Why neighbor-joining works

We show that the neighbor-joining algorithm is a robust quartet method for constructing trees from distances. This leads to a new performance guarantee that contains Atteson's optimal radius bound as a special case and explains many cases where neighbor-joining is successful even when Atteson's criterion is not satisfied. We also provide a proof for Atteson's conjecture on the optimal edge radius of the neighbor-joining algorithm. The strong performance guarantees we provide also hold for the quadratic time fast neighbor-joining algorithm, thus providing a theoretical basis for inferring very large phylogenies with neighbor-joining

Profiling molecular and behavioral circadian rhythms in the non-symbiotic sea anemone Nematostella vectensis

© The Author(s), 2015. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Scientific Reports 5 (2015): 11418, doi:10.1038/srep11418.Endogenous circadian clocks are poorly understood within early-diverging animal lineages. We have characterized circadian behavioral patterns and identified potential components of the circadian clock in the starlet sea anemone, Nematostella vectensis: a model cnidarian which lacks algal symbionts. Using automatic video tracking we showed that Nematostella exhibits rhythmic circadian locomotor activity, which is persistent in constant dark, shifted or disrupted by external dark/light cues and maintained the same rate at two different temperatures. This activity was inhibited by a casein kinase 1δ/ε inhibitor, suggesting a role for CK1 homologue(s) in Nematostella clock. Using high-throughput sequencing we profiled Nematostella transcriptomes over 48 hours under a light-dark cycle. We identified 180 Nematostella diurnally-oscillated transcripts and compared them with previously established databases of adult and larvae of the symbiotic coral Acropora millepora, revealing both shared homologues and unique rhythmic genes. Taken together, this study further establishes Nematostella as a non-symbiotic model organism to study circadian rhythms and increases our understanding about the fundamental elements of circadian regulation and their evolution within the Metazoa.This work was supported by the Israel-US Binational Science Foundation to OL and AMT (Award 2011187). Additional support was provided by the WHOI Early Career Scientist Award to AMT

Angular dependence of domain wall resistivity in SrRuO3_{{\bf 3}} films

${\rm SrRuO_3}$ is a 4d itinerant ferromagnet (T$_{c}$ $\sim$150 K) with stripe domain structure. Using high-quality thin films of SrRuO$_{3}$ we study the resistivity induced by its very narrow ($\sim 3$ nm) Bloch domain walls, $\rho_{DW}$ (DWR), at temperatures between 2 K and T$_{c}$ as a function of the angle, $\theta$, between the electric current and the ferromagnetic domains walls. We find that $\rho_{DW}(T,\theta)=\sin^2\theta \rho_{DW}(T,90)+B(\theta)\rho_{DW}(T,0)$ which provides the first experimental indication that the angular dependence of spin accumulation contribution to DWR is $\sin^2\theta$. We expect magnetic multilayers to exhibit a similar behavior.Comment: 5 pages, 5 figure

The ownership of digital infrastructure: Exploring the deployment of software libraries in a digital innovation cluster

Boundary resources have been shown to enable the arm’s-length relationships between platform owners and third-party developers that underlie digital innovation in platform ecosystems. While boundary resources that are owned by open-source communities and smaller-scale software vendors are also critical components in the digital infrastructure, their role in digital innovation has yet to be systematically explored. In particular, software libraries are popular boundary resources that provide functionality without the need for continued interaction with their owners. They are used extensively by commercial vendors to enable customization of their software products, by communities to disseminate open-source software, and by big-tech platform owners to provide functionality that does not involve control. This paper reports on the deployment of such software libraries in the web and mobile (Android) contexts by 107 startup companies in London. Our findings show that libraries owned by big-tech companies, product vendors, and communities coexist; that the deployment of big-tech libraries is unaffected by the scale of the deploying startup; and that context evolution paths are consequential for library deployment. These findings portray a balanced picture of digital infrastructure as neither the community-based utopia of early open-source research nor the dystopia of the recent digital dominance literature

