The novel Cln1(R151X) mouse model of infantile neuronal ceroid lipofuscinosis (INCL) for testing nonsense suppression therapy.

The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of autosomal recessive neurodegenerative disorders in children characterized by the progressive onset of seizures, blindness, motor and cognitive decline and premature death. Patients with mutations in CLN1 primarily manifest with infantile NCL (INCL or Haltia-Santavuori disease), which is second only to congenital NCL for its age of onset and devastating progression. CLN1 encodes a lysosomal enzyme, palmitoyl-protein thioesterase 1 (PPT1).

Prolactin modulates luteal regression from the coeliac ganglion via the superior ovarian nerve in the late-pregnant rat.

There is considerable evidence of the neuroendocrine control involved in luteal regression in the rat. In addition, circulating prolactin (PRL), which increases during the night before parturition, may gain access to the coeliac ganglion (CG), indirectly impacting the physiology of the ovary because of the known connection between the CG and the ovary via the superior ovarian nerve (SON). In this work we investigated in the CG-SON-ovary system and whether PRL added to the CG has an impact, indirectly via the SON, on luteal regression on Day 21 of pregnancy.

Anti-rheumatic agent auranofin induced apoptosis in chronic myeloid leukemia cells resistant to imatinib through both Bcr/Abl-dependent and -independent mechanisms.

Resistance to Imatinib mesylate (IM) is an emerging problem for patients with chronic myelogenous leukemia (CML). T315I mutation in the Bcr-Abl is the predominant mechanism of the acquired resistance to IM and second generation tyrosine kinase inhibitors (TKI). Therefore it is urgent to search for new measures to overcome TKI-resistance.

Child maltreatment and deliberate self-harm: a negative binomial hurdle model for explanatory constructs.

Emerging adults demonstrate the highest rates of deliberate self-harm (DSH) and thus represent a population in need of further study. While child maltreatment (CM) history is a risk factor for DSH, the mechanisms behind this relationship are not fully understood. This study tested a model of mechanisms linking CM with DSH (likelihood of engaging in the behavior and frequency among those who self-harm) via negative urgency (tendency to engage in impulsive behaviors under conditions of negative affect), distress tolerance, sense of control, and desire for control in a sample of college students.

What is new in polycystic ovary syndrome? Best articles from the past year.

This month, we focus on current research in polycystic ovary syndrome. Dr. Hansen discusses six recent publications, and each is concluded with a "bottom line" that is the take-home message.

pH-modulated molecular assemblies and surface properties of metal-organic supercontainers at the air-water interface.

The orientation of metal-organic supercontainer (MOSC) molecules in Langmuir films was systematically studied at the air-water interface. The acidity of the aqueous subphases plays a significant role in tuning the orientation of MOSC molecules in the Langmuir films. Furthermore, Langmuir-Blodgett films of MOSCs were prepared and the uniform multilayer structures demonstrated various surface properties, depending on their conditions of fabrication.

Thioredoxin-1 redox signaling regulates cell survival in response to hyperoxia.

The most common form of newborn chronic lung disease, bronchopulmonary dysplasia (BPD), is thought to be caused by oxidative disruption of lung morphogenesis, which results in decreased pulmonary vasculature and alveolar simplification. Although cellular redox status is known to regulate cellular proliferation and differentiation, redox-sensitive pathways associated with these processes in developing pulmonary epithelium are unknown. Redox-sensitive pathways are commonly regulated by cysteine thiol modifications.

Sumo E2 enzyme UBC9 is required for efficient protein quality control in cardiomyocytes.

Rationale: Impairment of proteasomal function is pathogenic in several cardiac proteinopathies and can eventually lead to heart failure. Loss of proteasomal activity often results in the accumulation of large protein aggregates. The ubiquitin proteasome system (UPS) is primarily responsible for cellular protein degradation, and although the role of ubiquitination in this process is well studied, the function of an ancillary post-translational modification, SUMOylation, in protein quality control is not fully understood.

The interplay between autophagy and the ubiquitin-proteasome system in cardiac proteotoxicity.

Proteotoxicity refers to the detrimental effects of damaged/misfolded proteins on the cell. Cardiac muscle is particularly susceptible to proteotoxicity because sustained and severe proteotoxic stress leads to cell death and the cardiac muscle has very limited self-renewal capacity. The ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway (ALP) are two major pathways responsible for degradation of most cellular proteins.

Strain-dependent brain defects in mouse models of primary ciliary dyskinesia with mutations in Pcdp1 and Spef2.

