Rihmamatolääkkeiden vaikutuskohteita. Betuliinin johdannaisia mahdollisiksi uusiksi yhdisteiksi

Jokisokeus eli onkosersiaasi on ihmisen loismatotauti, jota aiheuttaa Onchocerca volvulus -rihmamato. Tautia esiintyy trooppisilla alueilla Afrikassa ja Latinalaisessa Amerikassa. Tartunnan saaneita on noin 37 miljoonaa. Jokisokeus ilmenee iho- ja silmäoireina. Oireet johtuvat loisen nuorimmista muodoista eli mikrofilarioista. Jokisokeutta vastaan on käyty jakamalla lähinnä mikrofilarioihin tehoavaa ivermektiiniä. Tarvetta olisi lääkkeelle, joka tappaisi aikuiset madot tai steriloisi naaraat. Rokote olisi vielä parempi vaihtoehto. Antibiootit on uusi hoitokeino, sillä O. volvuluksella on elintärkeänä symbionttina Wolbachia-bakteeri. Doksisykliini tappaa vähintään 60 prosenttia aikuisista madoista ja steriloi naaraita, mutta kuuri kestää viikkoja. Yksi lupaava yhdiste on emodepsidi, jolla on loismatolääkkeille uusi vaikutusmekanismi. Rihmamatolääkkeiksi on testattu lukuisia yhdisteitä. Jotkut niistä inhiboivat entsyymejä, joilla madot kiertävät ihmisen immuunipuolustusta. Toiset häiritsevät neljä kertaa tapahtuvaa nahanvaihtoa. Hyvä lääkkeiden vaikutuskohde on loiselle välttämätön mutta puuttuu nisäkkäiltä. Betuliini on triterpeeni, jota on runsaasti koivun tuohessa. Betuliini ja monet sen johdannaiset ovat farmakologisesti aktiivisia yhdisteitä, joita tutkitaan etenkin syöpä- ja HIV-lääkkeiksi. Helsingin yliopiston lääkekemian ryhmä on syntetisoinut ja tutkinut lukuisia johdoksia. Jotkin niistä ovat lupaavia esimerkiksi Leishmania-alkueläimiin, Chlamydia pneumoniae -bakteeriin ja alfaviruksiin. Siksi yhdisteitä kannattaisi tutkia muihinkin taudinaiheuttajiin, kuten rihmamatoihin. Sekä Wolbachialla että C. pneumoniaella on sama lipidisynteesireitti, joka on kummallekin elintärkeä. Betuliinista syntetisoitiin johdoksia, joissa betuliinin alkoholeja on hapetettu karbonyyleiksi ja joihin on liitetty typpiheterorengas. Sekä Leishmania donovani että L. braziliensis -tutkimuksissa tehokkain oli formyylibetuliinin heterosykli. Vaikka valmistettuja yhdisteitä ei ole tutkittu rihmamatotesteissä, jatkossa voisi syntetisoida johdannaisia, joissa karbonyylien tilalla on typpirakenteita, koska C. pneumoniaehen hyvin tehonneessa yhdisteessä betuliinin OH-ryhmien tilalla on oksiimi.

Visual SLAM using straight lines

The present thesis is focuses on the problem of Simultaneous Localisation and Mapping (SLAM) using only visual data (VSLAM). This means to concurrently estimate the position of a moving camera and to create a consistent map of the environment. Since implementing a whole VSLAM system is out of the scope of a degree thesis, the main aim is to improve an existing visual SLAM system by complementing the commonly used point features with straight line primitives. This enables more accurate localization in environments with few feature points, like corridors. As a foundation for the project, ScaViSLAM by Strasdat et al. is used, which is a state-of-the-art real-time visual SLAM framework. Since it currently only supports Stereo and RGB-D systems, implementing a Monocular approach will be researched as well as an integration of it as a ROS package in order to deploy it on a mobile robot. For the experimental results, the Care-O-bot service robot developed by Fraunhofer IPA will be used.

