Beyond pairs: definition and interpretation of third-order structure in spatial point patterns

Spatial distributions of biological species are an important source of information for understanding local interactions at the scale of individuals. Technological advances have made it easier to measure these distributions as spatial point patterns, specifying the locations of individuals. Extensive attention has been devoted to analyzing the second-order structure of such point patterns by focusing on pairs of individuals, and it is well known that the local crowdedness of individuals can thus be quantified. Statistical measures such as a point pattern's pair correlation function or Ripley's K function show whether a given point pattern is clustered (excess of short-distance pairs) or overdispersed (shortage of short-distance pairs). These notions are naturally defined in comparison with control patterns exhibiting complete spatial randomness, i.e., an absence of any spatial structure. However, here is no rational reason why the analysis of point patterns should stop at the second order. In this paper, we focus on triplets of individuals in an attempt to quantify and interpret the third-order structure of a point pattern. We demonstrate that point patterns with 'bandedness', in which individuals are primarily distributed within bands, can be detected by an excess of thinner triplets at a characteristic spatial scale linked to the band's width. In this context, we show how the generation of control patterns as a reference for gauging a test pattern's triplet frequencies is critical for defining and interpreting the third-order structure of point patterns. Since perfect information on a point pattern's second-order structure typically suffices for its unique reconstruction (up to translation, rotation, and reflection), we conjecture that it is essential to minimally coarse-grain such second-order information before using it to generate control patterns for identifying a point pattern's third-order structure. We recommend the further exploration of this conjecture for future studies

Sequential optimal selection of a single-qubit gate and its relation to barren plateau in parameterized quantum circuits

We propose an algorithm for variational quantum algorithms (VQAs) to optimize the structure of parameterized quantum circuits (PQCs) efficiently. The algorithm optimizes the PQC structure on-the-fly in VQA by sequentially replacing a single-qubit gate with the optimal one to minimize the objective function. To directly find the optimal gate, our method uses the factorization of matrices whose elements are evaluated on a set of the slightly-modified circuits. The matrix factorization enables us to not only unify the existing sequential methods for further extension but also provide rigorous proofs of their limitation and potential in comparison with conventional gradient-based optimizers. Firstly, when the circuits are sufficiently deep, the sequential methods encounter a barren plateau that the spectrum of the matrix concentrates on a single value exponentially fast with respect to the number of qubits. Secondly, if the objective functions are local observables, they can avoid barren plateaus as long as the depth of the n-qubit PQCs is $O(\log{n})$. Although the family of these optimizers does not directly employ gradients of the objective function, our results establish their connection with conventional optimizations providing a consistent picture of the barren plateau. We also perform numerical experiments showing the advantages over conventional VQAs and confirm the successful optimization getting over the barren plateau in the ground state problem of the mixed field Ising model up to 12 qubits.Comment: 25 pages, 9 figure

A Novel Gene, fudoh, in the SCCmec Region Suppresses the Colony Spreading Ability and Virulence of Staphylococcus aureus

Staphylococcus aureus colonies can spread on soft agar plates. We compared colony spreading of clinically isolated methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA). All MSSA strains showed colony spreading, but most MRSA strains (73%) carrying SCCmec type-II showed little colony spreading. Deletion of the entire SCCmec type-II region from these MRSA strains restored colony spreading. Introduction of a novel gene, fudoh, carried by SCCmec type-II into Newman strain suppressed colony spreading. MRSA strains with high spreading ability (27%) had no fudoh or a point-mutated fudoh that did not suppress colony spreading. The fudoh-transformed Newman strain had decreased exotoxin production and attenuated virulence in mice. Most community-acquired MRSA strains carried SCCmec type-IV, which does not include fudoh, and showed high colony spreading ability. These findings suggest that fudoh in the SCCmec type-II region suppresses colony spreading and exotoxin production, and is involved in S. aureus pathogenesis

The mosquito effect: regulatory and effector T cells acquire cytoplasmic material from tumor cells through intercellular transfer

