The RAD51 S181P mutation shortens lifespan of female mice.

RAD51 is critical to the homologous recombination (HR) pathway that repairs DNA double strand breaks (DSBs) and protects replication forks (RFs). Previously, we showed that the S181P (SP) mutation in RAD51 causes defective RF maintenance but is proficient for DSB repair. Here we report that SP/SP female mice exhibit a shortened lifespan compared to +/+ females but not males.

CRISPR screening identifies T cell-intrinsic regulators of CD3-bispecific antibody responses.

CD3-engaging bispecific antibodies (BsAbs) enable the formation of an immune synapse between T cells and tumor cells, resulting in robust target cell killing not dependent on a preexisting tumor specific T cell receptor. While recent studies have shed light on tumor cell-specific factors that modulate BsAb sensitivity, the T cell-intrinsic determinants of BsAb efficacy and response durability are poorly understood. To better clarify the genes that shape BsAb-induced T cell responses, we conducted targeted analyses and a large-scale unbiased CRISPR/Cas9-based screen to identify negative regulators of BsAb-induced T cell proliferation.

Human placental cytotrophoblast epigenome dynamics over gestation and alterations in placental disease.

The human placenta and its specialized cytotrophoblasts rapidly develop, have a compressed lifespan, govern pregnancy outcomes, and program the offspring's health. Understanding the molecular underpinnings of these behaviors informs development and disease. Profiling the extraembryonic epigenome and transcriptome during the 2nd and 3rd trimesters revealed H3K9 trimethylation overlapping deeply DNA hypomethylated domains with reduced gene expression and compartment-specific patterns that illuminated their functions.

PCA062, a P-cadherin Targeting Antibody-Drug Conjugate, Displays Potent Antitumor Activity Against P-cadherin-expressing Malignancies.

The cell surface glycoprotein P-cadherin is highly expressed in a number of malignancies, including those arising in the epithelium of the bladder, breast, esophagus, lung, and upper aerodigestive system. PCA062 is a P-cadherin specific antibody-drug conjugate that utilizes the clinically validated SMCC-DM1 linker payload to mediate potent cytotoxicity in cell lines expressing high levels of P-cadherin , while displaying no specific activity in P-cadherin-negative cell lines. High cell surface P-cadherin is necessary, but not sufficient, to mediate PCA062 cytotoxicity.

Genetic background modifies phenotypic severity and longevity in a mouse model of Niemann-Pick disease type C1.

Niemann-Pick disease type C1 (NPC1) is a rare, fatal neurodegenerative disorder characterized by lysosomal accumulation of unesterified cholesterol and glycosphingolipids. These subcellular pathologies lead to phenotypes of hepatosplenomegaly, neurological degeneration and premature death. NPC1 is extremely heterogeneous in the timing of clinical presentation and is associated with a wide spectrum of causative mutations.

Intra-dialytic hypotension: Identifying patients most at risk.

Background: Intra-dialytic hypotension (IDH) remains a frequent but serious complication of haemodialysis.

Methods: We performed a retrospective observational analysis of our prevalent dialysis population extracting data from an online database.

Results: Four hundred and thirty-two patients underwent 21 consecutive outpatient dialysis sessions during the study period: Of the 9,072 dialysis sessions studied, 438 were complicated by episodes of IDH (4.

Innovative practice: Conversational use of English in bilingual adults with dementia.

Regression to mother tongue is common in those with dementia. In two long-term care facilities, we explored the use of bilinguals' two languages for five older adults with mild-moderate dementia who have begun to regress to Greek. We also examined the role of Montessori DementiAbility Methods: The Montessori Way-based English language activities in fostering conversational use of English.

Implementing Montessori Methods for Dementia™ in Ontario long-term care homes: Recreation staff and multidisciplinary consultants' perceptions of policy and practice issues.

