Single IP Research Articles

Comparative effect of atorvastatin and risperidone on modulation of TLR4/NF-κB/NOX-2 in a rat model of valproic acid-induced autism

BackgroundAutism spectrum disorder (ASD) is a complex neurodevelopmental condition that is significantly increasing, resulting in severe distress. The approved treatment for ASD only partially improves the sympoms, but it does not entirely reverse the symptoms. Developing novel disease-modifying drugs is essential for the continuous improvement of ASD. Because of its pleiotropic effect, atorvastatin has been garnered attention for treating neuronal degeneration. The present study aimed to investigate the therapeutic effects of atorvastatin in autism and compare it with an approved autism drug (risperidone) through the impact of these drugs on TLR4/NF-κB/NOX-2 and the apoptotic pathway in a valproic acid (VPA) induced rat model of autism.MethodsOn gestational day 12.5, pregnant rats received a single IP injection of VPA (500 mg/kg), for VPA induced autism, risperidone and atorvastatin groups, or saline for control normal group. At postnatal day 21, male offsprings were randomly divided into four groups (n = 6): control, VPA induced autism, risperidone, and atorvastatin. Risperidone and atorvastatin were administered from postnatal day 21 to day 51. The study evaluated autism-like behaviors using the three-chamber test, the dark light test, and the open field test at the end of the study. Biochemical analysis of TLR4, NF-κB, NOX-2, and ROS using ELISA, RT-PCR, WB, histological examination with hematoxylin and eosin and immunohistochemical study of CAS-3 were performed.ResultsMale offspring of prenatal VPA-exposed female rats exhibited significant autism-like behaviors and elevated TLR4, NF-κB, NOX-2, ROS, and caspase-3 expression. Histological analysis revealed structural alterations. Both risperidone and atorvastatin effectively mitigated the behavioral, biochemical, and structural changes associated with VPA-induced rat model of autism. Notably, atorvastatin group showed a more significant improvement than risperidone group.ConclusionsThe research results unequivocally demonstrated that atorvastatin can modulate VPA-induced autism by suppressing inflammation, oxidative stress, and apoptosis through TLR4/NF-κB/NOX-2 signaling pathway. Atorvastatin could be a potential treatment for ASD.Graphical

Functional analysis of a panel of molecular markers for diagnosis of systemic lupus erythematosus in rats.

Systemic lupus erythematosus (SLE) is a diverse autoimmune disease that arises from a combination of complex genetic factors and environmental influences. While circRNAs and miRNAs have recently been identified as promising biomarkers for disease diagnosis, their specific expression patterns, and clinical implications in SLE are not yet fully understood. The aim of the present study was to determine the role of a panel of noncoding-RNAs specifically circRNAs (circ-TubD1, circ-CDC27, and circ-Med14), along with miRNA (rno-miR-146a-5p) and mRNA (TRAF6), as novel minimally invasive diagnostic biomarkers for experimentally induced SLE. Additionally, the study involved an insilico bioinformatics analysis to explore potential pathways involved in the pathogenesis of SLE, aiming to enhance our understanding of the disease, enable early diagnosis, and facilitate improved treatment strategies. SLE was induced in rats using single IP injection of incomplete Freund's adjuvant (IFA). The Induction was confirmed by assessing the ANA and anti-ds DNA levels using ELSA technique. qPCR analysis was conducted to assess the expression of selected RNAs in sera collected from a group of 10 rats with induced SLE and a control group of 10 rats. In addition, bioinformatics and functional analysis were used to construct a circRNA-miRNA-mRNA network and to determine the potential function of these differentially expressed circRNAs. SLE rats demonstrated significantly higher expression levels of circ-CDC27, circ-Med14, and rno-miR-146a-5p as well as TRAF6, with lower expression level of circ-TubD1 in sera of SLE rats relative to controls. ROC curve analysis indicated that all the selected non-coding RNAs could serve as potential early diagnostic markers for SLE. In addition, the expression level of circ-TubD1 was negatively correlated with rno-miR-146a-5p, however, rno-miR-146a-5p was positively correlated with TRAF6. Bioinformatic analysis revealed the incorporation of the circRNAs targeted genes in various immune system and neurodegeneration pathways. Therefore, circRNAs; circ-TubD1, circ-CDC27, and circ-Med14, in addition to the miRNA (rno-miR-146a-5p) and mRNA (TRAF6) may be involved in the development of SLE and may have promising roles for future diagnosis and targeted therapy.