Detección de personas basada en HOG y SVM

El presente proyecto se centra en proteger a los peatones de las vías urbanas o de una fábrica donde conviven con robots móviles, pues son los mayores afectados en los acci- dentes producidos en estos entornos. El objetivo es diseñar un algoritmo basado en visión monocular capaz de detectar a los usuarios de forma rápida y precisa de tal forma que se tenga constancia en todo momento de los peatones que se encuentran delante del vehículo.

Wireless parylene-based retinal implant

The degeneration of the outer retina usually causes blindness by affecting the photoreceptor cells. However, the ganglion cells, which consist of optic nerves, on the middle and inner retina layers are often intact. The retinal implant, which can partially restore vision by electrical stimulation, soon becomes a focus for research. Although many groups worldwide have spent a lot of effort on building devices for retinal implant, current state-of-the-art technologies still lack a reliable packaging scheme for devices with desirable high-density multi-channel features. Wireless flexible retinal implants have always been the ultimate goal for retinal prosthesis. In this dissertation, the reliable packaging scheme for a wireless flexible parylene-based retinal implants has been well developed. It can not only provide stable electrical and mechanical connections to the high-density multi-channel (1000+ channels on 5 mm × 5 mm chip area) IC chips, but also survive for more than 10 years in the human body with corrosive fluids.

The device is based on a parylene-metal-parylene sandwich structure. In which, the adhesion between the parylene layers and the metals embedded in the parylene layers have been studied. Integration technology for high-density multi-channel IC chips has also been addressed and tested with dummy and real 268-channel and 1024-channel retinal IC chips. In addition, different protection schemes have been tried in application to IC chips and discrete components to gain the longest lifetime. The effectiveness has been confirmed by the accelerated and active lifetime soaking test in saline solution. Surgical mockups have also been designed and successfully implanted inside dog's and pig's eyes. Additionally, the electrodes used to stimulate the ganglion cells have been modified to lower the interface impedance and shaped to better fit the retina. Finally, all the developed technologies have been applied on the final device with a dual-metal-layer structure.

MEMS for Diabetic Retinopathy

As the worldwide prevalence of diabetes mellitus continues to increase, diabetic retinopathy remains the leading cause of visual impairment and blindness in many developed countries. Between 32 to 40 percent of about 246 million people with diabetes develop diabetic retinopathy. Approximately 4.1 million American adults 40 years and older are affected by diabetic retinopathy. This glucose-induced microvascular disease progressively damages the tiny blood vessels that nourish the retina, the light-sensitive tissue at the back of the eye, leading to retinal ischemia (i.e., inadequate blood flow), retinal hypoxia (i.e., oxygen deprivation), and retinal nerve cell degeneration or death. It is a most serious sight-threatening complication of diabetes, resulting in significant irreversible vision loss, and even total blindness.

Unfortunately, although current treatments of diabetic retinopathy (i.e., laser therapy, vitrectomy surgery and anti-VEGF therapy) can reduce vision loss, they only slow down but cannot stop the degradation of the retina. Patients require repeated treatment to protect their sight. The current treatments also have significant drawbacks. Laser therapy is focused on preserving the macula, the area of the retina that is responsible for sharp, clear, central vision, by sacrificing the peripheral retina since there is only limited oxygen supply. Therefore, laser therapy results in a constricted peripheral visual field, reduced color vision, delayed dark adaptation, and weakened night vision. Vitrectomy surgery increases the risk of neovascular glaucoma, another devastating ocular disease, characterized by the proliferation of fibrovascular tissue in the anterior chamber angle. Anti-VEGF agents have potential adverse effects, and currently there is insufficient evidence to recommend their routine use.

In this work, for the first time, a paradigm shift in the treatment of diabetic retinopathy is proposed: providing localized, supplemental oxygen to the ischemic tissue via an implantable MEMS device. The retinal architecture (e.g., thickness, cell densities, layered structure, etc.) of the rabbit eye exposed to ischemic hypoxic injuries was well preserved after targeted oxygen delivery to the hypoxic tissue, showing that the use of an external source of oxygen could improve the retinal oxygenation and prevent the progression of the ischemic cascade.

