| 1. |
- Al-Saffar, Anas Kh. 1969-
(författare)
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Gastrointestinal Permeability and Motility in Inflammatory Bowel Disease
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Synchronized motility, permeability and secretory (hormones and enzymes) events are integral to normal physiology. Smooth muscle syncytium operates with enteric nervous system (ENS) and endocrine signalling to accommodate, mix and control passage of ingested materials. The intestinal epithelial cells (IECs) drive digestion and absorption while repelling harmful compounds.This thesis investigated GI barrier function (permeability, mucosal integrity), motility and hormonal patterns in inflammatory bowel disease (IBD) by: 1) assessing GI motility using a wireless motility capsule (WMC, SmartPill®) and video capsule endoscopy (VCE, Pillcam®), 2) investigation of intestinal fatty acid binding protein (I-FABP) as a biomarker of Crohn’s disease (CD) disease activity, 3) evaluation of small intestinal permeability in IBD, 4) investigating meal-related WMC motility and simultaneous hormonal (e.g., Ghrelin, GLP-1, GIP, PYY) patterns in IBD. Reference WMC motility values for transit times for gastric emptying, small bowel, orocecal, small+large bowel, colon and whole gut were established. Software-generated estimates and visually determined values were nearly identical. Compared with VCE estimates (represents fasting conditions), the WMC records longer GET and SBTT. Variations in intra-subject reproducibility must be considered in clinical investigations. This data was then used to investigate IBD patients. I-FABP was primarily expressed in the epithelium of the small bowel and to lesser extent also in the colon and stomach. Circulating I-FABP was elevated in active CD with a magnitude comparable to TNFα. I-FABP lowers and rises again in parallel with TNFα and HBI during infliximab treatment. I-FABP can be used as a jejunum and ileum selective prognostic biomarker for monitoring disease activity. Increased small intestine mucosal barrier permeability to lactulose in both CD and UC was found. Sucralose can serve a dual purpose in quantifying small and large intestinal permeability. Small intestinal hyper-permeability was not revealed as a transporter dependent nutrient (riboflavin) malabsorption. Using the WMC, consistent motility disturbances in IBD were limited, as were differences in pH. However, disturbances within many individuals were found. As part of the investigation, defects in gut peptide and metabolic hormone meal responses were found, typically higher plasma levels. No clear associations between hormones and motility were found. Effects on hunger/satiety signaling in IBD are anticipated.The present thesis shows the utility of the WMC and gut barrier tests in monitoring IBD patients.
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| 2. |
- Chaourani, Panagiotis, 1989-
(författare)
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Sequential 3D Integration - Design Methodologies and Circuit Techniques
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sequential 3D (S3D) integration has been identified as a potential candidate for area efficient ICs. It entails the sequential processing of tiers of devices, one on top the other. The sequential nature of this processing allows the inter-tier vias to be processed like any other inter-metal vias, resulting in an unprecedented increase in the density of vertical interconnects. A lot of scientific attention has been directed towards the processing aspects of this 3-D integration approach, and in particular producing high-performance top-tier transistors without damaging the bottom tier devices and interconnects.As far as the applications of S3D integration are concerned, a lot of focus has been placed on digital circuits. However, the advent of Internet-of-Things applications has motivated the investigation of other circuits as well.As a first step, two S3D design platforms for custom ICs have been developed, one to facilitate the development of the in-house S3D process and the other to enable the exploration of S3D applications. Both contain device models and physical verification scripts. A novel parasitic extraction flow for S3D ICs has been also developed for the study of tier-to-tier parasitic coupling.The potential of S3D RF/AMS circuits has been explored and identified using these design platforms. A frequency-based partition scheme has been proposed, with high frequency blocks placed in the top-tier and low-frequency ones in the bottom. As a proof of concept, a receiver front-end for the ZigBee standard has been designed and a 35% area reduction with no performance trade-offs has been demonstrated.To highlight the prospects of S3D RF/AMS circuits, a study of S3D inductors has been carried out. Planar coils have been identified as the most optimal configuration for S3D inductors and ways to improve their quality factors have been explored. Furthermore, a set of guidelines has been proposed to allow the placement of bottom tier blocks under top-tier inductors towards very compact S3D integration. These guidelines take into consideration the operating frequencies and type of components placed in the bottom tier.Lastly, the prospects of S3D heterogeneous integration for circuit design have been analyzed with the focus lying on a Ge-over-Si approach. Based on the results of this analysis, track-and-hold circuits and digital cells have been identified as potential circuits that could benefit the most from a Ge-over-Si S3D integration scheme, thanks to the low on-resistance of Ge transistors in the triode region. To improve the performance of top-tier Ge transistors, a processing flow that enables the control of their back-gates has been also proposed, which allows controlling the threshold voltage of top-tier transistors a truntime.
