In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated network of various hormones and neuropeptides released mainly from the brain, pancreas, liver, intestine as well as adipose and muscle tissue. Within this network, the pancreas represents a key player by secreting the blood sugar-lowering hormone insulin and its opponent glucagon. However, disturbances in the interplay of the hormones and peptides involved may lead to metabolic disorders such as type 2 diabetes mellitus (T2DM) whose prevalence, comorbidities and medical costs take on a dramatic scale. Therefore, it is of utmost importance to uncover and understand the mechanisms underlying the various interactions to improve existing anti-diabetic therapies and drugs on the one hand and to develop new therapeutic approaches on the other. This review summarizes the interplay of the pancreas with various other organs and tissues that maintain glucose homeostasis. Furthermore, anti-diabetic drugs and their impact on signaling pathways underlying the network will be discussed.

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Pancreatic regulation of glucose homeostasis.

An iron-catalysed method for the direct 3H labelling of pharmaceuticals by hydrogen isotope exchange using tritium gas is reported; the site selectivity of the iron catalyst is orthogonal to currently used iridium catalysts and allows isotopic labelling of complementary positions in drug molecules. Radiolabelled compounds, usually containing 14C or 3H, are a powerful tool in pharmacokinetics and diagnostics. In this manuscript, the authors describe a new iron-catalysed method for the direct 3H labelling of pharmaceuticals by hydrogen isotope exchange using tritium gas as the source of the radioisotope. The site selectivity of the iron catalyst is orthogonal to currently used iridium catalysts and allows isotopic labeling of complementary positions in drug molecules, providing a new diagnostic tool in drug development. A thorough understanding of the pharmacokinetic and pharmacodynamic properties of a drug in animal models is a critical component of drug discovery and development1,2,3,4,5,6. Such studies are performed in vivo and in vitro at various stages of the development process—ranging from preclinical absorption, distribution, metabolism and excretion (ADME) studies to late-stage human clinical trials—to elucidate a drug molecule’s metabolic profile and to assess its toxicity2. Radiolabelled compounds, typically those that contain 14C or 3H isotopes, are one of the most powerful and widely deployed diagnostics for these studies4,5. The introduction of radiolabels using synthetic chemistry enables the direct tracing of the drug molecule without substantially altering its structure or function. The ubiquity of C–H bonds in drugs and the relative ease and low cost associated with tritium (3H) make it an ideal radioisotope with which to conduct ADME studies early in the drug development process2,4,6. Here we describe an iron-catalysed method for the direct 3H labelling of pharmaceuticals by hydrogen isotope exchange, using tritium gas as the source of the radioisotope. The site selectivity of the iron catalyst is orthogonal to currently used iridium catalysts and allows isotopic labelling of complementary positions in drug molecules, providing a new diagnostic tool in drug development.

Iron-catalysed tritiation of pharmaceuticals

The world is shifting to electric vehicles to mitigate climate change. Here, we quantify the future demand for key battery materials, considering potential electric vehicle fleet and battery chemistry developments as well as second-use and recycling of electric vehicle batteries. We find that in a lithium nickel cobalt manganese oxide dominated battery scenario, demand is estimated to increase by factors of 18–20 for lithium, 17–19 for cobalt, 28–31 for nickel, and 15–20 for most other materials from 2020 to 2050, requiring a drastic expansion of lithium, cobalt, and nickel supply chains and likely additional resource discovery. However, uncertainties are large. Key factors are the development of the electric vehicles fleet and battery capacity requirements per vehicle. If other battery chemistries were used at large scale, e.g. lithium iron phosphate or novel lithium-sulphur or lithium-air batteries, the demand for cobalt and nickel would be substantially smaller. Closed-loop recycling plays a minor, but increasingly important role for reducing primary material demand until 2050, however, advances in recycling are necessary to economically recover battery-grade materials from end-of-life batteries. Second-use of electric vehicles batteries further delays recycling potentials.

/pdf/future-material-demand-for-automotive-lithium-based-4ykqkg9bvy.pdf

Future material demand for automotive lithium-based batteries

Thermal radiation between parallel objects separated by deep subwavelength distances and subject to large thermal gradients (>100 K) can reach very high magnitudes, while being concentrated on a narrow frequency distribution. These unique characteristics could enable breakthrough technologies for thermal transport control and electricity generation (for example, by radiating heat exactly at the bandgap frequency of a photovoltaic cell). However, thermal transport in this regime has never been achieved experimentally due to the difficulty of maintaining large thermal gradients over nanometre-scale distances while avoiding other heat transfer mechanisms, namely conduction. Here, we show near-field radiative heat transfer between parallel SiC nanobeams in the deep subwavelength regime. The distance between the beams is controlled by a high-precision micro-electromechanical system (MEMS). We exploit the mechanical stability of nanobeams under high tensile stress to minimize thermal buckling effects, therefore keeping control of the nanometre-scale separation even at large thermal gradients. We achieve an enhancement of heat transfer of almost two orders of magnitude with respect to the far-field limit (corresponding to a 42 nm separation) and show that we can maintain a temperature gradient of 260 K between the cold and hot surfaces at ∼100 nm distance.

Near-field radiative heat transfer between parallel structures in the deep subwavelength regime

Metastatic cancer is a systemic disease, and metastasis determinants might elicit completely different effects in various target organs. Here we show that tumour-secreted DKK1 is a serological marker of breast cancer metastasis organotropism and inhibits lung metastasis. DKK1 suppresses PTGS2-induced macrophage and neutrophil recruitment in lung metastases by antagonizing cancer cell non-canonical WNT/PCP-RAC1-JNK signalling. In the lungs, DKK1 also inhibits WNT/Ca2+-CaMKII-NF-κB signalling and suppresses LTBP1-mediated TGF-β secretion of cancer cells. In contrast, DKK1 promotes breast-to-bone metastasis by regulating canonical WNT signalling of osteoblasts. Importantly, targeting canonical WNT may not be beneficial to treatment of metastatic cancer, while combinatory therapy against JNK and TGF-β signalling effectively prevents metastasis to both the lungs and bone. Thus, DKK1 represents a class of Janus-faced molecules with dichotomous roles in organotropic metastasis, and our data provide a rationale for new anti-metastasis approaches.

Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1

▪ 関節リウマチ（RA）の骨破壊が発症後2 年以内に進行することが報告されて以降，windowof opportunity（治療効果が高いと考えられている発症早期の限られた期間）を意識した治療管理が提唱されてきた．▪ 米国リウマチ学会（ACR）は2008 年の推奨で病歴6 ヵ月未満のRA を早期RA と定義し，生物学的製剤を含む積極的な管理を提案した．▪ 2010 年にはRA の分類基準が改定され，治療開始の基準が治療者の間で共有された．RA を目標達成に向けて治療するという指針，treat to target （T2T）が提唱され，以降国際的な基本方針になった．

大岩寛

Papers

早期関節リウマチ：brief overview

大岩 寛

Papers

早期関節リウマチ：brief overview

大岩寛