Nbn is essential for hair follicle maintenance and prevention of psoriasis

The stability of our genome is constantly threatened by endogenous and exogenous processes causing errors in the DNA. Those have to be repaired as otherwise mutations can give rise to disease or tumor development. This is accomplished by various ways of DNA damage signaling and repair. One of the main proteins involved in the signaling and repair of DNA double strand breaks is Nbrin (NBN). A mutation of this protein is known to cause Nijmegen breakage syndrome (NBS) (Varon et al.,1998). Patients with NBS present with various clinical conditions e.g. microcephaly, immunodeficiency, radio sensitivity and a predisposition for tumor development (Varon et al.,1998; Cybulski et al.,2004; Assaf et al.,2008; Bogdanova et al.,2008; Huang et al.,2008; Watanabe et al.,2009). NBS patients show different skin malignancies as abnormal pigmentation, Porokeratosis and thin and sparse hair (van der Burgt et al.,1996; Group,2000; Wolf and Shwayder,2009; Chrzanowska et al.,2012). Mutations of NBN were discovered in malignant melanoma (Debniak et al.,2003; Thirumaran et al.,2006; Meyer et al.,2007). As the skin is our protection against environmental threats and undergoes a continuous self-renewal, the repair of DNA damages is crucial. The skin malignancies of NBS patients point toward an involvement of NBN in the DNA damage signaling and repair in the skin. A mouse model of Nbn deletion after birth in the epidermis and hair follicles was created to investigate Nbn function in the skin. The NbnKrox20-Cre mice exhibited a hair loss starting with the first wave of hair follicle growth (anagen phase) after birth. The hair loss was due to an increase of DNA damages and a failure in repair of those. Apoptosis rate was elevated and epidermal stem cell properties were disrupted. The hair follicles were not able to regenerate. Additionally, a thickening of the epidermis was detected in Nbn deleted mice with 3 months of age. Analyses revealed that the mice exhibited a psoriasis-like phenotype. An enlargement of the epidermis, invasion of immune cells, activation and expression changes of psoriasis typical markers were observed. Combined inactivation with p53 led to a worsening of the phenotype of the mice. Precancerous lesions were present. These findings show the importance of Nbn in skin and hair follicle homeostasis and in the prevention of skin cancer and psoriasis. The role of Atm (Ataxia telangiectasia mutated) in combination with Nbn in the skin was also investigated using a deletion mouse model. The influence of Atm on Nbn was found to depend on the cell type. In keratinocytes only a minor role of Atm was detected. However, Atm played an important role in hair follicle cells, where it was needed for the phosphorylation of Histone H2A.X. The role of Atm in combination with Nbn in proliferating tissue was shown by this. Loss of Nbn activity in mice leads to the loss of hair follicle stem cells which causes hair loss and an increased proliferation of the basal keratinocytes gives rise to a psoriasis-like phenotype

Moltemplate: A Tool for Coarse-Grained Modeling of Complex Biological Matter and Soft Condensed Matter Physics

Coarse-grained models have long been considered indispensable tools in the investigation of biomolecular dynamics and assembly. However, the process of simulating such models is arduous because unconventional force fields and particle attributes are often needed, and some systems are not in thermal equilibrium. Although modern molecular dynamics programs are highly adaptable, software designed for preparing all-atom simulations typically makes restrictive assumptions about the nature of the particles and the forces acting on them. Consequently, the use of coarse-grained models has remained challenging. Moltemplate is a file format for storing coarse-grained molecular models and the forces that act on them, as well as a program that converts moltemplate files into input files for LAMMPS, a popular molecular dynamics engine. Moltemplate has broad scope and an emphasis on generality. It accommodates new kinds of forces as they are developed for LAMMPS, making moltemplate a popular tool with thousands of users in computational chemistry, materials science, and structural biology. To demonstrate its wide functionality, we provide examples of using moltemplate to prepare simulations of fluids using many-body forces, coarse-grained organic semiconductors, and the motor-driven supercoiling and condensation of an entire bacterial chromosome

