bluuebunny/crossref_metadata_2025_split huggingface dataset:
Corporate Governance, Debt, and Investment Policy During the Great Depression
Authors: Graham John R. , Hazarika Sonali , Narasimhan Krishnamoorthy 
Published: October 2011

We study a period of severe disequilibrium to investigate whether board characteristics are related to corporate investment, debt usage, and firm value. During the 1930–1938 Depression era, when the corporate sector was shocked by an unprecedented downturn, we document a relation between board characteristics and firm performance that varies in economically sensible ways: Complex firms (that would benefit more from board advice) exhibit a positive relation between board size and firm value, and simple firms exhibit a negative relation between board size and firm value. Moreover, simple firms with large boards do not downsize adequately in response to the severe economic contraction: they invest more (or shrink less) and use more debt during the 1930s. We document similar effects for the number of outside directors on the board. Finally, we also find that companies with properly aligned governance structures are more likely to replace the company president following poor performance. This paper was accepted by Wei Xiong, finance.
Theoretical prediction of drug-receptor interactions
Authors: Frecer Vladimir 
Published: October 2011

Abstract
The crucial event in the pharmacological action of drugs is the interaction between a drug molecule and its receptor. Molecular recognition and binding affinity of a drug is driven by a flexible steric fit and a molecular field match between two complementary molecular surfaces of the receptor and the approaching ligand. Rational drug design methods, which attempt to predict the free energy change resulting from ligand binding, rely on a detailed knowledge of the physical forces that govern the drug−receptor interactions in several populated configurations of the intermolecular complex. The overall strength of the interaction is determined by the fine balance between the forces contributed by the individual chemical function groups of the two entities and the physiological medium. This paper recounts some basic information about the description of molecular structures and highlights the methods and approximations commonly used to calculate the binding affinity of a drug to its receptor.
Gene dose effect of NAT2 variants on the pharmacokinetics of isoniazid and acetylisoniazid in healthy Chinese subjects
Authors: Bing Chen , Xiaomeia Cao , Jinhenga Li 
Published: October 2011

Abstract

Background: The aim of this study was to elucidate the gene dose effect of NAT2 and the effect on the pharmacokinetics of isoniazid (INH) and its metabolites acetylisoniazid (AcINH) in Chinese subjects.

Methods: A total of 24 healthy Chinese subjects, consisting of eight homozygous wild types (wt/wt), eight heterozygous mutants (m/wt) and eight homozygous mutants (m/m) for NAT2, were enrolled in the study. The blood samples (0–14 h) of the subjects were taken after oral administration of a single dose (300 mg) of INH. Concentrations of INH and AcINH in plasma were measured by a reversed-phase HPLC method.

Results: The ratio of AcINH and INH (RA/I) 3 h post-dose of wt/wt, m/wt and m/m groups were 3.22±1.34, 1.35±0.20 and 0.22±0.06, respectively (p<0.01). The area under concentration-time curve (AUC) values of three groups were 10.35±2.12, 16.34±3.05, 42.24±8.51 mg/h/L for INH and 42.19±8.80, 38.05±5.32, 19.78±3.72 mg/h/L for AcINH, res­pectively (p<0.01). There was a good linear relationship between pharmacokinetic parameters and the number of active NAT2 genes.

Conclusions: The results suggest that there is a conspicuous gene dose effect in the pharmacokinetics of INH and AcINH. This finding may be valuable in the personalized therapy of tuberculosis with INH.
Successful tacrolimus treatment following renal transplant in a HIV-infected patient with raltegravir previously treated with a protease inhibitor based regimen
Authors: Cousins Darren , Topping Kate , Lee Vincent , Sweeney John , Lawton Mark 
Published: October 2011

Abstract
A HIV positive patient who received a cadaveric renal transplantation developed tacrolimus toxicity as manifest by renal failure and decreased consciousness. This was due to atazanavir and ritonavir therapy for her HIV inhibiting the CYP3A4 hepatic enzyme resulting in accumulation of tacrolimus. Her HIV treatment was switched to raltegravir which is metabolized by UGT1A1 which does not affect tacrolimus. Tacrolimus was then reintroduced, and follow-up at 1 year demonstrated successful immunosuppression and undetectable HIV viral loads.
Increased circulating levels of FGF23: an adaptive response in primary hyperparathyroidism?
Authors: Witteveen Janneke E , van Lierop Antoon H , Papapoulos Socrates E , Hamdy Neveen A T 
Published: October 2011

IntroductionFibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) are major players in the bone–parathyroid–kidney axis controlling phosphate homeostasis. In patients with primary hyperparathyroidism (PHPT), data on the relationship between PTH and FGF23 are scarce and not always concordant.ObjectiveThe aim of our study was to evaluate the relationship between PTH and FGF23 in patients with PHPT and in euparathyroid patients cured after successful parathyroidectomy (PTx).Patients and methodsTwenty-one patients with PHPT and 24 patients in long-term cure after successful PTx (EuPTH) were studied. All patients underwent biochemical evaluation of renal function, parathyroid status, vitamin D status, bone turnover markers, and serum intact FGF23 levels.ResultsMean serum FGF23 concentration was significantly higher in PHPT than in EuPTH patients (50.8±6.1 vs 33.1±2.6 pg/ml,P=0.01). FGF23 levels significantly correlated with PTH levels (r=0.361,P=0.02), also after correction for 1,25(OH)2D levels (r=0.419,P=0.01). FGF23 levels showed a significant negative correlation with 1,25(OH)2D, which was more pronounced in PHPT than in EuPTH patients (r=−0.674,P=0.001, vsr=−0.509,P=0.01).ConclusionOur findings suggest that in PHPT, FGF23 levels are increased independent of 1,25(OH)2D levels. The more pronounced negative relationship between FGF23 and 1,25(OH)2D in the presence of high circulating PTH levels suggests that the increase in FGF23 levels may be an adaptive mechanism to counteract the PTH-induced increase in 1,25(OH)2D levels, although not completely overriding it.
β-Cell Uncoupling Protein 2 Regulates Reactive Oxygen Species Production, Which Influences Both Insulin and Glucagon Secretion
Authors: Robson-Doucette Christine A. , Sultan Sobia , Allister Emma M. , Wikstrom Jakob D. , Koshkin Vasilij , Bhattacharjee Alpana , Prentice Kacey J. , Sereda Samuel B. , Shirihai Orian S. , Wheeler Michael B. 
Published: October 2011

OBJECTIVEThe role of uncoupling protein 2 (UCP2) in pancreatic β-cells is highly debated, partly because of the broad tissue distribution of UCP2 and thus limitations of whole-body UCP2 knockout mouse models. To investigate the function of UCP2 in the β-cell, β-cell–specific UCP2 knockout mice (UCP2BKO) were generated and characterized.RESEARCH DESIGN AND METHODSUCP2BKO mice were generated by crossing loxUCP2 mice with mice expressing rat insulin promoter-driven Cre recombinase. Several in vitro and in vivo parameters were measured, including respiration rate, mitochondrial membrane potential, islet ATP content, reactive oxygen species (ROS) levels, glucose-stimulated insulin secretion (GSIS), glucagon secretion, glucose and insulin tolerance, and plasma hormone levels.RESULTSUCP2BKO β-cells displayed mildly increased glucose-induced mitochondrial membrane hyperpolarization but unchanged rates of uncoupled respiration and islet ATP content. UCP2BKO islets had elevated intracellular ROS levels that associated with enhanced GSIS. Surprisingly, UCP2BKO mice were glucose-intolerant, showing greater α-cell area, higher islet glucagon content, and aberrant ROS-dependent glucagon secretion under high glucose conditions.CONCLUSIONSUsing a novel β-cell–specific UCP2KO mouse model, we have shed light on UCP2 function in primary β-cells. UCP2 does not behave as a classical metabolic uncoupler in the β-cell, but has a more prominent role in the regulation of intracellular ROS levels that contribute to GSIS amplification. In addition, β-cell UCP2 contributes to the regulation of intraislet ROS signals that mediate changes in α-cell morphology and glucagon secretion.
Early Treatment of NOD Mice With B7-H4 Reduces the Incidence of Autoimmune Diabetes
Authors: Wang Xiaojie , Hao Jianqiang , Metzger Daniel L. , Mui Alice , Ao Ziliang , Akhoundsadegh Noushin , Langermann Solomon , Liu Linda , Chen Lieping , Ou Dawei , Verchere C. Bruce , Warnock Garth L. 
Published: October 2011

