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We introduce CellPhy, a maximum likelihood framework for inferring phylogenetic trees from somatic single-cell single-nucleotide variants. CellPhy leverages a finite-site Markov genotype model with 16 diploid states and considers amplification error and allelic dropout. We implement CellPhy into RAxML-NG, a widely used phylogenetic inference package that provides statistical confidence measurements and scales well on large datasets with hundreds or thousands of cells. Comprehensive simulations suggest that CellPhy is more robust to single-cell genomics errors and outperforms state-of-the-art methods under realistic scenarios, both in accuracy and speed. CellPhy is freely available at https://github.com/amkozlov/cellphy .

How and when tumoral clones start spreading to surrounding and distant tissues is currently unclear. Here we leveraged a model-based evolutionary framework to investigate the demographic and biogeographic history of a colorectal cancer. Our analyses strongly support an early monoclonal metastatic colonization, followed by a rapid population expansion at both primary and secondary sites. Moreover, we infer a hematogenous metastatic spread under positive selection, plus the return of some tumoral cells from the liver back to the colon lymph nodes. This study illustrates how sophisticated techniques typical of organismal evolution can provide a detailed, quantitative picture of the complex tumoral dynamics over time and space. The clonal origins of metastases and the timing of dissemination remains an open question for most cancer types. Using primary and metastatic samples taken from one colorectal cancer patient, Alves et al. use Bayesian phylogenetics to reconstruct the history of metastasis.

We present SIEVE, a statistical method for the joint inference of somatic variants and cell phylogeny under the finite-sites assumption from single-cell DNA sequencing. SIEVE leverages raw read counts for all nucleotides and corrects the acquisition bias of branch lengths. In our simulations, SIEVE outperforms other methods in phylogenetic reconstruction and variant calling accuracy, especially in the inference of homozygous variants. Applying SIEVE to three datasets, one for triple-negative breast (TNBC), and two for colorectal cancer (CRC), we find that double mutant genotypes are rare in CRC but unexpectedly frequent in the TNBC samples.

We propose a class of two Higgs doublet models where there are flavour changing neutral currents (FCNC) at tree level, but under control due to the introduction of a discrete symmetry in the full Lagrangian. It is shown that in this class of models, one can have simultaneously FCNC in the up and down sectors, in contrast to the situation encountered in the renormalisable and minimal flavour violating 2HDM models put forward by Branco et al. (Phys Lett B 380:119, 1996 ). The intensity of FCNC is analysed and it is shown that in this class of models one can respect all the strong constraints from experiment without unnatural fine-tuning. It is pointed out that the additional sources of flavour and CP violation are such that they can enhance significantly the generation of the Bbaryon asymmetry of the Universe, with respect to the standard model.

Background Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment, particularly in advanced non-small cell lung cancer (NSCLC) and muscle-invasive bladder cancer (MIBC). However, identifying reliable predictive biomarkers for ICI response remains a significant challenge. In this study, we analyzed real-world cohorts of advanced NSCLC and MIBC patients treated with ICI as first-line therapy. Methods Tumor samples underwent Whole Genome Sequencing (WGS) to identify specific somatic variants and assess tumor mutational burden (TMB). Additionally, mutational signature extraction and pathway enrichment analyses were performed to uncover the underlying mechanisms of ICI response. We also characterized HLA-I haplotypes and investigated LINE-1 retrotransposition. Results Distinct mutation patterns were identified in patients who responded to treatment, suggesting potential biomarkers for predicting ICI effectiveness. In NSCLC, tumor mutational burden (TMB) did not differ significantly between responders and non-responders, while in MIBC, higher TMB was linked to better responses. Specific mutational signatures and HLA haplotypes were associated with ICI response in both cancers. Pathway analysis showed that NSCLC responders had active inflammatory and immune pathways, while pathways enriched in non-responders related to FGFR3 and neural crest differentiation, associated to resistance mechanisms. In MIBC, responders had alterations in DNA repair, leading to more neoantigens and a stronger ICI response. Importantly, for the first time, we found that LINE-1 activation was positively linked to ICI response, especially in MIBC. Conclusion These findings reveal promising biomarkers and mechanistic insights, offering a new perspective on predicting ICI response and opening up exciting possibilities for more personalized immunotherapy strategies in NSCLC and MIBC.

