Hydatidiform mole (HM) is an abnormal human pregnancy with no embryo and cystic degeneration of placental villi. We report five mutations in the maternal gene NALP7 in individuals with familial and recurrent HMs. NALP7 is a member of the CATERPILLER protein family involved in inflammation and apoptosis. NALP7 is the first maternal effect gene identified in humans and is also responsible for recurrent spontaneous abortions, stillbirths and intrauterine growth retardation.

Advancements in computer vision and artificial intelligence (AI) carry the potential to make significant contributions to health care, particularly in diagnostic specialties such as radiology and pathology. The impact of these technologies on physician stakeholders is the subject of significant speculation. There is however a dearth of information regarding the opinions, enthusiasm, and concerns of the pathology community at large. Here, we report results from a survey of 487 pathologist-respondents practicing in 54 countries, conducted to examine perspectives on AI implementation in clinical practice. Despite limitations, including difficulty with quantifying response bias and verifying identity of respondents to this anonymous and voluntary survey, several interesting findings were uncovered. Overall, respondents carried generally positive attitudes towards AI, with nearly 75% reporting interest or excitement in AI as a diagnostic tool to facilitate improvements in workflow efficiency and quality assurance in pathology. Importantly, even within the more optimistic cohort, a significant number of respondents endorsed concerns about AI, including the potential for job displacement and replacement. Overall, around 80% of respondents predicted the introduction of AI technology in the pathology laboratory within the coming decade. Attempts to identify statistically significant demographic characteristics (e.g., age, sex, type/place of practice) predictive of attitudes towards AI using Kolmogorov–Smirnov (KS) testing revealed several associations. Important themes which were commented on by respondents included the need for increasing efforts towards physician training and resolving medical-legal implications prior to the generalized implementation of AI in pathology.

Induced pluripotent stem (iPS) cell reprogramming is a gradual epigenetic process that reactivates the pluripotent transcriptional network by erasing and establishing repressive epigenetic marks. In contrast to loci-specific epigenetic changes, heterochromatin domains undergo epigenetic resetting during the reprogramming process, but the effect on the heterochromatin ultrastructure is not known. Here, we characterize the physical structure of heterochromatin domains in full and partial mouse iPS cells by correlative electron spectroscopic imaging. In somatic and partial iPS cells, constitutive heterochromatin marked by H3K9me3 is highly compartmentalized into chromocentre structures of densely packed chromatin fibres. In contrast, chromocentre boundaries are poorly defined in pluripotent embryonic stem and full iPS cells, and are characterized by unusually dispersed 10 nm heterochromatin fibres in high Nanog-expressing cells, including pluripotent cells of the mouse blastocyst before differentiation. This heterochromatin reorganization accompanies retroviral silencing during conversion of partial iPS cells by MEK/GSK3 2i inhibitor treatment. Thus, constitutive heterochromatin is compacted in partial iPS cells but reorganizes into dispersed 10 nm chromatin fibres as the fully reprogrammed iPS cell state is acquired.

No abstract

The mammalian genome is compacted to fit within the confines of the cell nucleus. DNA is wrapped around nucleosomes, forming the classic 'beads-on-a-string' 10-nm chromatin fibre. Ten-nanometre chromatin fibres are thought to condense into 30-nm fibres. This structural reorganization is widely assumed to correspond to transitions between active and repressed chromatin, thereby representing a chief regulatory event. Here, by combining electron spectroscopic imaging with tomography, three-dimensional images are generated, revealing that both open and closed chromatin domains in mouse somatic cells comprise 10-nm fibres. These findings indicate that the 30-nm chromatin model does not reflect the true regulatory structure in vivo.Keywords: chromatin fibre; nuclear organization; electron tomography EMBO reports (2012) 13, 992-996.

Background: NLRP7 is responsible for recurrent hydatidiform moles, but its functional role is unknown. Results: NLRP7 mutations impair IL-1␤ and TNF secretion but do not affect IL-1␤ processing. NLRP7 co-localizes with the microtubule organizing center, and mutations impair cytokine trafficking. Conclusion: Patients with NLRP7 mutations have abnormal tolerance to aberrant pregnancies. Significance: We unravel a new mechanism for reproductive wastage.

MECP2 mutations cause the X-linked neurodevelopmental disorder Rett Syndrome (RTT) by consistently altering the protein encoded by the MECP2e1 alternative transcript. While mutations that simultaneously affect both MECP2e1 and MECP2e2 isoforms have been widely studied, the consequence of MECP2e1 deficiency on human neurons remains unknown. Here we report the first isoform-specific patient induced pluripotent stem cell (iPSC) model of RTT. RTTe1 patient iPS cell-derived neurons retain an inactive X-chromosome and express only the mutant allele. Single-cell mRNA analysis demonstrated they have a molecular signature of cortical neurons. Mutant neurons exhibited a decrease in soma size, reduced dendritic complexity and decreased cell capacitance, consistent with impaired neuronal maturation. The soma size phenotype was rescued cell-autonomously by MECP2e1 transduction in a level-dependent manner but not by MECP2e2 gene transfer. Importantly, MECP2e1 mutant neurons showed dysfunction in action potential generation, voltage-gated Na+ currents, and miniature excitatory synaptic current frequency and amplitude. We conclude that MECP2e1 mutation affects soma size, information encoding properties and synaptic connectivity in human neurons that are defective in RTT.

Glioblastoma is an aggressive form of brain cancer with well-established patterns of intra-tumoral heterogeneity implicated in treatment resistance and progression. While regional and single cell transcriptomic variations of glioblastoma have been recently resolved, downstream phenotype-level proteomic programs have yet to be assigned across glioblastoma’s hallmark histomorphologic niches. Here, we leverage mass spectrometry to spatially align abundance levels of 4,794 proteins to distinct histologic patterns across 20 patients and propose diverse molecular programs operational within these regional tumor compartments. Using machine learning, we overlay concordant transcriptional information, and define two distinct proteogenomic programs, MYC- and KRAS-axis hereon, that cooperate with hypoxia to produce a tri-dimensional model of intra-tumoral heterogeneity. Moreover, we highlight differential drug sensitivities and relative chemoresistance in glioblastoma cell lines with enhanced KRAS programs. Importantly, these pharmacological differences are less pronounced in transcriptional glioblastoma subgroups suggesting that this model may provide insights for targeting heterogeneity and overcoming therapy resistance.