Montessori-based activities use a person-centred approach to benefit persons living with dementia by increasing their participation in, and enjoyment of, daily life. This study investigated recreation staff and multidisciplinary consultants' perceptions of factors that affected implementing Montessori Methods for Dementia™ in long-term care homes in Ontario, Canada. Qualitative data were obtained during semi-structured telephone interviews with 17 participants who worked in these homes.

Join the Revolution: How Montessori for Aging and Dementia can Change Long-Term Care Culture.

Efforts to improve the quality of life of persons with dementia in long-term care through the implementation of various approaches to person-centered care have been underway for the past two decades. Studies have yielded conflicting reports evaluating the evidence for these approaches. The purpose of this article is to outline the findings of several systematic reviews of this literature, highlighting the areas of improvement needs, and to describe a new person-centered care model, DementiAbility Methods: The Montessori Way.

Disruption of Visc-2, a Brain-Expressed Conserved Long Noncoding RNA, Does Not Elicit an Overt Anatomical or Behavioral Phenotype.

Although long noncoding RNAs (lncRNAs) are proposed to play essential roles in mammalian neurodevelopment, we know little of their functions from their disruption in vivo. Combining evidence for evolutionary constraint and conserved expression data, we previously identified candidate lncRNAs that might play important and conserved roles in brain function. Here, we demonstrate that the sequence and neuronal transcription of lncRNAs transcribed from the previously uncharacterized Visc locus are conserved across diverse mammals.

When dementia is in the house: needs assessment survey for young caregivers.

Objective: To learn more about the needs and experiences of young carers for patients of frontotemporal dementia (FTD) in order to create a relevant support website for young caregivers to dementia patients.

Methods: Two focus groups were held with a total of fourteen young carers aged 11-18. The data corpus was collected through a semi-structured interview facilitated by a medical journalist who had prior experience as a caregiver to a patient with FTD.

Predisposition to cancer caused by genetic and functional defects of mammalian Atad5.

ATAD5, the human ortholog of yeast Elg1, plays a role in PCNA deubiquitination. Since PCNA modification is important to regulate DNA damage bypass, ATAD5 may be important for suppression of genomic instability in mammals in vivo. To test this hypothesis, we generated heterozygous (Atad5(+/m)) mice that were haploinsuffficient for Atad5.

Confirmation of 5p12 as a susceptibility locus for progesterone-receptor-positive, lower grade breast cancer.

Background: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium.

Methods: Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS), and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry.

Wnt signaling gradients establish planar cell polarity by inducing Vangl2 phosphorylation through Ror2.

It is fundamentally important that signaling gradients provide positional information to govern morphogenesis of multicellular organisms. Morphogen gradients can generate different cell types in specific spatial order at distinct threshold concentrations. However, it is largely unknown whether and how signaling gradients also control cell polarities by acting as global cues.

Synthesis of 5-(6-hydroxy-7H-purine-8-ylthio)- 2-(N-hydroxyformamido)pentanoic acid.

We have developed a synthetic route for the preparation of a hybrid bisubstrate small molecule based on a nucleoside. A prototype compound was designed and docked into the catalytic domain of the AdSS enzyme bridging the region between the magnesium center of the protein to the nucleoside region. The synthesis involves coupling a brominated peptide fragment capable of complexing magnesium to a thiolated nucleoside to obtain the hybrid model compound.

Identification of neural crest and glial enhancers at the mouse Sox10 locus through transgenesis in zebrafish.

Sox10 is a dynamically regulated transcription factor gene that is essential for the development of neural crest-derived and oligodendroglial populations. Developmental genes often require multiple regulatory sequences that integrate discrete and overlapping functions to coordinate their expression. To identify Sox10 cis-regulatory elements, we integrated multiple model systems, including cell-based screens and transposon-mediated transgensis in zebrafish, to scrutinize mammalian conserved, noncoding genomic segments at the mouse Sox10 locus.

Activation of biliverdin-IXalpha reductase by inorganic phosphate and related anions.

