Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal gamma subunit

Escobar syndrome is a form of arthrogryposis multiplex congenita and features joint contractures, pterygia, and respiratory distress. Similar findings occur in newborns exposed to nicotinergic acetylcholine receptor (AChR) antibodies from myasthenic mothers. We performed linkage studies in families with Escobar syndrome and identified eight mutations within the gamma -subunit gene (CHRNG) of the AChR. Our functional studies show that gamma -subunit mutations prevent the correct localization of the fetal AChR in human embryonic kidney-cell membranes and that the expression pattern in prenatal mice corresponds to the human clinical phenotype. AChRs have five subunits. Two alpha, one beta, and one delta subunit are always present. By switching gamma to epsilon subunits in late fetal development, fetal AChRs are gradually replaced by adult AChRs. Fetal and adult AChRs are essential for neuromuscular signal transduction. In addition, the fetal AChRs seem to be the guide for the primary encounter of axon and muscle. Because of this important function in organogenesis, human mutations in the gamma subunit were thought to be lethal, as they are in gamma -knockout mice. In contrast, many mutations in other subunits have been found to be viable but cause postnatally persisting or beginning myasthenic syndromes. We conclude that Escobar syndrome is an inherited fetal myasthenic disease that also affects neuromuscular organogenesis. Because gamma expression is restricted to early development, patients have no myasthenic symptoms later in life. This is the major difference from mutations in the other AChR subunits and the striking parallel to the symptoms found in neonates with arthrogryposis when maternal AChR auto-antibodies crossed the placenta and caused the transient inactivation of the AChR pathway.     

Differential pH-dependent cellular uptake pathways among foamy viruses elucidated using dual-colored fluorescent particles

ABSTRACT: BACKGROUND: It is thought that foamy viruses (FVs) enter host cells via endocytosis because all FV glycoproteins examined display pH-dependent fusion activities. Only the prototype FV (PFV) glycoprotein has also significant fusion activity at neutral pH, suggesting that its uptake mechanism may deviate from other FVs. To gain new insights into the uptake processes of FV in individual live host cells, we developed fluorescently labeled infectious FVs. RESULTS: N-terminal tagging of the FV envelope leader peptide domain with a fluorescent protein resulted in efficient incorporation of the fluorescently labeled glycoprotein into secreted virions without interfering with their infectivity. Double-tagged viruses consisting of an eGFP-tagged PFV capsid (Gag-eGFP) and mCherry-tagged Env (Ch-Env) from either PFV or macaque simian FV (SFVmac) were observed during early stages of the infection pathway. PFV Env, but not SFVmac Env, containing particles induced strong syncytia formation on target cells. Both virus types showed trafficking of double-tagged virions towards the cell center. Upon fusion and subsequent capsid release into the cytosol, accumulation of naked capsid proteins was observed within four hours in the perinuclear region, presumably representing the centrosomes. Interestingly, virions harboring fusion-defective glycoproteins still promoted virus attachment and uptake, but failed to show syncytia formation and perinuclear capsid accumulation. Non-fused or non-fusogenic viruses are rapidly cleared from the cells by putative lysosomal degradation. Monitoring the fraction of viruses containing both Env and capsid signals as a function of time demonstrated that PFV virions fused within the first few minutes, whereas fusion of SFVmac virions was less pronounced and observed over the entire 90 minutes measured. CONCLUSIONS: The characterized double-labeled FVs described here provide new mechanistic insights into FV early entry steps, demonstrating that productive viral fusion occurs early after target cell attachment and uptake. The analysis highlights apparent differences in the uptake pathways of individual FV species. Furthermore, the infectious double-labeled FVs promise to provide important tools for future detailed analyses on individual FV fusion events in real time using advanced imaging techniques.     

Spatial Hyperschematia without Spatial Neglect after Insulo-Thalamic Disconnection

Different spatial representations are not stored as a single multipurpose map in the brain. Right brain-damaged patients can show a distortion, a compression of peripersonal and extrapersonal space. Here we report the case of a patient with a right insulo-thalamic disconnection without spatial neglect. The patient, compared with 10 healthy control subjects, showed a constant and reliable increase of her peripersonal and extrapersonal egocentric space representations - that we named spatial hyperschematia - yet left her allocentric space representations intact. This striking dissociation shows that our interactions with the surrounding world are represented and processed modularly in the human brain, depending on their frame of reference.     