The proposed MEMS device transports oxygen from an oxygen-rich space to the oxygen-deficient vitreous, the gel-like fluid that fills the inside of the eye, and then to the ischemic retina. This oxygen transport process is purely passive and completely driven by the gradient of oxygen partial pressure (pO₂). Two types of devices were designed. For the first type, the oxygen-rich space is underneath the conjunctiva, a membrane covering the sclera (white part of the eye), beneath the eyelids and highly permeable to oxygen in the atmosphere when the eye is open. Therefore, sub-conjunctival pO₂ is very high during the daytime. For the second type, the oxygen-rich space is inside the device since pure oxygen is needle-injected into the device on a regular basis.

To prevent too fast or too slow permeation of oxygen through the device that is made of parylene and silicone (two widely used biocompatible polymers in medical devices), the material properties of the hybrid parylene/silicone were investigated, including mechanical behaviors, permeation rates, and adhesive forces. Then the thicknesses of parylene and silicone became important design parameters that were fine-tuned to reach the optimal oxygen permeation rate.

The passive MEMS oxygen transporter devices were designed, built, and tested in both bench-top artificial eye models and in-vitro porcine cadaver eyes. The 3D unsteady saccade-induced laminar flow of water inside the eye model was modeled by computational fluid dynamics to study the convective transport of oxygen inside the eye induced by saccade (rapid eye movement). The saccade-enhanced transport effect was also demonstrated experimentally. Acute in-vivo animal experiments were performed in rabbits and dogs to verify the surgical procedure and the device functionality. Various hypotheses were confirmed both experimentally and computationally, suggesting that both the two types of devices are very promising to cure diabetic retinopathy. The chronic implantation of devices in ischemic dog eyes is still underway.

The proposed MEMS oxygen transporter devices can be also applied to treat other ocular and systemic diseases accompanied by retinal ischemia, such as central retinal artery occlusion, carotid artery disease, and some form of glaucoma.

Control mechanisms in the human binocular oculomotor system

A study of human eye movements was made in order to elucidate the nature of the control mechanism in the binocular oculomotor system.

We first examined spontaneous eye movements during monocular and binocular fixation in order to determine the corrective roles of flicks and drifts. It was found that both types of motion correct fixational errors, although flicks are somewhat more active in this respect. Vergence error is a stimulus for correction by drifts but not by flicks, while binocular vertical discrepancy of the visual axes does not trigger corrective movements.

Second, we investigated the non-linearities of the oculomotor system by examining the eye movement responses to point targets moving in two dimensions in a subjectively unpredictable manner. Such motions consisted of hand-limited Gaussian random motion and also of the sum of several non-integrally related sinusoids. We found that there is no direct relationship between the phase and the gain of the oculomotor system. Delay of eye movements relative to target motion is determined by the necessity of generating a minimum afferent (input) signal at the retina in order to trigger corrective eye movements. The amplitude of the response is a function of the biological constraints of the efferent (output) portion of the system: for target motions of narrow bandwidth, the system responds preferentially to the highest frequency; for large bandwidth motions, the system distributes the available energy equally over all frequencies. Third, the power spectra of spontaneous eye movements were compared with the spectra of tracking eye movements for Gaussian random target motions of varying bandwidths. It was found that there is essentially no difference among the various curves. The oculomotor system tracks a target, not by increasing the mean rate of impulses along the motoneurons of the extra-ocular muscles, but rather by coordinating those spontaneous impulses which propagate along the motoneurons during stationary fixation. Thus, the system operates at full output at all times.

Fourth, we examined the relative magnitude and phase of motions of the left and the right visual axes during monocular and binocular viewing. We found that the two visual axes move vertically in perfect synchronization at all frequencies for any viewing condition. This is not true for horizontal motions: the amount of vergence noise is highest for stationary fixation and diminishes for tracking tasks as the bandwidth of the target motion increases. Furthermore, movements of the occluded eye are larger than those of the seeing eye in monocular viewing. This effect is more pronounced for horizontal motions, for stationary fixation, and for lower frequencies.