OBJECTIVEAutoimmune diabetes is a T cell–mediated disease in which insulin-producing β-cells are destroyed. Autoreactive T cells play a central role in mediating β-cell destruction. B7-H4 is a negative cosignaling molecule that downregulates T-cell responses. In this study, we aim to determine the role of B7-H4 on regulation of β-cell–specific autoimmune responses.RESEARCH DESIGN AND METHODSPrediabetic (aged 3 weeks) female NOD mice (group 1, n = 21) were treated with intraperitoneal injections of B7-H4.Ig at 7.5 mg/kg, with the same amount of mouse IgG (group 2, n = 24), or with no protein injections (group 3, n = 24), every 3 days for 12 weeks.RESULTSB7-H4.Ig reduced the incidence of autoimmune diabetes, compared with the control groups (diabetic mice 28.6% of group 1, 66.7% of group 2 [P = 0.0081], and 70.8% of group 3 [group 1 vs. 3, P = 0.0035]). Histological analysis revealed that B7-H4 treatment did not block islet infiltration but rather suppressed further infiltrates after 9 weeks of treatment (group 1 vs. 2, P = 0.0003). B7-H4 treatment also reduced T-cell proliferation in response to GAD65 stimulation ex vivo. The reduction of diabetes is not due to inhibition of activated T cells in the periphery but rather to a transient increase of Foxp3+ CD4+ T-cell population at one week posttreatment (12.88 ± 1.29 vs. 11.58 ± 1.46%; n = 8; P = 0.03).CONCLUSIONSOur data demonstrate the protective role of B7-H4 in the development of autoimmune diabetes, suggesting a potential means of preventing type 1 diabetes by targeting the B7-H4 pathway.
Brain Activation During Working Memory Is Altered in Patients With Type 1 Diabetes During Hypoglycemia
Authors: Bolo Nicolas R. , Musen Gail , Jacobson Alan M. , Weinger Katie , McCartney Richard L. , Flores Veronica , Renshaw Perry F. , Simonson Donald C. 
Published: October 2011

OBJECTIVE
To investigate the effects of acute hypoglycemia on working memory and brain function in patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS
Using blood oxygen level–dependent (BOLD) functional magnetic resonance imaging during euglycemic (5.0 mmol/L) and hypoglycemic (2.8 mmol/L) hyperinsulinemic clamps, we compared brain activation response to a working-memory task (WMT) in type 1 diabetic subjects (n = 16) with that in age-matched nondiabetic control subjects (n = 16). Behavioral performance was assessed by percent correct responses.

RESULTS
During euglycemia, the WMT activated the bilateral frontal and parietal cortices, insula, thalamus, and cerebellum in both groups. During hypoglycemia, activation decreased in both groups but remained 80% larger in type 1 diabetic versus control subjects (P &lt; 0.05). In type 1 diabetic subjects, higher HbA1c was associated with lower activation in the right parahippocampal gyrus and amygdala (R2 = 0.45, P &lt; 0.002). Deactivation of the default-mode network (DMN) also was seen in both groups during euglycemia. However, during hypoglycemia, type 1 diabetic patients deactivated the DMN 70% less than control subjects (P &lt; 0.05). Behavioral performance did not differ between glycemic conditions or groups.

CONCLUSIONS
BOLD activation was increased and deactivation was decreased in type 1 diabetic versus control subjects during hypoglycemia. This higher level of brain activation required by type 1 diabetic subjects to attain the same level of cognitive performance as control subjects suggests reduced cerebral efficiency in type 1 diabetes.
Glucose-Dependent Insulinotropic Polypeptide
Authors: Christensen Mikkel , Vedtofte Louise , Holst Jens J. , Vilsbøll Tina , Knop Filip K. 
Published: October 2011

OBJECTIVE
To evaluate the glucose dependency of glucose-dependent insulinotropic polypeptide (GIP) effects on insulin and glucagon release in 10 healthy male subjects ([means ± SEM] aged 23 ± 1 years, BMI 23 ± 1 kg/m2, and HbA1c 5.5 ± 0.1%).

RESEARCH DESIGN AND METHODS
Saline or physiological doses of GIP were administered intravenously (randomized and double blinded) during 90 min of insulin-induced hypoglycemia, euglycemia, or hyperglycemia.

RESULTS
During hypoglycemia, GIP infusion caused greater glucagon responses during the first 30 min compared with saline (76 ± 17 vs. 28 ± 16 pmol/L per 30 min, P &lt; 0.008), with similar peak levels of glucagon reached after 60 min. During euglycemia, GIP infusion elicited larger glucagon responses (62 ± 18 vs. −11 ± 8 pmol/L per 90 min, P &lt; 0.005). During hyperglycemia, comparable suppression of plasma glucagon (−461 ± 81 vs. −371 ± 50 pmol/L per 90 min, P = 0.26) was observed with GIP and saline infusions. In addition, during hyperglycemia, GIP more than doubled the insulin secretion rate (P &lt; 0.0001).

