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"Knight, David James"
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Human Rights
\"18 Mozambique, like other African countries, is both \"a source and a destination country\" for human trafficking19 and the new law was a promising step forward in a region that had previously done litde to combat either internal or cross-border trafficking.20 C. SOUTHEAST ASIA Leaders of China, Cambodia, Laos, Myanmar, Thailand, and Vietnam signed the Joint Declaration of the Coordinated Mekong Ministerial Initiative Against Human Trafficking (COMMIT Declaration) on December 14, 2007.21 The region is widely known as a hotbed of human trafficking,22 and the Declaration was \"aimed at identifying and protecting trafficked persons at every point in the trafficking cycle, and to ensure that all official actions with respect to trafficked persons protect their safety, dignity and rights.
Journal Article
CHRISTIAN ETHICS AND RESPONSIBLE CITIZENSHIP IN CHURCH-STATE AFFAIRS: THE DEBATE OVER PRAYER IN THE PUBLIC SCHOOLS
This dissertation examines the ongoing debate over school prayer (especially as it is chronicled in some of the periodical literature of the early 1980s) in an attempt to reach some conclusions about the appropriateness or inappropriateness of group devotional exercises in the public schools. The focus is on historical as well as contemporary guidelines for adjudicating the specific issue of school prayer, but the analysis also provides a normative framework for evaluating other topics dealing with religion and public education. Issues such as the establishment of religion, the free exercise of religion, equal access to school property, possible coercion in the classroom, the nature and purpose of prayer, and the rights of religious minorities and nonreligious groups are discussed in the context of competing values which are at stake in policy decisions in this area. Landmark decisions by the Supreme Court are used to analyze the constitutionality of school prayer according to the three tests of secular purpose, primary effect, and excessive entanglement. Another chapter explores some of the theological questions pertaining to school prayer. For instance, what view of God does school prayer tend to promote? Is such a conceptualization theologically valid and desirable? In this regard, the problem of acculturated Christianity is discussed in relation to governmentally sanctioned rituals. In addition, the normative approaches of separationism, accommodation, benevolent neutrality, \"religion blindness,\" and evenhandedness are evaluated in terms of their efficacy in achieving governmental neutrality in the area of religion and public education. The overall thrust of the dissertation is that state-authorized devotional exercises are not appropriate in the public schools. They violate the Establishment Clause of the First Amendment, they tend to obfuscate the doctrinal claims of particular religions, and they trample on the rights of the nonparticipants. In a pluralistic society, governmental neutrality is required in matters of religion. Therefore, the public schools should not be used to try to inculcate religious piety in the students; they should teach civic virtues associated with responsible citizenship in a democracy, including respect for each citizen's freedom of conscience.
Dissertation
Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice
The prevalence of inflammatory diseases is increasing in modern urban societies. Inflammation increases risk of stress-related pathology; consequently, immunoregulatory or antiinflammatory approaches may protect against negative stress-related outcomes. We show that stress disrupts the homeostatic relationship between the microbiota and the host, resulting in exaggerated inflammation. Repeated immunization with a heat-killed preparation of Mycobacterium vaccae, an immunoregulatory environmental microorganism, reduced subordinate, flight, and avoiding behavioral responses to a dominant aggressor in a murine model of chronic psychosocial stress when tested 1–2wk following the final immunization. Furthermore, immunization with M. vaccae prevented stress-induced spontaneous colitis and, in stressed mice, induced anxiolytic or fear-reducing effects as measured on the elevated plus-maze, despite stress-induced gut microbiota changes characteristic of gut infection and colitis. Immunization with M. vaccae also prevented stress-induced aggravation of colitis in a model of inflammatory bowel disease. Depletion of regulatory T cells negated protective effects of immunization with M. vaccae on stress-induced colitis and anxiety-like or fear behaviors. These data provide a framework for developing microbiome- and immunoregulation-based strategies for prevention of stress-related pathologies.
Journal Article
The Summer North Atlantic Oscillation
Summer climate in the North Atlantic–European sector possesses a principal pattern of year-to-year variability that is the parallel to the well-known North Atlantic Oscillation in winter. This summer North Atlantic Oscillation (SNAO) is defined here as the first empirical orthogonal function (EOF) of observed summertime extratropical North Atlantic pressure at mean sea level. It is shown to be characterized by a more northerly location and smaller spatial scale than its winter counterpart. The SNAO is also detected by cluster analysis and has a near-equivalent barotropic structure on daily and monthly time scales. Although of lesser amplitude than its wintertime counterpart, the SNAO exerts a strong influence on northern European rainfall, temperature, and cloudiness through changes in the position of the North Atlantic storm track. It is, therefore, of key importance in generating summer climate extremes, including flooding, drought, and heat stress in northwestern Europe. The El Niño–Southern Oscillation (ENSO) phenomenon is known to influence summertime European climate; however, interannual variations of the SNAO are only weakly influenced by ENSO. On interdecadal time scales, both modeling and observational results indicate that SNAO variations are partly related to the Atlantic multidecadal oscillation. It is shown that SNAO variations extend far back in time, as evidenced by reconstructions of SNAO variations back to 1706 using tree-ring records. Very long instrumental records, such as central England temperature, are used to validate the reconstruction. Finally, two climate models are shown to simulate the present-day SNAO and predict a trend toward a more positive index phase in the future under increasing greenhouse gas concentrations. This implies the long-term likelihood of increased summer drought for northwestern Europe.
