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Biomolecular condensates are formed by liquid-liquid phase separation (LLPS) of multivalent molecules. LLPS from a single ("homotypic") constituent is governed by buffering above a threshold, free monomer concentration is clamped, with all added molecules entering the condensed phase. However, both experiment and theory demonstrate that buffering fails for the concentration dependence of multicomponent ("heterotypic") LLPS. Using network-free stochastic modeling, we demonstrate that LLPS can be described by the solubility product constant (Ksp) the product of free monomer concentrations, accounting for the ideal stoichiometries governed by the valencies, displays a threshold above which additional monomers are funneled into large clusters; this reduces to simple buffering for homotypic systems. The Ksp regulates the composition of the dilute phase for a wide range of valencies and stoichiometries. The role of Ksp is further supported by coarse-grained spatial particle simulations. Thus, the solubility product offers a general formulation for the concentration dependence of LLPS.DNA double-strand breaks (DSBs) are the most harmful DNA lesions and their repair is crucial for cell viability and genome integrity. The readout of DSB repair may depend on whether DSBs occur at transcribed versus non-transcribed regions. Some studies have postulated that DNA-RNA hybrids form at DSBs to promote recombinational repair, but others have challenged this notion. To directly assess whether hybrids formed at DSBs promote or interfere with the recombinational repair, we have used plasmid and chromosomal-based systems for the analysis of DSB-induced recombination in Saccharomyces cerevisiae. We show that, as expected, DNA-RNA hybrid formation is stimulated at DSBs. In addition, mutations that promote DNA-RNA hybrid accumulation, such as hpr1∆ and rnh1∆ rnh201∆, cause high levels of plasmid loss when DNA breaks are induced at sites that are transcribed. Importantly, we show that high levels or unresolved DNA-RNA hybrids at the breaks interfere with their repair by homologous recombination. This interference is observed for both plasmid and chromosomal recombination and is independent of whether the DSB is generated by endonucleolytic cleavage or by DNA replication. GSK-3 beta phosphorylation These data support a model in which DNA-RNA hybrids form fortuitously at DNA breaks during transcription and need to be removed to allow recombinational repair, rather than playing a positive role.In animals, early-life stress can result in programmed changes in gene expression that can affect their adult phenotype. In C. elegans nematodes, starvation during the first larval stage promotes entry into a stress-resistant dauer stage until environmental conditions improve. Adults that have experienced dauer (postdauers) retain a memory of early-life starvation that results in gene expression changes and reduced fecundity. Here, we show that the endocrine pathways attributed to the regulation of somatic aging in C. elegans adults lacking a functional germline also regulate the reproductive phenotypes of postdauer adults that experienced early-life starvation. We demonstrate that postdauer adults reallocate fat to benefit progeny at the expense of the parental somatic fat reservoir and exhibit increased longevity compared to controls. Our results also show that the modification of somatic fat stores due to parental starvation memory is inherited in the F1 generation and may be the result of crosstalk between somatic and reproductive tissues mediated by the germline nuclear RNAi pathway.MGA, a transcription factor and member of the MYC network, is mutated or deleted in a broad spectrum of malignancies. As a critical test of a tumor suppressive role, we inactivated Mga in two mouse models of non-small cell lung cancer using a CRISPR-based approach. MGA loss significantly accelerated tumor growth in both models and led to de-repression of non-canonical Polycomb ncPRC1.6 targets, including genes involved in metastasis and meiosis. Moreover, MGA deletion in human lung adenocarcinoma lines augmented invasive capabilities. We further show that MGA-MAX, E2F6, and L3MBTL2 co-occupy thousands of promoters and that MGA stabilizes these ncPRC1.6 subunits. Lastly, we report that MGA loss also induces a pro-growth effect in human colon organoids. Our studies establish MGA as a bona fide tumor suppressor in vivo and suggest a tumor suppressive mechanism in adenocarcinomas resulting from widespread transcriptional attenuation of MYC and E2F target genes mediated by MGA-MAX associated with a non-canonical Polycomb complex.Temozolomide (TMZ), a DNA methylating agent, is the primary chemotherapeutic drug used in glioblastoma treatment. TMZ induces mostly N-alkylation adducts (N7-methylguanine and N3-methyladenine) and some O6-methylguanine (O6mG) adducts. Current models propose that during DNA replication, thymine is incorporated across from O6mG, promoting a futile cycle of mismatch repair (MMR) that leads to DNA double-strand breaks (DSBs). To revisit the mechanism of O6mG processing, we reacted plasmid DNA with N-methyl-N-nitrosourea (MNU), a temozolomide mimic, and incubated it in Xenopus egg-derived extracts. We have shown that in this system, MMR proteins are enriched on MNU-treated DNA and we observed robust, MMR-dependent, repair synthesis. Our evidence also suggests that MMR, initiated at O6mGC sites, is strongly stimulated in cis by repair processing of other lesions, such as N-alkylation adducts. Importantly, MNU-treated plasmids display DSBs in extracts, the frequency of which increases linearly with the square of alkylation dose. We suggest that DSBs result from two independent repair processes, one involving MMR at O6mGC sites and the other involving base excision repair acting at a nearby N-alkylation adduct. We propose a new, replication-independent mechanism of action of TMZ, which operates in addition to the well-studied cell cycle-dependent mode of action.The PIWI-interacting RNA (piRNA) pathway controls transposon expression in animal germ cells, thereby ensuring genome stability over generations. In Drosophila, piRNAs are intergenerationally inherited through the maternal lineage, and this has demonstrated importance in the specification of piRNA source loci and in silencing of I- and P-elements in the germ cells of daughters. Maternally inherited Piwi protein enters somatic nuclei in early embryos prior to zygotic genome activation and persists therein for roughly half of the time required to complete embryonic development. To investigate the role of the piRNA pathway in the embryonic soma, we created a conditionally unstable Piwi protein. This enabled maternally deposited Piwi to be cleared from newly laid embryos within 30 min and well ahead of the activation of zygotic transcription. Examination of RNA and protein profiles over time, and correlation with patterns of H3K9me3 deposition, suggests a role for maternally deposited Piwi in attenuating zygotic transposon expression in somatic cells of the developing embryo. In particular, robust deposition of piRNAs targeting roo, an element whose expression is mainly restricted to embryonic development, results in the deposition of transient heterochromatic marks at active roo insertions. We hypothesize that roo, an extremely successful mobile element, may have adopted a lifestyle of expression in the embryonic soma to evade silencing in germ cells.Identifying neural substrates of behavior requires defining actions in terms that map onto brain activity. Brain and muscle activity naturally correlate via the output of motor neurons, but apart from simple movements it has been difficult to define behavior in terms of muscle contractions. By mapping the musculature of the pupal fruit fly and comprehensively imaging muscle activation at single-cell resolution, we here describe a multiphasic behavioral sequence in Drosophila. Our characterization identifies a previously undescribed behavioral phase and permits extraction of major movements by a convolutional neural network. We deconstruct movements into a syllabary of co-active muscles and identify specific syllables that are sensitive to neuromodulatory manipulations. We find that muscle activity shows considerable variability, with sequential increases in stereotypy dependent upon neuromodulation. Our work provides a platform for studying whole-animal behavior, quantifying its variability across multiple spatiotemporal scales, and analyzing its neuromodulatory regulation at cellular resolution.Toxoplasma gondii is a highly prevalent zoonotic parasite in Brazil capable of infecting mammals and birds. The increase in the urban populations of pets and the narrowing of the human-animal relationship can facilitate the transmission of important public health zoonoses, such as toxoplasmosis. This study aimed to evaluate the frequency and spatial distribution of T. gondii infection and its risk factors in domiciled dogs and cats attended at the Jorge Vaitsman Institute, Rio de Janeiro. Serum samples from 400 dogs and 272 cats were evaluated by an indirect fluorescent antibody test (IFAT) for IgG anti-T. gondii antibodies. Epidemiological questionnaires were used to interview the animals' owners to identify risk factors for infection. Of the total, 34% (136/400) of dogs and 8.1% (22/272) of cats had anti-T. gondii antibodies. Breed (OR 2.10-95%, CI 1.27-3.46) was a risk factor for dogs, while sex (OR 3.40-95%, CI 1.10-10.52) and homemade food consumption (OR 8.49-95%, CI 2.48-29.05) were risk factors for cats. Offal consumption was considered a risk factor for both species evaluated (OR 2.74-95%, CI 1.38-5.43 for dogs; OR 7.66-95%, CI 1.24-47.29 for cats). The spatial analysis showed that T. gondii seropositive animals were widely distributed in the metropolitan region of Rio de Janeiro state, with a concentration observed mainly in the west and north zones of Rio de Janeiro city. The results emphasize the importance of adopting prophylactic measures to control T. gondii transmission in domiciled dogs and cats in Rio de Janeiro, contributing positively to public health.
To analyze muscle histopathology of myasthenia gravis (MG) patients and further explore the underlying mechanism comparing with previous literature.

