High proliferation and delamination during skin epidermal stratification.

The development of complex stratified epithelial barriers in mammals is initiated from single-layered epithelia. How stratification is initiated and fueled are still open questions. Previous studies on skin epidermal stratification suggested a central role for perpendicular/asymmetric cell division orientation of the basal keratinocyte progenitors. Here, we use centrosomes, that organize the mitotic spindle, to test whether cell division orientation and stratification are linked. Genetically ablating centrosomes from the developing epidermis leads to the activation of the p53-, 53BP1- and USP28-dependent mitotic surveillance pathway causing a thinner epidermis and hair follicle arrest. The centrosome/p53-double mutant keratinocyte progenitors significantly alter their division orientation in the later stages without majorly affecting epidermal differentiation. Together with time-lapse imaging and tissue growth dynamics measurements, the data suggest that the first and major phase of epidermal development is boosted by high proliferation rates in both basal and suprabasally-committed keratinocytes as well as cell delamination, whereas the second phase maybe uncoupled from the division orientation of the basal progenitors. The data provide insights for tissue homeostasis and hyperproliferative diseases that may recapitulate developmental programs

Collaborations in Liberal Arts Colleges in Support of Digital Humanities

The field of digital humanities has been rapidly expanding over the course of the last decade. As such, academic institutions have been working to identify ways of supporting these new endeavors in a time of economic struggles. The Digital Humanities Initiative (DHi) at Hamilton College was conceived as one possible model of supporting digital humanities scholarship at a liberal arts institution. The DHi model relies heavily on collaboration among different teams in the Library and Information Technology Services across campus, and with institutions across the United States. DHi also has international partnerships that promote its goals in research, learning, and public humanities. This chapter will describe the various collaborations of DHi and offer suggestions for how others can implement similar support models at their institutions

Requirements for an IoT-lock enabling asynchronous physical handovers of temi-trailers in road freight relay-transport

In long-distance road freight transport, capacity utilization of semi-trailers is less than 30 % due to mandatory steering and rest periods. Truck parking spaces are overcrowded while resulting parking search traffic leads to additional emissions. At the same time, the acute driver shortage and customers' expectations of ever faster functioning supply chains force the highest efficiency in transport means and personnel. Multi-carrier relay-transport represents an approach to solving these problems and exploiting untapped efficiency potentials: Via a digital platform, long distances are intelligently divided into short route sections which are distributed among different carriers. At predefined switching points, the asynchronous handover of semi-trailers to rested drivers takes place. To enable a secure cross-company physical handover, IoT-locking mechanisms play a crucial role. This paper details the asynchronous handover process and introduces the technical design of an IoT-lock which provides effective theft protection while the trailer is parked and reliably connects tractor and semi-trailer during transport. Based on an analysis of stakeholder requirements, software functionalities and mechanical properties of the IoT-lock are derived, which ensure effective theft protection as well as real-time data transmission for relay transports. In addition, legal requirements for asynchronous transfers are investigated to determine liability in case of damage or loss. These form the basis for digital handover protocols that record the condition of the freight and trailer during the handover process

Predicting Functional and Regulatory Divergence of a Drug Resistance Transporter Gene in the Human Malaria Parasite

Background: The paradigm of resistance evolution to chemotherapeutic agents is that a key coding mutation in a specific gene drives resistance to a particular drug. In the case of resistance to the anti-malarial drug chloroquine (CQ), a specific mutation in the transporter pfcrt is associated with resistance. Here, we apply a series of analytical steps to gene expression data from our lab and leverage 3 independent datasets to identify pfcrt-interacting genes. Resulting networks provide insights into pfcrt’s biological functions and regulation, as well as the divergent phenotypic effects of its allelic variants in different genetic backgrounds. Results: To identify pfcrt-interacting genes, we analyze pfcrt co-expression networks in 2 phenotypic states - CQ-resistant (CQR) and CQ-sensitive (CQS) recombinant progeny clones - using a computational approach that prioritizes gene interactions into functional and regulatory relationships. For both phenotypic states, pfcrt co-expressed gene sets are associated with hemoglobin metabolism, consistent with CQ’s expected mode of action. To predict the drivers of co-expression divergence, we integrate topological relationships in the co-expression networks with available high confidence protein-protein interaction data. This analysis identifies 3 transcriptional regulators from the ApiAP2 family and histone acetylation as potential mediators of these divergences. We validate the predicted divergences in DNA mismatch repair and histone acetylation by measuring the effects of small molecule inhibitors in recombinant progeny clones combined with quantitative trait locus (QTL) mapping. Conclusions: This work demonstrates the utility of differential co-expression viewed in a network framework to uncover functional and regulatory divergence in phenotypically distinct parasites. pfcrt-associated co-expression in the CQ resistant progeny highlights CQR-specific gene relationships and possible targeted intervention strategies. The approaches outlined here can be readily generalized to other parasite populations and drug resistances

