Differential functions of G protein and Baz–aPKC signaling pathways in Drosophila neuroblast asymmetric division

Drosophila melanogaster neuroblasts (NBs) undergo asymmetric divisions during which cell-fate determinants localize asymmetrically, mitotic spindles orient along the apical–basal axis, and unequal-sized daughter cells appear. We identified here the first Drosophila mutant in the Gγ1 subunit of heterotrimeric G protein, which produces Gγ1 lacking its membrane anchor site and exhibits phenotypes identical to those of Gβ13F, including abnormal spindle asymmetry and spindle orientation in NB divisions. This mutant fails to bind Gβ13F to the membrane, indicating an essential role of cortical Gγ1–Gβ13F signaling in asymmetric divisions. In Gγ1 and Gβ13F mutant NBs, Pins–Gαi, which normally localize in the apical cortex, no longer distribute asymmetrically. However, the other apical components, Bazooka–atypical PKC–Par6–Inscuteable, still remain polarized and responsible for asymmetric Miranda localization, suggesting their dominant role in localizing cell-fate determinants. Further analysis of Gβγ and other mutants indicates a predominant role of Partner of Inscuteable–Gαi in spindle orientation. We thus suggest that the two apical signaling pathways have overlapping but different roles in asymmetric NB division

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Soy Phospholipids Exert a Renoprotective Effect by Inhibiting the Nuclear Factor Kappa B Pathway in Macrophages

Complications associated with chronic kidney disease (CKD), which involves kidney inflammation, are a major health problem. Soy protein isolate (SPI) reportedly inhibits CKD exacerbation; however, its detailed action mechanism remains obscure. Therefore, the role of the polar lipid component of SPI in suppressing inflammation was investigated. Zucker fatty rats were divided into three groups and fed a diet containing casein, SPI, or casein + SPI ethanol extract (SPIEE) for 16 weeks. The isoflavones and phospholipids of SPIEE were evaluated for their anti-inflammatory effects. Rats in the SPI and casein + SPIEE groups showed reduced levels of the urinary N-acetyl-β-d-glucosaminidase and renal IL-1β mRNA (an inflammatory marker) compared with those in the casein group. In proximal tubular cells, genistein significantly inhibited monocyte chemoattractant protein-1 (MCP-1) expression induced by an IL-1β stimulus. In macrophages, soybean phospholipids suppressed lipopolysaccharide-induced IL-1β gene expression by inhibiting the phosphorylation of inhibitor κB and p65. Phosphatidylinositol (PI) was found to be essential for inhibition of IL-1β expression. SPIEE inhibited the exacerbation of kidney disease. Genistein and soybean phospholipids, especially soybean-specific phospholipids containing PI, effectively inhibited the inflammatory spiral in vitro. Hence, daily soybean intake may be effective for inhibiting chronic inflammation and slowing kidney disease progression

Demographic and clinical characteristics of patients with zinc deficiency: analysis of a nationwide Japanese medical claims database

Abstract Zinc deficiency, affecting more than 2 billion people globally, poses a significant public health burden due to its numerous unfavorable effects, such as impaired immune function, taste and smell disorders, pneumonia, growth retardation, visual impairment, and skin disorders. Despite its critical role, extensive large-scale studies investigating the correlation between patient characteristics and zinc deficiency still need to be completed. We conducted a retrospective, cross-sectional observational study using a nationwide Japanese claims database from January 2019 to December 2021. The study population included 13,100 patients with available serum zinc concentration data, excluding individuals under 20 and those assessed for zinc concentrations after being prescribed zinc-containing medication. Significant associations with zinc deficiency were noted among older adults, males, and inpatients. Multivariate analysis, adjusting for age and sex, indicated significant associations with comorbidities, including pneumonitis due to solids and liquids with an adjusted Odds Ratio (aOR) of 2.959; decubitus ulcer and pressure area (aOR 2.403), sarcopenia (aOR 2.217), COVID-19 (aOR 1.889), and chronic kidney disease (aOR 1.835). Significant association with medications, including spironolactone (aOR 2.523), systemic antibacterials (aOR 2.419), furosemide (aOR 2.138), antianemic preparations (aOR 2.027), and thyroid hormones (aOR 1.864) were also found. These results may aid clinicians in identifying patients at risk of zinc deficiency, potentially improving care outcomes

NF-kappa B signaling mediates acquired resistance after PARP inhibition

PARP inhibitors are a class of promising anti-cancer drugs, with proven activity in BRCA mutant cancers. However, as with other targeted agents, treatment with PARP inhibitors generates acquired resistance within these tumors. The mechanism of this acquired resistance is poorly understood. We established cell lines that are resistant to PARP inhibitor by continuous treatment with the drug, and then used RNA sequencing to compare gene expression. Pathway analysis on the RNA sequencing data indicates that NF-kappa B signaling is preferentially up-regulated in PARP inhibitor-resistant cells, and that knockdown of core components in NF-kappa B signaling reverses the sensitivity to PARP inhibitor in resistant cells. Of therapeutic relevance, we show that PARP inhibitor-resistant cells are sensitive to an NF-kappa B inhibitor in comparison to their parental controls. Malignancies with up-regulation of NF-kappa B are sensitive to bortezomib, a proteasome inhibitor that is currently used in the clinic. We also show that treatment with bortezomib results in cell death in the PARP inhibitor-resistant cells, but not in parental cells. Therefore we propose that up-regulation of NF-kappa B signaling is a key mechanism underlying acquired resistance to PARP inhibition, and that NF-kappa B inhibition, or bortezomib are potentially effective anti-cancer agents after the acquisition of resistance to PARP inhibitors.We thank Dr. Grahame McKenzie for the kind gift of plasmids for luciferase assay. This work was supported by St. Marianna University Grant.S

Highly Discriminative and Chemoselective Deprotection/Transformations of Acetals with the Combination of Trialkylsilyl Triflate/2,4,6-Collidine

Acetals are the most useful protecting groups for carbonyl functional groups. In addition to the role of protection, they can also be used as synthons of carbonyl functions. Previously, we developed a chemoselective deprotection and nucleophilic substitution of acetals from aldehydes in the presence of ketals. This article describes the highly discriminative and chemoselective transformations of acetals bearing different substitution patterns, different types of acetals, as well as mixed acetals. These reactions can achieve the transformations that cannot be attained by conventional methods, and their results strongly suggest the combination of R₃SiOTf/2,4,6-collidine to promote such unprecedented phenomena