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eckpoint inhibitors, multidisciplinary management of oncological patients is critical. The pituitary syndrome in oncological patients who underwent immunotherapy represents a challenge in the differential diagnosis between pituitary metastasis and drug-induced hypophysitis. This is the first case, described in the literature of diabetes insipidus in a patient suffering from nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis.Tuberculosis (TB) is a leading cause of death globally. Understanding the population dynamics of TB's causative agent Mycobacterium tuberculosis complex (Mtbc) in-host is vital for understanding the efficacy of antibiotic treatment. We use longitudinally collected clinical Mtbc isolates that underwent Whole-Genome Sequencing from the sputa of 200 patients to investigate Mtbc diversity during the course of active TB disease after excluding 107 cases suspected of reinfection, mixed infection or contamination. Of the 178/200 patients with persistent clonal infection >2 months, 27 developed new resistance mutations between sampling with 20/27 occurring in patients with pre-existing resistance. Low abundance resistance variants at a purity of ≥19% in the first isolate predict fixation in the subsequent sample. We identify significant in-host variation in 27 genes, including antibiotic resistance genes, metabolic genes and genes known to modulate host innate immunity and confirm several to be under positive selection by assessing phylogenetic convergence across a genetically diverse sample of 20,352 isolates.Across species, lifespan is highly variable among individuals within a population. Even genetically identical Caenorhabditis elegans reared in homogeneous environments are as variable in lifespan as outbred human populations. We hypothesized that persistent inter-individual differences in expression of key regulatory genes drives this lifespan variability. As a test, we examined the relationship between future lifespan and the expression of 22 microRNA promoterGFP constructs. Surprisingly, expression of nearly half of these reporters, well before death, could effectively predict lifespan. This indicates that prospectively long- vs. short-lived individuals have highly divergent patterns of transgene expression and transcriptional regulation. The gene-regulatory processes reported on by two of the most lifespan-predictive transgenes do not require DAF-16, the FOXO transcription factor that is a principal effector of insulin/insulin-like growth factor (IGF-1) signaling. Last, we demonstrate a hierarchy of redundancy in lifespan-predictive ability among three transgenes expressed in distinct tissues, suggesting that they collectively report on an organism-wide, cell non-autonomous process that acts to set each individual's lifespan.The origin recognition complex (ORC) cooperates with CDC6, MCM2-7, and CDT1 to form pre-RC complexes at origins of DNA replication. Here, using tiling-sgRNA CRISPR screens, we report that each subunit of ORC and CDC6 is essential in human cells. Using an auxin-inducible degradation system, we created stable cell lines capable of ablating ORC2 rapidly, revealing multiple cell division cycle phenotypes. The primary defects in the absence of ORC2 were cells encountering difficulty in initiating DNA replication or progressing through the cell division cycle due to reduced MCM2-7 loading onto chromatin in G1 phase. The nuclei of ORC2-deficient cells were also large, with decompacted heterochromatin. https://www.selleckchem.com/products/gdc-0068.html Some ORC2-deficient cells that completed DNA replication entered into, but never exited mitosis. ORC1 knockout cells also demonstrated extremely slow cell proliferation and abnormal cell and nuclear morphology. Thus, ORC proteins and CDC6 are indispensable for normal cellular proliferation and contribute to nuclear organization.Sequencing of cancer genomes has identified recurrent somatic mutations in histones, termed oncohistones, which are frequently poorly understood. Previously we showed that fission yeast expressing only the H3.3G34R mutant identified in aggressive pediatric glioma had reduced H3K36 trimethylation and acetylation, increased genomic instability and replicative stress, and defective homology-dependent DNA damage repair. Here we show that surprisingly distinct phenotypes result from G34V (also in glioma) and G34W (giant cell tumors of bone) mutations, differentially affecting H3K36 modifications, subtelomeric silencing, genomic stability; sensitivity to irradiation, alkylating agents, and hydroxyurea; and influencing DNA repair. In cancer, only 1 of 30 alleles encoding H3 is mutated. Whilst co-expression of wild-type H3 rescues most G34 mutant phenotypes, G34R causes dominant hydroxyurea sensitivity, homologous recombination defects, and dominant subtelomeric silencing. Together, these studies demonstrate the complexity associated with different substitutions at even a single residue in H3 and highlight the utility of genetically tractable systems for their analysis.Plaques of the amyloid beta (Aß) peptide are a pathological hallmark of Alzheimer's disease (AD), the most common form of dementia. Mutations in Aß also cause familial forms of AD (fAD). Here, we use deep mutational scanning to quantify the effects of >14,000 mutations on the aggregation of Aß. The resulting genetic landscape reveals mechanistic insights into fibril nucleation, including the importance of charge and gatekeeper residues in the disordered region outside of the amyloid core in preventing nucleation. Strikingly, unlike computational predictors and previous measurements, the empirical nucleation scores accurately identify all known dominant fAD mutations in Aß, genetically validating that the mechanism of nucleation in a cell-based assay is likely to be very similar to the mechanism that causes the human disease. These results provide the first comprehensive atlas of how mutations alter the formation of any amyloid fibril and a resource for the interpretation of genetic variation in Aß.Cells store energy in the form of neutral lipids (NLs) packaged into micrometer-sized organelles named lipid droplets (LDs). These structures emerge from the endoplasmic reticulum (ER) at sites marked by the protein seipin, but the mechanisms regulating their biogenesis remain poorly understood. Using a combination of molecular simulations, yeast genetics, and fluorescence microscopy, we show that interactions between lipids' acyl-chains modulate the propensity of NLs to be stored in LDs, in turn preventing or promoting their accumulation in the ER membrane. Our data suggest that diacylglycerol, which is enriched at sites of LD formation, promotes the packaging of NLs into LDs, together with ER-abundant lipids, such as phosphatidylethanolamine. On the opposite end, short and saturated acyl-chains antagonize fat storage in LDs and promote accumulation of NLs in the ER. Our results provide a new conceptual understanding of LD biogenesis in the context of ER homeostasis and function.
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