The phenomenon of intercellular transfer of cellular material, including membranes, cytoplasm, and even organelles, has been observed for decades. The functional impact and molecular mechanisms of such transfer in the immune system remain largely elusive due to the absence of a robust in vivo model. Here, we introduce a new tumor mouse model, where tumor cells express the soluble ultra-bright fluorescent protein ZsGreen, which allows detection and measurement of intercellular transfer of cytoplasm from tumor cells to infiltrating immune cells. We found that in addition to various types of myeloid lineage cells, a large fraction of T regulatory cells and effector CD8 T cells acquire tumor material. Based on the distribution of tumor-derived ZsGreen, the majority of T cells integrate captured cytoplasm into their own, while most myeloid cells store tumor material in granules. Furthermore, scRNA-seq analysis revealed significant alterations in transcriptomes of T cells that acquired tumor cell cytoplasm, suggesting potential impact on T cell function. We identified that the participation of T cells in intercellular transfer requires cell-cell contact and is strictly dependent on the activation status of T lymphocytes. Finally, we propose to name the described phenomenon of intercellular transfer for tumor infiltrating T cells the “mosquito effect”

Distribution and Regulation of the Mobile Genetic Element-Encoded Phenol-Soluble Modulin PSM-mec in Methicillin-Resistant Staphylococcus aureus

The phenol-soluble modulin PSM-mec is the only known staphylococcal toxin that is encoded on a mobile antibiotic resistance determinant, namely the staphylococcal cassette chromosome (SCC) element mec encoding resistance to methicillin. Here we show that the psm-mec gene is found frequently among methicillin-resistant Staphylococcus aureus (MRSA) strains of SCCmec types II, III, and VIII, and is a conserved part of the class A mec gene complex. Controlled expression of AgrA versus RNAIII in agr mutants of all 3 psm-mec-positive SCCmec types demonstrated that expression of psm-mec, which is highly variable, is controlled by AgrA in an RNAIII-independent manner. Furthermore, psm-mec isogenic deletion mutants showed only minor changes in PSMα peptide production and unchanged (or, as previously described, diminished) virulence compared to the corresponding wild-type strains in a mouse model of skin infection. This indicates that the recently reported regulatory impact of the psm-mec locus on MRSA virulence, which is opposite to that of the PSM-mec peptide and likely mediated by a regulatory RNA, is minor when analyzed in the original strain background. Our study gives new insight in the distribution, regulation, and role in virulence of the PSM-mec peptide and the psm-mec gene locus

An Invertebrate Hyperglycemic Model for the Identification of Anti-Diabetic Drugs

The number of individuals diagnosed with type 2 diabetes mellitus, which is caused by insulin resistance and/or abnormal insulin secretion, is increasing worldwide, creating a strong demand for the development of more effective anti-diabetic drugs. However, animal-based screening for anti-diabetic compounds requires sacrifice of a large number of diabetic animals, which presents issues in terms of animal welfare. Here, we established a method for evaluating the anti-diabetic effects of compounds using an invertebrate animal, the silkworm, Bombyx mori. Sugar levels in silkworm hemolymph increased immediately after feeding silkworms a high glucose-containing diet, resulting in impaired growth. Human insulin and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), an AMP-activated protein kinase (AMPK) activator, decreased the hemolymph sugar levels of the hyperglycemic silkworms and restored growth. Treatment of the isolated fat body with human insulin in an in vitro culture system increased total sugar in the fat body and stimulated Akt phosphorylation. These responses were inhibited by wortmannin, an inhibitor of phosphoinositide 3 kinase. Moreover, AICAR stimulated AMPK phosphorylation in the silkworm fat body. Administration of aminoguanidine, a Maillard reaction inhibitor, repressed the accumulation of Maillard reaction products (advanced glycation end-products; AGEs) in the hyperglycemic silkworms and restored growth, suggesting that the growth defect of hyperglycemic silkworms is caused by AGE accumulation in the hemolymph. Furthermore, we identified galactose as a hypoglycemic compound in jiou, an herbal medicine for diabetes, by monitoring its hypoglycemic activity in hyperglycemic silkworms. These results suggest that the hyperglycemic silkworm model is useful for identifying anti-diabetic drugs that show therapeutic effects in mammals