An Improved Link Model for Window Flow Control and Its Application to FAST TCP

This paper presents a link model which captures the queue dynamics in response to a change in a transmission control protocol (TCP) source's congestion window. By considering both self-clocking and the link integrator effect, the model generalizes existing models and is shown to be more accurate by both open loop and closed loop packet level simulations. It reduces to the known static link model when flows' round trip delays are identical, and approximates the standard integrator link model when there is significant cross traffic. We apply this model to the stability analysis of fast active queue management scalable TCP (FAST TCP) including its filter dynamics. Under this model, the FAST control law is linearly stable for a single bottleneck link with an arbitrary distribution of round trip delays. This result resolves the notable discrepancy between empirical observations and previous theoretical predictions. The analysis highlights the critical role of self-clocking in TCP stability, and the proof technique is new and less conservative than existing ones

High-frequency bistatic scattering by sub-bottom gas bubbles

Author Posting. © Acoustical Society of America, 1997. This article is posted here by permission of Acoustical Society of America for personal use, not for redistribution. The definitive version was published in Journal of the Acoustical Society of America 102 (1997): 806-814, doi:10.1121/1.419906.A previous study of high-frequency acoustic backscattering data collected at Eckernfoerde Bay, Germany revealed that scattering is mainly due to methane gas bubbles buried about a meter beneath the seafloor [Tang et al., J. Acoust. Soc. Am. 96, 2930–2936 (1994)]. A backscattering model was developed [Tang, Geo-Marine Lett. 16, 161–169 (1996)] where the gas bubbles were approximated by oblate spheroids. In this paper, a bistatic scattering model is proposed as an extension of the previously developed backscattering model. In this model, gas bubbles are again assumed to be oblate spheroids with varying aspect ratios and a single-scattering approximation is used. The model is compared to bistatic data acquired in Eckernfoerde Bay, Germany. In particular, the azimuthal dependence of the bistatic scattering strength predicted by the model is tested against experimental data and it is found that both the model and the bistatic scattering strength data exhibit a mild azimuthal dependence. Best agreement between model and data requires a 35% reduction in areal bubble density relative to that used in the backscattering model/data comparison. Possible reasons for this are discussed including multiple scattering effects.This work is supported by the Coastal Benthic Boundary Layer Special Research Program, Office of Navel Research Grant No. N00014-95-1-G904

Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids

Mutations in the gene encoding the type II transmembrane protease 3 (TMPRSS3) cause human hearing loss, although the underlying mechanisms that result in TMPRSS3-related hearing loss are still unclear. We combined the use of stem cell-derived inner ear organoids with single-cell RNA sequencing to investigate the role of TMPRSS3. Defective Tmprss3 leads to hair cell apoptosis without altering the development of hair cells and the formation of the mechanotransduction apparatus. Prior to degeneration, Tmprss3-KO hair cells demonstrate reduced numbers of BK channels and lower expressions of genes encoding calcium ion-binding proteins, suggesting a disruption in intracellular homeostasis. A proteolytically active TMPRSS3 was detected on cell membranes in addition to ER of cells in inner ear organoids. Our in vitro model recapitulated salient features of genetically associated inner ear abnormalities and will serve as a powerful tool for studying inner ear disorders

Diminished Antioxidant Activity of High-Density Lipoprotein–Associated Proteins in Systolic Heart Failure

Background— Diminished serum arylesterase activity, catalyzed by the high-density lipoprotein–associated paraoxonase-1, is associated with heightened systemic oxidative stress and atherosclerosis risk. In the present study, we sought to determine the prognostic role of serum arylesterase activity in subjects with systolic heart failure, particularly in relation to established cardiac biomarkers. Methods and Results— We measured serum arylesterase activity in 760 subjects with impaired left ventricular systolic function (left ventricular ejection fraction \u3c50%), and prospectively followed major adverse cardiac events (including death, nonfatal myocardial infarction, and stroke) for 3 years. In our study cohort (mean age, 64±11 years; 74% men; median left ventricular ejection fraction, 35%; median creatinine clearance, 96 mg/dL), mean serum arylesterase activity (98±25 μmol/L/min/mL) was lower compared with that in healthy control subjects (mean, 115±26 μmol/L/min/mL, P\u3c0.01) but higher compared with advanced decompensated heart failure subjects (mean, 69±22 μmol/L/min/mL, P\u3c0.01). Within our cohort, there was modest correlation between serum arylesterase activity and high-density lipoprotein cholesterol (r=0.33, P\u3c0.01) as well as B-type natriuretic peptide (r=−0.23, P\u3c0.01). Lower serum arylesterase activity was a strong predictor of poorer outcomes (hazard ratio, 2.94; 95% confidence interval, 1.54, 5.62; P\u3c0.001). After adjusting for traditional risk factors, medication use, B-type natriuretic peptide, and creatinine clearance, lower serum arylesterase still conferred an increased risk of major adverse cardiac events at 3 years (hazard ratio, 2.69; 95% confidence interval, 1.37 to 5.28; P=0.004). Conclusions— In patients with systolic heart failure, decreased serum arylesterase activity, a measure of diminished antioxidant properties of high-density lipoprotein, predicts higher risk of incident long-term adverse cardiac event independent of established clinical and biochemical risk factors

