Early Developmental Marginal Zinc Deficiency Affects Neurogenesis Decreasing Neuronal Number and Altering Neuronal Specification in the Adult Rat Brain

During pregnancy, a decreased availability of zinc to the fetus can disrupt the development of the central nervous system leading to defects ranging from severe malformations to subtle neurological and cognitive effects. We previously found that marginal zinc deficiency down-regulates the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway and affects neural progenitor cell (NPC) proliferation. This study investigated if marginal zinc deficiency during gestation in rats could disrupt fetal neurogenesis and affect the number and specification of neurons in the adult offspring brain cortex. Rats were fed a marginal zinc deficient or adequate diet throughout gestation and until postnatal day (P) 2, and subsequently the zinc adequate diet until P56. Neurogenesis was evaluated in the offspring at embryonic day (E)14, E19, P2, and P56 measuring parameters of NPC proliferation and differentiation by Western blot and/or immunofluorescence. At E14 and E19, major signals (i.e., ERK1/2, Sox2, and Pax6) that stimulate NPC proliferation and self-renewal were markedly downregulated in the marginal zinc deficient fetal brain. These alterations were associated to a lower number of Ki67 positive cells in the ventricular (VZs) and subventricular zones (SVZs). Following the progression of NPCs into intermediate progenitor cells (IPCs) and into neurons, Pax6, Tbr2 and Tbr1 were affected in the corresponding areas of the brain at E19 and P2. The above signaling alterations led to a lower density of neurons and a selective decrease of glutamatergic neurons in the young adult brain cortex exposed to maternal marginal zinc deficiency from E14 to P2. Current results supports the concept that marginal zinc deficiency during fetal development can disrupt neurogenesis and alter cortical structure potentially leading to irreversible neurobehavioral impairments later in life

The Failed Treatment of MDR-TB in Three Generations: A Case Study of the Household in Northeastern, Thailand

Introduction: In Thailand TB and MDR-TB treatment was found in all levels of the unit of health service system, but the failed treatment especially for MDRTB was found 8.2% in the lower part of northeastern Thailand. In the complex situation, only the medical care cannot eradicate MDR-TB.This study aimed to explain the failure treatment of patient with MDR-TB over 3 generations within 1household.Method: This qualitative method collected data by in-depth in the province located at northeast Thailand; 5 patients and failure treatment of MDR-TB were investigated. The data was analyzed using content analysis.Introduction: In Thailand TB and MDR-TB treatment was found in all levels of the unit of health service system, but the failed treatment especially for MDRTB was found 8.2% in the lower part of northeastern Thailand. In the complex situation, only the medical care cannot eradicate MDR-TB. This study aimed to explain the failure treatment of patient with MDR-TB over 3 generations within 1household. Method: This qualitative method collected data by in-depth in the province located at northeast Thailand; 5 patients and failure treatment of MDR-TB were investigated. The data was analyzed using content analysis. Result: One grandmother, 78 years old, have had twice received treatments and still alive. The mother failed treatment and died from MDR-TB at 54 years old aggravated by noncompliance to drug treatment. The father defaulted treatment due to alcohol consumption, and the second treatment was cured but the subject died at 61 years old. The son and daughter comprised default treatment caused from the household problem of low income, drug addiction, alcohol consumption and divorce. The elder brother did not return to treatment and his symptoms worsened. However, the younger sister, 21 years old, returned to treatment for 4 months. The supportive factors of failed treatment that led patients to cease taking drugs more than 2 months and deny continuing treatment included low income, household problems and drug addiction. Recommendation: Only the medication could not cure or achieve successful treatment, but socio-economic factors such as the understanding of the patient’s context was crucial equally the same as the MDR-TB drug. This factor was effecting to compliance of MDR-TB patient care and treatment

Gestational zinc deficiency impairs brain astrogliogenesis in rats through multistep alterations of the JAK/STAT3 signaling pathway