Journal Article
The intersection of COVID-19 and autoimmunity
Acute COVID-19, caused by SARS-CoV-2, is characterized by diverse clinical presentations, ranging from asymptomatic infection to fatal respiratory failure, and often associated with varied longer-term sequelae. Over the past 18 months, it has become apparent that inappropriate immune responses contribute to the pathogenesis of severe COVID-19. Researchers working at the intersection of COVID-19 and autoimmunity recently gathered at an American Autoimmune Related Diseases Association Noel R. Rose Colloquium to address the current state of knowledge regarding two important questions: Does established autoimmunity predispose to severe COVID-19? And, at the same time, can SARS-CoV-2 infection trigger de novo autoimmunity? Indeed, work to date has demonstrated that 10% to 15% of patients with critical COVID-19 pneumonia exhibit autoantibodies against type I interferons, suggesting that preexisting autoimmunity underlies severe disease in some patients. Other studies have identified functional autoantibodies following infection with SARS-CoV-2, such as those that promote thrombosis or antagonize cytokine signaling. These autoantibodies may arise from a predominantly extrafollicular B cell response that is more prone to generating autoantibody-secreting B cells. This Review highlights the current understanding, evolving concepts, and unanswered questions provided by this unique opportunity to determine mechanisms by which a viral infection can be exacerbated by, and even trigger, autoimmunity. The potential role of autoimmunity in post-acute sequelae of COVID-19 is also discussed.
Journal Article
Dopamine and Glutamate in Antipsychotic-Responsive Compared With Antipsychotic-Nonresponsive Psychosis: A Multicenter Positron Emission Tomography and Magnetic Resonance Spectroscopy Study (STRATA)
Abstract
The variability in the response to antipsychotic medication in schizophrenia may reflect between-patient differences in neurobiology. Recent cross-sectional neuroimaging studies suggest that a poorer therapeutic response is associated with relatively normal striatal dopamine synthesis capacity but elevated anterior cingulate cortex (ACC) glutamate levels. We sought to test whether these measures can differentiate patients with psychosis who are antipsychotic responsive from those who are antipsychotic nonresponsive in a multicenter cross-sectional study. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure glutamate levels (Glucorr) in the ACC and in the right striatum in 92 patients across 4 sites (48 responders [R] and 44 nonresponders [NR]). In 54 patients at 2 sites (25 R and 29 NR), we additionally acquired 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine (18F-DOPA) positron emission tomography (PET) to index striatal dopamine function (Kicer, min−1). The mean ACC Glucorr was higher in the NR than the R group after adjustment for age and sex (F1,80 = 4.27; P = .04). This was associated with an area under the curve for the group discrimination of 0.59. There were no group differences in striatal dopamine function or striatal Glucorr. The results provide partial further support for a role of ACC glutamate, but not striatal dopamine synthesis, in determining the nature of the response to antipsychotic medication. The low discriminative accuracy might be improved in groups with greater clinical separation or increased in future studies that focus on the antipsychotic response at an earlier stage of the disorder and integrate other candidate predictive biomarkers. Greater harmonization of multicenter PET and 1H-MRS may also improve sensitivity.
Journal Article
Neutralizing nanobodies bind SARS-CoV-2 spike RBD and block interaction with ACE2
The SARS-CoV-2 virus is more transmissible than previous coronaviruses and causes a more serious illness than influenza. The SARS-CoV-2 receptor binding domain (RBD) of the spike protein binds to the human angiotensin-converting enzyme 2 (ACE2) receptor as a prelude to viral entry into the cell. Using a naive llama single-domain antibody library and PCR-based maturation, we have produced two closely related nanobodies, H11-D4 and H11-H4, that bind RBD (KD of 39 and 12 nM, respectively) and block its interaction with ACE2. Single-particle cryo-EM revealed that both nanobodies bind to all three RBDs in the spike trimer. Crystal structures of each nanobody–RBD complex revealed how both nanobodies recognize the same epitope, which partly overlaps with the ACE2 binding surface, explaining the blocking of the RBD–ACE2 interaction. Nanobody-Fc fusions showed neutralizing activity against SARS-CoV-2 (4–6 nM for H11-H4, 18 nM for H11-D4) and additive neutralization with the SARS-CoV-1/2 antibody CR3022.Two nanobodies that bind SARS-CoV-2 spike RBD are shown to block interaction with receptor ACE2 and thus neutralize the virus, and have an additive effect with antibody CR3022.
Journal Article