CONCLUSIONS
In healthy subjects, GIP has no effect on glucagon responses during hyperglycemia while strongly potentiating insulin secretion. In contrast, GIP increases glucagon levels during fasting and hypoglycemic conditions, where it has little or no effect on insulin secretion. Thus, GIP seems to be a physiological bifunctional blood glucose stabilizer with diverging glucose-dependent effects on the two main pancreatic glucoregulatory hormones.
Wood properties and trunk allometry of co‐occurring rainforest canopy trees in a cyclone‐prone environment
Authors: Read Jennifer , Evans Robert , Sanson Gordon D. , Kerr Stuart , Jaffré Tanguy 
Published: October 2011

• Premise of study: New Caledonia commonly experiences cyclones, so trees there are expected to have enhanced wood traits and trunk allometry that confer resistance to wind damage. We ask whether there is evidence of a trade‐off between these traits and growth rate among species.• Methods: Wood traits, including density, microfibril angle (MFA), and modulus of elasticity (MOE), ratio of tree height to stem diameter, and growth rate were investigated in mature trees of 15 co‐occurring canopy species in a New Caledonian rainforest.• Key results: In contrast to some studies, wood density did not correlate negatively with growth increment. Among angiosperms, wood density and MOE correlated positively with diameter‐adjusted tree height, and MOE correlated positively with stem‐diameter growth increment. Tall slender trees achieved high stiffness with high efficiency with respect to wood density, in part by low MFA, and with a higher diameter growth increment but a lower buckling safety factor. However, some tree species of a similar niche differed in whole‐tree resistance to wind damage and achieved wood stiffness in different ways.• Conclusions: There was no evidence of a growth‐safety trade‐off in these trees. In forests that regularly experience cyclones, there may be stronger selection for high wood density and/or stiffness in fast‐growing trees of the upper canopy, with the potential growth trade‐off amortized by access to the upper canopy and by other plant traits. Furthermore, decreasing wood density does not necessarily decrease resistance to wind damage, resistance being influenced by other characteristics including cell‐level traits (e.g., MFA) and whole‐plant architecture.
Population differentiation and plasticity in vegetative ontogeny: Effects on life‐history expression in Erysimum capitatum (Brassicaceae)
Authors: Kim Eunsuk , Donohue Kathleen 
Published: October 2011

• Premise of the study: Distinguishing the contributions of phenotypic plasticity vs. population differentiation to variation in the life history of plants throughout their range is important for predicting their performance after dispersal or their responses to environmental change. In Erysimum capitatum, plants in alpine environments are iteroparous perennials, but those below tree line are semelparous perennials. We tested population differentiation and plasticity of life‐history variation and explored the effects of plastic responses at the prereproductive stage on life‐history expression.• Methods: Plants from alpine and below tree‐line populations were grown in a common greenhouse environment. Soil water content at the prereproductive stage was manipulated to simulate field condition. Because rosette ontogeny of E. capitatum (i.e., production of multiple rosettes, reproductive allocation, and degeneration of rosettes) was highly associated with in situ life‐history variation, water effects on rosette ontogeny and life history were assessed.• Key results: Plants from alpine populations showed higher postreproductive survival than those from low‐elevation populations in the greenhouse environment, and such difference can be explained by differential rosette ontogeny at both the prereproductive and reproductive stage. In addition, rosette development at the reproductive stage was plastic to water availability at the prereproductive stage, which influences life‐history expression as adults.• Conclusions: Because water availability is lower at low‐elevation sites, in situ population differentiation is likely caused by plasticity to water availability as well as by genetic differentiation or maternal effects. Plastic or evolutionary changes of prereproductive traits are expected to influence adult life‐history expression, which possibly influence population demography.
The Basis of Distinctive IL-2– and IL-15–Dependent Signaling: Weak CD122-Dependent Signaling Favors CD8+ T Central-Memory Cell Survival but Not T Effector-Memory Cell Development
Authors: Castro Iris , Yu Aixin , Dee Michael J. , Malek Thomas R. 
Published: October 2011

