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"Joachim, Hans"
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Subcellular targeting strategies for drug design and delivery
Key Points
Although great efforts have been made to address the bioavailability and tissue targeting of drugs, little is known about drug delivery to specific subcellular compartments that harbour the drug target. As cells constantly traffic their contents to these compartments, cell biology principles could be effectively used for drug targeting.
For a drug to reach particular subcellular compartments, the drug has to be modified to include the appropriate signal to target it to the subcellular site, without compromising its functional moiety.
Protein modifications or lipid conjugations that direct a drug to targets in the plasma membrane have been shown to increase drug efficacy. These modifications reduce the dimensionality of these otherwise soluble drugs, thereby leading to an increase in effective drug concentration.
Cells internalize various small molecules, nutrients and pathogens and sort them to specific intracellular compartments. Drug conjugation to either the nutrient moieties or part of the pathogens that carry the targeting signal are some of the strategies used to target specific organelles.
In addition to membrane-bound organelles, the cytosol could also be targeted by specific modifications. Cell-penetrating peptides from viruses, viral particles, bacterial toxins, liposomes and nanoparticles are various means to target the cytosol. Targeting the cytosol is also a method for reaching the nuclear compartment.
Specific targeting of drugs to subcellular compartments is still in the early stages of development but shows promise. Issues such as drug stability in intracellular compartments and tissue-specific targeting are still to be addressed.
Although considerable efforts have been made to deliver drugs to particular tissues, little is known about targeting drugs to specific cellular compartments. By examining the fundamental principles of membrane trafficking and subcellular organization, the authors outline strategies to increase drug concentrations specifically in the relevant subcellular locations.
Many drug targets are localized to particular subcellular compartments, yet current drug design strategies are focused on bioavailability and tissue targeting and rarely address drug delivery to specific intracellular compartments. Insights into how the cell traffics its constituents to these different cellular locations could improve drug design. In this Review, we explore the fundamentals of membrane trafficking and subcellular organization, as well as strategies used by pathogens to appropriate these mechanisms and the implications for drug design and delivery.
Journal Article
Lending to the borrower from hell : debt, taxes, and default in the age of Philip II
\"Why do lenders time and again loan money to sovereign borrowers who promptly go bankrupt? When can this type of lending work? As the United States and many European nations struggle with mountains of debt, historical precedents can offer valuable insights. Lending to the Borrower from Hell looks at one famous case--the debts and defaults of Philip II of Spain. Ruling over one of the largest and most powerful empires in history, King Philip defaulted four times. Yet he never lost access to capital markets and could borrow again within a year or two of each default. Exploring the shrewd reasoning of the lenders who continued to offer money, Mauricio Drelichman and Hans-Joachim Voth analyze the lessons from this important historical example.Using detailed new evidence collected from sixteenth-century archives, Drelichman and Voth examine the incentives and returns of lenders. They provide powerful evidence that in the right situations, lenders not only survive despite defaults--they thrive. Drelichman and Voth also demonstrate that debt markets cope well, despite massive fluctuations in expenditure and revenue, when lending functions like insurance. The authors unearth unique sixteenth-century loan contracts that offered highly effective risk sharing between the king and his lenders, with payment obligations reduced in bad times.A fascinating story of finance and empire, Lending to the Borrower from Hell offers an intelligent model for keeping economies safe in times of sovereign debt crises and defaults\"-- Provided by publisher.
