Assembling kidney tissues from cells: the long road from organoids to organs

The field of regenerative medicine has witnessed significant advances that can pave the way to creating de novo organs. Organoids of brain, heart, intestine, liver, lung and also kidney have been developed by directed differentiation of pluripotent stem cells. While the success in producing tissue-specific units and organoids has been remarkable, the maintenance of an aggregation of such units in vitro is still a major challenge. While cell cultures are maintained by diffusion of oxygen and nutrients, three- dimensional in vitro organoids are generally limited in lifespan, size, and maturation due to the lack of a vascular system. Several groups have attempted to improve vascularization of organoids. Upon transplantation into a host, ramification of blood supply of host origin was observed within these organoids. Moreover, sustained circulation allows cells of an in vitro established renal organoid to mature and gain functionality in terms of absorption, secretion and filtration. Thus, the coordination of tissue differentiation and vascularization within developing organoids is an impending necessity to ensure survival, maturation, and functionality in vitro and tissue integration in vivo. In this review, we inquire how the foundation of circulation is laid down during the course of organogenesis, with special focus on the kidney. We will discuss whether nature offers a clue to assist the generation of a nephro-vascular unit that can attain functionality even prior to receiving external blood supply from a host. We revisit the steps that have been taken to induce nephrons and provide vascularity in lab grown tissues. We also discuss the possibilities offered by advancements in the field of vascular biology and developmental nephrology in order to achieve the long-term goal of producing transplantable kidneys in vitro

Was ist gesichert in der Therapie der chronischen Nierenerkrankung? [What is confirmed in the treatment of chronic kidney disease?]

Chronic kidney disease (CKD) is defined as a relevant excretion of albumin into the urine or a reduction of the glomerular filtration rate (GFR) over a longer time period of ≥ 3 months. The causes of CKD are manifold, whereby the association with diabetes mellitus is the most frequent cause. Early stages of CKD affect approximately 10% of the total population. The frequency of cardiovascular events, the risk of dependency on dialysis and the all-cause mortality increase exponentially with a decrease in the GFR and an increase in albuminuria. The guidelines of the German College of General Practitioners and Family Physicians (DEGAM) and the organization Kidney Disease: Improving Global Outcomes (KDIGO) recommend referral to a nephrologist with a GFR of ≤ 30 or ≤ 60 ml/min/1.73 m(2) in the presence of various cofactors. This means that the majority of CKD patients are treated by general internists or general practitioners. This article gives a concise summary of current data on the treatment of CKD and its associated complications in clinical practice. It refers to the current guidelines and also new study results which could perspectively expand the therapeutic repertoire

Controlling fast transport of cold trapped ions

We realize fast transport of ions in a segmented micro-structured Paul trap. The ion is shuttled over a distance of more than 10^4 times its groundstate wavefunction size during only 5 motional cycles of the trap (280 micro meter in 3.6 micro seconds). Starting from a ground-state-cooled ion, we find an optimized transport such that the energy increase is as low as 0.10 $\pm$ 0.01 motional quanta. In addition, we demonstrate that quantum information stored in a spin-motion entangled state is preserved throughout the transport. Shuttling operations are concatenated, as a proof-of-principle for the shuttling-based architecture to scalable ion trap quantum computing.Comment: 5 pages, 4 figure

A tunable high-pass filter for simple and inexpensive size-segregation of sub-10-nm nanoparticles

© The Author(s) 2017. Recent advanced in the fields of nanotechnology and atmospheric sciences underline the increasing need for sizing sub-10-nm aerosol particles in a simple yet efficient way. In this article, we develop, experimentally test and model the performance of a High-Pass Electrical Mobility Filter (HP-EMF) that can be used for sizing nanoparticles suspended in gaseous media. Experimental measurements of the penetration of nanoparticles having diameters down to ca 1nm through the HP-EMF are compared with predictions by an analytic, a semi-empirical and a numerical model. The results show that the HPEMF effectively filters nanoparticles below a threshold diameter with an extremely high level of sizing performance, while it is easier to use compared to existing nanoparticle sizing techniques through design simplifications. What is more, the HP-EMF is an inexpensive and compact tool, making it an enabling technology for a variety of applications ranging from nanomaterial synthesis to distributed monitoring of atmospheric nanoparticles

Structural basis of gene regulation by the Grainyhead/CP2 transcription factor family

Grainyhead (Grh)/CP2 transcription factors are highly conserved in multicellular organisms as key regulators of epithelial differentiation, organ development and skin barrier formation. In addition, they have been implicated as being tumor suppressors in a variety of human cancers. Despite their physiological importance, little is known about their structure and DNA binding mode. Here, we report the first structural study of mammalian Grh/CP2 factors. Crystal structures of the DNA-binding domains of grainyhead-like (Grhl) 1 and Grhl2 reveal a closely similar conformation with immunoglobulin-like core. Both share a common fold with the tumor suppressor p53, but differ in important structural features. The Grhl1 DNA-binding domain binds duplex DNA containing the consensus recognition element in a dimeric arrangement, supporting parsimonious target-sequence selection through two conserved arginine residues. We elucidate the molecular basis of a cancer-related mutation in Grhl1 involving one of these arginines, which completely abrogates DNA binding in biochemical assays and transcriptional activation of a reporter gene in a human cell line. Thus, our studies establish the structural basis of DNA target-site recognition by Grh transcription factors and reveal how tumor-associated mutations inactivate Grhl proteins. They may serve as points of departure for the structure-based development of Grh/CP2 inhibitors for therapeutic applications