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| 3. |
- Halim, Md. Abdul, 1983-
(författare)
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Gut peptides in gastrointestinal motility and mucosal permeability
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Gut regulatory peptides, such as neuropeptides and incretins, play important roles in hunger, satiety and gastrointestinal motility, and possibly mucosal permeability. Many peptides secreted by myenteric nerves that regulate motor control are also produced in mucosal epithelial cells. Derangements in motility and mucosal permeability occur in many diseases. Current knowledge is fragmentary regarding gut peptide actions and mechanisms in motility and permeability.This thesis aimed to 1) develop probes and methods for gut permeability testing, 2) elucidate the role of neuropeptide S (NPS) in motility and permeability, 3) characterize nitrergic muscle relaxation and 4) characterize mechanisms of glucagon-like peptide 1 (GLP-1) and the drug ROSE-010 (GLP-1 analog) in motility inhibition.A rapid fluorescent permeability test was developed using riboflavin as a transcellular transport probe and the bisboronic acid 4,4'oBBV coupled to the fluorophore HPTS as a sensor for lactulose, a paracellular permeability probe. This yielded a lactulose:riboflavin ratio test.NPS induced muscle relaxation and increased permeability through NO-dependent mechanisms. Organ bath studies revealed that NPS induced NO-dependent muscle relaxation that was tetrodotoxin (TTX) sensitive. In addition to the epithelium, NPS and its receptor NPSR1 localized at myenteric nerves. Circulating NPS was too low to activate NPSR1, indicating NPS uses local autocrine/paracrine mechanisms.Nitrergic signaling inhibition by nitric oxide synthase inhibitor L-NMMA elicited premature duodenojejunal phase III contractions in migrating motility complex (MMC) in humans. L-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. Intestinal contractions were stimulated by L-NMMA, but not TTX. NOS immunoreactivity was detected in the myenteric plexus but not smooth muscle.Food-intake increased motility of human antrum, duodenum and jejunum. GLP-1 and ROSE-010 relaxed bethanechol-induced contractions in muscle strips. Relaxation was blocked by GLP-1 receptor antagonist exendin(9-39) amide, L-NMMA, adenylate cyclase inhibitor 2´5´-dideoxyadenosine or TTX. GLP-1R and GLP-2R were expressed in myenteric neurons, but not muscle.In conclusion, rapid chemistries for permeability were developed while physiological mechanisms of NPS, nitrergic and GLP-1 and ROSE-010 signaling were revealed. In the case of NPS, a tight synchrony between motility and permeability was found.
