Fasting induces ketoacidosis and hypothermia in PDHK2/PDHK4-double-knockout mice

The importance of PDHK (pyruvate dehydrogenase kinase) 2 and 4 in regulation of the PDH complex (pyruvate dehydrogenase complex) was assessed in single- and double-knockout mice. PDHK2 deficiency caused higher PDH complex activity and lower blood glucose levels in the fed, but not the fasted, state. PDHK4 deficiency caused similar effects, but only after fasting. Double deficiency intensified these effects in both the fed and fasted states. PDHK2 deficiency had no effect on glucose tolerance, PDHK4 deficiency produced only a modest effect, but double deficiency caused a marked improvement and also induced lower insulin levels and increased insulin sensitivity. In spite of these beneficial effects, the double-knockout mice were more sensitive than wild-type and single-knockout mice to long-term fasting, succumbing to hypoglycaemia, ketoacidosis and hypothermia. Stable isotope flux analysis indicated that hypoglycaemia was due to a reduced rate of gluconeogenesis and that slightly more glucose was converted into ketone bodies in the double-knockout mice. The findings establish that PDHK2 is more important in the fed state, PDHK4 is more important in the fasted state, and survival during long-term fasting depends upon regulation of the PDH complex by both PDHK2 and PDHK4

Libraries on the Frontlines: Neutrality and Social Justice

Purpose This article examines libraries’ responsibility to engage with and support communities of color as they challenge systemic racism, engage in the political process, and exercise their right to free speech. Many libraries have ignored the Black Lives Matter movement, citing the need to maintain neutrality. Despite extensive scholarship questioning the validity of this concept, the framing of library neutrality as nonpartisanship continues. This article examines librarianship’s engagement with, and disengagement from Black communities through the lens of the Black Lives Matter movement. It also explores the implications of education, engagement, and activism for people of color and libraries today. Design/methodology/approach The authors have engaged the topic from a critical race perspective as a practice in exercising voice - telling stories, presenting counterstories, and practicing advocacy (Ladson-Billings, 1998). Findings The assertion that libraries have been socially and politically neutral organizations is ahistorical. When libraries decide not to address issues relevant to people of color, they are not embodying neutrality; they are actively electing not to support the information and service needs of a service population. In order for libraries to live up to their core values, they must engage actively with communities, especially when those communities are in crisis. Originality/value As a service field, librarianship has an ethos, values, and history that parallel those of many other service fields. This paper has implications for developing understanding of questions about equitable service provision

STRENGTHENING ECONOMIC FOUNDATIONS: ADDRESSING THE RELATIONSHIP BETWEEN HOUSING AND NUTRITION SECURITY AMONG MAJORITY-MINORITY COMMUNITIES IN DURHAM COUNTY, NORTH CAROLINA

To better address the broad spectrum of health in Durham County, North Carolina, this capstone offers a series of housing and nutritional policy reforms that aim to improve the economic security of Durham County residents by addressing the bidirectional nature of housing and food insecurity. The following proposal explains the impact economic precarity and instability has on Durham County residents’ health and how it impacts how residents live, work, and play. The proposal details how reforming zoning laws for affordable housing, coupled with community gardens and nutrition education can help improve economic security for Durham County residents and how such policies will improve the County’s public health. These proposals also include a detailed budget its zoning reform policy and program evaluation for its community gardens program. The proposal also includes an appendix with an additional housing reform policy to build additional permanent low-income housing.Master of Science in Public Healt

Libraries on the frontlines: Neutrality and social justice

Purpose The purpose of this paper is to examine libraries’ responsibility to engage with and support communities of color as they challenge systemic racism, engage in the political process, and exercise their right to free speech. Many libraries have ignored the Black Lives Matter (BLM) movement, citing the need to maintain neutrality. Despite extensive scholarship questioning the validity of this concept, the framing of library neutrality as nonpartisanship continues. This paper examines librarianship’s engagement with, and disengagement from black communities through the lens of the BLM movement. It also explores the implications of education, engagement, and activism for people of color and libraries today. Design/methodology/approach The authors have engaged the topic from a critical race perspective as a practice in exercising voice – telling stories, presenting counterstories, and practicing advocacy (Ladson-Billings, 1998). Findings The assertion that libraries have been socially and politically neutral organizations is ahistorical. When libraries decide not to address issues relevant to people of color, they are not embodying neutrality; they are actively electing not to support the information and service needs of a service population. In order for libraries to live up to their core values, they must engage actively with communities, especially when those communities are in crisis. Originality/value As a service field, librarianship has an ethos, values, and history that parallel those of many other service fields. This paper has implications for developing understanding of questions about equitable service provision

