Epitaxy: Programmable Atom Equivalents

The programmability of DNA makes it an attractive structure-directing ligand for the assembly of nanoparticle (NP) superlattices in a manner that mimics many aspects of atomic crystallization. However, the synthesis of multilayer single crystals of defined size remains a challenge. Though previous studies considered lattice mismatch as the major limiting factor for multilayer assembly, thin film growth depends on many interlinked variables. Here, a more comprehensive approach is taken to study fundamental elements, such as the growth temperature and the thermodynamics of interfacial energetics, to achieve epitaxial growth of NP thin films. Both surface morphology and internal thin film structure are examined to provide an understanding of particle attachment and reorganization during growth. Under equilibrium conditions, single crystalline, multilayer thin films can be synthesized over 500 × 500 μm² areas on lithographically patterned templates, whereas deposition under kinetic conditions leads to the rapid growth of glassy films. Importantly, these superlattices follow the same patterns of crystal growth demonstrated in atomic thin film deposition, allowing these processes to be understood in the context of well-studied atomic epitaxy and enabling a nanoscale model to study fundamental crystallization processes. Through understanding the role of epitaxy as a driving force for NP assembly, we are able to realize 3D architectures of arbitrary domain geometry and size.United States. Air Force Office of Scientific Research (AFOSR FA9550-11-1-0275)United States. Air Force Office of Scientific Research (FA9550-12-1-0280)United States. Department of Defense (N00014-15-1-0043)United States. Department of Energy (Grant DE-SC0000989-0002)National Science Foundation (U.S.) (Award DMR-1121262

Priming Picture Naming with a Semantic Task: An fMRI Investigation

Prior semantic processing can enhance subsequent picture naming performance, yet the neurocognitive mechanisms underlying this effect and its longevity are unknown. This functional magnetic resonance imaging study examined whether different neurological mechanisms underlie short-term (within minutes) and long-term (within days) facilitation effects from a semantic task in healthy older adults. Both short- and long-term facilitated items were named significantly faster than unfacilitated items, with short-term items significantly faster than long-term items. Region of interest results identified decreased activity for long-term facilitated items compared to unfacilitated and short-term facilitated items in the mid-portion of the middle temporal gyrus, indicating lexical-semantic priming. Additionally, in the whole brain results, increased activity for short-term facilitated items was identified in regions previously linked to episodic memory and object recognition, including the right lingual gyrus (extending to the precuneus region) and the left inferior occipital gyrus (extending to the left fusiform region). These findings suggest that distinct neurocognitive mechanisms underlie short- and long-term facilitation of picture naming by a semantic task, with long-term effects driven by lexical-semantic priming and short-term effects by episodic memory and visual object recognition mechanisms

The neural correlates of picture naming facilitated by auditory repetition

Background: Overt repetition of auditorily presented words can facilitate picture naming performance in both unimpaired speakers and individuals with word retrieval difficulties, but the underlying neurocognitive mechanisms and longevity of such effects remain unclear. This study used functional magnetic resonance imaging to examine whether different neurological mechanisms underlie short-term (within minutes) and long-term (within days) facilitation effects from an auditory repetition task in healthy older adults

Diazoxide choline extended‐release tablet in people with Prader‐Willi syndrome: results from long‐term open‐label study

Objective: This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi syndrome (PWS). Methods: The authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open-label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety. Results: DCCR administration resulted in significant improvements in HQ-CT (mean [SE] −9.9 [0.77], p < 0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ-CT > 22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment-emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%). Conclusions: DCCR administration to people with PWS was well tolerated and associated with broad-ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families

Statins enhance efficacy of venetoclax in blood cancers.

Statins have shown promise as anticancer agents in experimental and epidemiologic research. However, any benefit that they provide is likely context-dependent, for example, applicable only to certain cancers or in combination with specific anticancer drugs. We report that inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) using statins enhances the proapoptotic activity of the B cell lymphoma-2 (BCL2) inhibitor venetoclax (ABT-199) in primary leukemia and lymphoma cells but not in normal human peripheral blood mononuclear cells. By blocking mevalonate production, HMGCR inhibition suppressed protein geranylgeranylation, resulting in up-regulation of proapoptotic protein p53 up-regulated modulator of apoptosis (PUMA). In support of these findings, dynamic BH3 profiling confirmed that statins primed cells for apoptosis. Furthermore, in retrospective analyses of three clinical studies of chronic lymphocytic leukemia, background statin use was associated with enhanced response to venetoclax, as demonstrated by more frequent complete responses. Together, this work provides mechanistic justification and clinical evidence to warrant prospective clinical investigation of this combination in hematologic malignancies

Statins enhance efficacy of venetoclax in blood cancers.

Statins have shown promise as anticancer agents in experimental and epidemiologic research. However, any benefit that they provide is likely context-dependent, for example, applicable only to certain cancers or in combination with specific anticancer drugs. We report that inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) using statins enhances the proapoptotic activity of the B cell lymphoma-2 (BCL2) inhibitor venetoclax (ABT-199) in primary leukemia and lymphoma cells but not in normal human peripheral blood mononuclear cells. By blocking mevalonate production, HMGCR inhibition suppressed protein geranylgeranylation, resulting in up-regulation of proapoptotic protein p53 up-regulated modulator of apoptosis (PUMA). In support of these findings, dynamic BH3 profiling confirmed that statins primed cells for apoptosis. Furthermore, in retrospective analyses of three clinical studies of chronic lymphocytic leukemia, background statin use was associated with enhanced response to venetoclax, as demonstrated by more frequent complete responses. Together, this work provides mechanistic justification and clinical evidence to warrant prospective clinical investigation of this combination in hematologic malignancies