Diminished Antioxidant Activity of High-Density Lipoprotein–Associated Proteins in Systolic Heart Failure

Background— Diminished serum arylesterase activity, catalyzed by the high-density lipoprotein–associated paraoxonase-1, is associated with heightened systemic oxidative stress and atherosclerosis risk. In the present study, we sought to determine the prognostic role of serum arylesterase activity in subjects with systolic heart failure, particularly in relation to established cardiac biomarkers. Methods and Results— We measured serum arylesterase activity in 760 subjects with impaired left ventricular systolic function (left ventricular ejection fraction \u3c50%), and prospectively followed major adverse cardiac events (including death, nonfatal myocardial infarction, and stroke) for 3 years. In our study cohort (mean age, 64±11 years; 74% men; median left ventricular ejection fraction, 35%; median creatinine clearance, 96 mg/dL), mean serum arylesterase activity (98±25 μmol/L/min/mL) was lower compared with that in healthy control subjects (mean, 115±26 μmol/L/min/mL, P\u3c0.01) but higher compared with advanced decompensated heart failure subjects (mean, 69±22 μmol/L/min/mL, P\u3c0.01). Within our cohort, there was modest correlation between serum arylesterase activity and high-density lipoprotein cholesterol (r=0.33, P\u3c0.01) as well as B-type natriuretic peptide (r=−0.23, P\u3c0.01). Lower serum arylesterase activity was a strong predictor of poorer outcomes (hazard ratio, 2.94; 95% confidence interval, 1.54, 5.62; P\u3c0.001). After adjusting for traditional risk factors, medication use, B-type natriuretic peptide, and creatinine clearance, lower serum arylesterase still conferred an increased risk of major adverse cardiac events at 3 years (hazard ratio, 2.69; 95% confidence interval, 1.37 to 5.28; P=0.004). Conclusions— In patients with systolic heart failure, decreased serum arylesterase activity, a measure of diminished antioxidant properties of high-density lipoprotein, predicts higher risk of incident long-term adverse cardiac event independent of established clinical and biochemical risk factors

Intestinal Microbiota-Dependent Phosphatidylcholine Metabolites, Diastolic Dysfunction, and Adverse Clinical Outcomes in Chronic Systolic Heart Failure

Background: Trimethylamine-N-oxide (TMAO) has been linked to increased cardiovascular risk. We aimed to determine the prognostic value of TMAO and its dietary precursors, choline and betaine, in heart failure (HF). Methods and Results: In 112 patients with chronic systolic HF with comprehensive echocardiographic evaluation, we measured plasma TMAO, choline, and betaine by mass spectrometry. Median (interquartile range) TMAO levels, choline, and betaine levels were 5.8 (3.6–12.1) μmol/L, 10.9 (8.4–14.0) μmol/L, and 43.8 (37.1–53.0) μmol/L, respectively, and were correlated with each other (all P \u3c .0001 for both). TMAO levels were significantly higher in patients with diabetes mellitus (9.4 [4.9–13.2] vs 4.8 [3.4–9.8] μmol/L; P = .005) and in subjects with New York Heart Association functional class III or greater (7.0 [4.7–14.8] vs 4.7 [3.4–11.3] μmol/L; P = .02). Elevated TMAO, choline, and betaine levels were each associated with higher plasma N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels and more advanced left ventricular diastolic dysfunction, but not systolic dysfunction or inflammatory and endothelial biomarkers. Higher choline (hazard ratio [HR] 1.64, 95% CI 1.22–2.20; P = .001), betaine (HR 1.51, 95% CI 1.10–2.08; P = .01), and TMAO (HR 1.48, 95% CI 1.10–1.96; P = .01) predicted increased risk for 5-year adverse clinical events (death/transplantation). Only higher TMAO levels predicted incident adverse clinical events independently from age, estimated glomerular filtration rate, mitral E/septal Ea, and NT-proBNP levels (HR 1.46, 95% CI 1.03–2.14; P = .03). Conclusion: Elevated plasma TMAO, choline, and betaine levels are each associated with more advanced left ventricular diastolic dysfunction and portend poorer long-term adverse clinical outcomes in chronic systolic HF. However, only higher plasma TMAO was associated with poor prognosis after adjustment for cardiorenal indices

