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"Mehta, N"
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Delaying doomsday : the politics of nuclear reversal
\"Why are states willing to give up their nuclear weapons programs? This book presents a new theory for how external inducements supplied by the United States can convince even the most committed of proliferators to abandon weapons pursuit. Existing theories focus either on carrots or sticks. I explore how using both positive and negative inducements, in the shadow of military force, can persuade both friends and foes not to continue their nuclear weapons pursuit. I draw on worldwide cross-national data on nuclear reversal, case studies of Iran and North Korea among others, and interviews with diplomats, policy-makers, and analysts. I show that the majority of states have been persuaded to reverse their nuclear weapons programs when offered incentives from the United States. Moreover, I demonstrate that these tools are especially effective during periods of leadership transition and can work on both allies and adversaries. My theory and evidence also suggest a broader conception of counterproliferation than currently exists, identifying how carrots and sticks used together can accomplish one of the international community's most important policy objectives\"-- Provided by publisher.
Book
Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus
Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study’s primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels (
p
= 0.0006, CI 95%: 4.12, 13.32) and particle number (
p
= 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration (
p
= 0.024, CI 95%: 1.1, −26.5), cholesterol efflux capacity (
p
= 0.08, CI 95%: −0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with
STAT4
risk allele.
Increased risk of premature cardiovascular disease in systemic lupus erythematosus (SLE) is not well understood, but in animal models, the Janus kinase inhibitor tofacitinib improves related phenotypes. Here the authors report a Phase 1 double-blind randomized trial that shows tofacitinib is safe and well tolerated in in patients with SLE.
Journal Article
Quantum electrodynamics of a superconductor–insulator phase transition
A chain of Josephson junctions represents one of the simplest many-body models undergoing a superconductor–insulator quantum phase transition1,2. Apart from zero resistance, the superconducting state is necessarily accompanied by a sound-like mode due to collective oscillations of the phase of the complex-valued order parameter3,4. Little is known about the fate of this mode on entering the insulating state, where the order parameter’s amplitude remains non-zero, but the phase ordering is ‘melted’ by quantum fluctuations5. Here, we show that the phase mode survives far into the insulating regime, such that megaohm-resistance chains can carry gigahertz-frequency alternating currents as nearly ideal superconductors. The insulator reveals itself through interaction-induced broadening and random frequency shifts of collective mode resonances. Our spectroscopic experiment puts forward the problem of quantum electrodynamics of a Bose glass for both theory and experiment6–8. By pushing the chain parameters deeper into the insulating state, we achieved a wave impedance of the phase mode exceeding the predicted critical value by an order of magnitude9–14. The effective fine structure constant of such a one-dimensional electromagnetic vacuum exceeds unity, promising transformative applications to quantum science and technology.
Journal Article
Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells
The molecular mechanisms governing orderly shutdown and retraction of CD4+ type 1 helper T (TH1) cell responses remain poorly understood. Here we show that complement triggers contraction of TH1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ+ TH1 cells to suppressive interleukin-10+ cells. This process was primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4+ T cells of patients with COVID-19 were TH1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.During homeostasis TH1 cells activate a cell-intrinsic inflammatory shutdown program and shift to IL-10 production. Chauss et al. find that this TH1 homeostatic program is dependent on vitamin D signaling and is disrupted in severe COVID-19.
Journal Article
BMI-adjusted adipose tissue volumes exhibit depot-specific and divergent associations with cardiometabolic diseases
For any given body mass index (BMI), individuals vary substantially in fat distribution, and this variation may have important implications for cardiometabolic risk. Here, we study disease associations with BMI-independent variation in visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) fat depots in 40,032 individuals of the UK Biobank with body MRI. We apply deep learning models based on two-dimensional body MRI projections to enable near-perfect estimation of fat depot volumes (R
2
in heldout dataset = 0.978-0.991 for VAT, ASAT, and GFAT). Next, we derive BMI-adjusted metrics for each fat depot (e.g. VAT adjusted for BMI, VATadjBMI) to quantify local adiposity burden. VATadjBMI is associated with increased risk of type 2 diabetes and coronary artery disease, ASATadjBMI is largely neutral, and GFATadjBMI is associated with reduced risk. These results – describing three metabolically distinct fat depots at scale – clarify the cardiometabolic impact of BMI-independent differences in body fat distribution.
