ALBERT

Description: Mucopolysaccharidosis-I (MPS-I) is a lysosomal storage disease (LSD) caused by inactivating mutations of IDUA , encoding the glycosaminoglycan-degrading enzyme α-l-iduronidase. Although MPS-I is associated with skeletal abnormalities, the impact of IDUA deficiency on bone remodeling is poorly defined. Here we report that Idua -deficient mice progressively develop a high bone mass phenotype with pathological lysosomal storage in cells of the osteoblast lineage. Histomorphometric quantification identified shortening of bone-forming units and reduced osteoclast numbers per bone surface. This phenotype was not transferable into wild-type mice by bone marrow transplantation (BMT). In contrast, the high bone mass phenotype of Idua -deficient mice was prevented by BMT from wild-type donors. At the cellular level, BMT did not only normalize defects of Idua -deficient osteoblasts and osteocytes but additionally caused increased osteoclastogenesis. Based on clinical observations in an individual with MPS-I, previously subjected to BMT and enzyme replacement therapy (ERT), we treated Idua -deficient mice accordingly and found that combining both treatments normalized all histomorphometric parameters of bone remodeling. Our results demonstrate that BMT and ERT profoundly affect skeletal remodeling of Idua -deficient mice, thereby suggesting that individuals with MPS-I should be monitored for their bone remodeling status, before and after treatment, to avoid long-term skeletal complications.

Description: Two of the five unlinked genes theoretically capable of encoding 5-phosphoribosyl-1(α)-pyrophosphate (PRPP) synthetase (Prs) in Saccharomyces cerevisiae , PRS1 and PRS5 , contain in-frame insertions which separate the cation- and PRPP-binding sites, diagnostic of Prs polypeptides. The impairment of cell wall integrity (CWI) mitogen-activated protein kinase (MAPK) cascade in strains lacking PRS1 and the synthetic lethality associated with loss of PRS1 and PRS5 imply that these insertions are not gratuitous. Coimmunoprecipitation revealed that Prs1 interacts with the CWI MAPK pathway, only when Slt2 has been phosphorylated by Mkk1/2. Three serine residues identified by phosphoproteome analysis (Ficarro et al . 2002 ) are located in one of the insertions of PRS5 thereby defining Prs5 as one of the 11 triply phosphorylated proteins in yeast. Mutation of these phosphosites compromised the transcriptional readout of one endpoint of the CWI pathway, Rlm1, as well as the expression of the gene encoding the stress-activated 1,3 β-glucan synthase, Fks2, regulated by a second endpoint of the CWI pathway, Swi4/Swi6 (SBF transcription factor). Therefore, the unexpected impairment of the CWI phenotype encountered in yeast strains either mutated or deleted for PRS1 or PRS5 can be explained by disruption of the communication between primary cell metabolism and CWI signalling.

Description: In this work, we show that the standard method to obtain nucleation rate-predictions with the aid of atomistic Monte Carlo simulations leads to nucleation rate predictions that deviate 3 − 5 orders of magnitude from the recent brute-force molecular dynamics simulations [Diemand et al. , J. Chem. Phys. 139 , 074309 (2013)] conducted in the experimental accessible supersaturation regime for Lennard-Jones argon. We argue that this is due to the truncated state space the literature mostly relies on, where the number of atoms in a nucleus is considered the only relevant order parameter. We here formulate the nonequilibrium statistical mechanics of nucleation in an extended state space, where the internal energy and momentum of the nuclei are additionally incorporated. We show that the extended model explains the lack in agreement between the molecular dynamics simulations by Diemand et al. and the truncated state space. We demonstrate additional benefits of using the extended state space; in particular, the definition of a nucleus temperature arises very naturally and can be shown without further approximation to obey the fluctuation law of McGraw and LaViolette. In addition, we illustrate that our theory conveniently allows to extend existing theories to richer sets of order parameters.

Description: Nature Physics 11, 162 (2015). doi:10.1038/nphys3171 Authors: M. Aidelsburger, M. Lohse, C. Schweizer, M. Atala, J. T. Barreiro, S. Nascimbène, N. R. Cooper, I. Bloch & N. Goldman Sixty years ago, Karplus and Luttinger pointed out that quantum particles moving on a lattice could acquire an anomalous transverse velocity in response to a force, providing an explanation for the unusual Hall effect in ferromagnetic metals. A striking manifestation of this transverse transport was then revealed in the quantum Hall effect where the plateaux depicted by the Hall conductivity were attributed to a topological invariant characterizing the Bloch bands: the Chern number. Until now, topological transport associated with non-zero Chern numbers has only been observed in electronic systems. Here we use the transverse deflection of an atomic cloud in response to an optical gradient to measure the Chern number of artificially generated Hofstadter bands. These topological bands are very flat and thus constitute good candidates for the realization of fractional Chern insulators. Combining these deflection measurements with the determination of the band populations, we obtain an experimental value for the Chern number of the lowest band νexp = 0.99(5). This first Chern-number measurement in a non-electronic system is facilitated by an all-optical artificial gauge field scheme, generating uniform flux in optical superlattices.