Finally, we have related our findings to previously known facts about the pertinent nerve pathways in order to postulate a model for the neurological binocular control of the visual axes.

A valorização a mulher na obra de José Saramago: Blimunda e a mulher do médico, olhares que se cruzam

A presente pesquisa objetiva ressaltar a valorização da mulher na obra do autor português José Saramago. Buscou-se encontrar os argumentos que justificam esta proposta através da leitura sistemática de dois de seus textos: Memorial do convento e Ensaio sobre a cegueira. Serviram de objeto de estudo as trajetórias percorridas pelas personagens Blimunda, do primeiro título, e a mulher do médico, do segundo e, assim, foi possível destacar e analisar, com o auxílio de teóricos da literatura e de especialistas na vida e na obra de Saramago, traços que comprovam a importância das mulheres, de modo geral, em suas histórias. Além disso, observou-se, nos excertos aqui contidos e retirados das obras estudadas, o modo como estas mulheres assumem o controle das narrativas das quais fazem parte, assumindo a função de protagonistas. Insta registrar que, assim como elas passam a figurar como personagens principais, também foi importante constatar o olhar analítico lançado por José Saramago, através de suas criações, sobre a condição humana na sociedade contemporânea, apresentanto a mulher como saída para as crises que acometem o homem moderno

Aquatic ecology monitoring: water quality, fish, fish catch, sanitation and disease vectors: monitoring No. 5, 6th-9th October 2009

The survey covered by this report was undertaken between 6 th and 9th October 2009 as a follow-up on the during construction surveys of the Bujagali Hydropwer Project (BHPP). In addition to two pre-construction baseline surveys in April 2000 and April 2006, four monitoring surveys have so far been undertaken i.e. in September 2007, April 2008, April 2009 and the present one, in October 2009. The 2009 biannual monitoring surveys were conducted at an upstream and a downstream transect of the BHPP with emphasis on the following aspects: 1. water quality determinants 2. biology and ecology of fishes and food webs 3. fish stock and fish catch including economic aspects of catch and 4. sanitation/vector studies (bilharzias and river blindness)

Aquatic ecology monitoring: water quality, fish, fish catch, sanitation and disease vectors: monitoring no. 8, 6– 10th April 2011

The result reported were from a monitoring survey no.8 undertaken between 6th and 10th April 2011 during construction period of the Bujagali Hydropwer Project (BHPP). Two pre-construction, baseline surveys in April 2000 and April 2006 were conducted and so far,durin construction phase of the project, seven monitoring surveys have been undertaken i.e. in September 2007, April 2008, April 2009,October 2009, April 2010, September 2010 and the present one, in April 2011. Since 2009 biannual monitoring surveys have been conducted at an upstream and a downstream transect of the BHPP with emphasis on the following aspects: Water quality determinants Biology and ecology of fishes and food webs Fish stock and fish catch including economic aspects of catch and Sanitation/vector studies (bilharzias and river blindness)

Aquatic ecology monitoring: water quality, fish, fish catch, sanitation and disease vectors: monitoring no. 10 and reservoir baseline, 23rd – 30th April 2012

The results reported on were from a monitoring survey No. 10 undertaken between 23 rd and 29th April 2012 during construction period of the Bujagali Hydropower Project (BHPP). Two pre-construction, baseline surveys in April 2000 and April 2006 were conducted and so far, during construction phase of the project, nine monitoring surveys have been undertaken i.e. in September 2007, April 2008, April 2009, October 2009, April 2010, September 2010, April 2011, September 2011and the present one, in April 2012. Since 2009 biannual monitoring surveys have been conducted at an upstream and a downstream transect of the BHPP with emphasis on the following aspects: water quality determinants biology and ecology of fishes and food webs fish stock and fish catch including economic aspects of catch and sanitation/vector studies (bilharzias and river blindness) During this survey, baseline assessment of the above mentioned studies was conducted in the reservoir behind the dam, including studies on algae, zooplankton and benthic macroinvertebrates which had been restrained since April 2008. The findings of baseline assessment of the reservoir are also contained in this report and are compared with those obtained from Transect 1(Upstream) and Transect 2 (Downstream).

