterine cancer cell line (SKUT2). Supplementary Figure 3. In vivo effects of therapy with onapristone in uterine cancer model. Supplementary Figure 4. In vivo effect of onapristone, trametinib, and the combination of both drugs on total PR expression in the ISHIKAWA model.

Advanced peritoneal carcinomatosis including high-grade ovarian cancer has poor prognoses and a poor response rate to current checkpoint inhibitor immunotherapies; thus, there is an unmet need for effective therapeutics that would provide benefit to these patients. Here we present the preclinical development of SENTI-101, a cell preparation of bone marrow-derived mesenchymal stromal (also known as stem) cells (MSC), which are engineered to express two potent immune-modulatory cytokines, IL12 and IL21. Intraperitoneal administration of SENTI-101 results in selective tumor-homing and localized and sustained cytokine production in murine models of peritoneal cancer. SENTI-101 has extended half-life, reduced systemic distribution, and improved antitumor activity when compared with recombinant cytokines, suggesting that it is more effective and has lower risk of systemic immunotoxicities. Treatment of tumor-bearing immune-competent mice with a murine surrogate of SENTI-101 (mSENTI-101) results in a potent and localized immune response consistent with increased number and activation of antigen presenting cells, T cells and B cells, which leads to antitumor response and memory-induced long-term immunity. Consistent with this mechanism of action, co-administration of mSENTI-101 with checkpoint inhibitors leads to synergistic improvement in antitumor response. Collectively, these data warrant potential clinical development of SENTI-101 for patients with peritoneal carcinomatosis and high-grade ovarian cancer.Graphical abstract: SENTI-101 schematic and mechanism of actionSENTI-101 is a novel cell-based immunotherapeutic consisting of bone marrow–derived mesenchymal stromal cells (BM-MSC) engineered to express IL12 and IL21 intended for the treatment of peritoneal carcinomatosis including high-grade serous ovarian cancer. Upon intraperitoneal administration, SENTI-101 homes to peritoneal solid tumors and secretes IL12 and IL21 in a localized and sustained fashion. The expression of these two potent cytokines drives tumor infiltration and engagement of multiple components of the immune system: antigen-presenting cells, T cells, and B cells, resulting in durable antitumor immunity in preclinical models of cancer.

For mucinous ovarian cancer (MOC), standard platinum-based therapy is largely ineffective. We sought to identify possible mechanisms of oxaliplatin resistance of MOC and develop strategies to overcome this resistance. A kinome-based siRNA library screen was carried out using human MOC cells to identify novel targets to enhance the efficacy of chemotherapy. In vitro and in vivo validations of antitumor effects were performed using mouse MOC models. Specifically, the role of PRKRA/PACT in oxaliplatin resistance was interrogated. We focused on PRKRA, a known activator of PKR kinase, and its encoded protein PACT because it was one of the five most significantly downregulated genes in the siRNA screen. In orthotopic mouse models of MOC, we observed a significant antitumor effect of PRKRA siRNA plus oxaliplatin. In addition, expression of miR-515-3p was regulated by PACT–Dicer interaction, and miR-515-3p increased the sensitivity of MOC to oxaliplatin. Mechanistically, miR-515-3p regulated chemosensitivity, in part, by targeting AXL. The PRKRA/PACT axis represents an important therapeutic target in MOC to enhance sensitivity to oxaliplatin.

Delta-like ligand 4 (Dll4), one of the Notch ligands, is overexpressed in ovarian cancer, especially in tumors resistant to anti-VEGF therapy. Here, we examined the biologic effects of dual anti-Dll4 and anti-VEGF therapy in ovarian cancer models. Using Dll4-Fc blockade and anti-Dll4 antibodies (murine REGN1035 and human REGN421), we evaluated the biologic effects of Dll4 inhibition combined with aflibercept or chemotherapy in orthotopic mouse models of ovarian cancer. We also examined potential mechanisms by which dual Dll4 and VEGF targeting inhibit tumor growth using immunohistochemical staining for apoptosis and proliferation markers. Reverse-phase protein arrays were used to identify potential downstream targets of Dll4 blockade. Dual targeting of VEGF and Dll4 with murine REGN1035 showed superior antitumor effects in ovarian cancer models compared with either monotherapy. In the A2780 model, REGN1035 (targets murine Dll4) or REGN421 (targets human Dll4) reduced tumor weights by 62% and 82%, respectively; aflibercept alone reduced tumor weights by 90%. Greater therapeutic effects were observed for Dll4 blockade (REGN1035) combined with either aflibercept or docetaxel (P < 0.05 for the combination vs. aflibercept). The superior antitumor effects of REGN1035 and aflibercept were related to increased apoptosis in tumor cells compared with the monotherapy. We also found that GATA3 expression was significantly increased in tumor stroma from the mice treated with REGN1035 combined with docetaxel or aflibercept, suggesting an indirect effect of these combination treatments on the tumor stroma. These findings identify that dual targeting of Dll4 and VEGF is an attractive therapeutic approach. Mol Cancer Ther; 15(6); 1344–52. ©2016 AACR.