Proceedings of the Working Group Session on Fertility Preservation for Individuals with Gender and Sex Diversity

Children and adolescents with gender and sex diversity include (1) gender-nonconforming and transgender individuals for whom gender identity or expression are incongruent with birth-assigned sex (heretofore, transgender) and (2) individuals who have differences in sex development (DSD). Although these are largely disparate groups, there is overlap in the medical expertise necessary to care for individuals with both gender and sex diversity. In addition, both groups face potential infertility or sterility as a result of desired medical and surgical therapies. The Ann and Robert H. Lurie Children's Hospital of Chicago (Lurie Children's) gender and sex development program (GSDP) provides specialized multidisciplinary care for both transgender and DSD patients. In response to patient concerns that recommended medical treatments have the potential to affect fertility, the Lurie Children's GSDP team partnered with experts from the Oncofertility Consortium at Northwestern University to expand fertility preservation options to gender and sex diverse youth. This article summarizes the results of a meeting of experts across this field at the annual Oncofertility Consortium conference with thoughts on next steps toward a unified protocol for this patient group.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140296/1/trgh.2016.0008.pd

Functionality of fatty acid chemoreception : a potential factor in the development of obesity?

Excess dietary fat consumption is recognized as a strong contributing factor in the development of overweight and obesity. Understanding why some individuals are better than others at regulating fat intake will become increasingly important and emerging associative evidence implicates attenuated fatty acid sensing in both the oral cavity and gastrointestinal (GI) tract in the development of obesity. Functional implications of impaired fatty acid chemoreception include diminished activation of the gustatory system, the cephalic response and satiety. This review will focus on knowledge from animal and human studies supporting the existence of oral fatty acid chemoreception including putative oral detection mechanisms, and how sensitivity to fatty acids is associated with fat consumption and fatty food preference

Human subjects protection issues in QUERI implementation research: QUERI Series

<p>Abstract</p> <p>Background</p> <p>Human Subjects protections approaches, specifically those relating to research review board oversight, vary throughout the world. While all are designed to protect participants involved in research, the structure and specifics of these institutional review boards (IRBs) can and do differ. This variation affects all types of research, particularly implementation research.</p> <p>Methods</p> <p>In 2001, we began a series of inter-related studies on implementing evidence-based collaborative care for depression in Veterans Health Administration primary care. We have submitted more than 100 IRB applications, amendments, and renewals, and in doing so, we have interacted with 13 VA and University IRBs across the United States (U.S.). We present four overarching IRB-related themes encountered throughout the implementation of our projects, and within each theme, identify key challenges and suggest approaches that have proved useful. Where applicable, we showcase process aids developed to assist in resolving a particular IRB challenge.</p> <p>Results</p> <p>There are issues unique to implementation research, as this type of research may not fit within the traditional Human Subjects paradigm used to assess clinical trials. Risks in implementation research are generally related to breaches of confidentiality, rather than health risks associated with traditional clinical trials. The implementation-specific challenges discussed are: external validity considerations, Plan-Do-Study-Act cycles, risk-benefit issues, the multiple roles of researchers and subjects, and system-level unit of analysis.</p> <p>Discussion</p> <p>Specific aspects of implementation research interact with variations in knowledge, procedures, and regulatory interpretations across IRBs to affect the implementation and study of best methods to increase evidence-based practice. Through lack of unambiguous guidelines and local liability concerns, IRBs are often at risk of applying both variable and inappropriate or unnecessary standards to implementation research that are not consistent with the spirit of the Belmont Report (a summary of basic ethical principles identified by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research), and which impede the conduct of evidence-based quality improvement research. While there are promising developments in the IRB community, it is incumbent upon implementation researchers to interact with IRBs in a manner that assists appropriate risk-benefit determinations and helps prevent the process from having a negative impact on efforts to reduce the lag in implementing best practices.</p