Sensitivity to Change (Responsiveness) and Minimal Important Differences of the LupusQoL in patients with Systemic Lupus Erythematosus

Objective: The LupusQoL is a reliable and valid health-related quality of life (HRQoL) measure for adults with systemic lupus erythematosus (SLE). This study evaluates the responsiveness and minimal important differences (MID) for the eight LupusQoL domains. Methods: Patients experiencing a flare were recruited from nine UK centres. At each of the ten monthly visits, HRQoL (LupusQoL, SF-36), global rating of change (GRC) and disease activity (DA) using the BILAG-2004 index were assessed. The responsiveness of the LupusQoL and the SF-36 was evaluated primarily when patients reported an improvement or deterioration on the GRC scale and, secondly, with changes in physician-reported DA. MIDs were estimated as mean changes when minimal change was reported on the GRC scale. Results: 101 patients were recruited. For all LupusQoL domains, mean HRQoL worsened when patients reported deterioration and improved when patients reported an improvement in GRC; SF-36 domains showed comparable responsiveness. Improvement in some domains of the LupusQoL/SF-36 was observed with a decrease in DA but when DA worsened, there was no significant change. LupusQoL MID estimates for deterioration ranged from -2.4 to -8.7 and for improvement, 3.5 to 7.3; for the SF-36, -2.0 to -11.1, and 2.8 to 10.9 respectively. Conclusion: All LupusQoL domains are sensitive to change with patient-reported deterioration or improvement in health status. For DA, some LupusQoL domains showed responsiveness when there was improvement but none for deterioration. LupusQoL items were derived from SLE patients and provide the advantage of disease-specific domains, important to them, not captured by the SF-36

Mixed T Lymphocyte Chimerism after Allogeneic Hematopoietic Transplantation Is Predictive for Relapse of Acute Myeloid Leukemia and Myelodysplastic Syndromes.

Chimerism testing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) represents a promising tool for predicting disease relapse, although its precise role in this setting remains unclear. We investigated the predictive value of T lymphocyte chimerism analysis at 90 to 120 days after allo-HSCT in 378 patients with AML/MDS who underwent busulfan/fludarabine-based myeloablative preparative regimens. Of 265 (70%) patients with available T lymphocyte chimerism data, 43% of patients in first or second complete remission (CR1/CR2) at the time of transplantation had complete (100%) donor T lymphocytes at day +90 to +120 compared with 60% of patients in the non-CR1/CR2 cohort (P = .005). In CR1/CR2 patients, donor T lymphocyte chimerism ≤ 85% at day +90 to +120 was associated with a higher frequency of 3-year disease progression (29%; 95% confidence interval [CI], 18% to 46% versus 15%; 95% CI, 9% to 23%; hazard ratio [HR], 2.1; P = .04). However, in the more advanced, non-CR1/CR2 cohort, mixed T lymphocyte chimerism was not associated with relapse (37%; 95% CI, 20% to 66% versus 34%; 95% CI, 25% to 47%; HR, 1.3; P = .60). These findings demonstrate that early T lymphocyte chimerism testing at day +90 to +120 is a useful approach for predicting AML/MDS disease recurrence in patients in CR1/CR2 at the time of transplantation

Reveal the viscoplastic behaviour and microstructure evolution of stainless steel 316L

Stainless steel 316L is a widely used structural material in the nuclear industry because of its excellent corrosion resistance and mechanical properties. However, very little research can be found on its viscoplastic behaviour and microstructure evolution at warm and hot deformation conditions, which hinder the possible application of advanced manufacturing technologies for producing complex parts, such as superplastic forming or hydroforming. The aims of this study are to explore stainless steel 316L’s viscoplastic behaviour, to determine its strain rate sensitivities, and to reveal its underlying microstructure evolution; this will allow appropriate manufacturing (forming) technologies and the optimal forming condition to be determined. Hence, isothermal tensile tests at 700 °C, 800 °C, 900 °C, and 1000 °C at strain rates of 0.01 s−1 and 0.001 s−1 have been conducted. Moreover, the corresponding microstructure evolution, including the grain orientation and geometrically necessary dislocation density, has been revealed by the electron backscatter diffraction method. The data show the viscoplastic behaviour of stainless steel 316L under various thermomechanical deformation conditions and how microstructure evolution influences the viscoplastic flow stress

Reversal of Hypertriglyceridemia, Fatty Liver Disease, and Insulin Resistance by a Liver-Targeted Mitochondrial Uncoupler