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| 4. |
- Hellström, Charlotta, 1973-
(författare)
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Adolescent Gaming and Gambling in Relation to Negative Social Consequences and Health
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aims of the thesis were to study relationships between the effects of online gaming and gambling and negative social consequences and ill health among adolescents and to determine whether gaming and gambling activities occur together.The papers in this thesis used epidemiological methods to obtain self-report information from Swedish adolescents aged 13–18 years. Time spent in online gaming was associated with negative social consequences, and this relationship was explained by online gaming motives. Gaming for fun and social motives was associated with a reduced risk of negative social consequences, whereas gaming to escape problems, gain status, or meet demands from others was associated with an increased risk.Increased online gaming time on weekdays increased the probability of having depressive, musculoskeletal, or psychosomatic symptoms, and was related to online gaming motives. The probability of ill health was low in those who reported gaming for fun or social motives. Adolescents with symptoms of attention deficit hyperactivity disorder (ADHD) were more sensitive to gambling frequency and to developing a gambling problem. However, among those identified as susceptible, adolescents with ADHD were equally affected compared with other susceptible participants in terms of their gambling frequency.Boys had a higher probability than girls of participating in online gambling in association with online gaming. Having at least one parent born outside Scandinavia was associated with a higher probability of online gambling, especially among girls. The effect of alcohol use as a factor contributing to online gambling was greater among boys than among girls.The results of this thesis contribute new knowledge about sex differences in online gaming and gambling behaviours and add to the limited research on online gaming and online gambling behaviours among adolescent girls. Gaming motives may be helpful for identifying online gamers needing support to reduce their unhealthy gaming behaviour. Information about factors related to gaming and gambling problems may be of interest to clinicians in psychiatry, psychology and social work, as well as to policymakers, parents and teachers involved in adolescent health and development. Effect preventive strategies should consider the sex differences in gaming and gambling behaviour in adolescents.
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| 5. |
- Hou, Shuoben
(författare)
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Silicon Carbide High Temperature Photodetectors and Image Sensor
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Silicon Carbide (SiC) has the advantages of ultraviolet (UV) sensing and high temperature characteristics because of its wide band gap. Both merits make SiC photodetectors very attractive in astronomy, oil drilling, combustion detection, biology and medical applications. Driven by the objective of probing the high temperature surface of Venus (460 °C), this thesis develops SiC photodetectors and an image sensor for extremely high temperature functions. The devices and circuits are demonstrated through the procedure of layout design, in-house processing and characterizations on two batches.The process flow has been optimized to be suitable for large scale integration (LSI) of SiC bipolar integrated circuits (IC). The improved processing steps are SiC dry etching, ohmic contacts and two-level metal interconnect with chemical-mechanical polishing (CMP). The optimized process flow is applied in the fabrication of discrete devices, a transistor-transistor logic (TTL) process design kit (PDK) and LSI circuits.The photodetectors developed in this thesis, including photodiodes with various mesa areas, a phototransistor and a phototransistor Darlington pair have stable characteristics in a wide temperature range (25 °C ~ 500 °C). The maximum operational temperature of the p-i-n photodiode (550 °C) is the highest recorded temperature accomplished ever by a photodiode. The optical responsivity of the photodetectors covers the spectrum from 220 nm to 380 nm, which is UV-only.The SiC pixel sensor and image sensor developed in this thesis are pioneer works. The pixel sensor overcomes the challenge of monolithic integration of SiC photodiode and transistors by sharing the same epitaxial layers and topside contacts. The pixel sensor is characterized from 25 °C to 500 °C. The whole image sensor circuit has 256 (16 ×16) pixel sensors and one 8-bit counter together with two 4-to-16 decoders for row/column selection. The digital circuits are built by the standard logic gates selected from the TTL PDK. The image sensor has 1959 transistors in total. The function of the image sensor up to 400 °C is verified by taking basic photos of nonuniform UV illumination on the pixel sensor array.This thesis makes an important attempt on the demonstration of SiC opto-electronic on-chip integration. The results lay a foundation on the development of future high temperature high resolution UV image sensors.