Effect of Lactoferrin versus Dexamethasone on Induced Acute Lung Injury in Adult Rat: A Histological Study

Abstract Introduction acute lung injury (ALI) is one of the most critical illnesses affecting the lung and is commonly associated with severe complications. management of ALI without major side effects remains a continuous challenge. Lactoferrin (LF) is an iron-binding glycoprotein having potential anti-inflammatory effects. Aim the study was conducted to compare the therapeutic role of lactoferrin (LF) versus dexamethasone (DEXA) on the microscopic structure of the lung in a model of lipopolysaccharide (LP) induced acute lung injury. Material and Methods thirty-five adult male albino rats weighing (180-200gm) were divided randomly into 4 groups. Group I (control group), Group II (LP group): rats received a single IP injection of Lipopolysaccharide (3mg/kg). Group III (LP+LF group): rats received LP as in group II followed one hour later by IP injection of lactoferrin (5mg/rat). Group IV (LP+DEXA group): rats received LP as in group II followed one hour later by IP injection of dexamethasone (5mg/kg). after 24 hours, lung specimens were proceeded for light microscopic examination, as well as Morphometrical and statistical analyses. Results H&E-stained section of Group II showed marked inflammatory changes, interalveolar septa were significantly thickened and were heavily infiltrated with inflammatory cells and extravasated red blood cells were occasionally detected. Many alveoli appeared collapsed. The lining epithelium of bronchi appeared occasionally desquamated and peri-bronchial lymphoid aggregation were observed. An apparent increase in mucus production and significant increase in number of goblet cells were detected by PAS-stain. Orcein-stained section showed disruption of elastic fibers. immunohistochemical stain revealed a significantly increased reaction to iNOS antibodies. On the other hand, the lung structure in group III and group IV were much more improved, with group IV very similar to the control group. Conclusion Both lactoferrin and dexamethasone showed therapeutic and anti-inflammatory effects in LP induced ALI. These effects were more prominent in dexamethasone than lactoferrin as detected by microscopic, morphometric, and statistical studies.

Making stateless and stateful network performance measurements unbiased

The Benchmarking Working Group (BMWG) of the Internet Engineering Task Force (IETF) has defined a series of Requests for Comments (RFC) to standardize the benchmarking of network interconnect devices (e.g., bridges, routers, different IPv6 transition solutions). The paper points out that there are cases where the performance results are significantly different when a single IP address pair or multiple IP addresses are used. The cause of this phenomenon is rooted in the recent hardware and software advancements: Receive Side Scaling (RSS) makes it possible to distribute packet processing workload over multiple CPU cores. However, this may be implemented in two ways: the first way only includes the IP addresses into the hash function used to distribute the workload among the CPU cores, whereas the second one also includes the port numbers. RFC 4814 proposed an excellent solution for the second case by recommending the usage of pseudorandom port numbers during benchmarking; however, the first case was not handled properly, because no explicit recommendation was given regarding the usage of multiple IP addresses. This paper attempts to bridge this methodological gap; a practical solution is proposed for using pseudorandom IP addresses in various scenarios including the benchmarking of IPv4 and IPv6 routers and Network Address Translation from IPv6 Clients to IPv4 Servers (stateful NAT64) gateways. Its feasibility is shown by disclosing the details of its implementation in siitperf. Then the proposed solution is validated by both stateless and stateful tests. It is shown that the measurement results of the tests following the proposed solution can better characterize the true performance of the network interconnect devices that follow the first type of RSS implementation than the results of the tests using a single IP address pair.

Acetazolamide Challenge Changes Outer Retina Bioenergy-Linked and Anatomical OCT Biomarkers Depending on Mouse Strain.

The purpose of this study was to test the hypothesis that optical coherence tomography (OCT) bioenergy-linked and anatomical biomarkers are responsive to an acetazolamide (ACZ) provocation. C57BL/6J mice (B6J, a strain with relatively inefficient mitochondria) and 129S6/ev mice (S6, a strain with relatively efficient mitochondria) were given a single IP injection of ACZ (carbonic anhydrase inhibitor) or vehicle. In each mouse, the Mitochondrial Configuration within Photoreceptors based on the profile shape Aspect Ratio (MCP/AR) index was determined from the hyper-reflective band immediately posterior to the external limiting membrane (ELM). In addition, we tested for ACZ-induced acidification by measuring contraction of the external limiting membrane-retinal pigment epithelium (ELM-RPE) thickness; the hyporeflective band (HB) signal intensity at the photoreceptor tips was also examined. Finally, the nuclear layer thickness was measured. In response to ACZ, MCP/AR was greater-than-vehicle in B6J mice and lower-than-vehicle in S6 mice. ACZ-treated B6J and S6 mice both showed ELM-RPE contraction compared to vehicle-treated mice, consistent with dehydration in response to subretinal space acidification. The HB intensity at the photoreceptor tips and the outer nuclear layer thickness (B6J and S6), as well as the inner nuclear layer thickness of B6J mice, were all lower than vehicle following ACZ. Photoreceptor respiratory efficacy can be evaluated in vivo based on distinct rod mitochondria responses to subretinal space acidification measured with OCT biomarkers and an ACZ challenge, supporting and extending our previous findings measured with light-dark conditions.