Different location of adipose tissue may have different consequences to cardiometabolic risk. Here the authors report that deep learning enabled accurate prediction of specific adipose tissue volumes, and that after adjustment for BMI, visceral adiposity was associated with increased risk of cardiometabolic disease, while gluteofemoral adiposity was associated with reduced risk.
Journal Article
Hyperlipidemia-induced cholesterol crystal production by endothelial cells promotes atherogenesis
Endothelial cells (EC) play a key role in atherosclerosis. Although EC are in constant contact with low density lipoproteins (LDL), how EC process LDL and whether this influences atherogenesis, is unclear. Here we show that EC take up and metabolize LDL, and when overburdened with intracellular cholesterol, generate cholesterol crystals (CC). The CC are deposited on the basolateral side, and compromise endothelial function. When hyperlipidemic mice are given a high fat diet, CC appear in aortic sinus within 1 week. Treatment with cAMP-enhancing agents, forskolin/rolipram (F/R), mitigates effects of CC on endothelial function by not only improving barrier function, but also inhibiting CC formation both in vitro and in vivo. A proof of principle study using F/R incorporated into liposomes, designed to target inflamed endothelium, shows reduced atherosclerosis and CC formation in
ApoE
−/−
mice. Our findings highlight an important mechanism by which EC contribute to atherogenesis under hyperlipidemic conditions.
Atherosclerosis is characterized by subendothelial lipid retention believed to be the result of endothelial trancytosis. Here, the authors show that endothelium can take up and process LDL, generating cholesterol crystals that are deposited on the basolateral side of the cells, causing their dysfunction that can be prevented by forskolin/rolipram treatment.
Journal Article
Thermogravimetric insights into decomposition and lifetime prediction in STSI glass-ceramics
This article investigates the thermal kinetics, degradation behavior, and lifetime prediction of Se
78-x
Te
20
Sn
2
In
x
(0 ≤ x ≤ 6) chalcogenide alloys using thermogravimetric analysis (TGA) over a temperature range of 300 °C–600 °C. Kinetic parameters were extracted using isothermal methods, including the Matusita-Sakka, Augis-Bennett, and Kissinger methods. By applying model-fitting approaches, we calculate the degradation energy (
E
d
) using the maximum degradation temperature (
T
d
) extracted from the DTG plots. The degradation temperature shows a dependence consistent with the Lasocka relation. Iso-conversional methods were also employed, utilizing the model-free approaches. A newly discovered logistic decay function is introduced to model mass loss phenomena, enabling the extraction of kinetic parameters such as the decomposition rate constant (
λ
d
) and decomposition time (
t
d
). Compositions STSI-1 and STSI-3 exhibit prolonged lifetimes and thermal resilience, underscoring their potential for applications in non-volatile memory devices, photonic switches, and radiation shielding.
Journal Article
Evidence for effective interventions to reduce mental health-related stigma and discrimination in the medium and long term: Systematic review
Most research on interventions to counter stigma and discrimination has focused on short-term outcomes and has been conducted in high-income settings.
To synthesise what is known globally about effective interventions to reduce mental illness-based stigma and discrimination, in relation first to effectiveness in the medium and long term (minimum 4 weeks), and second to interventions in low- and middle-income countries (LMICs).
We searched six databases from 1980 to 2013 and conducted a multi-language Google search for quantitative studies addressing the research questions. Effect sizes were calculated from eligible studies where possible, and narrative syntheses conducted. Subgroup analysis compared interventions with and without social contact.