Teaching ethics and moral competence beyond education to the value and virtue

Grupa naukowców z Uniwersytetu Humboldta w Berlinie prezentuje zarys koncepcji i wstępne wyniki prac badawczych przeprowadzonych w ramach projektu opatrzonego skrótem ETiK. Empirycznemu sprawdzeniu poddano w nim efekty nauczania etyki na poziomie odpowiadającym polskiemu gimnazjum. Niemieccy badacze wychodząc z założenia, że celem publicznego nauczania etyki nie może być ani wdrażanie wartości, ani wychowanie do cnoty w sensie jej urabiania, skonstruowali model kompetencji moralnej, w którym główny nacisk pada na przekaz podstawowych wiadomości moralnych i rozwijanie władzy sądzenia i działania moralnego. Ta ostatnia oznacza przygotowanie uczniów do samodzielnego działania w życiu dorosłym przez wspieranie w nich refleksji nad czynami własnymi i innych ludzi, podejmowanie osobistych wyborów i projektowanie ich realizacji

Epidermal Nbn deletion causes premature hair loss and a phenotype resembling psoriasiform dermatitis

Nijmegen Breakage Syndrome is a disease caused by NBN mutations. Here, we report a novel function of Nbn in skin homeostasis. We found that Nbn deficiency in hair follicle (HF) progenitors promoted increased DNA damage signaling, stimulating p16Ink4a up-regulation, Trp53 stabilization and cytokines secretion leading to HF-growth arrest and hair loss. At later stages, the basal keratinocytes layer exhibited also enhanced DNA damage response but in contrast to the one in HF progenitor was not associated with pro-inflammatory cytokines expression, but rather increased proliferation, lack of differentiation and immune response resembling psoriasiform dermatitis. Simultaneous Nbn and Trp53 inactivation significantly exacerbated this phenotype, due to the lack of inhibition of pro-inflammatory cytokines secretion by Trp53. Altogether, we demonstrated novel functions of Nbn in HF maintenance and prevention of skin inflammation and we provide a mechanistic explanation that links cell intrinsic DNA maintenance with large scale morphological tissue alterations

Nbn and Atm Cooperate in a Tissue and Developmental Stage-Specific Manner to Prevent Double Strand Breaks and Apoptosis in Developing Brain and Eye

<div><p>Nibrin (NBN or NBS1) and ATM are key factors for DNA Double Strand Break (DSB) signaling and repair. Mutations in <i>NBN</i> or <i>ATM</i> result in Nijmegen Breakage Syndrome and Ataxia telangiectasia. These syndromes share common features such as radiosensitivity, neurological developmental defects and cancer predisposition. However, the functional synergy of Nbn and Atm in different tissues and developmental stages is not yet understood. Here, we show <i>in vivo</i> consequences of conditional inactivation of both genes in neural stem/progenitor cells using <i>Nestin-Cre</i> mice. Genetic inactivation of <i>Atm</i> in the central nervous system of Nbn-deficient mice led to reduced life span and increased DSBs, resulting in increased apoptosis during neural development. Surprisingly, the increase of DSBs and apoptosis was found only in few tissues including cerebellum, ganglionic eminences and lens. In sharp contrast, we showed that apoptosis associated with <i>Nbn</i> deletion was prevented by simultaneous inactivation of <i>Atm</i> in developing retina. Therefore, we propose that Nbn and Atm collaborate to prevent DSB accumulation and apoptosis during development in a tissue- and developmental stage-specific manner.</p></div

Inactivation of <i>Nbn</i> and <i>Atm</i> leads to precocious DSBs accumulation and apoptosis in embryonic lens.

