Pluripotent embryonic stem cells (ESCs) have a shortened cell cycle that enables their rapid proliferation. The ESC-specific miR-290 and miR-302 microRNA families promote proliferation whereas let-7 microRNAs inhibit self-renewal and promote cell differentiation. Lin28 suppresses let-7 expression in ESCs. Here, to gain further insight into mechanisms controlling ESC self-renewal we explore the molecular and cellular role of the let-7 target Trim71 (mLin41). We show that Trim71 associates with Argonaute2 (Ago2) and microRNAs and represses expression of Cdkn1a, a cyclin-dependent kinase inhibitor that negatively regulates the G1–S transition. We identify protein domains required for Trim71 association with Ago2, localization to P-bodies, and for repression of reporter mRNAs. Trim71 knockdown prolongs the G1 phase of the cell cycle and slows ESC proliferation, a phenotype that was rescued by depletion of Cdkn1a. Thus, we demonstrate Trim71 is a factor that facilitates the G1–S transition to promote rapid ESC self-renewal.
Background
Human Polyomavirus 6 (HPyV6) and Human Polyomavirus 7 (HPyV7) are shed chronically from human skin. HPyV7, but not HPyV6, has been linked to a pruritic skin eruption of immunosuppression.
Objective
We determined whether biopsies showing a characteristic pattern of dyskeratosis and parakeratosis might be associated with polyomavirus infection.
Methods
We screened biopsies showing “peacock plumage” histology by PCR for human polyomaviruses. Cases positive for HPyV 6 or 7 were then analyzed by immunohistochemistry, electron microscopy (EM), immunofluorescence, quantitative PCR, and complete sequencing, including unbiased, next generation sequencing (NGS).
Results
We identified three additional cases of HPyV6 or 7 skin infections. Expression of T antigen and viral capsid was abundant in lesional skin. Dual immunofluorescence staining experiments confirmed that HPyV7 primarily infects keratinocytes. High viral loads in lesional skin compared to normal skin and the identification of intact virions by both EM and NGS support a role for active viral infections in these skin diseases.
Limitation
This was a small case-series of archived materials.
Conclusion
We have found that HPyV6 and HPyV7 are associated with rare, pruritic skin eruptions with a unique histologic pattern and describe this entity as “HPyV6- and HPyV7-associated pruritic and dyskeratotic dermatosis (H6PD and H7PD).”
Protein motion is often the link between structure and function and a substantial fraction of proteins move through a domain hinge bending mechanism. Predicting the location of the hinge from a single structure is thus a logical first step towards predicting motion. Here, we describe ways to predict the hinge location by grouping residues with correlated normal-mode motions. We benchmarked our normal-mode based predictor against a gold standard set of carefully annotated hinge locations taken from the Database of Macromolecular Motions. We then compared it with three existing structure-based hinge predictors (TLSMD, StoneHinge, and FlexOracle), plus HingeSeq, a sequence-based hinge predictor. Each of these methods predicts hinges using very different sources of information-normal modes, experimental thermal factors, bond constraint networks, energetics, and sequence, respectively. Thus it is logical that using these algorithms together would improve predictions. We integrated all the methods into a combined predictor using a weighted voting scheme. Finally, we encapsulated all our results in a web tool which can be used to run all the predictors on submitted proteins and visualize the results.
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