We previously showed that zinc (Zn) deficiency affects the STAT3 signaling pathway in part through redox-regulated mechanisms. Given that STAT3 is central to the process of astrogliogenesis, this study investigated the consequences of maternal marginal Zn deficiency on the developmental timing and key mechanisms of STAT3 activation, and its consequences on astrogliogenesis in the offspring. This work characterized the temporal profile of cortical STAT3 activation from the mid embryonic stage up to young adulthood in the offspring from dams fed a marginal Zn deficient diet (MZD) throughout gestation and until postnatal day (P) 2. All rats were fed a Zn sufficient diet (control) from P2 until P56. Maternal zinc deficiency disrupted cortical STAT3 activation at E19 and P2. This was accompanied by altered activation of JAK2 kinase due to changes in PTP1B phosphatase activity. The underlying mechanisms mediating the adverse impact of a decreased Zn availability on STAT3 activation in the offspring brain include: (i) impaired PTP1B degradation via the ubiquitin/proteasome pathway; (ii) tubulin oxidation, associated decreased interactions with STAT3 and consequent impaired nuclear translocation; and (iii) decreased nuclear STAT3 acetylation. Zn deficiency-associated decreased STAT3 activation adversely impacted astrogliogenesis, leading to a lower astrocyte number in the early postnatal and adult brain cortex. Thus, a decreased availability of Zn during early development can have a major and irreversible adverse effect on astrogliogenesis, in part via multistep alterations in the STAT3 pathway.Fil: Supasai, Suangsuda. University of California at Davis; Estados UnidosFil: Adamo, Ana María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Mathieu, Patricia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Marino, Regina C.. University of California at Davis; Estados UnidosFil: Hellmers, Adelaide C.. University of California at Davis; Estados UnidosFil: Cremonini, Eleonora. University of California at Davis; Estados UnidosFil: Oteiza, Patricia Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentin

Gestational zinc deficiency impairs brain astrogliogenesis in rats through multistep alterations of the JAK/STAT3 signaling pathway

We previously showed that zinc (Zn) deficiency affects the STAT3 signaling pathway in part through redox-regulated mechanisms. Given that STAT3 is central to the process of astrogliogenesis, this study investigated the consequences of maternal marginal Zn deficiency on the developmental timing and key mechanisms of STAT3 activation, and its consequences on astrogliogenesis in the offspring. This work characterized the temporal profile of cortical STAT3 activation from the mid embryonic stage up to young adulthood in the offspring from dams fed a marginal Zn deficient diet (MZD) throughout gestation and until postnatal day (P) 2. All rats were fed a Zn sufficient diet (control) from P2 until P56. Maternal zinc deficiency disrupted cortical STAT3 activation at E19 and P2. This was accompanied by altered activation of JAK2 kinase due to changes in PTP1B phosphatase activity. The underlying mechanisms mediating the adverse impact of a decreased Zn availability on STAT3 activation in the offspring brain include: (i) impaired PTP1B degradation via the ubiquitin/proteasome pathway; (ii) tubulin oxidation, associated decreased interactions with STAT3 and consequent impaired nuclear translocation; and (iii) decreased nuclear STAT3 acetylation. Zn deficiency-associated decreased STAT3 activation adversely impacted astrogliogenesis, leading to a lower astrocyte number in the early postnatal and adult brain cortex. Thus, a decreased availability of Zn during early development can have a major and irreversible adverse effect on astrogliogenesis, in part via multistep alterations in the STAT3 pathway.Fil: Supasai, Suangsuda. University of California at Davis; Estados UnidosFil: Adamo, Ana María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Mathieu, Patricia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Marino, Regina C.. University of California at Davis; Estados UnidosFil: Hellmers, Adelaide C.. University of California at Davis; Estados UnidosFil: Cremonini, Eleonora. University of California at Davis; Estados UnidosFil: Oteiza, Patricia Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentin

Triangulating evidence from observational and Mendelian randomization studies of ketone bodies for cognitive performance