Hydrocephalus is caused by the accumulation of cerebrospinal fluid (CSF) in the cerebral ventricular system which results in an enlargement of the cranium due to increased intraventricular pressure. The increase in pressure within the brain typically results in sloughing of ciliated ependymal cells, loss of cortical gray matter, and increased gliosis. Congenital hydrocephalus is associated with several syndromes including primary ciliary dyskinesia (PCD), a rare, genetically heterogeneous, pediatric syndrome that results from defects in motile cilia and flagella.

Aggressive variant of a solid pseudopapillary neoplasm: a case report and literature review.

Solid pseudopapillary neoplasm, a lesion of uncertain cellular differentiation, is an unusual tumor of the pancreas with an indolent clinical course that typically arises in young females. We report a case of solid pseudopapillary neoplasm arising in a 17-year-old adolescent girl who presented with progressive abdominal pain. The patient underwent surgical resection of an 18 × 14 × 8-cm pancreatic mass that displayed the usual histologic features of a solid pseudopapillary neoplasm in addition to prominent nuclear atypia, increased proliferative index, and extensive necrosis.

Clinically used antirheumatic agent auranofin is a proteasomal deubiquitinase inhibitor and inhibits tumor growth.

Proteasomes are attractive emerging targets for anti-cancer therapies. Auranofin (Aur), a gold-containing compound clinically used to treat rheumatic arthritis, was recently approved by US Food and Drug Administration for Phase II clinical trial to treat cancer but its anti-cancer mechanism is poorly understood. Here we report that (i) Aur shows proteasome-inhibitory effect that is comparable to that of bortezomib/Velcade (Vel); (ii) different from bortezomib, Aur inhibits proteasome-associated deubiquitinases (DUBs) UCHL5 and USP14 rather than the 20S proteasome; (iii) inhibition of the proteasome-associated DUBs is required for Aur-induced cytotoxicity; and (iv) Aur selectively inhibits tumor growth in vivo and induces cytotoxicity in cancer cells from acute myeloid leukemia patients.

Autophagic-lysosomal inhibition compromises ubiquitin-proteasome system performance in a p62 dependent manner in cardiomyocytes.

Intracellular protein degradation is primarily performed by the ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway (ALP). The interplay between these two pathways has been rarely examined in intact animals and the mechanism underlying the interplay remains unclear. Hence, we sought to test in vivo and in vitro the impact of inhibition of the ALP on UPS proteolytic performance in cardiomyocytes and to explore the underlying mechanism.

Emotion differentiation and alcohol-related problems: the mediating role of urgency.

Deficits in emotional and behavioral regulation figure prominently in etiological models of alcohol-related problems. This study tests a model linking poor differentiation of emotion to alcohol-related problems via urgency. The sample consisted of 102 undergraduates between the ages 18 and 24 who reported moderate to heavy alcohol consumption.

The many faces of affect: a multilevel model of drinking frequency/quantity and alcohol dependence symptoms among young adults.

This research tested a multilevel structural equation model of associations between 3 aspects of affective functioning (state affect, trait affect, and affective lability) and 3 alcohol outcomes (likelihood of drinking, quantity on drinking days, and dependence symptoms) in a sample of 263 college students. Participants provided 49 days of experience sampling data over 1.3 years in a longitudinal burst design.

Is the omega-3 index a valid marker of intestinal membrane phospholipid EPA+DHA content?

Despite numerous studies investigating n-3 long chain polyunsaturated fatty acid (LCPUFA) supplementation and inflammatory bowel diseases (IBD), the extent to which dietary n-3 LCPUFAs incorporate in gastrointestinal (GI) tissues and correlate with red blood cell (RBC) n-3 LCPUFA content is unknown. In this study, mice were fed three diets with increasing percent of energy (%en) derived from eicosapentaenoic acid (EPA)+docosahexaenoic acid (DHA). Dietary levels reflected recommended intakes of fish/fish oil by the American Heart Association.

A novel proteasome inhibitor suppresses tumor growth via targeting both 19S proteasome deubiquitinases and 20S proteolytic peptidases.

The successful development of bortezomib-based therapy for treatment of multiple myeloma has established proteasome inhibition as an effective therapeutic strategy, and both 20S proteasome peptidases and 19S deubiquitinases (DUBs) are becoming attractive targets of cancer therapy. It has been reported that metal complexes, such as copper complexes, inhibit tumor proteasome. However, the involved mechanism of action has not been fully characterized.

Gastrointestinal bleeding.