SummaryNonalcoholic fatty liver disease (NAFLD) affects one in three Americans and is a major predisposing condition for the metabolic syndrome and type 2 diabetes (T2D). We examined whether a functionally liver-targeted derivative of 2,4-dinitrophenol (DNP), DNP-methyl ether (DNPME), could safely decrease hypertriglyceridemia, NAFLD, and insulin resistance without systemic toxicities. Treatment with DNPME reversed hypertriglyceridemia, fatty liver, and whole-body insulin resistance in high-fat-fed rats and decreased hyperglycemia in a rat model of T2D with a wide therapeutic index. The reversal of liver and muscle insulin resistance was associated with reductions in tissue diacylglycerol content and reductions in protein kinase C epsilon (PKCε) and PKCθ activity in liver and muscle, respectively. These results demonstrate that the beneficial effects of DNP on hypertriglyceridemia, fatty liver, and insulin resistance can be dissociated from systemic toxicities and suggest the potential utility of liver-targeted mitochondrial uncoupling agents for the treatment of hypertriglyceridemia, NAFLD, metabolic syndrome, and T2D

Antibodies from rabbits immunized with HIV-1 clade B SOSIP trimers can neutralize multiple clade B viruses by destabilizing the envelope glycoprotein

The high HIV-1 viral diversity is a formidable hurdle for the development of an HIV-1 vaccine. Elicitation of broadly neutralizing antibodies (bNAbs) would offer a solution, but so far immunization strategies have failed to elicit bNAbs efficiently. To overcome the obstacles, it is important to understand the immune responses elicited by current HIV-1 envelope glycoprotein (Env) immunogens. To gain more insight, we characterized monoclonal antibodies (mAbs) isolated from rabbits immunized with Env SOSIP trimers based on the clade B isolate AMC008. Four rabbits that were immunized three times with AMC008 trimer developed robust autologous and sporadic low-titer heterologous neutralizing responses. Seventeen AMC008 trimer-reactive mAbs were isolated using antigen-specific single B cell sorting. Four of these mAbs neutralized the autologous AMC008 virus and several other clade B viruses. When visualized by electron microscopy, the complex of the neutralizing mAbs with the AMC008 trimer showed binding to the gp41 subunit with unusual approach angles and we observed that their neutralization ability depended on their capacity to induce Env trimer dissociation. Thus, AMC008 SOSIP trimer immunization induced clade B neutralizing mAbs with unusual approach angles with neutralizing effects that involve trimer destabilization. Optimizing these responses might provide an avenue to the induction of trimer dissociating bNAbs. IMPORTANCE Roughly 32 million people have died as a consequence of HIV-1 infection since the start of the epidemic and still 1.7 million people get infected with HIV-1 annually. Therefore, a vaccine to prevent HIV-1 infection is urgently needed. Current HIV-1 immunogens are not able to elicit the broad immune responses needed to provide protection against the large variation of HIV-1 strains circulating globally. A better understanding of the humoral immune responses elicited by immunization with state-of-the-art HIV-1 immunogens should facilitate the design of improved HIV-1 vaccine candidates. We identified antibodies with the ability to neutralize multiple HIV-1 viruses by destabilization of the envelope glycoprotein. Their weak but consistent cross-neutralization ability indicates the potential of this epitope to elicit broad responses. The trimer-destabilizing effect of the neutralizing mAbs combined with detailed characterization of the neutralization epitope can be used to shape the next generation of HIV-1 immunogens to elicit improved humoral responses after vaccination

The BILAG-2004 index is associated with development of new damage in SLE

OBJECTIVE: To determine whether BILAG-2004 index is associated with the development of damage in a cohort of SLE patients. Mortality and development of damage were examined.METHODS: This was a multicentre longitudinal study. Patients were recruited within 12 months of achieving 4th ACR classification criterion for SLE. Data were collected on disease activity, damage, SLE-specific drug exposure, cardiovascular risk factors, antiphospholipid syndrome status and death at every visit. This study ran from 1st January 2005 to 31st December 2017. Descriptive statistics were used to analyse mortality and development of new damage. Poisson regression was used to examine potential explanatory variables for development of new damage.RESULTS: 273 SLE patients were recruited with total follow-up of 1767 patient-years (median 73.4 months). There were 6348 assessments with disease activity scores available for analysis. During follow-up, 13 deaths and 114 new damage items (in 83 patients) occurred. The incidence rate for development of damage was higher in the first 3 years before stabilising at a lower rate. Overall rate for damage accrual was 61.1 per 1000 person-years (95% CI : 50.6, 73.8). Analysis showed that active disease scores according to BILAG-2004 index (systems scores of A or B, counts of systems with A and BILAG-2004 numerical score) were associated with development of new damage. Low disease activity (LDA) states (BILAG-2004 LDA and BILAG Systems Tally (BST) persistent LDA) were inversely associated with development of damage.CONCLUSIONS: BILAG-2004 index is associated with new damage. BILAG-2004 LDA and BST persistent LDA can be considered as treatment targets.</p