In Still Time

In Still Time is an experimental animation that investigates the catastrophic image and spectacle through direct animation of still images onto 16mm film. The film uses still images found on the internet from the current Syrian civil war; these were laser printed directly onto the film, simultaneously abstracting these images and re-animating them. These images are juxtaposed with audio from news sources, interviews and YouTube videos posted by Syrian civilians, activists and journalists on the ground of different events that have taken place during the crisis. Through clues of shape, line, colour, and sound these abstracted images of catastrophe attempt to facilitate questions about the moral imperative to look, our ability or inability to bear witness to unthinkable human suffering and our complicity in the violence documented in the image. What are the limits of the catastrophic image? How can trauma and the unthinkable ever be properly represented? How do we give meaning to an event that stops and disrupts time

地熱水環境におけるヒ素の移動性の鉱物学的・地球化学的研究

取得学位：博士(理学)，学位授与番号：博甲第822号，学位授与年月日：平成18年3月22日,学位授与年：200

State of Play of Risk Transfer Mechanisms for Small-Scale Farmers and Entrepreneurs

Extreme weather and slow onset events have direct and indirect impacts on agriculture, with risks to productivity and well-being of vulnerable agricultural communities. Building the resilience of the agricultural sector through adaptation interventions often face issues of effectivity, coverage, and timely delivery. This paper presents the scoping research for the Synergy Program in the Philippines of the Province of West Flanders, Belgium, composed of higher education institutions, cooperatives, and organizations, to explore the viability of weather index–based insurance (WII) as a way of addressing the sector’s exposure to climate risks. Methods that include interviews, literature review, and a discussion forum provide a multi-perspective overview of WII and other types of agricultural insurance vis-à-vis their relevance and implementation. Overall, there is high agreement on the potential of WII as an effective and inclusive climate change adaptation mechanism, which is science-based and localized. The research’s policy recommendations highlight the need for enabling mechanisms that promote multisectoral partnerships with access to accurate and localized data in identifying weather indices as basis for monitoring and payout schemes, along with mainstreaming insurance information and education among stakeholders to strengthen the market. Additionally, policy reforms to enhance the engagement of nongovernment insurance providers for a leveled playing field, promoting competition, and innovations to lower the premium rates are also recommended. The research also provided a cooperation platform to further discuss the best ways to develop agricultural risk transfer products and services that would allow farmers to develop amidst the challenges brought about by climate change

Dantrolene is neuroprotective in Huntington's disease transgenic mouse model

<p>Abstract</p> <p>Background</p> <p>Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine expansion in the Huntingtin protein which results in the selective degeneration of striatal medium spiny neurons (MSNs). Our group has previously demonstrated that calcium (Ca²⁺) signaling is abnormal in MSNs from the yeast artificial chromosome transgenic mouse model of HD (YAC128). Moreover, we demonstrated that deranged intracellular Ca²⁺signaling sensitizes YAC128 MSNs to glutamate-induced excitotoxicity when compared to wild type (WT) MSNs. In previous studies we also observed abnormal neuronal Ca²⁺signaling in neurons from spinocerebellar ataxia 2 (SCA2) and spinocerebellar ataxia 3 (SCA3) mouse models and demonstrated that treatment with dantrolene, a ryanodine receptor antagonist and clinically relevant Ca²⁺signaling stabilizer, was neuroprotective in experiments with these mouse models. The aim of the current study was to evaluate potential beneficial effects of dantrolene in experiments with YAC128 HD mouse model.</p> <p>Results</p> <p>The application of caffeine and glutamate resulted in increased Ca²⁺release from intracellular stores in YAC128 MSN cultures when compared to WT MSN cultures. Pre-treatment with dantrolene protected YAC128 MSNs from glutamate excitotoxicty, with an effective concentration of 100 nM and above. Feeding dantrolene (5 mg/kg) twice a week to YAC128 mice between 2 months and 11.5 months of age resulted in significantly improved performance in the beam-walking and gait-walking assays. Neuropathological analysis revealed that long-term dantrolene feeding to YAC128 mice significantly reduced the loss of NeuN-positive striatal neurons and reduced formation of Htt^expnuclear aggregates.</p> <p>Conclusions</p> <p>Our results support the hypothesis that deranged Ca²⁺signaling plays an important role in HD pathology. Our data also implicate the RyanRs as a potential therapeutic target for the treatment of HD and demonstrate that RyanR inhibitors and Ca²⁺signaling stabilizers such as dantrolene should be considered as potential therapeutics for the treatment of HD and other polyQ-expansion disorders.</p

Bilingual problem-solving training for caregivers of adults with dementia: A randomized, factorial-design protocol for the CaDeS trial

Objective: Caregivers of individuals with Alzheimer\u27s disease and related dementias (ADRD) often experience debilitating caregiver burden and emotional distress. To address these negative emotional consequences of caregiving, we will test and refine a strategy training intervention - Problem-Solving Training (PST) - that promotes self-efficacy and reduces caregiver burden and depressive symptoms. Previous research supports efficacy of PST; however, we do not know exactly how many PST sessions are needed or if post-training boosters are required to maintain PST benefits. Additionally, we translated and culturally-adapted PST into Descubriendo Soluciones Juntos (DSJ), our novel intervention for Spanish-speaking caregivers. Method: In this 2 × 2 factorial design randomized controlled trial, we will test remotely-delivered PST/DSJ sessions for both English- and Spanish-speaking caregivers of persons with ADRD to determine the optimal number of PST/DSJ sessions and ongoing booster sessions needed to best help caregivers navigate their current and future needs. Aims: 1) Compare the efficacy of three vs. six PST/DSJ sessions each with and without booster sessions for decreasing caregiver burden and depression and enhancing caregiver problem-solving; 2) Identify key factors associated with efficacy of PST/DSJ, including age, gender, primary language, relationship to care recipient, and uptake of the PST/DSJ strategy. Results: These results will establish guidelines needed for an evidence-based, culturally-adapted, and implementable problem-solving intervention to reduce caregiver stress and burden and improve caregiver health and well-being. Conclusion: This work promotes inclusion of diverse and underserved populations and advances therapeutic behavioral interventions that improve the lives of caregivers of individuals with chronic conditions

Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease

BACKGROUND: Brain-predicted age estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology. METHODS: We modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-β-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE ε4 carrier status, sex, and education. RESULTS: Advanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG. CONCLUSIONS: We extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI

The Neonatal Fc Receptor (FcRn) Enhances Human Immunodeficiency Virus Type 1 (HIV-1) Transcytosis across Epithelial Cells

The mechanisms by which human immunodeficiency virus type 1 (HIV-1) crosses mucosal surfaces to establish infection are unknown. Acidic genital secretions of HIV-1-infected women contain HIV-1 likely coated by antibody. We found that the combination of acidic pH and Env-specific IgG, including that from cervicovaginal and seminal fluids of HIV-1-infected individuals, augmented transcytosis across epithelial cells as much as 20-fold compared with Env-specific IgG at neutral pH or non-specific IgG at either pH. Enhanced transcytosis was observed with clinical HIV-1 isolates, including transmitted/founder strains, and was eliminated in Fc neonatal receptor (FcRn)-knockdown epithelial cells. Non-neutralizing antibodies allowed similar or less transcytosis than neutralizing antibodies. However, the ratio of total:infectious virus was higher for neutralizing antibodies, indicating that they allowed transcytosis while blocking infectivity of transcytosed virus. Immunocytochemistry revealed abundant FcRn expression in columnar epithelia lining the human endocervix and penile urethra. Acidity and Env-specific IgG enhance transcytosis of virus across epithelial cells via FcRn and could facilitate translocation of virus to susceptible target cells following sexual exposure

Multivalent vaccines demonstrate immunogenicity and protect against Coxiella burnetii aerosol challenge

Vaccines are among the most cost-effective public health measures for controlling infectious diseases. Coxiella burnetii is the etiological agent of Q fever, a disease with a wide clinical spectrum that ranges from mild symptoms, such as fever and fatigue, to more severe disease, such as pneumonia and endocarditis. The formalin-inactivated whole-cell vaccine Q-VAX® contains hundreds of antigens and confers lifelong protection in humans, but prior sensitization from infection or vaccination can result in deleterious reactogenic responses to vaccination. Consequently, there is great interest in developing non-reactogenic alternatives based on adjuvanted recombinant proteins. In this study, we aimed to develop a multivalent vaccine that conferred protection with reduced reactogenicity. We hypothesized that a multivalent vaccine consisting of multiple antigens would be more immunogenic and protective than a monovalent vaccine owing to the large number of potential protective antigens in the C. burnetii proteome. To address this, we identified immunogenic T and B cell antigens, and selected proteins were purified to evaluate with a combination adjuvant (IVAX-1), with or without C. burnetii lipopolysaccharide (LPS) in immunogenicity studies in vivo in mice and in a Hartley guinea pig intratracheal aerosol challenge model using C. burnetii strain NMI RSA 493. The data showed that multivalent vaccines are more immunogenic than monovalent vaccines and more closely emulate the protection achieved by Q-VAX. Although six antigens were the most immunogenic, we also discovered that multiplexing beyond four antigens introduces detectable reactogenicity, indicating that there is an upper limit to the number of antigens that can be safely included in a multivalent Q-fever vaccine. C. burnetii LPS also demonstrates efficacy as a vaccine antigen in conferring protection in an otherwise monovalent vaccine formulation, suggesting that its addition in multivalent vaccines, as demonstrated by a quadrivalent formulation, would improve protective responses

Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease

BackgroundBrain-predicted age estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology.MethodsWe modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-beta-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE epsilon 4 carrier status, sex, and education.ResultsAdvanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG.ConclusionsWe extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI

Identification of tetrahydrocarbazoles as novel multifactorial drug candidates for treatment of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder and the most frequent cause of dementia. To date, there are only a few approved drugs for AD, which show little or no effect on disease progression. Impaired intracellular calcium homeostasis is believed to occur early in the cascade of events leading to AD. Here, we examined the possibility of normalizing the disrupted calcium homeostasis in the endoplasmic reticulum (ER) store as an innovative approach for AD drug discovery. High-throughput screening of a small-molecule compound library led to the identification of tetrahydrocarbazoles, a novel multifactorial class of compounds that can normalize the impaired ER calcium homeostasis. We found that the tetrahydrocarbazole lead structure, first, dampens the enhanced calcium release from ER in HEK293 cells expressing familial Alzheimer's disease (FAD)-linked presenilin 1 mutations. Second, the lead structure also improves mitochondrial function, measured by increased mitochondrial membrane potential. Third, the same lead structure also attenuates the production of amyloid-beta (A beta) peptides by decreasing the cleavage of amyloid precursor protein (APP) by beta-secretase, without notably affecting alpha- and gamma-secretase cleavage activities. Considering the beneficial effects of tetrahydrocarbazoles addressing three key pathological aspects of AD, these compounds hold promise for the development of potentially effective AD drug candidates