Hepatoprotective effect of Nobiletin against 5-fluorouracil induce hepatotoxicity

5-florouracil is a widely used anticancer/anti-metabolite drug used to treat solid tumor like colon cancer, head and neck, rectum, stomach, pancreas and breast cancer; but, it can cause hepatotoxicity by induction of apoptosis through activation of caspases enzymes and oxidative stress. Nobiletin is a citrus fruit-derived flavonoid that possess significant biological activity, including anticancer, and anti-inflammatory. This study was design to investigate the effects of nobiletin against 5-florouracil-indcued hepatotoxicity in male rats through the measurement of selected -inflammatory, -apoptosis, and -oxidative stress markers. By use male Albino rats weighing 150-250gm around 28 animals; giving them tap water ad libitum and fed commercial pellets; and randomized into four groups (7animals/group) as following arrangement: Group I oral administered only corn oil for rats 1 ml for each kilogram for day by using of oral gavage for rat for 14 days. Group II: oral administered Nobiletin at dose 10 mg for each kilogram for each day (dissolved in corn oil) via oral gavage for 14 days. Group III: oral administered corn oil via oral gavage for 14 days after that single IP injection of 5-FU (150 mg/kg) on the day fourteenth (14). Group VI: Rats oral administered nobiletin dissolved in corn oil daily by oral gavage at a dose 10 mg/kg for each day for 14 days and a single IP injection of (150 mg/kg) 5-florouracil was given on day 14. All groups, seven animals of each group were sacrificed at day fifteenth (15); and, serum was collected to measure inflammatory and anti-inflammatory markers (interlukin-6 and interlukin-10) and liver function tests(ALT, LDH and AST); furthermore, liver tissue samples were collected to measure level of caspase-3, malondialdehyde and reduced form of glutathione, assessment of Hemeoxygenase-1 and NADPH quinone dehydrogenase-1 enzymes. In addition, histopathological study of the liver tissue of rats was perform to detect difference between architecture of liver cells in all rats’ groups. The protective effect of Nobiletin noted by decrease in apoptosis of hepatocytes by decreasing of caspase-3 and reduction on free radical through reduce in malondialdehyde level, also increase in Hemeoxygenase-1gene expression. Increase in NADPH quinone dehydrogenase-1 dehydrogenase enzyme. On histopath reduce in congestion and some inflammatory infiltration by using of nobiletin prior to give 5-florouracil.

#144 : Randomized Controlled Trial Evaluating Efficacy of Autologous Platelet-Rich Plasma Therapy for Patients with Recurrent Implantation Failure in Frozen-Thawed Embryo Transfer After PGT-A

Background and Aims: Despite keen development of ART, recurrent implantation failure (RIF) remains a challenging dilemma for fertility specialists. As it contains significant growth factors involved in delicate process of implantation, platelet–rich plasma (PRP) therapy should promote endometrial receptivity and improve ART. Objective: To evaluate if the intrauterine perfusion with autologous PRP enhances frozen-thawed embryo transfer effectiveness in patients with RIF after PGT-A. Methods: Study type: Interventional. Design: randomized controlled study Intervention Model: Parallel Assignment Masking: open label After obtaining institutional review board approval, 232 women aged 28-42 years were involved. Matching criteria: RIF, normal karyotype, absence of uterine factors of infertility, availability of euploid embryos after PGT-A (NGS). 2 groups of patients: study group (N = 118): single IP with 2.0 ml of autologous PRP on day 10-11 of menstrual cycle; Control group: no therapy (N = 114). Endometrium preparation was carried out according to standardized protocol. Primary outcome measure was clinical pregnancy rate. Secondary outcome measures were pregnancy loss rate, endometrial thickness and adverse event. Results: The clinical pregnancy rate was higher in the study group (63.55% vs 38.59%) ([Formula: see text]2=14.462, OR=2.775, 95% CI 1.630 - 4.722, p<0,001). The endometrium thickness before intervention didn’t between groups (7.3 vs 7.4 mm), however, endometrium thickness measured just before embryo transfer was significantly higher in the study group (10.5 vs 8.4 mm, Student’s t-test value: 11.87; number of degrees of freedom f=230; Critical value of Student’s t-test=1.972, at significance level [Formula: see text]= 0.05). The pregnancy rate loss did not differ between groups ([Formula: see text]2=0.033, OR=0.908, 95% CI 0.324 – 2.546, p>0,05). No adverse event was noted. Conclusions : – The PRP intrauterine perfusion should be considered perspective, safe and cost-effective therapy method for patients with RIF. – PRP does not influence on pregnancy loss rate – Meta-analysis is required. Support: None

How Polynomial Regression Improves DeNATing

The ubiquity of Network Address Translation (NAT) and mobile hotspots that aggregate source IP addresses of connected devices to a single IP address makes it difficult for an observer in the Internet to learn anything about the internal network. The IP Identification header field of Domain Name System requests and the TCP Timestamp (TCP TS) header field of TCP SYN packets are the main features for counting devices in the internal network and association of packets to these devices, also known as DeNATing. This paper introduces a new method that relies on polynomial least-squares curve fitting for DeNATing. Evaluation of our model is performed on multiple real-world datasets containing Windows and Unix devices behind a router using NAT and a mobile hotspot. The proposed method outperforms other state-of-the-art methods for all of the used datasets on all types of devices. Successful DeNATing may help in cybersecurity, anti-fraud, and other use cases.