Supplementary Figure1 shows MSC homing to tumor and other organs in vivo using a bioluminescent reporter. Supplementary Figure 2. Characterization of tumor immune infiltrate of syngeneic preclinical intraperitoneal tumor models CT26-ip and B16F10-ip using IHC and flow cytometry. Supplementary Figure 3. Kaplan Meier Survival in B16F10-ip model comparing multiple combinations of effector cytokines expressed by MSCs. Supplementary Figure 4. Shows data supporting the construct optimization for SENTI-101 including promoter, orientation and signal sequence changes. Supplementary Figure 5. IL-21 functional validation using UO2S IL-21 receptor dimerization reporter assay. Supplementary Table 1. Shows the DNA sequence of SB00880, the lentiviral construct used to engineer SENTI-101. Supplementary Figure 6. Shows the SENTI-101 manufacturing process overview. Supplementary Figure 7. Shows supporting data for the study of pharmacokinetics and pharmacodynamics of SENTI-101. Supplementary Figure 8. Shows individual tumor burden for each mouse measured by bioluminescence imaging (BLI) after treatment with SENTI-101 or controls. Supplementary Figure 9. Percent change in mouse body weight after treatment. Supplementary Figure 10. Shows the controls and supporting data for the selective depletion of immune cell types. Supplementary Figure 11. Characterization of tumor infiltrating lymphocytes (TILs) in the B16F10-ip tumor model after treatment with mSENTI-101. Supplementary Figure 12. Anti-tumor immune response induced by SENTI-101 in CT-26ip model. Supplementary Figure 13. Shows individual tumor burden for each mouse measured by BLI after treatment with SENTI-101 and in combination with checkpoint inhibitor anti-PD-1.

Despite being among the most common oncogenes in human cancer, to date, there are no effective clinical options for inhibiting KRAS activity. We investigated whether systemically delivered KRAS siRNAs have therapeutic potential in KRAS-mutated cancer models. We identified KRAS siRNA sequences with notable potency in knocking down KRAS expression. Using lung and colon adenocarcinoma cell lines, we assessed antiproliferative effects of KRAS silencing in vitro. For in vivo experiments, we used a nanoliposomal delivery platform, DOPC, for systemic delivery of siRNAs. Various lung and colon cancer models were used to determine efficacy of systemic KRAS siRNA based on tumor growth, development of metastasis, and downstream signaling. KRAS siRNA sequences induced >90% knockdown of KRAS expression, significantly reducing viability in mutant cell lines. In the lung cancer model, KRAS siRNA treatment demonstrated significant reductions in primary tumor growth and distant metastatic disease, while the addition of CDDP was not additive. Significant reductions in Ki-67 indices were seen in all treatment groups, whereas significant increases in caspase-3 activity were only seen in the CDDP treatment groups. In the colon cancer model, KRAS siRNA reduced tumor KRAS and pERK expression. KRAS siRNAs significantly reduced HCP1 subcutaneous tumor growth, as well as outgrowth of liver metastases. Our studies demonstrate a proof-of-concept approach to therapeutic KRAS targeting using nanoparticle delivery of siRNA. This study highlights the potential translational impact of therapeutic RNA interference, which may have broad applications in oncology, especially for traditional “undruggable” targets. Mol Cancer Ther; 13(12); 2876–85. ©2014 AACR.

Supplementary figure 1 provides a schematic of DOPC:siRNA nanoliposomal preparation, and Supplementary figure 2 shows tumor volumetric measurements of the A549 orthotopic lung cancer therapeutic experiment described in the main figure 2.

Although progesterone receptor (PR)–targeted therapies are modestly active in patients with uterine cancer, their underlying molecular mechanisms are not well understood. The clinical use of such therapies is limited because of the lack of biomarkers that predict response to PR agonists (progestins) or PR antagonists (onapristone). Thus, understanding the underlying molecular mechanisms of action will provide an advance in developing novel combination therapies for cancer patients. Nuclear translocation of PR has been reported to be ligand-dependent or -independent. Here, we identified that onapristone, a PR antagonist, inhibited nuclear translocation of ligand-dependent or -independent (EGF) phospho-PR (S294), whereas trametinib inhibited nuclear translocation of EGF-induced phospho-PR (S294). Using orthotopic mouse models of uterine cancer, we demonstrated that the combination of onapristone and trametinib results in superior antitumor effects in uterine cancer models compared with either monotherapy. These synergistic effects are, in part, mediated through inhibiting the nuclear translocation of EGF-induced PR phosphorylation in uterine cancer cells. Targeting MAPK-dependent PR activation with onapristone and trametinib significantly inhibited tumor growth in preclinical uterine cancer models and is worthy of further clinical investigation. Mol Cancer Ther; 17(2); 464–73. ©2017 AACR.