We analyzed the clinicopathological features of 8 MG patients who had muscle biopsy examinations.

Eight patients with a diagnosis of MG were retrospectively recruited from the Chinese PLA General Hospital. One patient had positive anti-MuSK antibodies, 5 patients had positive anti-AChR antibodies (1 of whom had additional positive anti-Titin antibodies), and 2 patients were seronegative. Seronegative-MG presented normal muscle histology, occasionally with lipid deposition. Small angular atrophy (mainly in type II fibers) and necrosis in H & E stain were found in AChR-MG, furthermore, patterns of polymyositis (PM) could be found in AChR-MG with anti-Titin antibodies. Mitochondrial abnormalities were found only in MuSK-MG.

Muscle histological abnormalities mimicking myopathy may be found in MG patients. Patients with different antibodies present with different muscle histopathology. PM pattern pathology is a special pattern of muscle histology in MG that should not be misdiagnosed. Our study has extended the muscle pathological features of MG in addition to deepening the understanding of MG.
Muscle histological abnormalities mimicking myopathy may be found in MG patients. Patients with different antibodies present with different muscle histopathology. PM pattern pathology is a special pattern of muscle histology in MG that should not be misdiagnosed. Our study has extended the muscle pathological features of MG in addition to deepening the understanding of MG.
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