Zinpentraxin Alfa Reduces Myelofibrosis in a JAK2-V617F Mouse Model of Myeloproliferative Neoplasms

Background: Myeloproliferative neoplasms (MPNs) are clonal disorders of the hematopoietic stem cell (HSC), caused by somatic mutations in JAK2, MPL or CALR . Myelofibrosis, characterized by increased deposition of reticulin and/or collagen fibers, is found in advanced stages of MPN. Pentraxin-2 (PTX2, serum amyloid P component/SAP) belongs to the family of short pentraxins and acts as an inhibitor of fibrocyte differentiation and modulator of macrophage polarization. Zinpentraxin alfa (PRM-151, ZPN), a recombinant form of human PTX2, was reported to reduce myelofibrosis in a retroviral model of MPN driven by MPL-W515L (Verstovsek S et al, J Exp Med 2016). ZPN has also been investigated as monotherapy and in combination with ruxolitinib (RUX) in a phase 2 clinical study in patients with myelofibrosis (NCT01981850; Verstovsek S et al, Haematologica 2023). Evidence of clinical activity and tolerable safety as monotherapy and in combination with RUX was shown in that open-label, non-randomized trial. Here, we examined the effects of ZPN alone or in combination with RUX in a mouse model of MPN driven by Cre-inducible expression of human JAK2-V617F (Tiedt R et al, Blood 2008). Methods: To obtain sufficient numbers of mice for drug testing, bone marrow cells from JAK2-V617F mice were transplanted into lethally irradiated C57BL/6 recipients (Kubovcakova L et al., Blood 2013), and groups of 6 mice were sacrificed at 16, 20, and 24 weeks to determine the histological grade of reticulin fibrosis. 24 weeks post transplantation, grade 1-2 fibrosis was confirmed in these satellite mice and treatment was initiated. During treatment, weight and complete blood counts were monitored (n=8 mice per group). At terminal work-up, spleen weight and fibrosis grade were determined, along with flow cytometry of bone marrow and peripheral blood, single cell RNA sequencing of bulk bone marrow, and proteomics analysis by mass spectrometry of bone marrow and plasma. Additionally, we characterized the plasma pharmacokinetics (PK) in these mice following single IP (10 mg/kg) administration of ZPN. Results: Systemic exposure after IP administration was confirmed in each animal (T max at 4 h, C max 27.9 ug/mL,AUC 0-48 381 h*ug/mL). No weight loss or mortality were observed in ZPN monotherapy cohorts, and the slight weight loss observed in RUX treated animals was not potentiated by the addition of ZPN. A trend towards lower platelet, monocyte and total leukocyte counts was observed for ZPN treatment groups compared to vehicle controls (Figure 1A). RUX alone largely normalized hemoglobin values, while ZPN alone or in combination with RUX had less effect on hemoglobin. Terminal work-up showed grade 1-2 fibrosis in the vehicle group, whereas reticulin fibrosis decreased in the majority of mice with ZPN monotherapy or in combination with RUX (Figure 1B). ZPN monotherapy did not reduce spleen weight. Single cell RNA sequencing and proteomics analyses are currently being analyzed and data will be shown. Conclusion: ZPN treatment in a JAK2-V617F mouse model of MPN with myelofibrosis was well tolerated as monotherapy and in combination with RUX. A reduction in the grade of myelofibrosis was observed in all ZPN treatment groups. ZPN showed promising trends in reducing platelet and monocyte counts, while the decrease in hemoglobin by RUX was in part prevented in combination with ZPN.

Protective Effect of Cranberry Extract against Cisplatin-Induced Nephrotoxicity by Improving Oxidative Stress in Mice

Cranberry (Vaccinium macrocarpon) is a North American natural fruit. consumed as food and used for health promotion and prevention of various diseases. Aim. The present study was designed to evaluate the protective effect of cranberry fruit extract on nephrotoxicity induced by cisplatin in mice by measuring selected oxidative stress markers. Methods. Twenty-eight male albino mice were used in this study. The animals were divided into 4 groups as follows: Group I [Negative Control]/orally-administered normal saline for 7 successive days; Group II [Orally-administered cranberry fruit extract alone (200 mg/kg) for 7 successive days; Group III/Mice IP injection with cisplatin (12mg/kg) on day 7 and; Group IV [Orally-administered cranberry fruits extract for 7 successive days followed by single IP injection of cisplatin on day 7. After euthanization of each animal by diethyl ether (on day 8th), serum and renal tissue samples were collected for analysis. Results. Administration of cranberry fruit extract resulted in a significant decline in serum creatinine level (0.87±0.120) and a significant elevation in renal reduced glutathione level (197.42±62.958) (P<0.05) with the improvement in the histological analysis of renal tissue of mice of Group IV compared to that in cisplatin intraperitoneally-injected Group III mice. Conclusions. Orally-administrated cranberry extract prior to cisplatin exerts a protective effect against nephrotoxicity induced by cisplatin via improving the oxidative stress process in mice.

