The ErbB2ΔEx16 splice variant is a major oncogenic driver in breast cancer that promotes a pro-metastatic tumor microenvironment.

Amplification and overexpression of erbB2/neu proto-oncogene is observed in 20-30% human breast cancer and is inversely correlated with the survival of the patient. Despite this, somatic activating mutations within erbB2 in human breast cancers are rare. However, we have previously reported that a splice isoform of erbB2, containing an in-frame deletion of exon 16 (herein referred to as ErbB2ΔEx16), results in oncogenic activation of erbB2 because of constitutive dimerization of the ErbB2 receptor. Here, we demonstrate that the ErbB2ΔEx16 is a major oncogenic driver in breast cancer that constitutively signals from the cell surface. We further show that inducible expression of the ErbB2ΔEx16 variant in mammary gland of transgenic mice results in the rapid development of metastatic multifocal mammary tumors. Genetic and biochemical characterization of the ErbB2ΔEx16-derived mammary tumors exhibit several unique features that distinguish this model from the conventional ErbB2 ones expressing the erbB2 proto-oncogene in mammary epithelium. Unlike the wild-type ErbB2-derived tumors that express luminal keratins, ErbB2ΔEx16-derived tumors exhibit high degree of intratumoral heterogeneity co-expressing both basal and luminal keratins. Consistent with these distinct pathological features, the ErbB2ΔEx16 tumors exhibit distinct signaling and gene expression profiles that correlate with activation of number of key transcription factors implicated in breast cancer metastasis and cancer stem cell renewal

On the accuracy of language trees

Historical linguistics aims at inferring the most likely language phylogenetic tree starting from information concerning the evolutionary relatedness of languages. The available information are typically lists of homologous (lexical, phonological, syntactic) features or characters for many different languages. From this perspective the reconstruction of language trees is an example of inverse problems: starting from present, incomplete and often noisy, information, one aims at inferring the most likely past evolutionary history. A fundamental issue in inverse problems is the evaluation of the inference made. A standard way of dealing with this question is to generate data with artificial models in order to have full access to the evolutionary process one is going to infer. This procedure presents an intrinsic limitation: when dealing with real data sets, one typically does not know which model of evolution is the most suitable for them. A possible way out is to compare algorithmic inference with expert classifications. This is the point of view we take here by conducting a thorough survey of the accuracy of reconstruction methods as compared with the Ethnologue expert classifications. We focus in particular on state-of-the-art distance-based methods for phylogeny reconstruction using worldwide linguistic databases. In order to assess the accuracy of the inferred trees we introduce and characterize two generalizations of standard definitions of distances between trees. Based on these scores we quantify the relative performances of the distance-based algorithms considered. Further we quantify how the completeness and the coverage of the available databases affect the accuracy of the reconstruction. Finally we draw some conclusions about where the accuracy of the reconstructions in historical linguistics stands and about the leading directions to improve it.Comment: 36 pages, 14 figure

The Settlement of Madagascar: What Dialects and Languages Can Tell Us

The dialects of Madagascar belong to the Greater Barito East group of the Austronesian family and it is widely accepted that the Island was colonized by Indonesian sailors after a maritime trek that probably took place around 650 CE. The language most closely related to Malagasy dialects is Maanyan, but Malay is also strongly related especially for navigation terms. Since the Maanyan Dayaks live along the Barito river in Kalimantan (Borneo) and they do not possess the necessary skill for long maritime navigation, they were probably brought as subordinates by Malay sailors. In a recent paper we compared 23 different Malagasy dialects in order to determine the time and the landing area of the first colonization. In this research we use new data and new methods to confirm that the landing took place on the south-east coast of the Island. Furthermore, we are able to state here that colonization probably consisted of a single founding event rather than multiple settlements.To reach our goal we find out the internal kinship relations among all the 23 Malagasy dialects and we also find out the relations of the 23 dialects to Malay and Maanyan. The method used is an automated version of the lexicostatistic approach. The data from Madagascar were collected by the author at the beginning of 2010 and consist of Swadesh lists of 200 items for 23 dialects covering all areas of the Island. The lists for Maanyan and Malay were obtained from a published dataset integrated with the author's interviews

Triadin Knockout Syndrome Is Absent in a Multi-Center Molecular Autopsy Cohort of Sudden Infant Death Syndrome and Sudden Unexplained Death in the Young and Is Extremely Rare in the General Population

Background: Triadin knockout syndrome (TKOS) is a potentially lethal arrhythmia disorder caused by recessively inherited null variants in TRDN-encoded cardiac triadin. Despite its malignant phenotype, the prevalence of TKOS in sudden infant death syndrome and sudden unexplained death in the young is unknown. Methods: Exome sequencing was performed on 599 sudden infant death syndrome and 258 sudden unexplained death in the young cases. Allele frequencies of all TRDN null variants identified in the cardiac-specific isoform of TRDN in the Genome Aggregation Database were used to determine the estimated prevalence and ethnic distribution of TKOS. Results: No triadin null individuals were identified in 599 sudden infant death syndrome and 258 sudden unexplained death in the young exomes. Using the Genome Aggregation Database, we estimate the overall prevalence of TKOS to be ≈1:22.7 million individuals. However, TKOS prevalence is 5.5-fold higher in those of African descent (≈1:4.1 million). Conclusions: TKOS is an exceedingly rare clinical entity that does not contribute meaningfully to either sudden infant death syndrome or sudden unexplained death in the young. However, despite its rarity and absence in large sudden death cohorts, TKOS remains a malignant and potentially lethal disorder which requires further research to better care for these patients