Description: CLN7 disease is an autosomal recessive, childhood-onset neurodegenerative lysosomal storage disorder caused by the defective lysosomal membrane protein CLN7. We have disrupted the Cln7 / Mfsd8 gene in mice by targeted deletion of exon 2 generating a novel knockout (KO) mouse model for CLN7 disease, which recapitulates key features of human CLN7 disease pathology. Cln7 KO mice showed increased mortality and a neurological phenotype including hind limb clasping and myoclonus. Lysosomal dysfunction in the brain of mutant mice was shown by the storage of autofluorescent lipofuscin-like lipopigments, subunit c of mitochondrial ATP synthase and saposin D and increased expression of lysosomal cathepsins B, D and Z. By immunohistochemical co-stainings, increased cathepsin Z expression restricted to Cln7-deficient microglia and neurons was found. Ultrastructural analyses revealed large storage bodies in Purkinje cells of Cln7 KO mice containing inclusions composed of irregular, curvilinear and rectilinear profiles as well as fingerprint profiles. Generalized astrogliosis and microgliosis in the brain preceded neurodegeneration in the olfactory bulb, cerebral cortex and cerebellum in Cln7 KO mice. Increased levels of LC3-II and the presence of neuronal p62- and ubiquitin-positive protein aggregates suggested that impaired autophagy represents a major pathomechanism in the brain of Cln7 KO mice. The data suggest that loss of the putative lysosomal transporter Cln7 in the brain leads to lysosomal dysfunction, impaired constitutive autophagy and neurodegeneration late in disease.

Description: 〈span〉〈div〉Abstract〈/div〉The high morphological variability observed in the genus 〈span〉Ammonia〈/span〉, together with its global distribution, led to the description of a plethora of species, subspecies, and varieties. Until now, many researchers used a limited number of (morpho-)species, and considered the numerous varieties as ecophenotypes. Recently, molecular studies show that these putative ecophenotypes are, in reality, well-separated genetically and should rather be considered as separate species. This study aims to investigate the morphological characteristics of three phylotypes (T1, T2, and T6) belonging to the genus 〈span〉Ammonia〈/span〉, encountered along European coasts. For this purpose, 〈span〉Ammonia〈/span〉 specimens were sampled at 22 locations between 2014 and 2016 and were imaged using an environmental SEM (Scanning Electron Microscope). For 96 specimens, images of the spiral, umbilical, and peripheral sides were obtained and pore features were investigated using 1000x magnified images of the penultimate chamber on the spiral side. Sixty-one morphometric parameters were measured for each individual. To assign specimens to their respective phylotypes, we employed molecular analyses using SSU (Small Sub-Unit) rDNA fragments. A multivariate approach (Factorial Analysis of Mixed Data, FAMD), allowing the joint analysis of quantitative and qualitative measurements, was used to determine the most reliable morphometric parameters to discriminate the three phylotypes. Our results show that the use of only two morphological characteristics is sufficient to differentiate the three pseudocryptic species: the raised or flush character of the sutures on the central part of the spiral side and the mean pore diameter. These two criteria, which can be observed with a standard stereomicroscope, provide an efficient method to discriminate T1, T2, and T6 with at least 90% accuracy. We consider that there is still insufficient information to reliably assign previously defined formal scientific names to the three phylotypes, and therefore we recommend the continued use of phylotype designations T1, T2, and T6. Our results make it possible to study the distribution of these three pseudocryptic species (T1, T2, and T6) on the basis of stereomicroscope examination alone, which means these species can also be more easily recognized in dead/fossil assemblages. Among other things, this will allow verification in sediment cores of the putative recent introduction in European coastal areas of T6, which is often considered an exotic species originating from East Asia.〈/span〉

Description: Author(s): C. Schweizer, M. Lohse, R. Citro, and I. Bloch A spin pump is experimentally demonstrated using ultracold boson atoms in an optical superlattice. [Phys. Rev. Lett. 117, 170405] Published Fri Oct 21, 2016

Description: To understand the functional meaning of morphological features, we need to relate what we know about morphology and ecology in a meaningful, quantitative framework. Closely related species usually share more phenotypic features than distant ones, but close relatives do not necessarily have the same ecologies. Rodents are the most diverse group of living mammals, with impressive ecomorphological diversification. We used museum collections and ecological literature to gather data on morphology, diet and locomotion for 208 species of rodents from different bioregions to investigate how morphological similarity and phylogenetic relatedness are associated with ecology. After considering differences in body size and shared evolutionary history, we find that unrelated species with similar ecologies can be characterized by a well-defined suite of morphological features. Our results validate the hypothesized ecological relevance of the chosen traits. These cranial, dental and external (e.g. ears) characters predicted diet and locomotion and showed consistent differences among species with different feeding and substrate use strategies. We conclude that when ecological characters do not show strong phylogenetic patterns, we cannot simply assume that close relatives are ecologically similar. Museum specimens are valuable records of species' phenotypes and with the characters proposed here, morphology can reflect functional similarity, an important component of community ecology and macroevolution.