Antioxidant and anti-inflammatory potential of spirulina and thymoquinone mitigate the methotrexate-induced neurotoxicity

The objective of this study was to investigate whether the neurotoxic effects caused by methotrexate (MTX), a frequently used chemotherapy drug, could be improved by administering Spirulina platensis (SP) and/or thymoquinone (TQ). Seven groups of seven rats were assigned randomly for duration of 21 days. The groups consisted of a control group that was given saline only. The second group was given 500 mg/kg of SP orally; the third group was given 10 mg/kg of TQ orally. The fourth group was given a single IP dose of 20 mg/kg of MTX on the 15th day of the experiment. The fifth group was given both SP and MTX, the sixth group was given both TQ and MTX, and the seventh group was given SP, TQ, and MTX. After MTX exposure, the study found that AChE inhibition, depletion of glutathione, and increased levels of MDA occurred. MTX also decreased the activity of SOD and CAT, as well as the levels of inflammatory mediators such as IL-1, IL-6, and tumor necrosis factor-α. MTX induced apoptosis in brain tissue. However, when MTX was combined with either SP or TQ, the harmful effects on the body were significantly reduced. This combination treatment resulted in a faster return to normal levels of biochemical, oxidative markers, inflammatory responses, and cell death. In conclusion, supplementation with SP or TQ could potentially alleviate MTX-induced neuronal injury, likely due to their antioxidant, anti-inflammatory, and anti-apoptotic effects.

HYbrid DegRAding Copolymer (HYDRAC): Heterobifunctional polymers for targeted degradation of undruggable proteins.

22 Background: Of the ~20,000 proteins encoded by the human genome, only a small subset can be modulated via traditional pharmacological approaches. Included in the list of “undruggable” proteins are ones with pivotal roles in cancer. We aim to expand the arsenal of compounds able to affect the activity of these therapeutically relevant targets by introducing a modular proteomimetic platform technology designed to carry side chains consisting of targeting warheads and recruiters of cellular protein degradation machinery. We term these compounds HYbrid DegRAding Copolymers (HYDRACs) in reference to the multiplexing of different protein binders and degradation inducing sequences. Peptides arranged as HYDRACs exhibit favorable emergent properties including resistance to proteolysis, high levels of cell uptake, and payload-specific activity. Initial studies were conducted focusing on a undruggable transcription factor MYC, which is widely dysregulated in human cancers. Methods: A library of HYDRACs and control polymers were synthesized and were cell-penetrating with antiproliferative effects at sub-micromolar IC50s in a formulation- and MYC-dependent manner across multiple cell lines. Results: HYDRAC treatment resulted in significant decreases in MYC protein levels, which was rescued by proteasome inhibitor MG132 and neddylation inhibitor MLN4924, without changes in mRNA levels. RNAseq showed selective overexpression of MYC pathway genes only in HYDRAC treated cells, confirming on-target effects. Circular dichroism showed strong HYDRAC-MYC interactions, which was supported by the presence of MYC following pull-down of biotin-terminated HYDRACs. Removal of the RRRG degron, scrambling the H1 sequence, and disassociation of the two domains on separate polymers all abrogated MYC-degradation. Mice bearing transplanted Myc-CaP tumors showed delayed tumor growth and reduced tumor cell proliferation following HYDRAC treatment. Mice bearing luminescent Luc-MV-411 tumors treated with Cy5.5-labeled HDRACs showed selective tumor accumulation with detectable fluorescent signal in the tumor up to 72 hours following a single IP administration. The versatility of the platform was demonstrated by substituting the degron for recruiters of three different E3 ligases (VHL, KEAP1, and CRBN), which all maintained ability to degrade MYC. HYDRACs were also able to selectively degrade other protein targets including alpha-syn and RAS. Conclusions: We present a platform technology that addresses challenges inherent to small molecule drug design. HYDRACs have the potential to dramatically alter the drug discovery landscape, allowing for development of modulators of "undruggable" targets. We envision the HYDRAC platform as a generalizable approach to designing degraders of proteins of interest, greatly expanding the therapeutic armamentarium for target protein degradation.

Protective Effect of Platelet-Rich Plasma on Cisplatin-Induced Nephrotoxicity in Adult Male Albino Rats: Histological and Immunohistochemical Study.