Membrane anchored IL-18 linked to constitutively active TLR4 and CD40 improves human T cell antitumor capacities for adoptive cell therapy

BACKGROUND: Adoptive transfer of tumor-infiltrating lymphocytes (TILs) or blood T cells genetically redirected by an antitumor TCR or CAR induces a strong antitumor response in a proportion of patients with cancer; however, the therapeutic efficacy is often limited by rapid decline in T cell functions. Coadministering supportive cytokines frequently provokes systemic side effects preventing their broad clinical application. We recently showed that cytokines can be anchored to the cell membrane in a functional fashion and that cytokine receptor signaling can synergize with TLR4 and CD40 signaling. Here, we aimed at augmenting T cell activation by simultaneous signaling through the cytokine receptor, toll-like receptor and TNF-type receptor using IL-18, TLR4 and CD40 as prototypes. METHODS: Genes were expressed on electroporation of in vitro-transcribed mRNA in CD4(+) and CD8(+) T cells from healthy donors redirected against melanoma cells with an anti-melanotransferrin CAR and in TILs derived from melanoma patients. Functional assays included the activation of signaling pathways, expression of activation and differentiation markers, cytokine secretion and killing of melanoma target cells. RESULTS: To provide IL-18 costimulation to T cells in-cis while avoiding systemic effects, we genetically anchored IL-18 to the T cell membrane, either alone (memIL-18) or fused with constitutively active (ca)TLR4 and caCD40 signaling domains arranged in tandem, creating a synthetic ‘all-in-one’ memIL-18-TLR4-CD40 receptor. MemIL-18-TLR4-CD40, but not memIL-18, triggered strong NF-κB activation in cells lacking the IL-18 receptor, attesting to functionality of the TLR-CD40 moiety. While the membrane-anchored cytokine was found to act mainly in-cis, some T cell activation in-trans was also observed. The electroporated T cells exhibited spontaneous T-bet upregulation and IFN-γ and TNF-α secretion. Melanoma-induced activation of CAR-T cells and TILs as manifested by cytokine secretion and cytolytic activity was substantially augmented by both constructs, with memIL-18-TLR4-CD40 exerting stronger effects than memIL-18 alone. CONCLUSIONS: Linking membrane anchored IL-18 with caTLR4 and caCD40 signaling in one hybrid transmembrane protein provides simultaneous activation of three T cell costimulatory pathways through one genetically engineered membrane molecule, strongly amplifying T cell functions for adoptive T cell therapy of cancer

Analysis of common and rare VPS13C variants in late-onset Parkinson disease

Objective We aimed to study the role of coding VPS13C variants in a large cohort of patients with lateonset Parkinson disease (PD) (LOPD). Methods VPS13C and its untranslated regions were sequenced using targeted next-generation sequencing in 1,567 patients with PD and 1,667 controls from 3 cohorts. Association tests of rare potential homozygous and compound heterozygous variants and burden tests for rare heterozygous variants were performed. Common variants were analyzed using logistic regression adjusted for age and sex in each of the cohorts, followed by a meta-analysis. Results No biallelic carriers of rare VPS13C variants were found among patients, and 2 carriers of compound heterozygous variants were found in 2 controls. There was no statistically significant burden of rare (minor allele frequency [MAF] <1%) or very rare (MAF <0.1%) coding VPS13C variants in PD. A VPS13C haplotype including the p.R153H-p.I398I-p.I1132V-p.Q2376Q variants was nominally associated with a reduced risk for PD (meta-analysis of the tagging SNP p.I1132V [odds ratio = 0.48, 95% confidence interval = 0.28–0.82, p = 0.0052]). This haplotype was not in linkage disequilibrium with the known genome-wide association study top hit. Conclusions Our results do not support a role for rare heterozygous or biallelic VPS13C variants in LOPD. Additional genetic replication and functional studies are needed to examine the role of the haplotype identified here associated with reduced risk for PD