Neural Correlates of Syntactic Comprehension: A Longitudinal Study

Broca’s area is frequently implicated in sentence comprehension but its specific role is debated. Most lesion studies have investigated deficits at the chronic stage. We aimed (1) to use acute imaging to predict which left hemisphere stroke patients will recover sentence comprehension; and (2) to better understand the role of Broca’s area in sentence comprehension by investigating acute deficits prior to functional reorganization. We assessed comprehension of canonical and noncanonical sentences in 15 patients with left hemisphere stroke at acute and chronic stages. LASSO regression was used to conduct lesion symptom mapping analyses. Patients with more severe word-level comprehension deficits and a greater proportion of damage to supramarginal gyrus and superior longitudinal fasciculus were likely to experience acute deficits prior to functional reorganization. Broca’s area was only implicated in chronic deficits. We propose that when temporoparietal regions are damaged, intact Broca’s area can support syntactic processing after functional reorganization occurs

Augmented reality in medical education: a systematic review

Introduction: The field of augmented reality (AR) is rapidly growing with many new potential applications in medical education. This systematic review investigated the current state of augmented reality applications (ARAs) and developed an analytical model to guide future research in assessing ARAs as teaching tools in medical education. Methods: A literature search was conducted using PubMed, Embase, Web of Science, Cochrane Library, and Google Scholar. This review followed PRISMA guidelines and included publications from January 1, 2000 to June 18, 2018. Inclusion criteria were experimental studies evaluating ARAs implemented in healthcare education published in English. Our review evaluated study quality and determined whether studies assessed ARA validity using criteria established by the GRADE Working Group and Gallagher et al., respectively. These findings were used to formulate an analytical model to assess the readiness of ARAs for implementation in medical education. Results: We identified 100,807 articles in the initial literature search; 36 met inclusion criteria for final review and were categorized into three categories: Surgery (23), Anatomy (9), and Other (4). The overall quality of the studies was poor and no ARA was tested for all five stages of validity. Our analytical model evaluates the importance of research quality, application content, outcomes, and feasibility of an ARA to gauge its readiness for implementation. Conclusion: While AR technology is growing at a rapid rate, the current quality and breadth of AR research in medical training is insufficient to recommend the adoption into educational curricula. We hope our analytical model will help standardize AR assessment methods and define the role of AR technology in medical education

Development of a hybrid sleep and physical activity improvement intervention for adults with osteoarthritis-related pain and sleep disturbance : a focus group study with potential users

Objective: Suboptimal sleep and physical activity are common among people living with osteoarthritis (OA) and simultaneous improvements in both may have a beneficial impact on pain. This study aimed to gather perspectives of people living with OA on important aspects to incorporate in a hybrid sleep and physical activity improvement intervention for OA pain management. Design: Qualitative study using two rounds of two focus groups. Setting and participants: Focus groups were conducted with adults living with OA-related chronic pain and sleep disturbances. Eighteen people attended focus groups in January 2020 and, of these, 16 attended subsequent focus groups in February 2020. Methods: Discussion at the first round of focus groups informed generation of prototype intervention materials that were shared, discussed and refined at the second round of focus groups. Thematic analysis was used to identify themes and sub-themes from the data. Results: Three themes, each with three sub-themes, were identified: facilitators of engagement with the intervention (sub-themes: motivational language, accountability and education); barriers to engagement (sub-themes: suboptimal interaction with healthcare practitioners, recording behaviour as burdensome/disruptive and uncertainty about technique) and characteristics of a physical activity intervention component (sub-themes: tailored, sustainable and supported). Conclusion: We have identified important aspects to incorporate into the design and delivery of a hybrid sleep and physical activity improvement intervention for OA pain management. Insights will be incorporated into intervention materials and protocols, with feasibility and acceptability assessed in a future study

The role of Sirt7 and Sirt1 in adipocyte differentiation and maintenance of metabolic homeostasis