Cisplatin is a potent antineoplastic drug that is used for treatment of many solid tumors. It has a wide range of adverse effects. Nephrotoxicity is the most common one of them. Platelet-rich plasma (PRP) is an autologous human plasma that activates the tissue regeneration through cell proliferation and differentiation. Study the role of PRP in amelioration of cisplatin-induced nephrotoxicity on the kidney of adult male albino rats by biochemical, morphometric, histological, and immunohistochemical studies. Thirty-five adult male albino rats were used. Thirty rats were included as experimental group and five were used to obtain the PRP. The experimental group was classified into as follows: control group which received 1mL of sterile saline by intraperitoneal injection (IP), cisplatin-treated group which received cisplatin 7.5 mg/kg IP in a single dose and cisplatin and PRP-treated group rats received cisplatin 7.5 mg/kg single IP dose followed by 1ml of PRP IP after 24 h of cisplatin injection. There was a significant increase in urea and creatinine levels in cisplatin-treated group in comparison to the control and the PRP groups. The kidneys of cisplatin-treated group showed distorted renal structure, where specimens of PRP-treated group revealed restoration of the classical appearance of the renal tissue similar to the control group. PRP has protective effects on renal structure and functions and it helps to ameliorate the histological changes induced by cisplatin.

RAVEN: Stateless Rapid IP Address Variation for Enterprise Networks

Enterprise networks face increasing threats against the privacy of their clients. Existing enterprise services like Network Address Translation (NAT) offer limited privacy protection, at the cost of requiring per-flow state. In this paper, we introduce RAVEN (Rapid Address Variation for Enterprise Networks), a network-based privacy solution that is complementary to application-layer defenses. RAVEN protects privacy by frequently changing the client's public IP address. With RAVEN, a client is not limited to using a single IP address at a given time, or even for a given connection. RAVEN goes further, breaking the association between packets that belong to the same connection by frequently changing the client's IP address within a single connection. RAVEN achieves this through a novel division of labor: the client uses a transport protocol, like QUIC, that supports seamless connection migration, and decides when to switch its IP address, while the enterprise network actually changes the client's IP address in a stateless manner at line rate and ensures end-to-end packet delivery. We implement RAVEN using QUIC and off-the-shelf programmable switches. We deploy RAVEN in a test IPv6 network and evaluate its defense against webpage fingerprinting attacks. Even with a strong adversary, the average precision of the best adaptive attacks drops from 0.96 to 0.84, with a 0.5% degradation in client throughput. When RAVEN changes IP addresses at unpredictable frequency, the precision of the best attacks falls to 0.78---the same effectiveness as WTF-PAD.

Alternative splicing (AS) regulation as a novel therapeutic target in soft-tissue sarcoma (STS).

11546 Background: There is an urgent clinical need to identify novel treatments for advanced STS, since all the clinical trials testing chemotherapy combinations have failed to improve survival compared to doxorubicin (dox) alone. AS deregulation has been associated with cancer initiation, progression and resistance to therapy. This deregulation can occur due to mutations or imbalanced expression or activity of splicing factors (SF). The alteration SF can alter thousands of pre-mRNAs, increasing cellular complexity and facilitating tumour progression. CDC-like kinases (CLK) that phosphorylate serine-arginine-rich SF (SRSFs), are key regulators of AS. SM09419 is an oral pan CLK/DYRK inhibitor that has been shown to inhibit SRSF phosphorylation, selectively modify spliceosome activity and decrease tumour growth by multiple mechanisms including the downregulation of Wnt/β-catenin signalling, a pathway that we reported to be important in sarcoma. Methods: A panel of 9 STS cell lines, including LMS (CP0024, IEC005, AA, SK-UT-1), LPS (93T449), synovial sarcoma (MCP037) and UPS (MCP016, MCP021, MCP025) were used to analyse the effect of SM09419 (provided by Biosplice) or PRI-724 (Wnt/β-catenin inhibitor) on cell viability (MTS assays). TOP flash β-catenin/TCF-responsive reporter assay was performed to evaluate the inhibition of the Wnt/β-catenin pathway in response to SM09419. In vivo experiments tested the combination of SM09419 (25mg/kg 5 days on and 2 off, for 21 days cycle) plus IP dox (5mg/kg once a week for 21 days cycle) in LMS (IEC005) and synovial sarcoma (FJD-SS-001) PDX models. Results: Our results showed that SM09419 had superior activity in STS cells compared to specific Wnt/β-catenin inhibitors with IC50 values starting at 29.8 nM in SK-UT-1 cell line, whereas PRI-724 IC50 values were clearly higher, starting from 5.18 µM in 93T449 cells. SM09419 treatment significantly inhibited the transcriptional activity of β-catenin by 40% in the MCP021 cells, demonstrating the regulatory activity of AS inhibitors on this pathway. I n vivo studies confirmed the higher efficacy of SM09419 in monotherapy compared to dox, in inhibiting tumour growth (p < 0.05), which was potentiated when combined with dox. The combination was increasingly active in synovial sarcoma with tumour regressions in 3 out of 4 mice, including one complete response. Treatment schedule was adapted to a single IP administration of dox (5mg/kg) and 5 administrations of SM09419 (25mg/kg), to improve the tolerability of the combination. Conclusions: The effects of pan CLK/DYRK inhibition on growth and survival of STS cancer cell lines and PDX models, indicate that can STS may be therapeutically addressed with these AS-modulators. The combination of SM09419 with dox was active in STS preclinical models known for their resilience toward treatment. Based on these results, the exploration of such combinations in clinical trials is warranted.