Abstract
Recent work suggests that IL-2 and IL-15 induce distinctive levels of signaling through common receptor subunits and that such varied signaling directs the fate of Ag-activated CD8+ T cells. In this study, we directly examined proximal signaling by IL-2 and IL-15 and CD8+ T cell primary and memory responses as a consequence of varied CD122-dependent signaling. Initially, IL-2 and IL-15 induced similar p-STAT5 and p-S6 activation, but these activities were only sustained by IL-2. Transient IL-15–dependent signaling is due to limited expression of IL-15Rα. To investigate the outcome of varied CD122 signaling for CD8+ T cell responses in vivo, OT-I T cells were used from mouse models where CD122 signals were attenuated by mutations within the cytoplasmic tail of CD122 or intrinsic survival function was provided in the absence of CD122 expression by transgenic Bcl-2. In the absence of CD122 signaling, generally normal primary response occurred, but the primed CD8+ T cells were not maintained. In marked contrast, weak CD122 signaling supported development and survival of T central-memory (TCM) but not T effector-memory (TEM) cells. Transgenic expression of Bcl-2 in CD122−/− CD8+ T cells also supported the survival and persistence of TCM cells but did not rescue TEM development. These data indicate that weak CD122 signals readily support TCM development largely through providing survival signals. However, stronger signals, independent of Bcl-2, are required for TEM development. Our findings are consistent with a model whereby low, intermediate, and high CD122 signaling support TCM memory survival, TEM programming, and terminal T effector cell differentiation, respectively.
Regulation of the Germinal Center Reaction by Foxp3+ Follicular Regulatory T Cells
Authors: Wollenberg Ivonne , Agua-Doce Ana , Hernández Andrea , Almeida Catarina , Oliveira Vanessa G. , Faro Jose , Graca Luis 
Published: October 2011

Abstract
Follicular helper T (TFH) cells participate in humoral responses providing selection signals to germinal center B cells. Recently, expression of CXCR5, PD-1, and the transcription factor Bcl-6 has allowed the identification of TFH cells. We found that a proportion of follicular T cells, with phenotypic characteristics of TFH cells and expressing Foxp3, are recruited during the course of a germinal center (GC) reaction. These Foxp3+ cells derive from natural regulatory T cells. To establish the in vivo physiologic importance of Foxp3+ follicular T cells, we used CXCR5-deficient Foxp3+ cells, which do not have access to the follicular region. Adoptive cell transfers of CXCR5-deficient Foxp3+ cells have shown that Foxp3+ follicular T cells are important regulators of the GC reaction following immunization with a thymus-dependent Ag. Our in vivo data show that Foxp3+ follicular T cells can limit the magnitude of the GC reaction and also the amount of secreted Ag-specific IgM, IgG1, IgG2b, and IgA. Therefore, Foxp3+ follicular regulatory T cells appear to combine characteristics of TFH and regulatory T cells for the control of humoral immune responses.
Convergent and Divergent Development among M Cell Lineages in Mouse Mucosal Epithelium
Authors: Wang Jing , Gusti Veronica , Saraswati Andrea , Lo David D. 
Published: October 2011

Abstract
M cells are specialized epithelial cells mediating immune surveillance of the mucosal lumen by transepithelial delivery of Ags to underlying dendritic cells (DC). At least three M cell phenotypes are known in the airways and intestine, but their developmental relationships are unclear. We used reporter transgenic mouse strains to follow the constitutive development of M cell subsets and their acute induction by cholera toxin (CT). M cells overlying intestinal Peyer’s patches (PPs), isolated lymphoid follicles, and nasal-associated lymphoid tissue are induced by distinct settings, yet show convergent phenotypes, such as expression of a peptidoglycan recognition protein-S (PGRP-S) transgene reporter. By contrast, though PP, isolated lymphoid follicle, and villous M cells are all derived from intestinal crypt stem cells, their phenotypes were clearly distinct; for example, PP M cells frequently appeared to form M cell-DC functional units, whereas villous M cells did not consistently engage underlying DC. B lymphocytes are critical to M cell function by forming a basolateral pocket and possible signaling through CD137; however, initial commitment to all M cell lineages is B lymphocyte and CD137 independent. CT causes induction of new M cells in the airway and intestine without cell division, suggesting transdifferentiation from mature epithelial cells. In contrast with intestinal PP M cells, CT-induced nasal-associated lymphoid tissue M cells appear to be generated from ciliated Foxj1+PGRP-S+ cells, indicative of a possible precommitted progenitor. In summary, constitutive and inducible differentiation of M cells is toward strictly defined context-dependent phenotypes, suggesting specialized roles in surveillance of mucosal Ags.