Book
Glomerulonephritis: immunopathogenesis and immunotherapy
‘Glomerulonephritis’ (GN) is a term used to describe a group of heterogeneous immune-mediated disorders characterized by inflammation of the filtration units of the kidney (the glomeruli). These disorders are currently classified largely on the basis of histopathological lesion patterns, but these patterns do not align well with their diverse pathological mechanisms and hence do not inform optimal therapy. Instead, we propose grouping GN disorders into five categories according to their immunopathogenesis: infection-related GN, autoimmune GN, alloimmune GN, autoinflammatory GN and monoclonal gammopathy-related GN. This categorization can inform the appropriate treatment; for example, infection control for infection-related GN, suppression of adaptive immunity for autoimmune GN and alloimmune GN, inhibition of single cytokines or complement factors for autoinflammatory GN arising from inborn errors in innate immunity, and plasma cell clone-directed or B cell clone-directed therapy for monoclonal gammopathies. Here we present the immunopathogenesis of GN and immunotherapies in use and in development and discuss how an immunopathogenesis-based GN classification can focus research, and improve patient management and teaching.The authors propose a new grouping of glomerulonephritis disorders based on their underlying immunopathogenesis, with a view to improving diagnosis, mechanistic understanding and treatment of these immune-mediated kidney diseases.
Journal Article
Bowling for Fascism
Using newly collected data on association density in 229 towns and cities in interwar Germany, we show that denser social networks were associated with faster entry into the Nazi Party. The effect is large: one standard deviation higher association density is associated with at least 15 percent faster Nazi Party entry. Party membership, in turn, predicts electoral success. Social networks thus aided the rise of the Nazis that destroyed Germany’s first democracy. The effects of social capital depended on the political context: in federal states with more stable governments, higher association density was not correlated with faster Nazi Party entry.
Journal Article
Quasiresonant amplification of planetary waves and recent Northern Hemisphere weather extremes
In recent years, the Northern Hemisphere has suffered several devastating regional summer weather extremes, such as the European heat wave in 2003, the Russian heat wave and the Indus river flood in Pakistan in 2010, and the heat wave in the United States in 2011. Here, we propose a common mechanism for the generation of persistent longitudinal planetary-scale high-amplitude patterns of the atmospheric circulation in the Northern Hemisphere midlatitudes. Those patterns—with zonal wave numbers m = 6, 7, or 8—are characteristic of the above extremes. We show that these patterns might result from trapping within midlatitude waveguides of free synoptic waves with zonal wave numbers k ≈ m. Usually, the quasistationary dynamical response with the above wave numbers m to climatological mean thermal and orographic forcing is weak. Such midlatitude waveguides, however, may favor a strong magnification of that response through quasiresonance.
Journal Article
Lupus nephritis-related chronic kidney disease
Lupus nephritis is a common complication of systemic lupus erythematosus (SLE) and a determinant of overall morbidity and mortality, as lupus nephritis-related chronic kidney disease (CKD) drives cardiovascular disease and secondary immunodeficiency. Two lines of action are required to prevent the progression of lupus nephritis-related CKD: suppression of autoimmune SLE activity, which is a risk factor for immunopathology-related irreversible kidney injury, and management of non-immune risk factors that contribute to CKD progression. As each episode or relapse of active lupus nephritis implicates CKD progression, preventing flares of lupus nephritis is a key treatment target. Non-immune risk factors of CKD mostly include causes of nephron hyperfiltration, such as obesity, hypertension, sodium- or protein-rich diets and type 2 diabetes mellitus, as well as pregnancy. Nephrotoxic agents and smoking also drive kidney cell loss. Intrinsic risk factors for CKD progression include poor nephron endowment because of prematurity at birth, nephropathic genetic variants, ageing, male sex and previous or concomitant kidney diseases. Care for lupus nephritis involves the control of all modifiable risk factors of CKD progression. In addition, remnant nephron overload can be reduced using early dual therapy with inhibitors of the renin–angiotensin system and sodium–glucose transporter-2, whereas further renoprotective drug interventions are underway. As patients with lupus nephritis are at risk of CKD progression, they would all benefit from interdisciplinary care to minimize the risk of kidney failure, cardiovascular disease and infections.Each episode of lupus nephritis causes irreversible kidney injury, initiating and, subsequently, exacerbating chronic kidney disease. This Review discusses how interdisciplinary care that considers all immune and non-immune risk factors for chronic kidney disease progression can benefit patients with lupus nephritis.
Journal Article