Aquatic ecology monitoring: water quality, fish, fish catch, sanitation and disease vectors: monitoring No.7, 4-7th September 2010

The results reported on were from a monitoring survey No.7 undertaken between 4 th and 7th September 2010 during construction period of the Bujagali Hydropower Project (BHPP). Two pre-construction, baseline surveys in April 2000 and April 2006 were conducted and so far, during construction phase of the project, six monitoring surveys have been undertaken i.e. in September 2007, April 2008, April 2009, October 2009, April 2010 and the present one, in September 2010. Since 2009 biannual monitoring surveys have been conducted at an upstream and a downstream transect of the BHPP with emphasis on the following aspects: I. water quality determinants 2. biology and ecology of fishes and food webs 3. fish stock and fish catch including economic aspects of catch and 4. sanitation/vector studies (bilharzias and river blindness)

Aquatic ecology monitoring: water quality, fish, fish catch, sanitation and disease vectors: monitoring no.12, 25th-30th April 2013

Bujagali hydropower dam construction is now completed and a reservoir behind the dam has been created, extending all the way up to Kalange-Makwanzi, an upstream transects. During the 10th monitoring survey-April 2012, a third transect was established in the mid of the reservoir where it runs up to 30 m deep and sampled similarly as at the two original sampling transects, Kalange-Makwanzi and Buyala-Kikubamutwe for comparative purposes. This monitoring survey No. 12 undertaken between 25th and 30th April 2013 is the third one to be conducted after completion of construction of Bujagali Hydropower Dam. Two pre-construction baseline surveys in April 2000 and April 2006 were conducted and during construction phase, eight monitoring surveys (September 2007, April 2008, April 2009, October 2009, April 2010, September 2010, April 2011, September 2011) were conducted. Since 2009 biannual monitoring surveys have been conducted at an upstream and a downstream transect of the BHPP with emphasis on the following aspects: water quality determinants, biology and ecology of fishes and food webs, fish stock and fish catch including economic aspects of catch and sanitation/vector studies (bilharzias and river blindness). In the post-construction monitoring surveys, the assessments of algae, zooplankton and benthic macro-invertebrates which had been restrained since April 2008 were also included.

Aquatic ecology monitoring: water quality, fish, fish catch and parasites: monitoring no.4, 3rd-7th April 2009

The survey covered by this report was undertaken between 3rd and 7th April 2009 as a follow-up on the during construction surveys. Two pre-construction baseline surveys were undertaken in April 2000 and April 2006. During the construction phase which started in 2007, three surveys including the current one have been undertaken i.e. in September 2007, April 2008 and the present one, in April 2009. Unlike in all previous surveys in which monitoring was conducted at one transect upstream and three downstream transects, in the current survey, two transects, one upstream and the other,downstream of the BHPP were sampled with emphasis on the following aspects: 1. water quality determinants 2. biology and ecology of fishes and food webs 3. fish stock and fish catch including economic aspects of catch and 4. sanitation/vector studies (bilharzias and river blindness)

Comparison of Camera Motion Estimation Methods for 3D Reconstruction of Infrastructure

Camera motion estimation is one of the most significant steps for structure-from-motion (SFM) with a monocular camera. The normalized 8-point, the 7-point, and the 5-point algorithms are normally adopted to perform the estimation, each of which has distinct performance characteristics. Given unique needs and challenges associated to civil infrastructure SFM scenarios, selection of the proper algorithm directly impacts the structure reconstruction results. In this paper, a comparison study of the aforementioned algorithms is conducted to identify the most suitable algorithm, in terms of accuracy and reliability, for reconstructing civil infrastructure. The free variables tested are baseline, depth, and motion. A concrete girder bridge was selected as the "test-bed" to reconstruct using an off-the-shelf camera capturing imagery from all possible positions that maximally the bridge's features and geometry. The feature points in the images were extracted and matched via the SURF descriptor. Finally, camera motions are estimated based on the corresponding image points by applying the aforementioned algorithms, and the results evaluated.