<p>(<b>A</b>) BrdU immunohistochemistry of <i>Nbn^Ctrl</i>, <i>Nbn^Nes-Cre</i> and <i>Nbn/Atm</i>^Nes-Cre lens at E15.5 (Magnification ×200). (<b>B</b>) BrdU immunohistochemistry of <i>Nbn^Ctrl</i>, <i>Nbn^Nes-Cre</i> and <i>Nbn/Atm</i>^Nes-Cre lens at E17.5 (Magnification ×200). (<b>C</b>) Quantification of BrdU positive cells within lens anterior epithelia at E15.5 (<i>Nbn^Ctrl</i>, n = 3; <i>Nbn^Nes-Cre,</i> n = 3; and <i>Nbn/Atm^Nes-Cre</i>, n = 3) and E17.5 (<i>Nbn^Ctrl</i>, n = 7; <i>Nbn^Nes-Cre,</i> n = 6; and <i>Nbn/Atm^Nes-Cre</i>, n = 3). (<b>D</b>) γ-H2AX immunohistochemistry of <i>Nbn^Ctrl</i>, <i>Nbn^Nes-Cre</i> and <i>Nbn/Atm</i>^Nes-Cre lens at E15.5 (Magnification ×1000). (<b>E</b>) γ-H2AX immunohistochemistry of <i>Nbn^Ctrl</i>, <i>Nbn^Nes-Cre</i> and <i>Nbn/Atm</i>^Nes-Cre lens at E17.5 (Magnification ×1000). (<b>F</b>) Quantification of γ-H2AX positive cells within lens anterior epithelia at E15.5 (<i>Nbn^Ctrl</i>, n = 3; <i>Nbn^Nes-Cre,</i> n = 3 and <i>Nbn/Atm^Nes-Cre</i>, n = 5) and E17.5 (<i>Nbn^Ctrl</i>, n = 3; <i>Nbn^Nes-Cre,</i> n = 3 and <i>Nbn/Atm^Nes-Cre</i>, n = 3). (<b>G</b>) TUNEL staining of <i>Nbn^Ctrl</i>, <i>Nbn^Nes-Cre</i> and <i>Nbn/Atm</i>^Nes-Cre lens at E15.5 (Magnification ×400). (<b>H</b>) TUNEL immunohistochemistry of <i>Nbn^Ctrl</i>, <i>Nbn^Nes-Cre</i> and <i>Nbn/Atm</i>^Nes-Cre lens at E17.5 (Magnification ×400). (<b>I</b>) Quantification of TUNEL cells within lens anterior epithelia at E15.5 (<i>Nbn^Ctrl</i>, n = 20; <i>Nbn^Nes-Cre,</i> n = 2 and <i>Nbn/Atm^Nes-Cre</i>, n = 5) and E17.5 (<i>Nbn^Ctrl</i>, n = 7; <i>Nbn^Nes-Cre,</i> n = 3 and <i>Nbn/Atm^Nes-Cre</i>, n = 5). DSB accumulation and apoptotic cell death occurs earlier in Nbn/Atm-deficient lens as compared to Nbn-deficient lens. (<b>J</b>) Phospho-histone 3 (H3-P) immunohistochemistry of <i>Nbn^Ctrl</i>, <i>Nbn^Nes-Cre</i> and <i>Nbn/Atm</i>^Nes-Cre lens at E15.5 (Magnification ×400). (<b>K</b>) Phospho-histone 3 (H3-P) immunohistochemistry of <i>Nbn^Ctrl</i>, <i>Nbn^Nes-Cre</i> and <i>Nbn/Atm</i>^Nes-Cre lens at E17.5 (Magnification ×400). (<b>L</b>) Quantification of Phospho-histone 3 positive cells (H3-P+) cells within lens anterior epithelia at E15.5 (<i>Nbn^Ctrl</i>, n = 6; <i>Nbn^Nes-Cre,</i> n = 5 and <i>Nbn/Atm^Nes-Cre</i>, n = 2) and E17.5 (<i>Nbn^Ctrl</i>, n = 13; <i>Nbn^Nes-Cre,</i> n = 3 and <i>Nbn/Atm^Nes-Cre</i>, n = 5). Error bars indicate SEM. (* p<0,05, ** p<0,01, *** p<0,001, ns: non-significant).</p

Inactivation of <i>Nbn</i> and <i>Atm</i> leads to increase of DSBs and apoptosis in medial ganglionic eminence (MGE).

<p>(<b>A</b>) Accumulation of γ-H2AX foci in MGE of <i>Nbn^Nes-Cre</i> and <i>Nbn/Atm^Nes-Cre</i> brains at E15.5 (Magnification ×200). (<b>B</b>) Immunohistochemistry indicates stabilization of p53 protein in the E15.5 MGE following <i>Nbn</i> and <i>Atm</i> inactivation (Magnification ×200). (<b>C</b>) Increased apoptosis in the SVZ from E15.5 MGE indicated by cleaved caspase-3 positive cells. Cx: Cortex, MGE: Medial Ganglionic Eminence, VZ:Ventricular Zone, SVZ:Sub ventricular Zone (Magnification ×200).</p