Modeling, Analysis, and Hard Real-time Scheduling of Adaptive Streaming Applications

In real-time systems, the application's behavior has to be predictable at compile-time to guarantee timing constraints. However, modern streaming applications which exhibit adaptive behavior due to mode switching at run-time, may degrade system predictability due to unknown behavior of the application during mode transitions. Therefore, proper temporal analysis during mode transitions is imperative to preserve system predictability. To this end, in this paper, we initially introduce Mode Aware Data Flow (MADF) which is our new predictable Model of Computation (MoC) to efficiently capture the behavior of adaptive streaming applications. Then, as an important part of the operational semantics of MADF, we propose the Maximum-Overlap Offset (MOO) which is our novel protocol for mode transitions. The main advantage of this transition protocol is that, in contrast to self-timed transition protocols, it avoids timing interference between modes upon mode transitions. As a result, any mode transition can be analyzed independently from the mode transitions that occurred in the past. Based on this transition protocol, we propose a hard real-time analysis as well to guarantee timing constraints by avoiding processor overloading during mode transitions. Therefore, using this protocol, we can derive a lower bound and an upper bound on the earliest starting time of the tasks in the new mode during mode transitions in such a way that hard real-time constraints are respected.Comment: Accepted for presentation at EMSOFT 2018 and for publication in IEEE Transactions on Computer-Aided Design of Integrated Circuits and Systems (TCAD) as part of the ESWEEK-TCAD special issu

Use of Antihypertensive Drugs and Risk of Malignant Melanoma: A Meta-analysis of Observational Studies

Introduction Several antihypertensive drugs are photosensitizing and may promote the development of malignant melanoma (MM), but evidence remains inconsistent. We sought to quantify the association between use of antihypertensive drugs and MM risk. Methods We systematically searched PubMed, Embase, and CENTRAL from inception to August 17, 2017 to identify observational studies that reported the MM risk associated with the use of antihypertensive drugs. A random-effects meta-analysis was used to estimate the odds ratio (OR) with 95% confidence interval (CI). Results Overall, we included eight observational studies (two cohort studies and six case–control studies). Compared with non-use, use of diuretics (OR 1.10; 95% CI 1.03–1.17) or β-adrenergic blocking agents (OR 1.19; 95% CI 1.04–1.37) was significantly associated with increased risk of MM. The use of angiotensin-converting enzyme inhibitors (OR 1.08; 95% CI 0.95–1.23), angiotensin II receptor blockers (OR 1.12; 95% CI 0.95–1.31), and calcium channel blockers (OR 1.12; 95% CI 0.72–1.74) was not significantly associated with increased risk of MM. Conclusions Current evidence from observational studies suggests that use of diuretics or β-adrenergic blocking agents may be associated with increased risk of MM. Further large well-conducted prospective studies are required to confirm our findings

SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials

Aims/hypothesis The association between sodium–glucose cotransporter 2 (SGLT2) inhibitors and the risk of cancer in individuals with type 2 diabetes remains uncertain. This study aimed to evaluate the risk of cancer associated with SGLT2 inhibitor treatment of type 2 diabetes. Methods We systematically searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov from inception to 15 February 2017 to identify eligible randomised controlled trials (RCTs) that report cancer events in individuals with type 2 diabetes treated with SGLT2 inhibitors for at least 24 weeks. We performed pairwise and network meta-analyses as well as a cumulative meta-analysis to calculate ORs and 95% CIs. Results In total, 580 incidences of cancer among 34,569 individuals were identified from 46 independent RCTs with a mean trial duration of 61 weeks. When compared with comparators (placebo or other active glucose-lowering treatments), SGLT2 inhibitors were not significantly associated with an increased risk of overall cancer (OR 1.14 [95% CI 0.96, 1.36]). For pre-specified cancer types, the risk of bladder cancer might be increased with SGLT2 inhibitors (OR 3.87 [95% CI 1.48, 10.08]), especially empagliflozin (OR 4.49 [95% CI 1.21, 16.73]). Interestingly, canagliflozin might be protective against gastrointestinal cancers (OR 0.15 [95% CI 0.04, 0.60]). Conclusions/interpretation Current evidence from short-term RCTs did not indicate a significantly increased risk of overall cancer among individuals with type 2 diabetes using SGLT2 inhibitors. Given the short-term trial durations and uncertainty of evidence, future long-term prospective studies and post-marketing surveillance studies are warranted