Background Worldwide, bacterial vaginosis (BV) is the most common vaginal disorder. It is associated with risk for preterm birth and HIV infection. The etiology of the condition has been debated for nearly half a century and the lack of knowledge about its cause and progression has stymied efforts to improve therapy and prevention. Gardnerella vaginalis was originally identified as the causative agent, but subsequent findings that it is commonly isolated from seemingly healthy women cast doubt on this claim. Recent studies shedding light on the virulence properties of G. vaginalis , however, have drawn the species back into the spotlight. Results In this study, we sequenced the genomes of a strain of G. vaginalis from a healthy woman, and one from a woman with bacterial vaginosis. Comparative analysis of the genomes revealed significant divergence and in vitro studies indicated disparities in the virulence potential of the two strains. The commensal isolate exhibited reduced cytotoxicity and yet the cytolysin proteins encoded by the two strains were nearly identical, differing at a single amino acid, and were transcribed at similar levels. The BV-associated strain encoded a different variant of a biofilm associated protein gene and demonstrated greater adherence, aggregation, and biofilm formation. Using filters with different pore sizes, we found that direct contact between the bacteria and epithelial cells is required for cytotoxicity. Conclusions The results indicated that contact is required for cytotoxicity and suggested that reduced cytotoxicity in the commensal isolate could be due to impaired adherence. This study outlines two distinct genotypic variants of G. vaginalis , one apparently commensal and one pathogenic, and presents evidence for disparate virulence potentials.

In this paper, we introduce unitary flavour violation to produce multi-Higgs doublets models where all flavour par ameters are contained within three unitary matrices. After that, we identify two of its subclasses, the left and right models, which have naturally suppressed tree-lev el flavour changing neutral couplings that easily avoid the experimental constraints derived from neutral meson mi xing. Then, we show that left models can accomodate spontaneous CP violation when all quarks have flavour changing neutr al couplings. Finally, we illustrate these concepts by considering a specific implementation with three Higgs doublets.

We conjecture the existence of a relation between elementary scalars and fermions, making it plausible the existence of three Higgs doublets. We introduce a Trinity Principle (TP) which, given the fact that there are no massless quarks, requires the existence of a minimum of three Higgs doublets. The TP states that each row of the mass matrix of a quark of a given charge should receive the contribution from one and only one scalar doublet and furthermore a given scalar doublet should contribute to one and only one row of the mass matrix of a quark of a given charge. This principle is analogous to the Natural Flavour Conservation (NFC) of Glashow and Weinberg with the key distinction that NFC required the introduction of a flavour blind symmetry, while the TP requires a flavoured symmetry, to be implemented in a natural way. We provide two examples which satisfy the Trinity Principle based on Z 3 and Z 2 × Z 2 ′ flavoured symmetries, and show that they are the minimal multi-Higgs extensions of the Standard Model where CP can be imposed as a symmetry of the full Lagrangian and broken by the vacuum, without requiring soft-breaking terms. We show that the vacuum phases are sufficient to generate a complex CKM matrix, in agreement with experiment. The above mentioned flavoured symmetries lead to a strong reduction in the number of parameters in the Yukawa interactions, enabling a control of the Scalar Flavour Changing Neutral Couplings (SFCNC). We analyse some of the other physical implications of the two models, including an estimate of the enhancement of the Baryon Asymmetry of the Universe provided by the new sources of CP violation, and a discussion of the strength of their tree-level SFCNC.

The Leishmaniinae subfamily of the Trypanosomatidae contains both genus Zelonia (monoxenous) and Endotrypanum (dixenous). They are amongst the nearest known relatives of Leishmania, which comprises many human pathogens widespread in the developing world. These closely related lineages are models for the genomic biology of monoxenous and dixenous parasites. Herein, we used comparative genomics to identify the orthologous groups (OGs) shared among 26 Leishmaniinae species to investigate gene family expansion/contraction and applied two phylogenomic approaches to confirm relationships within the subfamily. The Endotrypanum monterogeii and Zelonia costaricensis genomes were assembled, with sizes of 29.9 Mb and 38.0 Mb and 9.711 and 12.201 predicted protein-coding genes, respectively. The genome of E. monterogeii displayed a higher number of multicopy cell surface protein families, including glycoprotein 63 and glycoprotein 46, compared to Leishmania spp. The genome of Z. costaricensis presents expansions of BT1 and amino acid transporters and proteins containing leucine-rich repeat domains, as well as a loss of ABC-type transporters. In total, 415 and 85 lineage-specific OGs were identified in Z. costaricensis and E. monterogeii. The evolutionary relationships within the subfamily were confirmed using the supermatrix (3384 protein-coding genes) and supertree methods. Overall, this study showed new expansions of multigene families in monoxenous and dixenous parasites of the subfamily Leishmaniinae.

We study two-Higgs-doublet models (2HDM) where Abelian symmetries have been introduced, leading to a drastic reduction in the number of free parameters in the 2HDM. Our analysis is inspired in BGL models, where, as the result of a symmetry of the Lagrangian, there are tree-level scalar mediated Flavour-Changing-Neutral-Currents, with the flavour structure depending only on the CKM matrix. A systematic analysis is done on the various possible schemes, which are classified in different classes, depending on the way the extra symmetries constrain the matrices of couplings defining the flavour structure of the scalar mediated neutral currents. All the resulting flavour textures of the Yukawa couplings are stable under renormalisation since they result from symmetries imposed at the Lagrangian level. We also present a brief phenomenological analysis of the most salient features of each class of symmetry constrained 2HDM.