Eighty studies (n = 422 653) were included in the review. For studies with medium or long-term follow-up (72, of which 21 had calculable effect sizes) median standardised mean differences were 0.54 for knowledge and -0.26 for stigmatising attitudes. Those containing social contact (direct or indirect) were not more effective than those without. The 11 LMIC studies were all from middle-income countries. Effect sizes were rarely calculable for behavioural outcomes or in LMIC studies.
There is modest evidence for the effectiveness of anti-stigma interventions beyond 4 weeks follow-up in terms of increasing knowledge and reducing stigmatising attitudes. Evidence does not support the view that social contact is the more effective type of intervention for improving attitudes in the medium to long term. Methodologically strong research is needed on which to base decisions on investment in stigma-reducing interventions.
Journal Article
Psoriasis
Psoriasis is a chronic, immune-mediated disorder with cutaneous and systemic manifestations and substantial negative effects on patient quality of life. Psoriasis has a strong, albeit polygenic, genetic basis. Whereas approximately half of the accountable genetic effect of psoriasis maps to the major histocompatibility complex, >70 other loci have been identified, many of which implicate nuclear factor-κB, interferon signalling and the IL-23–IL-23 receptor axis. Psoriasis pathophysiology is characterized by abnormal keratinocyte proliferation and immune cell infiltration in the dermis and epidermis involving the innate and adaptive immune systems, with important roles for dendritic cells and T cells, among other cells. Frequent comorbidities are rheumatological and cardiovascular in nature, in particular, psoriatic arthritis. Current treatments for psoriasis include topical agents, photo-based therapies, traditional systemic drugs and biologic agents. Treatments can be used in combination or as monotherapy. Biologic therapies that target specific disease mediators have become a mainstay in the treatment of moderate-to-severe disease, whereas advances in the treatment of mild-to-moderate disease have been limited.
Psoriasis is a chronic, immune-mediated disease that can severely affect patient quality of life. Various kinds of skin manifestations are possible; psoriatic arthritis is a common but underdiagnosed comorbidity. Treatments for psoriasis include topical agents, phototherapy and systemic and biologic agents.
Journal Article
Obesity and muscle strength as long-term determinants of all-cause mortality—a 33-year follow-up of the Mini-Finland Health Examination Survey
Objective:
To examine the independent and combined associations of obesity and muscle strength with mortality in adult men and women.
Design:
Follow-up study with 33 years of mortality follow-up.
Subjects:
A total of 3594 men and women aged 50–91 years at baseline with 3043 deaths during the follow-up.
Measurement:
Body mass index (BMI) and handgrip strength were measured at baseline.
Results:
Based on Cox models adjusted for age, sex, education, smoking, alcohol use, physical activity and chronic conditions, baseline obesity (BMI⩾30 kg m
−2
) was associated with mortality among participants aged 50–69 years (hazard ratio (HR) 1.14, 95% confidence interval (CI), 1.01–1.28). Among participants aged 70 years and older, overweight and obesity were protective (HR 0.77, 95% CI, 0.66–0.89 and HR 0.76, 95% CI, 0.62–0.92). High handgrip strength was inversely associated with mortality among participants aged 50–69 (HR 0.89, 95% CI, 0.80–1.00) and 70 years and older (HR 0.78, 95% CI, 0.66–0.93). Compared to normal-weight participants with high handgrip strength, the highest mortality risk was observed among obese participants with low handgrip strength (HR 1.23, 95% CI, 1.04–1.46) in the 50–69 age group and among normal-weight participants with low handgrip strength (HR 1.30, 95% CI, 1.09–1.54) among participants aged 70+ years. In addition, in the old age group, overweight and obese participants with high handgrip strength had significantly lower mortality than normal-weight participants with high handgrip strength (HR 0.79, 95% CI, 0.67–0.92 and HR 0.77, 95% CI, 0.63–0.94).
Conclusion:
Both obesity and low handgrip strength, independent of each other, predict the risk of death in adult men and women with additive pattern. The predictive value of obesity varies by age, whereas low muscle strength predicts mortality in all age groups aged>50 years and across all BMI categories. When promoting health among older adults, more attention should be paid to physical fitness in addition to body weight and adiposity.
Journal Article