Fever and inflammatory cytokine response in rats injected subcutaneously with viral double-stranded RNA analog, polyinosinic:polycytidylic acid (Poly-I:C)

The objective of this study was to determine whether viral double-stranded RNA analog, polyinosinic:polycytidylic acid (Poly-I:C), is pyrogenic in rats when administered subcutaneously, thus determining whether rats can serve as an experimental model to investigate the regulation of local and systemic inflammatory responses to a Toll-like receptor(TLR)-3 agonist. Rats implanted intraperitoneally with temperature-sensitive radiotelemeters were injected subcutaneously in the skin of the tail with saline, 100 μg kg⁻¹ Poly-I:C, or 1000 μg kg⁻¹ Poly-I:C. In a separate group of rats blood and tail-skin samples were taken 3 and 24 h after injections to assess changes in local and systemic inflammatory cytokine release. Injection of 1000 μg kg⁻¹ Poly-I:C induced an acute fever, which lasted for approximately seven hours. The fever was associated with elevated local tissue concentrations of interleukin(IL)-1β, IL-6, and cytokine-induced neutrophil chemoattractant (CINC)-1, and elevated plasma concentration of CINC-1. Cytokine concentrations had returned to background concentrations by 24 h after the injection. Injection of 100 μg kg⁻¹ Poly-I:C failed to induce fever, but did induce significant increases in the local tissue, but not circulating, concentration of CINC-1 within 3 h of the injection. Tissue CINC-1 concentrations had returned to background concentrations by 24 h after the injection. In conclusion, when administered at great enough concentrations, subcutaneously injected Poly-I:C is pyretic in rats, and the pyresis is associated with elevated concentrations of local and systemic inflammatory mediators. Thus the rat can be used to study signaling pathways induced by localized, subcutaneous administration of this TLR-3 agonist that mimics viral infection.     

IDH1-Associated Primary Glioblastoma in Young Adults Displays Differential Patterns of Tumour and Vascular Morphology

Glioblastoma is a highly aggressive tumour with marked heterogeneity at the morphological level in both the tumour cells and the associated highly prominent vasculature. As we begin to develop an increased biological insight into the underlying processes driving the disease, fewer attempts have thus far been made to understand these phenotypic differences. We sought to address this by carefully assessing the morphological characteristics of both the tumour cells and the associated vasculature, relating these observations to the IDH1/MGMT status, with a particular focus on the early onset population of young adults who develop primary glioblastoma. 276 primary glioblastoma specimens were classified into their predominant cell morphological type (fibrillary, gemistocytic, giant cell, small cell, oligodendroglial, sarcomatous), and assessed for specific tumour (cellularity, necrosis, palisades) and vascular features (glomeruloid structures, arcades, pericyte proliferation). IDH1 positive glioblastomas were associated with a younger age at diagnosis, better clinical outcome, prominent oligodendroglial and small cell tumour cell morphology, pallisading necrosis and glomeruloid vascular proliferation in the absence of arcade-like structures. These features widen the phenotype of IDH1 mutation-positive primary glioblastoma in young adults and provide correlative evidence for a functional role of mutant IDH1 in the differential nature of neo-angiogenesis in different subtypes of glioblastoma.     

Social Influence and the Collective Dynamics of Opinion Formation

Social influence is the process by which individuals adapt their opinion, revise their beliefs, or change their behavior as a result of social interactions with other people. In our strongly interconnected society, social influence plays a prominent role in many self-organized phenomena such as herding in cultural markets, the spread of ideas and innovations, and the amplification of fears during epidemics. Yet, the mechanisms of opinion formation remain poorly understood, and existing physics-based models lack systematic empirical validation. Here, we report two controlled experiments showing how participants answering factual questions revise their initial judgments after being exposed to the opinion and confidence level of others. Based on the observation of 59 experimental subjects exposed to peer-opinion for 15 different items, we draw an influence map that describes the strength of peer influence during interactions. A simple process model derived from our observations demonstrates how opinions in a group of interacting people can converge or split over repeated interactions. In particular, we identify two major attractors of opinion: (i) the expert effect, induced by the presence of a highly confident individual in the group, and (ii) the majority effect, caused by the presence of a critical mass of laypeople sharing similar opinions. Additional simulations reveal the existence of a tipping point at which one attractor will dominate over the other, driving collective opinion in a given direction. These findings have implications for understanding the mechanisms of public opinion formation and managing conflicting situations in which self-confident and better informed minorities challenge the views of a large uninformed majority.     