Documenting the NICU design dilemma: comparative patient progress in open-ward and single family room units

Objective:To test the efficacy of single family room (SFR) neonatal intensive care unit (NICU) designs, questions regarding patient medical progress and relative patient safety were explored. Addressing these questions would be of value to hospital staff, administrators and designers alike. Study Design:This prospective study documented, by means of Institution Review Board-approved protocols, the progress of patients in two contrasting NICU designs. Noise levels, illumination and air quality measurements were included to define the two NICU physical environments. Result:Infants in the SFR unit had fewer apneic events, reduced nosocomial sepsis and mortality, as well as earlier transitions to enteral nutrition. More mothers sustained stage III lactation, and more infants were discharged breastfeeding in the SFR. Conclusion:This study showed the SFR to be more conducive to family-centered care, and to enhance infant medical progress and breastfeeding success over that of an open ward

Identification of Specific Circular RNA Expression Patterns and MicroRNA Interaction Networks in Mesial Temporal Lobe Epilepsy

Circular RNAs (circRNAs) regulate mRNA translation by binding to microRNAs (miRNAs), and their expression is altered in diverse disorders, including cancer, cardiovascular disease, and Parkinson’s disease. Here, we compare circRNA expression patterns in the temporal cortex and hippocampus of patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) and healthy controls. Nine circRNAs showed significant differential expression, including circRNA-HOMER1, which is expressed in synapses. Further, we identified miRNA binding sites within the sequences of differentially expressed (DE) circRNAs; expression levels of mRNAs correlated with changes in complementary miRNAs. Gene set enrichment analysis of mRNA targets revealed functions in heterocyclic compound binding, regulation of transcription, and signal transduction, which maintain the structure and function of hippocampal neurons. The circRNA–miRNA–mRNA interaction networks illuminate the molecular changes in MTLE, which may be pathogenic or an effect of the disease or treatments and suggests that DE circRNAs and associated miRNAs may be novel therapeutic targets

The biological origin of linguistic diversity

In contrast with animal communication systems, diversity is characteristic of almost every aspect of human language. Languages variously employ tones, clicks, or manual signs to signal differences in meaning; some languages lack the noun-verb distinction (e.g., Straits Salish), whereas others have a proliferation of fine-grained syntactic categories (e.g., Tzeltal); and some languages do without morphology (e.g., Mandarin), while others pack a whole sentence into a single word (e.g., Cayuga). A challenge for evolutionary biology is to reconcile the diversity of languages with the high degree of biological uniformity of their speakers. Here, we model processes of language change and geographical dispersion and find a consistent pressure for flexible learning, irrespective of the language being spoken. This pressure arises because flexible learners can best cope with the observed high rates of linguistic change associated with divergent cultural evolution following human migration. Thus, rather than genetic adaptations for specific aspects of language, such as recursion, the coevolution of genes and fast-changing linguistic structure provides the biological basis for linguistic diversity. Only biological adaptations for flexible learning combined with cultural evolution can explain how each child has the potential to learn any human language

On finite monoids of cellular automata.

For any group G and set A, a cellular automaton over G and A is a transformation τ:AG→AGτ:AG→AG defined via a finite neighbourhood S⊆GS⊆G (called a memory set of ττ) and a local function μ:AS→Aμ:AS→A. In this paper, we assume that G and A are both finite and study various algebraic properties of the finite monoid CA(G,A)CA(G,A) consisting of all cellular automata over G and A. Let ICA(G;A)ICA(G;A) be the group of invertible cellular automata over G and A. In the first part, using information on the conjugacy classes of subgroups of G, we give a detailed description of the structure of ICA(G;A)ICA(G;A) in terms of direct and wreath products. In the second part, we study generating sets of CA(G;A)CA(G;A). In particular, we prove that CA(G,A)CA(G,A) cannot be generated by cellular automata with small memory set, and, when G is finite abelian, we determine the minimal size of a set V⊆CA(G;A)V⊆CA(G;A) such that CA(G;A)=⟨ICA(G;A)∪V⟩CA(G;A)=⟨ICA(G;A)∪V⟩

Low-frequency cortical activity is a neuromodulatory target that tracks recovery after stroke.

Recent work has highlighted the importance of transient low-frequency oscillatory (LFO; <4 Hz) activity in the healthy primary motor cortex during skilled upper-limb tasks. These brief bouts of oscillatory activity may establish the timing or sequencing of motor actions. Here, we show that LFOs track motor recovery post-stroke and can be a physiological target for neuromodulation. In rodents, we found that reach-related LFOs, as measured in both the local field potential and the related spiking activity, were diminished after stroke and that spontaneous recovery was closely correlated with their restoration in the perilesional cortex. Sensorimotor LFOs were also diminished in a human subject with chronic disability after stroke in contrast to two non-stroke subjects who demonstrated robust LFOs. Therapeutic delivery of electrical stimulation time-locked to the expected onset of LFOs was found to significantly improve skilled reaching in stroke animals. Together, our results suggest that restoration or modulation of cortical oscillatory dynamics is important for the recovery of upper-limb function and that they may serve as a novel target for clinical neuromodulation

On the Expansion for Surface Displacement in the Neighborhood of a Crack Tip

It is shown that in the expansion of the crack opening displacement vs distance from the tip, there is no linear term present. This should lead to improved accuracy of the near tip fields and improved stress intensity factor results. The two-dimensional discussion should be able to be carried over to three dimensions