Phosphodiesterase type 5 inhibitors and risk of melanoma: A meta-analysis

Background The association between phosphodiesterase type 5 (PDE5) inhibitors and melanoma risk is controversial. Objective We quantify the association between use of PDE5 inhibitors and melanoma. Methods We systematically searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov for studies that were conducted up to July 13, 2016, and evaluated the association between PDE5 inhibitors and skin cancer. Random effects meta-analyses were used to calculate the adjusted odds ratio (OR) with the 95% confidence interval (CI). Results Five observational studies were included. Compared with PDE5 inhibitor nonuse, PDE5 inhibitor use was slightly but significantly associated with an increased risk for development of melanoma (OR, 1.12; 95% CI, 1.03-1.21) and basal cell carcinoma (OR, 1.14; 95% CI, 1.09-1.19) but not squamous cell carcinoma. For melanoma risk, none of the prespecified factors (dose of PDE5 inhibitor, study design, and study region) significantly affected the results (P > .05). Our sensitivity analysis confirmed the stability of the results. Limitations We included only observational studies, which had some heterogeneities and inconsistent controlling for potential confounders. Conclusions Use of PDE5 inhibitors may be associated with a slightly increased risk for development of melanoma and basal cell carcinoma but not squamous cell carcinoma. However, further large well-conducted prospective studies with adequate adjustment for potential confounders are required for confirmation

Use of antihypertensive drugs and risk of keratinocyte carcinoma: A meta‐analysis of observational studies

Purpose Current epidemiologic evidence on the association between antihypertensive drugs and keratinocyte carcinoma (KC) risk is inconsistent. We sought to quantify this association by meta‐analysis of observational studies. Methods We systematically reviewed observational studies published through August 2016 and reported the KC risk (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]) associated with antihypertensive drugs, including diuretics, angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta‐adrenergic blocking agents (β‐blockers), and calcium channel blockers (CCBs). Random‐effects meta‐analysis was used to estimate the odds ratio (OR) with 95% confidence interval (CI). Results Ten eligible studies were included. Compared with nonuse, diuretic use was significantly associated with increased risk of both BCC (OR, 1.10; 95% CI, 1.01‐1.20) and SCC (OR, 1.40; 95% CI, 1.19‐1.66). Use of β‐blockers or CCBs was associated with increased risk of BCC (but not SCC); the OR with β‐blockers was 1.09 (95% CI, 1.04‐1.15) and with CCBs was 1.15 (95% CI, 1.09‐1.21). Use of ACE inhibitors or ARBs was associated with decreased risk of both BCC (OR, 0.53; 95% CI, 0.39‐0.71) and SCC (OR, 0.58; 95% CI, 0.42‐0.80) in high‐risk individuals. Conclusions Current evidence indicates that use of diuretics might be associated with increased risk of KC, while ACE inhibitors or ARBs might be associated with decreased risk in high‐risk individuals. β‐blockers or CCBs might be positively associated with BCC risk. Further postmarketing surveillance studies and investigations to clarify the possible underlying mechanisms are warranted

Pioglitazone and bladder cancer risk: a systematic review and meta-analysis

Current evidence about the association between pioglitazone and bladder cancer risk remains conflict. We aimed to assess the risk of bladder cancer associated with the use of pioglitazone and identify modifiers that affect the results. We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception to 25 August 2016 for randomized controlled trials (RCTs) and observational studies that evaluated the association between pioglitazone and bladder cancer risk. Conventional and cumulative meta-analyses were used to calculate the odds ratio (OR) with 95% confidence interval (CI). A restricted spline regression analysis was used to examine the dose-response relationship with a generalized least-squares trend test. We included two RCTs involving 9114 patients and 20 observational studies (n = 4,846,088 individuals). An increased risk of bladder cancer in patients treated with pioglitazone versus placebo was noted from RCTs (OR, 1.84; 95%CI, 0.99 to 3.42). In observational studies, the increased risk of bladder cancer was slight but significant among ever-users of pioglitazone versus never-users (OR, 1.13; 95%CI, 1.03 to 1.25), which appeared to be both time- (P = 0.003) and dose-dependent (P = 0.05). In addition, we observed the association differed by region of studies (Europe, United States, or Asia) or source of funding (sponsored by industry or not). Current evidence suggests that pioglitazone may increase the risk of bladder cancer, possibly in a dose- and time-dependent manner. Patients with long-term and high-dose exposure to pioglitazone should be monitored regularly for signs of bladder cancer

Real-time calcium uptake monitoring of a single renal cancer cell based on an all-solid-state potentiometric microsensor