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| 6. |
- Jayakumar, Ganesh, 1987-
(författare)
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Silicon nanowire based devices for More than Moore Applications
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Silicon nanowires (SiNW) are in the spotlight for a few years in the research community as a good candidate for biosensing applications. This is attributed to their small dimensions in nanometer scale that offers high sensitivity, label-free detection and at the same time utilizing small amount of sample. While the recent research has concentrated predominantly on utilizing single or multiple SiNW for biosensing applications, very few attempts have been made to integrate SiNW with complementary-metal-oxide- semiconductor (CMOS) integration to arrive at a complete lab-on-chip (LOC) sensor. Further, the manufacturing methods reported thus far in the production of SiNW for biosensing applications have not fully exploited both the front-end-of-line (FEOL) as well as back-end-of-line (BEOL) methods in CMOS integration. Neither does the research community address CMOS integration based methods to realize multi and specific target detection that are important attributes for an ideal LOC biosensor.Integration of SiNW with CMOS circuitry will facilitate real time detection of the output signal and in addition provide a compact small sized sensor that is fully portable operating at high speed. In order to avail the benefits of CMOS circuits and develop a large scale production friendly LOC sensor, the scheme of SiNW fabrication has to facilitate either the FEOL or BEOL CMOS integration schemes. This thesis work is focused on revealing a novel FEOL as well as BEOL scheme for integration of SiNW with CMOS circuitry. The major part of the FEOL research work is concentrated on developing a high volume SiNW manufacturing method that is suitable for industrial production. Likewise, in the BEOL scheme, predominant focus was to develop a wafer scale scheme to integrate network of nanowires (nanonets) with CMOS circuitry to manufacture a monolithic 3D above-IC LOC biosensor.In the FEOL scheme, the SiNWs are fabricated using a revised pattern transfer technique called sidewall transfer lithography (STL). The STL method is identified as one of the efficient methods of fabricating SiNW as it uses CMOS industry grade materials that is fully compatible with the FEOL fabrication scheme. Thanks to the usage of single lithography and controlled selective etching techniques used in the STL process, the line width and aspect ratio of the SiNW can be tailored to suit the requirements for DNA hybridization detection. A fabrication process flow matching standard CMOS process integration flows has been developed to integrate SiNW with HfO2 and TiN metal gate MOSFETS. An emphasis has been placed in the design of a novel pixel matrix based SiNW LOC sensor. Specific and multi-target detection has been kept as top priority in the design of the SiNW LOC sensor. The possibility to monitor the potential of the electrolyte during the detection process using a fluid gate has been accounted in this design. Furthermore, the SiNW pixel design eliminates the intricate microfluidics and eases access to the SiNW test site using a simple photolithography mask and RIE. The SiNW and MOSFETS demonstrate excellent electrical characteristics. For the very first time, the concept to access single as well as multiple array SiNW pixels using a transistor has been successfully demonstrated.In the BEOL scheme, the nanonets are fabricated using the bottom-up method and transferred onto a pre-fabricated CMOS wafer supplied by ams foundry. The connection between the nanonets lying above-IC and the underlying CMOS layer was established by employing a thin metal backgate electrode, backgate dielectric and metal source/drain contact pads. Many challenges in the BEOL scheme have been identified and overcome by incorporating efficient device architecture and careful selection of materials. To the first of its kind, a wafer scale process was developed to integrate nanonets with CMOS to form a monolithic 3D IC. The devices exhibit excellent electrical characteristics and lower leakage currents compared to standalone nanonet sensors fabricated on Si/SiN substrate. Further, the FEOL and BEOL integration schemes are compared and the various pro’s and con’s of both approaches for integration of SiNW with CMOS circuits to build a LOC biosensor are discussed in detail.Finally, dry environment DNA hybridization detection is demonstrated on the surface of thin HfO2 encapsulated SiNW sensors. Upon DNA hybridization, SiNW devices exhibit threshold voltage shift larger than the noise introduced by the exposition to saline solutions used for the bio-processes. More specifically, based on a statistical analysis, it is demonstrated that 85% of the tested devices were efficient for DNA hybridization detection. The estimated density of hybridized DNA was in the order of 1010 cm-2. These promising results of realizing a SiNW based lab-on-chip platform through the FEOL and BEOL monolithic integration of SiNW and CMOS circuitry further strengthen the profile of SiNW as a nano biosensor. Indeed, this is expected to pave the way for more than Moore applications of SiNW based devices and integrated circuits.
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