• On the basis of strong research evidence, children with severe upper gastrointestinal tract bleeding should be treated with intravenous proton pump inhibitors. • On the basis of some research evidence and consensus, children with severe gastrointestinal bleeding should be evaluated by endoscopy. • On the basis of some research evidence and consensus, children in whom endoscopy has not been able to confirm a bleeding source should be considered for capsule endoscopy.

Vitamin-C delivery from CoCr alloy surfaces using polymer-free and polymer-based platforms for cardiovascular stent applications.

Antiproliferative drugs such as paclitaxel and sirolimus are delivered from stents to inhibit the growth of smooth muscle cells (SMCs) for preventing neointimal hyperplasia. However, these drugs delay the growth of endothelial cells (ECs) as well and cause late stent thrombosis. We recently demonstrated the use of Vitamin-C (l-ascorbic acid, l-AA) over paclitaxel and sirolimus for inhibiting SMCs growth and promoting EC growth simultaneously.

Synthetic supercontainers exhibit distinct solution versus solid state guest-binding behavior.

The phase-dependent host-guest binding behavior of a new family of synthetic supercontainers has been probed in homogeneous solution and at liquid-liquid, solid-liquid, and solid-gas interfaces. The synthetic hosts, namely, type II metal-organic supercontainers (MOSCs), are constructed from the assembly of divalent metal ions, 1,4-benzenedicarboxylate (BDC) linker, and sulfonylcalix[4]arene-based container precursors. One member of the MOSCs, MOSC-II-tBu-Ni, which is derived from Ni(II), BDC, and p-tert-butylsulfonylcalix[4]arene (TBSC), crystallizes in the space group R3 and adopts pseudo face-centered cubic (fcc) packing, whereas other MOSCs, including TBSC analogue MOSC-II-tBu-Co, p-tert-pentylsulfonylcalix[4]arene (TPSC) analogues MOSC-II-tPen-Ni/Co, and p-tert-octylsulfonylcalix[4]arene (TOSC) analogues MOSC-II-tOc-Ni/Mg/Co, all crystallize in the space group I4/m and assume a pseudo body-centered cubic (bcc) packing mode.

Cortical innervation of the hypoglossal nucleus in the non-human primate (Macaca mulatta).

The corticobulbar projection to the hypoglossal nucleus was studied from the frontal, parietal, cingulate, and insular cortices in the rhesus monkey by using high-resolution anterograde tracers and stereology. The hypoglossal nucleus received bilateral input from the face/head region of the primary (M1), ventrolateral pre- (LPMCv), supplementary (M2), rostral cingulate (M3), and caudal cingulate (M4) motor cortices. Additional bilateral corticohypoglossal projections were found from the dorsolateral premotor cortex (LPMCd), ventrolateral proisocortical motor area (ProM), ventrolateral primary somatosensory cortex (S1), rostral insula, and pregenual region of the anterior cingulate gyrus (areas 24/32).

A polymer-free Paclitaxel eluting coronary stent: effects of solvents, drug concentrations and coating methods.

Some polymer coatings used in drug-eluting stents (DES) cause adverse reactions. Hence, the use of self-assembled monolayers (SAMs) as a polymer-free platform to deliver an anti-proliferative drug (paclitaxel-PAT) from 2D metal substrates was previously demonstrated. In this study, we optimized the PAT coating on SAMs coated 3D coronary stents.

Ubiquitin-like (UBX)-domain-containing protein, UBXN2A, promotes cell death by interfering with the p53-Mortalin interactions in colon cancer cells.

Mortalin (mot-2) induces inactivation of the tumor suppressor p53's transcriptional and apoptotic functions by cytoplasmic sequestration of p53 in select cancers. The mot-2-dependent cytoprotective function enables cancer cells to support malignant transformation. Abrogating the p53-mot-2 interaction can control or slow down the growth of cancer cells.

Building a whole new mind: an interprofessional experience in patient safety and quality improvement education using the IHI Open School.

Introduction: Throughout the last decade, there has been a significant move toward integrating patient safety and quality improvement concepts into health professions education, essentially building a whole new mind in terms of medical knowledge. While existing literature has suggested possible means of implementation, little research has described outcomes and specific examples of integration. The Institute for Healthcare Improvement (IHI) Open School offers a curriculum that could be incorporated in most health professions training.

Dietary intake, nutrition, and fetal alcohol spectrum disorders in the Western Cape Province of South Africa.

In this study, we describe the nutritional status of women from a South African community with very high rates of fetal alcohol spectrum disorders (FASD). Nutrient intake (24-h recall) of mothers of children with FASD was compared to mothers of normal controls. Nutrient adequacy was assessed using Dietary Reference Intakes (DRIs).