Introduction: In addition to many cellular processes, Ca2+ is also involved in tumor initiation, progression, angiogenesis, and metastasis. The development of new tools for single-cell Ca2+ measurement could open a new avenue for cancer therapy.Methods: The all-solid-state calcium ion-selective microelectrode (Ca2+-ISμE) based on carbon fiber modified with PEDOT (PSS) as solid-contact was developed in this work, and the characteristics of the Ca2+-ISμE have also been investigated.Results: The Ca2+-ISμE exhibits a stable Nernstian response in CaCl2 solutions in the active range of 1.0 × 10−8 - 3.1 × 10−3 M with a low detection limit of 8.9 × 10−9 M. The Ca2+-ISμE can be connected to a patch clamp to fabricate a single-cell analysis platform for in vivo calcium monitoring of a single renal carcinoma cell. The calcium signal decreased significantly (8.6 ± 3.2 mV, n = 3) with severe fluctuations of 5.9 ± 1.8 mV when the concentration of K+ in the tumor microenvironment is up to 20 mM.Discussion: The results indicate a severe cell response of a single renal carcinoma cell under high K+ stimuli. The detection system could also be used for single-cell analysis of other ions by changing different ion-selective membranes with high temporal resolution

Leukemia cells remodel marrow adipocytes via TRPV4-dependent lipolysis

Remodeling of adipocyte morphology and function plays a critical role in prostate cancer development. We previously reported that leukemia cells secrete growth differentiation factor 15 (GDF15)，which remodels the residual bone marrow (BM) adipocytes into small adipocytes and is associated with a poor prognosis in acute myeloid leukemia (AML) patients. However, little is known about how GDF15 drives BM adipocyte remodeling. In this study, we examined the role of the transient receptor potential vanilloid (TRPV) channels in the remodeling of BM adipocytes exposed to GDF15. We found that TRPV4 negatively regulated GDF15-induced remodeling of BM adipocytes. Furthermore, transforming growth factor-β type II receptor (TGFβRII) was identified as the main receptor for GDF15 on BM adipocytes. PI3K inhibitor treatment reduced GDF15-induced pAKT, identifying PI3K/AKT as the downstream stress response pathway. Subsequently, GDF15 reduced the expression of the transcription factor Forkhead box C1 (FOXC1) in BM adipocytes subjected to RNA-seq screening and Western blot analyse. Moreover, it was also confirmed that FOXC1 combined with the TRPV4 promoter by the Chip-qPCR experiments, which suggests that FOXC1 mediates GDF15 regulation of TRPV4. In addition, an AML mouse model exhibited smaller BM adipocytes, whereas the TRPV4 activator 4α-phorbol 12,13-didecanoate (4αPDD) partly rescued this process and increased survival. In conclusion, TRPV4 plays a critical role in BM adipocyte remodeling induced by leukemia cells, suggesting that targeting TRPV4 may constitute a novel strategy for AML therapy

Nicotinamide mononucleotide adenylyltransferase uses its NAD+ substrate-binding site to chaperone phosphorylated Tau.

Funder: Science and Technology Commission of Shanghai Municipality; FundRef: http://dx.doi.org/10.13039/501100003399Funder: Dr. John T. MacDonald Foundation; FundRef: http://dx.doi.org/10.13039/100010239Tau hyper-phosphorylation and deposition into neurofibrillary tangles have been found in brains of patients with Alzheimer's disease (AD) and other tauopathies. Molecular chaperones are involved in regulating the pathological aggregation of phosphorylated Tau (pTau) and modulating disease progression. Here, we report that nicotinamide mononucleotide adenylyltransferase (NMNAT), a well-known NAD+ synthase, serves as a chaperone of pTau to prevent its amyloid aggregation in vitro as well as mitigate its pathology in a fly tauopathy model. By combining NMR spectroscopy, crystallography, single-molecule and computational approaches, we revealed that NMNAT adopts its enzymatic pocket to specifically bind the phosphorylated sites of pTau, which can be competitively disrupted by the enzymatic substrates of NMNAT. Moreover, we found that NMNAT serves as a co-chaperone of Hsp90 for the specific recognition of pTau over Tau. Our work uncovers a dedicated chaperone of pTau and suggests NMNAT as a key node between NAD+ metabolism and Tau homeostasis in aging and neurodegeneration

Protein adsorption at oil-water interfaces interfacial structure and function of proteins in emulsions