Bayesian outbreak detection algorithm for monitoring reported cases of campylobacteriosis in Germany

In infectious disease epidemiology, statistical methods are an indispensable component for the automated detection of outbreaks in routinely collected surveillance data. So far, methodology in this area has been largely of frequentist nature and has increasingly been taking inspiration from statistical process control. The present work is concerned with strengthening Bayesian thinking in this field. We extend the widely used approach of Farrington et al. and Heisterkamp et al. to a modern Bayesian framework within a time series decomposition context. This approach facilitates a direct calculation of the decision‐making threshold while taking all sources of uncertainty in both prediction and estimation into account. More importantly, with the methodology it is now also possible to integrate covariate processes, e.g. weather influence, into the outbreak detection. Model inference is performed using fast and efficient integrated nested Laplace approximations, enabling the use of this method in routine surveillance at public health institutions. Performance of the algorithm was investigated by comparing simulations with existing methods as well as by analysing the time series of notified campylobacteriosis cases in Germany for the years 2002–2011, which include absolute humidity as a covariate process. Altogether, a flexible and modern surveillance algorithm is presented with an implementation available through the R package ‘surveillance’.     

The many faces of Peridinium cinctum (Peridiniaceae,Peridiniales): morphological and molecular variability in a common dinophyte

Peridinium cinctum is a common freshwater dinophyte with a long history of research. Erich Lindemann was the first to assess intraspecific variability in this species focusing on plate pattern variation. Since then, this issue has been neglected but with the application of DNA sequence diagnostics, a combination of morphological and molecular characters may enable taxonomic delimitations. Our aim was to identify distinct morphotypes using plate pattern as the main characteristic and then compare them to the geographic occurrence of particular ribotypes (as inferred from sequences of the Internal Transcribed Spacer: ITS) in samples from Central Europe. Approximately 200 observations were carried out under the inverse light microscope for each of a total of 15 strains. We observed two main variations from the abundant plate pattern in P. cinctum, namely an unusual position of the 2a plate and the irregular shape of the 1a plate. In 88 (predominantly clonal) strains, we identified five different ribotypes (submitted as 71 new GenBank entries) which had no clear correlation to the defined morphotypes and/or spatial occurrences. In four cases, we detected two distinct ribotypes at the same locality. However, samples collected south of the Danube River presented a different predominant morphotype from the rest of the samples, thus implying a potential biogeographic signal as inferred from morphology. In general, there is morphological and molecular variability in P. cinctum, which is under-studied and which may uncover geographic or ecological correlations or even the existence of cryptic species.     

Synthesis of tricyclic vinylcyclobutanes and their application in photoinduced electron transfer chemistry.

The synthesis of new tricyclic vinylcyclobutanes is reported. These compounds were prepared in good yields from the ketones via a two step Peterson olefination. Under conditions of photoinduced electron transfer some tricyclic vinylcyclobutanes show interesting skeleton rearrangements.     

A Convenient Trip: an Analysis of the Impact of Hitchhiker Ants on Forager Transport Rates

During foraging, leaf-cutting ant workers of different size classes perform various tasks along foraging trails. Commonly, small workers called hitchhikers climb on leaf fragments imposing an extra transport cost, so their presence is thought to reduce the individual foraging performance. There are four main hypotheses which may explain the occurrence of hitchhikers and a different behavioral act related to their role can be predicted for each. Hitchhiker behavior was observed considering these hypotheses and the effect of the hitchhikers on the walking speed and transport rate of foragers was evaluated. The behavioral registers were obtained from 1371 hitchhikers on foraging trails of Acromyrmex subterraneus subterraneus nests in the field. To verify the influence of hitchhikers on walking speed and transport rate, 239 foragers with hitchhikers and 250 foragers transporting only leaf fragments were analyzed. The walking speed, burden and transport rate of each forager were calculated. Data indicated not only that hitchhikers are vigilant but that they remain motionless on the leaf fragment probably in order to reduce the impact of their presence for the loaded forager. The impact of their presence is verified through walking speed reduction but as they ride preferentially on larger workers who transport larger leaf fragments, there are no losses in the individual transport rate. The transporter selection made by the hitchhiker ensures at the same time enhanced protection against phorid parasitoids and the maintenance of the leaf transport rate.