Sirtuins are NAD+-dependent protein deacetylases or ADP-ribosyltransferases, which play decisive roles in chromatin silencing, cell cycle regulation, cellular differentiation, metabolism, stress resistance and tumorigenesis. In mammals, sirtuins emerged as key metabolic sensors in various tissues and play a prominent role in metabolic adaptation to energy/nutrient stress. Sirt1 and Sirt6 are believed to act synergistically to prevent liver steatosis, especially under high-fat diet. Sirt1 and Sirt2 inhibit adipogenesis, and Sirt1 promotes the brown remodeling of white adipose tissue to control the metabolic balance in adipose tissue. Sirt7 was postulated to regulate rDNA transcription by associating with RNA polymerase I (Pol I) and maintain oncogenic transformation through deacetylation of histone H3K18, but the role of Sirt7 in metabolic regulation has remained enigmatic. Here, using the Sirt7 knockout mice and Sirt7 knock down approaches, my results describe the role of Sirt7 in maintenance of metabolic homeostasis in liver and the adipocytes differentiation in white adipose tissue. In liver, Sirt7 is required for the stimulation of hepatic rDNA transcription in response to insulin and is necessary for the fasting/refeeding adaptation. The second part of the study demonstrates the essential role of Sirt7 in adipocytes differentiation and white adipose tissue homeostasis. Absence of Sirt7 resulted in increased protein accumulation and activity of Sirt1 and restricted formation of white adipose tissue. In addition, my thesis shows that Sirt7 interacts with Sirt1 and restricts Sirt1 activity by inhibition of Sirt1 auto-deacetylation. These data uncover a new level of complexity in regulation of sirtuin activity and identify autocatalytic posttranscriptional modification as a new principle for regulation of Sirt1 activity. The antagonistic interactions between the two nuclear sirtuins are crucial to establish a well-balanced signalling network required for the maintenance of metabolic homeostasis. In the last part of this thesis, two Sirt1 targeting mouse strains were generated, which allow conditional, tissue specific inactivation of the Sirt1 gene and double knock out Sirt1 and Sirt7 in mice. These mouse models will help to further evaluate the sirtuin functions and the cross-regulatory network between Sirt1 and Sirt7 in the whole body or in the individual tissues.Sirtuine sind NAD+-abhängige Protein Deacetylasen und/oder ADP-Ribosyltransferasen, die entscheidende Rollen in einer Vielzahl von Prozessen spielen. Dazu gehören: Zellzyklusregulation, Differenzierung, metabolische Regulation, Stressresistenz sowie Tumorentstehung und Chromatin-Remodellierung. In Säugetieren nehmen Sirtuine eine Schlüsselrolle als metabolische Sensoren ein und regulieren die Adaptation auf Energie- und Nährstoffveränderungen. Synergistische Funktionen wurden für Sirt1 und Sirt6 in der Leber beschrieben. Beide Sirtuine wirken der Entwicklung von Lebersteatose, insbesondere bei fettreicher Ernährung, entgegen. Bei der Differenzierung von weißem Fettgewebe (Adipogenese) wurde eine hemmende Wirkung von Sirt1 und Sirt2 beobachtet. Des Weiteren, fördert Sirt1 die Entstehung von braunem Fettgewebe aus weißem Fett und kontrolliert somit die metabolische Balance im Fettgewebe. Für Sirt7 wurde bislang eine Funktion in der Regulation der rDNA Transkription durch die Interaktion mit der RNA-Polymerase I postuliert, eine Rolle in der Regulation metabolischer Prozesse konnte bis jetzt aber noch nicht nachgewiesen werden. In meiner Arbeit konnte ich mittels der Sirt7 Knock Out Maus bzw. verschiedener Sirt7 Knock Down Versuche belegen, dass Sirt7 eine Rolle in der Aufrechterhaltung der metabolischen Homöostase in der Leber und in der Differenzierung von Adipozyten in weißem Fettgewebe spielt. In der Leber ist Sirt7 für die Anregung der rDNA Transkription als Antwort auf eine Stimulation durch Insulin notwendig. Zudem konnte belegt werden, dass Sirt7 für eine Anpassung an Hungerphasen und anschließender Nahrungsaufnahme erforderlich ist. Im zweiten Teil meiner Arbeit konnte ich zeigen, dass die Funktion von Sirt7 in der Differenzierung von Adipozyten und in der Homöostase des weißen Fettgewebes essentiell ist. Hier resultiert der Verlust von Sirt7 in einer vermehrten Proteinakkumulation und einer erhöhten Aktivität von Sirt1, die der Fettgewebsentstehung entgegen wirkt. Hier konnte durch meine Arbeit eine Interaktion zwischen Sirt7 und Sirt1 belegt werden, welche mit einem Aktivitätsverlust von Sirt1 durch Inhibierung dessen Auto-Deacetylasefunktion einhergeht. Diese Ergebnisse decken eine neue Stufe der Komplexität der Aktivitätsanpassung der Sirtuine auf und identifizieren eine posttranskriptionelle Modifizierung als einen neuen Weg der Sirt1 Regulation durch dessen autokatalytische Aktivität. Die antagonistische Interaktion zwischen diesen zwei nukleären Sirtuinen ist entscheidend um eine ausgewogene Verknüpfung einzelner Signalwege herzustellen, die für die Aufrechterhaltung der metabolischen Homöostase notwendig sind. Im letzten Teil meiner Arbeit wurden zwei konditionelle Sirt1 Knock Out Mausstämme generiert, welche einerseits eine gewebsspezifische Inaktivierung von Sirt1 und zum anderen die gleichzeitige Ausschaltung von Sirt1 und Sirt7 in Mäusen erlauben. Die entstandenen Mausmodelle können helfen, die Funktionen von Sirt1 und Sirt7 und deren gegenseitige Beeinflussung im gesamten Organismus oder speziell in einzelnen Organen genauer zu untersuchen