Energy Management for a Port Integrated Energy System Based on Distributed Dual Decomposition Mixed Integer Linear Programming

This paper proposes a distributed energy management strategy, based on dual decomposition mixed integer linear programming for port integrated energy systems (PIESs), to improve the utilization of renewable energy, and to foster green ports. Firstly, due to the distributed characteristics presented by various heterogeneous devices, a polymorphic network-based PIES was established, instead of the traditional single IP protocol, incorporating electricity replacement and energy conversion devices. Secondly, taking into account the coupling of various energy flows, an energy management model was constructed, to ensure reliable operation for the PIES. Thirdly, an energy management strategy based on distributed dual decomposition mixed integer linear programming for the PIES was proposed, which took into account the distributed characteristic of the PIES. Finally, the effectiveness of the proposed strategy was demonstrated, by simulation cases in different scenarios for the PIES. The obtained energy management results were similar to the centralized algorithm.

Fasciola hepaticaFh15 promote survival in a mouse septic shock model and downregulates inflammatory cytokines

Abstract Parasitic helminths and helminth-derived molecules, possess an inherent anti-inflammatory capacity. Fasciola hepatica has been reported to decrease in vivo particular Th1 immune responses caused by concurrent bacterial infections. Studies have shown that some Fasciola hepatica’s excretory-secretory products has the capacity to reduce phagocytic activity, affect cell recruitment, and induce activation of alternative activated macrophages. We hypothesized that recombinant F. hepatica FABP (Fh15) may be an excellent target for the development of new anti-inflammatory drugs against sepsis. For this, we developed a mouse model of septic shock to determine the capacity of Fh15 to suppress the cytokine storm and prevent the mortality rate of mice exposed to lethal doses of LPS. BALB/c mice were allotted into two experimental groups of 5 animals each, which received an IP injection with 12mg/kg body wt. of LPS from E. coli 0111: B4. One hour after LPS injection one group received a single IP injection with 100 μg Fh15 and the other group received two injections of 100 μg Fh15 two hours apart. Control groups received IP injection with LPS, Fh15 or PBS alone. Animals were monitored for mortality for 72 hrs. Blood samples were collected from all animals at baseline and by the time they were about to die or survived the LPS lethal challenge. As expected, all animals from LPS-control group succumbed between 12 to 24h following the LPS challenge. In contrast, between 40 to 100% of animals that received the Fh15 treatment survived to the LPS challenge. This notable increase in the survival rate was found associated to significant suppression in the production of pro-inflammatory cytokines such as IL-12, TNF-a and IFN-g, which were measured in serum by BioPlex.

Evaluation the Effect of Chronic Obestatin Therapy on the Serum Glucose, Insulin And Lipid Levels in Type 2 Diabetic Rats

Background: Diabetes mellitus (DM) is one of the most common health disorders, which has become increasingly common in recent years. Type 2 diabetes affects about 90-95% of all diabetic patients, and is often associated with obesity and insulin resistance in most patients. The medical treatment aims to reduce insulin resistance and increase the production of insulin by pancreatic β-cells. Obestatin is a new hormone encoded by the Preghrelin gene. Obestatin is an anorexic hormone that reduces food intake. It has also been shown to play an important role in regulating glucose and lipid levels in the blood. Study Aim: Our study aims to evaluate the therapeutic benefit of obestatin in rats with experimental type 2 diabetes in reducing blood glucose and improving insulin levels, and its effect on insulin resistance, TG, TC and pancreatic β-cell survival. Methods: A total of 30 male Wister rats (150 -200g) were randomly divided into three groups: group I (control group), group II (T2DM group) induced by administration fructose solution 10% for 14 days, and single injection IP of streptozotocin (STZ) (35 mg/Kg), group III (T2DM treated with obestatin) (25 μg/kg) IP twice daily for 30 days. Blood samples were collected at the end of the experiment by terminal intracardiac sampling for bioassays to estimate fasting glucose, insulin, triglyceride (TG), total cholesterol (TC), and assessment of HOMA-IR. Body weight was also measured. Mean ± STD was calculated. The statistical significance of differences across the groups was determined by one-way ANOVA followed by a post Hoc Turkey’s test. The differences were considered significant at 0.05˃P. Results: After 30 days of obestatin treatment, the diabetic group showed a significant increase in glucose, TG, TC and HOMA-IR values and a significant decrease in insulin levels compared to the control group. In comparison, the obestatin-treated group of diabetic patients showed a significant decrease in glucose, TG and TC levels, with a slight increase in the insulin level compared to the diabetic group. In addition, the histological study (H&E) of isolated pancreatic tissue from the second group showed deformed, shrunken Langerhans islets with significant loss of their β- cells, and some cells with vacuolated cytoplasm. Moreover, the histological features of the treatment group were somewhat similar to those of the control group. Conclusion: The results of our study showed the efficacy of obestatin as a treatment in reducing the levels of all glucose, triglycerides and total cholesterol in the blood to normal limits in induced experimental rats with type 2 diabetes. Moreover, the improvement of insulin levels in the blood, and the results of the histological study showed an improvement in the size of the islet and an increase in the number of β-cells. Thus, obestatin can be used as a promising target in the treatment of metabolic diseases such as diabetes and obesity.