Protein adsorption at oil-water interfaces of emulsions is an important process in the manufacture of many emulsion-based products in food and pharmaceutical industries. It is widely known that for protein-stabilized oil-in-water emulsions, the interfacial structure of proteins adsorbed at oil-water interfaces plays an active role in controlling the physical stability of the emulsions. However, the colloidal properties of emulsions such as the strong scattering and high absorbance of light have severely limited the ability of spectroscopic techniques to measure the interfacial structure of proteins. The lack of studies that systematically investigate the interfacial structure of proteins adsorbed at oil-water interfaces has limited our understanding of how the adsorption process mediates protein structural change and in turn the physical stability of the protein-stabilized emulsions. To address this issue, there is therefore great need to employ novel biophysical techniques that provide molecular level understanding of the interfacial structure of proteins adsorbed at oil-water interfaces. This thesis explores three biophysical techniques, i.e. synchrotron radiation circular dichroism (SRCD) spectroscopy, front-face tryptophan fluorescence (FFTF) spectroscopy and dual polarization interferometry (DPI), to study the interfacial structure of proteins adsorbed at oil-water interfaces of emulsions. The strong light from the synchrotron radiation source significantly enhanced the sensitivity of SRCD spectroscopy in measuring optically turbid emulsions. SRCD spectroscopy proved to be a powerful technique providing information on both the secondary and tertiary structure of proteins adsorbed at oil-water interfaces. Studies using FFTF spectroscopy in this thesis provided specific information on changes in the tertiary folding of globular proteins adsorbed at oil-water interfaces. DPI was employed in this thesis as a sensing technique to measure the geometric dimensions of proteins (thickness and density) adsorbed at planar hydrophobic interfaces mimicking oil-water interfaces of emulsions. Using the techniques of SRCD, FFTF and DPI, the interfacial structures of three proteins, i.e. β-lactoglobulin (β-Lg), α-lactalbumin (α-La) and β-casein, adsorbed at oil-water interfaces were therefore characterized at a molecular level. These milk proteins are common components of emulsifiers used in many food emulsions and have been frequently used as model proteins in studies of protein adsorption. Studies on the interfacial structure of β-Lg adsorbed at oil-water interfaces of two model emulsions (hexadecane-in-water and tricaprylin-in-water emulsions) showed that upon adsorption to oil-water interfaces, β-Lg changed from its native globular structure (3.6 nm in diameter) rich in β-sheet into an open flat structure with a non-native secondary structure with heat-resistant, α-helical-rich characteristics. The β-Lg layer adsorbed at planar hydrophobic surfaces mimicking oil-water interfaces of emulsions was shown to be thin (~1 nm) and dense (~1 g/cm3). The droplet surfaces surrounded by the β-Lg interfacial layers were negatively charged (approximately -60 mV of ζ-potential), providing electrostatic repulsion between the emulsion droplets. Parallel studies on the physical stability of β-Lg-stabilized emulsions showed that these emulsions were resistant to droplet flocculation under the condition of heating up to 90 °C. However, increasing the ionic strength by adding 120 mM NaCl reduced the strength of the electrostatic interactions and thus caused β-Lg-stabilized emulsions to undergo heat-induced droplet flocculation. Studies on the interfacial structure of α-La adsorbed at oil-water interfaces showed that α-La also underwent a significant structural change. Adsorption caused a loss of the well-defined globular structure of α-La (2.5 x 3.2 x 3.7 nm in crystal structure dimension) accompanied by the formation of a non-native, heat-resistant, α-helical-rich secondary structure. This structural change resulted in a thin (~1 nm) and dense (~1 g/cm3) layer of α-La, which was negatively charged (approximately -49 mV of ζ-potential). The main stabilization mechanism of α-La-stabilized emulsions was therefore also electrostatic repulsion. Like β-Lg-stabilized emulsions, α-La-stabilized emulsions were resistant to droplet flocculation under the condition of heating up to 90 °C. Interestingly, α-La-stabilized emulsions displayed better stability than β-Lg-stabilized emulsions under the condition of heating in the presence of 120 mM NaCl, mainly due to the lack of inter-droplet disulfide bonding reactions between the interfacial α-La layers. Studies on β-casein, a flexible protein with a large amount of unordered secondary structure, showed that adsorption to oil-water interfaces induced the formation of the non-native α-helical structure in β-casein. The β-casein layer adsorbed at the planar hydrophobic surface was thicker (~5 nm) and more diffuse (0.4 g/cm3) than the β-Lg and α-La layers. The droplet surfaces surrounded by the β-casein layers were also negatively charged (-40 mV of ζ-potential). This interfacial structure of β-casein provided both electrostatic and steric repulsion between the droplets of β-casein-stabilized emulsions, which showed excellent resistance to droplet flocculation under conditions of heating up to 90 °C and 120 mM NaCl addition. This interfacial structure and function of β-casein in oil-in-water emulsions led to a study exploring the ability of β-casein as a stabilizer in another colloidal system, i.e. lipid liquid crystalline nanostructured particles, which are important systems in drug delivery applications. Results obtained from this study revealed that β-casein adsorbed to lipid-water interfaces, provided steric stabilization and favoured the formation of the hexagonal liquid crystalline phase in these lipid nanostructured particles. Overall, studies in this thesis have advanced our understanding of how adsorption to oil-water or lipid-water interfaces leads to changes in the structure of proteins and in turn how it impacts on their function as stabilizers for colloids containing oil or lipid particles, which have implications in areas such as improvement of food emulsion stability and development of new drug delivery systems