Improved bone defect healing by a superagonistic GDF5 variant derived from a patient with multiple synostoses syndrome

Multiple synostoses syndrome 2 (SYNS2) is a rare genetic disease characterized by multiple fusions of the joints of the extremities, like phalangeal joints, carpal and tarsal joints or the knee and elbows. SYNS2 is caused by point mutations in the Growth and Differentiation Factor 5 (GDF5), which plays an essential role during skeletal development and regeneration. We selected one of the SYNS2-causing GDF5 mutations, p.N445T, which is known to destabilize the interaction with the Bone Morphogenetic Protein (BMP) antagonist NOGGIN (NOG), in order to generate the superagonistic GDF5 variant GDF5(N445T). In this study, we tested its capacity to support regeneration in a rat critical-sized defect model in vivo. MicroCT and histological analyses indicate that GDF5(N445T)-treated defects show faster and more efficient healing compared to GDF5 wild type (GDF5(wt))-treated defects. Microarray-based gene expression and quantitative PCR analyses from callus tissue point to a specific acceleration of the early phases of bone healing, comprising the inflammation and chondrogenesis phase. These results support the concept that disease-deduced growth factor variants are promising lead structures for novel therapeutics with improved clinical activities

The rp-process and new measurements of beta-delayed proton decay of light Ag and Cd isotopes

Recent network calculations suggest that a high temperature rp-process could explain the abundances of light Mo and Ru isotopes, which have long challenged models of p-process nuclide production. Important ingredients to network calculations involving unstable nuclei near and at the proton drip line are $\beta$-halflives and decay modes, i.e., whether or not $\beta$-delayed proton decay takes place. Of particular importance to these network calculation are the proton-rich isotopes $^{96}$Ag, $^{98}$Ag, $^{96}$Cd and $^{98}$Cd. We report on recent measurements of $\beta$-delayed proton branching ratios for $^{96}$Ag, $^{98}$Ag, and $^{98}$Cd at the on-line mass separator at GSI.Comment: 4 pages, uses espcrc1.sty. Proceedings of the 4th International Symposium Nuclei in the Cosmos, June 1996, Notre Dame/IN, USA, Ed. M. Wiescher, to be published in Nucl.Phys.A. Also available at ftp://ftp.physics.ohio-state.edu/pub/nucex/nic96-gs

Target structure independent 7Li⃗^7\vec{Li} elastic scattering at low momentum transfers

Analyzing powers and cross sections for the elastic scattering of polarized 7Li by targets of 6Li, 7Li and 12C are shown to depend only on the properties of the projectile for momentum transfers of less than 1.0 fm-1. The result of a detailed analysis of the experimental data within the framework of the coupled channels model with ground state reorientation and transitions to the excited states of the projectile and targets included in the coupling schemes are presented. This work suggests that nuclear properties of weakly-bound nuclei can be tested by elastic scattering experiments, independent of the target used, if data are acquired for momentum transfers less than ~1.0 fm-1.Comment: 9 pages, 4 figures, 1 table, accepted in Phys. Lett.

Immediate tumor resection in patients with locally advanced gastroesophageal adenocarcinoma with nonresponse to chemotherapy after 4 weeks of treatment versus resection after completion of chemotherapy (OPTITREAT trial, DRKS00004668): study protocol for a randomized controlled pilot trial

Background: Neoadjuvant chemotherapy is a standard of care for patients with adenocarcinoma of the esophagus and stomach in Europe, but still only 20–40 % respond to therapy and the critical issue; how to treat nonresponding patients is still unclear. So far, there is no randomized trial evaluating the impact of early termination of neoadjuvant chemotherapy and immediate tumor resection in nonresponding patients with locally advanced gastroesophageal cancer on postoperative outcome. With this exploratory pilot trial, we want to get first estimates about the effect of discontinuation of chemotherapy with the aim to plan and conduct a further definitive trial. Methods/design: OPTITREAT is designed as a single-center, randomized controlled pilot trial with two parallel study groups. Four weeks after starting neoadjuvant chemotherapy in all patients, clinical response will be assessed by endoscopy and endosonographic ultrasound. Then, nonresponding patients (n = 84) will be randomized in a 1:1 ratio to intervention group with stopping chemotherapy and immediate tumor resection or control group with completion of chemotherapy before surgery. Outcome measures are overall survival, R0 resection rate, perioperative morbidity and mortality, histopathological response, and quality of life. Statistical analysis will be based on the intention-to-treat population. Due to the study design as an explorative pilot trial, no formal sample size calculation was performed. The planned total sample size of 120 patients is considered ethical and large enough to show the feasibility and safety of the concept. First data on differences between the study groups in the defined endpoints will also be generated. Discussion: Individualized therapy is of utmost interest in the treatment of locally advanced gastroesophageal adenocarcinoma as less than half of the patients show objective response to current chemotherapy regimens. The findings of the OPTITREAT trial will help to get first data about clinical response evaluation followed by immediate tumor resection in nonresponding patients after 4 weeks of neoadjuvant chemotherapy. Based on the results of this pilot study, a future confirmatory trial will be planned to prove efficacy and evaluate significance. Trial registration: German Clinical Trial Register number: DRKS0000466