BACKGROUND: Ketone bodies (KBs) are an alternative energy supply for brain functions when glucose is limited. The most abundant ketone metabolite, 3-β-hydroxybutyrate (BOHBUT), has been suggested to prevent or delay cognitive impairment, but the evidence remains unclear. We triangulated observational and Mendelian randomization (MR) studies to investigate the association and causation between KBs and cognitive function. METHODS: In observational analyses of 5506 participants aged ≥ 45 years from the Whitehall II study, we used multiple linear regression to investigate the associations between categorized KBs and cognitive function scores. Two-sample MR was carried out using summary statistics from an in-house KBs meta-analysis between the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium and Kettunen et al. (N = 45,031), and publicly available summary statistics of cognitive performance and Alzheimer's disease (AD) from the Social Science Genetic Association Consortium (N = 257,841), and the International Genomics of Alzheimer's Project (N = 54,162), respectively. Both strong (P < 5 × 10-8) and suggestive (P < 1 × 10-5) sets of instrumental variables for BOHBUT were applied. Finally, we performed cis-MR on OXCT1, a well-known gene for KB catabolism. RESULTS: BOHBUT was positively associated with general cognitive function (β = 0.26, P = 9.74 × 10-3). In MR analyses, we observed a protective effect of BOHBUT on cognitive performance (inverse variance weighted: βIVW = 7.89 × 10-2, PIVW = 1.03 × 10-2; weighted median: βW-Median = 8.65 × 10-2, PW-Median = 9.60 × 10-3) and a protective effect on AD (βIVW =  - 0.31, odds ratio: OR = 0.74, PIVW = 3.06 × 10-2). Cis-MR showed little evidence of therapeutic modulation of OXCT1 on cognitive impairment. CONCLUSIONS: Triangulation of evidence suggests that BOHBUT has a beneficial effect on cognitive performance. Our findings raise the hypothesis that increased BOHBUT may improve general cognitive functions, delaying cognitive impairment and reducing the risk of AD

Than Samai in Modern Thai Architecture: Case Studies of Crypto-colonialism

Thesis (Ph.D.)--University of Washington, 2022Though Thailand has never been formally colonized, emerging Thai Studies scholarship suggests that a more accurate term for Thailand's relationship to the west is “crypto-colonial.” This indicates cultural and economic, rather than political, subordination, and largely arose as direct colonization was on the wane in the rest of Southeast Asia. Crypto-colonialism is particularly evident in the transplantation of western Modern architecture into a Thai setting. Tracing Thai architectonics through the emergence of western disciplines in the Thai architectural field and a consolidation of Modern architectural consumerism in Thailand shows three separate facets of crypto-colonialism. The first, subordination, is shown in the distinct characteristics of Modern Thai architecture imposed by the West. The architectural design of subordination is dominated by spatial concerns privileging the powerful U.S. presence in Thailand over traditional Thai planning. The second facet, autonomy, refers to the way in which the Thai elite maintained local power through conspicuous consumption of western culture and ideas, in this context carried out by western-educated Thai architects. The final facet, ambiguity, refers to the architectural characteristics that have contributed to the ambivalences, multiplicities, and hybridity of Thai engagement with the ambiguous allure of the West. An examination of the peculiarity of crypto-colonialism in Modern Thai architecture not only challenges the idea that colonial and postcolonial discourses were only confined to countries or regions directly occupied by western nations, but also it deepens our understanding of the western hegemonic presence in Thailand by illuminating Thailand’s paradoxical path towards western civilization and modernization

Primitivism, Regionalism, and the Vernacular in Le Corbusier's middle years, 1929-1945

Thesis (Master's)--University of Washington, 2016-06This thesis examines Le Corbusier’s middle years from 1929-1945, a period that is not often a subject of architectural historians’ interest. This work is largely overshadowed by the two phases that represent the peak moments of Le Corbusier’s career which are: the early years from the Maison Dom-ino (1913) to the Villa Savoye (1929) and the later years from the Marseilles block (1946) to the Capitol of Chandigarh (1952-1965). In studying this phase in Le Corbusier’s career, it is fascinating that this connecting period reveals how the characteristics of his design progressed and were altered—from a focus on machine beauty to a humanistic approach. Three qualities stood out during the investigation of this mediation, which were; the architect’s rational understanding of the three terms—primitivism, regionalism, and the vernacular; the architect’s study of these three terms through a self-searching experience; and the gradual emergence of the second-phase of his modern architecture. The concrete realization of this process can be explicitly seen in his urban plans for North Africa and South America and his small-scale domestic projects in France starting from the late-1920s onward. Overall, this thesis attempts to understand the relationship and position of primitivism, regionalism, and the vernacular in modern architectural perceptions through the designs of a leading modernist architect, Le Corbusier and, at the same time, to understand the importance of the study of transitional phases in an individual architect’s work