The effect of pH on the initial-rate kinetic behaviour of BVR-A (biliverdin-IXalpha reductase) exhibits an alkaline optimum with NADPH as cofactor, but a neutral optimum with NADH as cofactor. This has been described as dual cofactor and dual pH dependent behaviour; however, no mechanism has been described to explain this phenomenon. We present evidence that the apparent peak of activity observed at neutral pH with phosphate buffer and NADH as cofactor is an anion-dependent activation, where inorganic phosphate apparently mimics the role played by the 2'-phosphate of NADPH in stabilizing the interaction between NADH and the enzyme.

Basal forebrain cholinergic lesions reduce heat shock protein 72 response but not pathology induced by the NMDA antagonist MK-801 in the rat cingulate cortex.

Non-competitive N-methyl-D-aspartate (NMDA) antagonists, in addition to their neuroprotective potential, possess neurotoxic properties and induce seizures and psychosis. MK-801 induces cytoplasmic vacuoles and heat shock protein in pyramidal neurones in the rodent posterior cingulate and retrosplenial cortex. The mechanism of this neurotoxicity is unclear, involving many neurotransmitter systems.

Potential physiological role of plant glycosidase inhibitors.

Carbohydrate-active enzymes including glycosidases, transglycosidases, glycosyltransferases, polysaccharide lyases and carbohydrate esterases are responsible for the enzymatic processing of carbohydrates in plants. A number of carbohydrate-active enzymes are produced by microbial pathogens and insects responsible of severe crop losses. Plants have evolved proteinaceous inhibitors to modulate the activity of several of these enzymes.

Myocardial protection with monophosphoryl lipid-A against aortic cross clamping-induced global stunning.

Background: Monophosphoryl lipid-A (MLA) has a late window (24 hours) of cardioprotection against acute myocardial infarction. It is not known whether MLA, administered, 24 hours before surgery, attenuates intraoperative ventricular dysfunction "stunning" associated with aortic cross-clamping and reperfusion during elective cardiac surgery. We determined the dose-response relationship between MLA and ventricular function in a canine model of global myocardial stunning in the absence of necrosis.

Factors in standardizing automated cholinesterase assays.

A scientific panel assembled by the U.S. Environmental Protection Agency (EPA) determined that variability in cholinesterase (ChE) activities in the agency's pesticide/animal study database likely was due to a lack of accepted guidelines for ChE methodology.

Constitutive expression of the mature array of neurofilament proteins by a CNS neuronal cell line.

Neurofilament protein expression was examined immunochemically in a neuronal cell line derived from postnatal day 21 septal tissue. The SN48.1p cell line was found to constitutively synthesize an array of neurofilament proteins typical of a mature neuron.

Confirmation of the structure of nisin and its major degradation product by FAB-MS and FAB-MS/MS.

FAB-MS has been applied to the analysis of a nisin complex and FAB-MS and FAB-MS/MS data from the major component used to provide confirmation of the amino sequence and positions of the sulphur-bridged rings in these highly modified peptides.

In vitro antiproliferative activity of 2'-(2-hydroxyphenyl)-2'-thiazoline-4'-carboxylic acid and its methyl ester on L1210 and P388 murine neoplasms.

The activity of three iron chelators, methyl [2'-(2-hydroxyphenyl)-2'-thiazoline-4'-carboxylate] (MTL); 2'-(2-hydroxyphenyl)-2'-thiazoline-4'-carboxylic acid (TFAL); and 2-hydroxyphenyl-imido-ethyl-ether (Imidate), regarding antiproliferative, cytocidal, and cell-cycle effects are reported and compared with hydroxyurea (HU). In vitro, against L1210 and P388 murine neoplasms, MTL and TFAL displayed substantially greater antiproliferative activity than HU, although Imidate displayed no appreciable activity. MTL also induced a statistically more complete G1/S cell-boundary block than did HU at equimolar concentrations (100 microM).