Ethyl 4-hydroxy­methyl-2-methyl­pyridine-5-carboxyl­ate

The title compound, C10H13NO3, was obtained as a by-product of the aldolization reaction of furo[3,4-c]pyridin-3(1H)-one with thio­phene-2-carboxaldehyde. The substituents on the pyridine ring are nearly coplanar, with an 8.1 (2)° rotation of the hydroxmethyl group from this plane. The mol­ecules assemble in the crystal structure as chains via O—H⋯N hydrogen bonding between the pyridine N atom and a neighbouring hydroxy­methyl OH group

Does an Interactive Health Promotion Website Facilitate Workplace Peer-to-Peer Substance Abuse Prevention?

Operation RedBlock, a substance abuse prevention and early intervention program at Amtrak, implemented an interactive health promotion website (On The Right Track, OTRT) for its volunteers, other employees and their families. OTRT was customized from the Substance Abuse and Mental Health Services Administration (SAMHSA) -sponsored [email protected] website and implemented with the purpose of facilitating the peer-to-peer substance abuse prevention efforts of Operation RedBlock volunteers. SAMHSA’s GetFit website combines broad health and wellness messages with current substance abuse prevention resources. The OTRT customization adds Amtrak relevant and specific content concerning substance abuse prevention resources and treatment options, drug and alcohol use policies, health care coverage, support group meeting locations and dates, and local Operation RedBlock and Employee Assistance Program contact information. Using a retrospective pretest-posttest design this study evaluates whether and how OTRT facilitated peer-to-peer efforts in substance abuse prevention and early intervention. The evaluation revealed that the website significantly improved access to information and resources that helped Operation RedBlock volunteers’ in their peer-to-peer efforts. Volunteers valued the ready availability of reliable information, the confidential nature, and the ease of use of OTRT. Facilitated access to information and resources may help reduce substance abuse among employees at high risk

A proteomic evaluation of urinary changes associated with cardiopulmonary bypass

Additional file 4: Table S4. Correlation filtered 2D DDA/IDA and SWATH protein difference values

Effects of a Small-Molecule Perforin Inhibitor in a Mouse Model of CD8 T Cell-Mediated Neuroinflammation.

BACKGROUND AND OBJECTIVES Alteration of the blood-brain barrier (BBB) at the interface between blood and CNS parenchyma is prominent in most neuroinflammatory diseases. In several neurologic diseases, including cerebral malaria and Susac syndrome, a CD8 T cell-mediated targeting of endothelial cells of the BBB (BBB-ECs) has been implicated in pathogenesis. METHODS In this study, we used an experimental mouse model to evaluate the ability of a small-molecule perforin inhibitor to prevent neuroinflammation resulting from cytotoxic CD8 T cell-mediated damage of BBB-ECs. RESULTS Using an in vitro coculture system, we first identified perforin as an essential molecule for killing of BBB-ECs by CD8 T cells. We then found that short-term pharmacologic inhibition of perforin commencing after disease onset restored motor function and inhibited the neuropathology. Perforin inhibition resulted in preserved BBB-EC viability, maintenance of the BBB, and reduced CD8 T-cell accumulation in the brain and retina. DISCUSSION Therefore, perforin-dependent cytotoxicity plays a key role in the death of BBB-ECs inflicted by autoreactive CD8 T cells in a preclinical model and potentially represents a therapeutic target for CD8 T cell-mediated neuroinflammatory diseases, such as cerebral malaria and Susac syndrome

EMT Inducers Catalyze Malignant Transformation of Mammary Epithelial Cells and Drive Tumorigenesis towards Claudin-Low Tumors in Transgenic Mice

The epithelial-mesenchymal transition (EMT) is an embryonic transdifferentiation process consisting of conversion of polarized epithelial cells to motile mesenchymal ones. EMT–inducing transcription factors are aberrantly expressed in multiple tumor types and are known to favor the metastatic dissemination process. Supporting oncogenic activity within primary lesions, the TWIST and ZEB proteins can prevent cells from undergoing oncogene-induced senescence and apoptosis by abolishing both p53- and RB-dependent pathways. Here we show that they also downregulate PP2A phosphatase activity and efficiently cooperate with an oncogenic version of H-RAS in malignant transformation of human mammary epithelial cells. Thus, by down-regulating crucial tumor suppressor functions, EMT inducers make cells particularly prone to malignant conversion. Importantly, by analyzing transformed cells generated in vitro and by characterizing novel transgenic mouse models, we further demonstrate that cooperation between an EMT inducer and an active form of RAS is sufficient to trigger transformation of mammary epithelial cells into malignant cells exhibiting all the characteristic features of claudin-low tumors, including low expression of tight and adherens junction genes, EMT traits, and stem cell–like characteristics. Claudin-low tumors are believed to be the most primitive breast malignancies, having arisen through transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Challenging this prevailing view, we propose that these aggressive tumors arise from cells committed to luminal differentiation, through a process driven by EMT inducers and combining malignant transformation and transdifferentiation

Inhibition of the cellular function of perforin by 1-amino-2, 4-dicyanopyrido[1,2-a]benzimidazoles

A high throughput screen showed the ability of a 1-amino-2,4-dicyanopyrido[1,2-a]benzimidazole analogue to directly inhibit the lytic activity of the pore-forming protein perforin. A series of analogues were prepared to study structure-activity relationships (SAR) for the this activity, either directly added to cells or released in situ by KHYG-1 NK cells, at non-toxic concentrations. These studies showed that the pyridobenzimidazole moiety was required for effective activity, with strongly basic centres disfavoured. This class of compounds was relatively unaffected by the addition of serum, which was not the case for a previous class of direct inhibitors

Community Protections in American Indian and Alaska Native Participatory Research—A Scoping Review

Experiences with unethical research practices have caused some American Indian and Alaska Native (AIAN) individuals, organizations, and tribes to mistrust health research. To build trust and repair relationships, current research with AIAN peoples often involves participatory research (PR) approaches. This article assesses community-level protections described in the scientific literature on PR involving AIAN communities. A scoping review search in PubMed and PsychInfo for articles published between January 2000 and June 2017 yielded an AIAN PR article dataset. Of 178 articles, a subset of 23 articles that described aspects of community protections were analyzed for descriptions of community-level protection practices. We identified the presence or absence of a description of four community protection measures in each article: a tribal research department, the development of community-level mechanisms for research regulation if not present, community collaboration throughout the research process, and project employment of a community member. The development of community-level mechanisms for research regulation was described in 39% of the articles. Ninety-one percent of these articles described community collaboration during the research process. Seventeen percent included descriptions of all four community-level protection measures. The extent and consistency to which community-level protections are described is variable; the current literature lacks reporting on community-level protection practices specific to tribal communities