Protective Eff ects of Aqueous Cranberry Fruit Extract against Genotoxicity Induced by Cisplatin in Mice Bone Marrow Cells

The cranberry (Vaccinium macrocarpon) is a North American native fruit and contains a very wide variety of phytochemicals which has several benefi cial eff ects on humans. Aim: The study was designed to assess the protective eff ect of cranberry fruit extract on selected genotoxic parameters induced by cisplatin in mice’s bone marrow. Methods: 56 male albino mice were randomLy divided into two equal numbers (28 mice)/for each part of the study [Part one: for the evaluation of chromosomal aberrations and the mitotic index; and Part two: for the evaluation of micronucleus index]; and for each part, mice were randomLy divided into 4 groups: Group I [negative Control/orally-administered normal saline]; Group II [Orally-administered cranberry fruit extract alone]; Group III [Single IP injection of cisplatin]; Group IV [Orally-administered cranberry fruits extract followed by a single IP injection of cisplatin]. Results: Treatment with cisplatin signifi cantly-increased total chromosomal aberration (0.159 ± 0.006) and micronucleus appearance (9.740 ± 0.531) but, it has a signifi cant decrease in mitotic index (6.020 ± 0.589) compared to that in negative control bone marrow cells. In addition, results showed that there were signifi cant changes in the total chromosomal aberration, micronucleus appearance, and mitotic index among the Groups (II, III, IV) (0.093 ± 0.015; 0.159 ± 0.006; 0.117 ± 0.002), (5.940 ± 0.568; 9.740 ± 0.531; 8.000 ± 0.479) and (8.720 ± 0.432; 6.020 ± 0.589; 7.480 ± 0.664), respectively in bone marrow cells. Conclusion: Cisplatin produced a pronounced eff ect on total chromosomal aberrations, micronucleus appearance, and mitotic index; and the cranberry fruit extract confers a protective eff ect against cisplatin-induced genotoxicity in mice.

Evaluation the Effect Of Chronic Obestatin Therapy on the Serum Glucose, Insulin And Lipid Levels in Type 2 Diabetic Rats

Background: Diabetes mellitus (DM) is one of the most common health disorders, which has become increasingly common in recent years. Type 2 diabetes affects about 90-95% of all diabetic patients, and is often associated with obesity and insulin resistance in most patients. The medical treatment aims to reduce insulin resistance and increase the production of insulin by pancreatic β-cells. Obestatin is a new hormone encoded by the Preghrelin gene. Obestatin is an anorexic hormone that reduces food intake. It has also been shown to play an important role in regulating glucose and lipid levels in the blood. Study Aim: Our study aims to evaluate the therapeutic benefit of obestatin in rats with experimental type 2 diabetes in reducing blood glucose and improving insulin levels, and its effect on insulin resistance, TG, TC and pancreatic β-cell survival. Methods: A total of 30 male Wister rats (150 -200g) were randomly divided into three groups: group I (control group), group II (T2DM group) induced by administration fructose solution 10% for 14 days, and single injection IP of streptozotocin (STZ) (35 mg/Kg), group III (T2DM treated with obestatin) (25 μg/kg) IP twice daily for 30 days. Blood samples were collected at the end of the experiment by terminal intracardiac sampling for bioassays to estimate fasting glucose, insulin, triglyceride (TG), total cholesterol (TC), and assessment of HOMA-IR. Body weight was also measured. Mean ± STD was calculated. The statistical significance of differences across the groups was determined by one-way ANOVA followed by a post Hoc Turkey’s test. The differences were considered significant at 0.05˃P. Results: After 30 days of obestatin treatment, the diabetic group showed a significant increase in glucose, TG, TC and HOMA-IR values and a significant decrease in insulin levels compared to the control group. In comparison, the obestatin-treated group of diabetic patients showed a significant decrease in glucose, TG and TC levels, with a slight increase in the insulin level compared to the diabetic group. In addition, the histological study (H&E) of isolated pancreatic tissue from the second group showed deformed, shrunken Langerhans islets with significant loss of their β- cells, and some cells with vacuolated cytoplasm. Moreover, the histological features of the treatment group were somewhat similar to those of the control group. Conclusion: The results of our study showed the efficacy of obestatin as a treatment in reducing the levels of all glucose, triglycerides and total cholesterol in the blood to normal limits in induced experimental rats with type 2 diabetes. Moreover, the improvement of insulin levels in the blood, and the results of the histological study showed an improvement in the size of the islet and an increase in the number of β-cells. Thus, obestatin can be used as a promising target in the treatment of metabolic diseases such as diabetes and obesity.